Overdose deaths remain epidemic throughout the U.S. The rates of unintentional overdose deaths, increasing by 137% between 2000 and 2014, have been driven by a 4-fold increase in prescription opioid overdoses during that period.^1-3

Veterans died of accidental overdose at a rate of 19.85 deaths/ 100,000 people compared with a rate of 10.49 deaths in the general population, based on 2005 data.⁴ There is wide state-by-state variation with the lowest age-adjusted opioid overdose death rate of 1.9 deaths/100,000 person-years among veterans in Mississippi and the highest rate in Utah of 33.9 deaths/100,000 person-years, using 2001 to 2009 data.⁵ These data can be compared with a crude general population overdose death rate of 10.6 deaths per 100,000 person-years in Mississippi and 18.4 deaths per 100,000 person-years in the general Utah population during that same period.⁶

Overdose deaths in the U.S. occur most often in persons aged 25 to 54 years.⁷ Older age has been associated with iatrogenic opioid overdose in hospitalized patients.⁸ Pulmonary, cardiovascular, and psychiatric disorders, including past or present substance use, have been associated with an increased risk of opioid overdose.⁹ However, veterans with substance use disorders are less likely to be prescribed opioids than are nonveterans with substance use disorders.¹⁰ Also, concomitant use of sedating medications, such as benzodiazepines (BZDs), can increase mortality from opioid overdose.¹¹ Patients prescribed opioids for chronic pain conditions often take BZDs for various reasons.¹² Veterans seem more likely to receive opioids to treat chronic pain but at lower average daily doses than the doses that nonveterans receive.¹⁰

Emergency management of life-threatening opioid overdose includes prompt administration of naloxone.¹³ Naloxone is FDA approved for complete or partial reversal of opioid-induced clinical effects, most critically respiratory depression.^14,15 Naloxone administration in the emergency department (ED) may serve as a surrogate for an overdose event. During the study period, naloxone take-home kits were not available in the VA setting.

A 2010 ED study described demographic information and comorbidities in opioid overdose, but the study did not include veterans.¹⁶ The clinical characteristics of veterans treated for opioid overdose have not been published. Because identifying characteristics of veterans who overdose may help tailor overdose prevention efforts, the objective of this study is to describe clinical characteristics of veterans treated for opioid overdose.

Methods

A retrospective chart review and archived data study was approved by the University of Utah and VA institutional review boards, and conducted at the George E. Wahlen VAMC in Salt Lake City, Utah. This chart review included veterans who were admitted to the ED and treated with naloxone between January 1, 2009 and January 1, 2013.

The authors used the Pharmacy Benefits Management Data Manager to extract data from the VA Data Warehouse and verified the data by open chart review (Table). The following data were collected: ED visit date (overdose date); demographic information, including age, gender, and race; evidence of next-of-kin or other contact at the same address as the veteran; diagnoses based on ICD-9 codes, including sleep apnea, obesitycardiac disease, pulmonary disease, mental health diagnoses (ICD-9 codes 290-302 [wild card characters (*) included many subdiagnoses]),
cancer, and substance use disorders and/or dependencies (SUDD); tobacco use; VA-issued prescription opioid and BZD availability, including dose, fill dates, quantities dispensed, and day supplies; specialty of opioid prescriber; urine drug screening (UDS) results; and outcome of the overdose.

No standardized research criteria identify overdose in medical chart review.¹⁷ For each identified patient, the authors reviewed provider and nursing notes charted during an ED visit that included naloxone administration. The event was included as an opioid overdose when notes indicated that the veteran was unresponsive and given naloxone, which resulted in increased respirations or increased responsiveness. Cases were excluded if the reason for naloxone administration was anything other than opioid overdose.

Medical, mental health, and SUDD diagnoses were included only if the veteran had more than 3 patient care encounters (PCE) with ICD-9 codes for a specific diagnosis entered by providers. A PCE used in the electronic medical record (EMR) helps collect, manage, and display outpatient encounter data, including providers, procedure codes, and diagnostic codes. Tobacco use was extracted from health factors documented during primary care visit screenings. (Health factors help capture data entered in note templates in the EMR and can be used to query trends.) A diagnosis of obesity was based on a calculated body mass index of > 30 kg/m² on the day of the ED visit date or the most recently charted height and weight. The type of SUDD was stratified into opioids (ICD-9 codes 304.0*), sedatives (ICD-9 code 304.1*), alcohol (ICD-9 code 303.*), and other (ICD-9 codes 304.2-305.9).

The dosage of opioids and BZDs available to a veteran was determined by using methods similar to those described by Gomes and colleagues: the dose of opioids and BZDs available based on prescriptions dispensed during the 120 days prior to the ED visit date and the dose available on the day of the ED visit date if prescription instructions were being followed.¹⁸ Prescription opioids and BZDs were converted to daily morphine equivalent dose (MED) and daily lorazepam-equivalent dose (LED), using established methods.^19,20

Veterans were stratified into 4 groups based on prescribed medication availability: opioids only, BZDs only, opioids and BZDs, and neither opioids nor BZDs. The specialty of the opioid prescribers was categorized as primary care, pain specialist, surgeon, emergency specialist, or hospitalist (discharge prescription). Veteran EMRs contain a list of medications obtained outside the VA facility, referred to as non-VA prescriptions. These medications werenot included in the analysis because accuracy could not be verified.

A study author reviewed the results of any UDS performed up to 120 days before the ED visit date to determine whether the result reflected the currently prescribed prescription medications. If the UDS was positive for the prescribed opioids and/or BZDs and for any nonprescribed drug, including alcohol, the UDS was classified as not reflective. If the prescribed BZD was alprazolam, clonazepam, or lorazepam, a BZD-positive UDS was not required for the UDS to be considered reflective because of the sensitivity of the UDS BZD immunoassay
used at the George E. Wahlen VAMC clinical laboratory.²¹

Outcomes of the overdose were categorized as discharged, hospitalized, or deceased. Descriptive statistical analyses were performed using Microsoft Excel. Group comparisons were performed using Pearson chi-square or Student t test.

Results

The ED at the George E. Wahlen VAMC averages 64 visits per day, almost 94,000 visits within the study period. One hundred seventy ED visits between January 1, 2009 and January 1, 2013, involved naloxone administration. Ninety-two visits met the inclusion criteria of opioid overdose, representing about 0.002% of all ED visits at this facility (Figure 1). Six veterans had multiple ED visits within the study period, including 4 veterans who were in the opioid-only group.

The majority of veterans in this study were non-Hispanic white (n = 83, 90%), male (n = 88, 96%), with a mean age of 63 years. Less than 40% listed a next-of-kin or contact person living at their address.

Based on prescriptions available within 120 days before the overdose, 67 veterans (73%) possessed opioid and/or BZD prescriptions. In this group, the MED available on the day of the ED visit ranged from 7.5 mg to 830 mg. The MED was ≤ 200 mg in 71.6% and ≤ 50 mg in 34.3% of these cases. Veterans prescribed both opioids and BZDs had higher MED (average, 259 mg) available within 120 days of the ED visit than did those prescribed opioids only (average, 118 mg) (P = .015; SD, 132.9). The LED ranged from 1 mg to 12 mg for veterans with available BZDs.

Based on prescriptions available on the day of opioid overdose, 53 veterans (58%) had opioid prescriptions. The ranges of MED and LED available on the day of overdose were the same as the 120-day availability period. The average MED was 183 mg in veterans prescribed both opioids and BZDs and 126 mg in those prescribed opioids only (P = .283; SD, 168.65; Figure 2). The time between the last opioid fill date and the overdose visit date averaged 20 days (range, 0 to 28 days) in veterans prescribed opioids.

All veterans had at least 1 diagnosis that in previous studies was associated with increased risk of overdose.^9,15 The most common diagnoses included cardiovascular diseases, mental health disorders, pulmonary diseases, and cancer. Other SUDDs not including tobacco use were documented in at least half the veterans with prescribed opioids and/or BZDs. No veteran in the sample had a documented history of opioid SUDD.

Hydrocodone products were available in > 50% of cases. None of the veterans were prescribed buprenorphine products; other opioids, including tramadol, comprised the remainder (Figure 3). Primary care providers prescribed 72% of opioid prescriptions, with pain specialists, discharge physicians, ED providers, and surgeons prescribing the rest. When both opioids and BZDs were available, combinations of a hydrocodone product plus clonazepam or lorazepam were most common. The time between the last opioid fill date and the overdose visit date averaged 20 days (range, 0 to 28 days) in veterans prescribed opioids.

Overall, 64% of the sample had UDS results prior to the ED visit. Of veterans prescribed opioids and/or BZDs, 53% of UDSs reflected prescribed regimens.

On the day of the ED visit, 1 death occurred. Ninety-one veterans (99%) survived the overdose; 79 veterans (86%) were hospitalized, most for < 24 hours.

Discussion

This retrospective review identified 92 veterans who were treated with naloxone in the ED for opioid overdose during a 4-year period at the George E. Wahlen VAMC. Seventy-eight cases were excluded because the reason entered in charts for naloxone administration was itching, constipation, altered mental status, or unclear documentation.

Veterans in this study were older on average than the overdose fatalities in the U.S. Opioid overdose deaths in the U.S. and in Utah occur most frequently in non-Hispanic white men aged between 35 and 54 years.^7,22,23 In the 2010 Nationwide Emergency Department Sample of 136,000 opioid overdoses, of which 98% survived, most were aged 18 to 54 years.¹⁶ The older age in this study most likely reflects the age range of veterans served in the VHA; however, as more young veterans enter the VHA, the age range of overdose victims may more closely resemble the age ranges found in previous studies. Post hoc analysis showed 8 veterans (9%) with probable intentional opioid overdose based on chart review, whereas the incidence of intentional prescription drug overdose in the U.S. is 17.1%.²⁴

In Utah, almost 93% of fatal overdoses occur at a residential location.²² Less than half the veterans in this study had a contact or next-of-kin listed as living at the same address. Although veterans may not have identified someone living with them, in many cases, it is likely another person witnessed the overdose. Relying on EMRs to identify who should receive prevention education, in addition to the veteran, may result in missed opportunities to include another person likely to witness an overdose.²⁵ Prescribers should make a conscious effort to ask veterans to identify someone who may be able to assist with rescue efforts in the event of an overdose.

Diagnoses associated with increased risk of opioid overdose death include sleep apnea, morbid obesity, pulmonary or cardiovascular diseases, and/or a history of psychiatric disorders and SUDD.^8,9,16 In a large sample of older veterans, only 64% had at least 1 medical or psychiatric diagnosis.²⁶ Less than half the 18,000 VA primary care patients in 5 VA centers had any psychiatric condition, and < 65% had cardiovascular disease, pulmonary disease, or cancer.²⁷ All veterans in this study had medical and psychiatric comorbidity.

In contrast, a large ED sample described by Yokell and colleagues found chronic mental conditions in 33.9%, circulatory disorders in 29.1%, and respiratory conditions in 25.6% of their sample.¹⁶ Bohnert and associates found a significantly elevated hazard ratio (HR) for any psychiatric disorder in a sample of nearly 4,500 veterans. There was variation in the HR when individual psychiatric diagnoses were broken out, with bipolar disorder having the largest HR and schizophrenia having the lowest but still elevated HR.⁹ In this study, individual diagnoses were not broken out because the smaller sample size could diminish the clinical significance of any apparent differences.

Edlund and colleagues found that < 8% of veterans treated with opioids for chronic noncancer pain had nonopioid SUDD.¹⁰ Bohnert and colleagues found an HR of 21.95 for overdose death among those with opioid-use disorders.⁹ The sample in this study had a much higher incidence of nonopioid SUDD compared with that ub the study by Edlund and colleagues, but none of the veterans in this study had a documented history of opioid use disorder. The absence of opioid use disorders in this sample is unexpected and points to a need for providers to screen for opioid use disorder whenever opioids are prescribed or renewed. If prevention practices were directed only to those with opioid SUDDs, none of the veterans in this study would have been included in those efforts. Non-SUDD providers should address the risks of opioid overdose in veterans with sleep apnea, morbid obesity, pulmonary or cardiovascular diseases, and/or a history of psychiatric disorders.

Gomes and colleagues found that > 100 mg MED available on the day of overdose doubled the risk of opioid-related mortality.¹⁸ The VA/DoD Clinical Practice Guideline for Management of Opioid Therapy for Chronic Pain identifies 200 mg MED as a threshold to define high-dose opioid therapy.²⁸ Fulton-Kehoe and colleagues found that 28% of overdose victims were prescribed < 50 mg MED.²⁹ In this study, the average dose available to veterans was > 100 mg MED; however, one-third of all study veterans had < 50 mg MED available. Using a threshold dose of 50 mg MED to target prevention efforts would capture only two-thirds of those who experienced overdose; a 200 mg MED threshold would exclude the majority, based on the average MED in each group in this study. Overdose education should be provided to veterans with access to any dose of opioids.

Use of BZDs with opioids may result in greater central nervous system (CNS) depression, pharmacokinetic interactions, or pharmacodynamic interactions at the µ opioid receptor.^30-32 About one-third of veterans in this study were prescribed opioids and BZDs concurrently, a combination noted in about 33% of opioid overdose deaths reported by the CDC.²⁴ Individuals taking methadone combined with BZDs have been found to have severe medical outcomes.³³ If preventive efforts are targeted to those receiving opioids and other CNS depressants, such as BZDs, about half (42%) the veterans in this study would not receive a potentially life-saving message about preventing overdoses. All veterans with opioids should be educated about the additional risk of overdose posed by drug interactions with other CNS depressants.

The time since the last fill of opioid prescription ranged from 0 to 28 days. This time frame indicates that some overdoses may have occurred on the day an opioid was filled but most occurred near the end of the expected days’ supply. Because information about adherence or use of the opioid was not studied, it cannot be assumed that medication misuse is the primary reason for the overdose. Delivering prevention efforts only at the time of medication dispensing would be insufficient. Clinicians should review local and remote prescription data, including via their states’ prescription drug monitoring program when discussing the risk of overdose with veterans.

Most veterans had at least 1 UDS result in the chart. Although half the UDSs obtained reflected prescribed medications, the possibility of aberrant behaviors, which increases the risk of overdose, cannot be ruled out with the methods used in this study.³⁴ Medication management agreements that require UDSs for veterans with chronic pain were not mandatory at the George E. Wahlen VAMC during the study period, and those used did not mandate discontinuation of opioid therapy if suspected aberrant behaviors were present.

A Utah study based on interviews of overdose victims’ next-of-kin found that 76% were concerned about victims’ aberrant behaviors, such as medication misuse, prior to the death.²² In contrast, a study of commercial and Medicaid recipients estimated medication misuse rates in
≤ 30% of the sample.³⁵ Urine drug screening results not reflective of the prescribed regimens have been found in up to 50% of patients receiving chronic opioid therapy.

The UDS findings in this study were determined by the authors and did not capture clinical decisions or interpretations made after results were available or whether these decisions resulted in overdose prevention strategies, such as targeted education or changes in prescription availability. Targeting preventive efforts toward veterans only with UDS results suggesting medication misuse would have missed more than half the veterans in this study. Urine drug screening should be used as a clinical monitoring tool whenever opioids, BZDs, or other substances are used or prescribed.

The VA now has a nationwide program, Opioid Overdose Education and Naloxone Distribution (OEND) promoting overdose education and take-home naloxone distribution for providers and patients to prevent opioid-related overdose deaths. A national SharePoint site has been created within the VA that lists resources to support this effort.

Almost all veterans in this review survived the overdose and were hospitalized following the ED visit. Other investigators also have found that the majority (51% to 98%) of overdose victims reaching the ED survived, but fewer patients (3% to 51%) in those studies were hospitalized.^16,36 It is unknown whether there are differences in risk factors associated with survived or fatal overdoses.

Limitations

Although Utah ranked third for drug overdose death rates in 2008 and had the highest death rate among veterans from 2001 to 2009, this review captured only overdoses among veterans treated during the study period at the George E. Wahlen VAMC ED.^5,6 The number and characteristics of veterans during this same period who were treated for overdose in other community EDs or urgent care centers throughout Utah is unknown.

The definition of opioid and BZD dose available in this study may not represent actual use of opioids or BZDs because it was based on chart review of prescription dispensing information and UDS procedures at the George E. Wahlen VAMC, and medication misuse cannot be ruled out. This study did not evaluate specific aberrant behaviors.

Conclusion

Current overdose prevention screening efforts primarily identify patients on high-dose opioids and those with SUDD. Many veterans in this study were older than the average U.S. victims’ age, did not have SUDD, were prescribed opioid doses not considered high risk by current guidelines, were nearer the end of their medication supply, and had UDS reflective of prescribed medications. This study suggests that any veteran with access to opioids, whether prescribed or not, is at risk for an opioid overdose. Established risk factors may aid in developing overdose prevention programs, but prevention should not be limited to veterans with prescribed opioids and known risk factors. Prescribers should screen for opioid use disorder whenever opioids are prescribed and continue to screen throughout therapy. Broader screening for overdose risk is needed to avoid missing important opportunities for overdose prevention.

Acknowledgments
Gale Anderson, VISN 19 PBM Data Manager, performed initial data query for the study.

Overdose deaths remain epidemic throughout the U.S. The rates of unintentional overdose deaths, increasing by 137% between 2000 and 2014, have been driven by a 4-fold increase in prescription opioid overdoses during that period.^1-3

Veterans died of accidental overdose at a rate of 19.85 deaths/ 100,000 people compared with a rate of 10.49 deaths in the general population, based on 2005 data.⁴ There is wide state-by-state variation with the lowest age-adjusted opioid overdose death rate of 1.9 deaths/100,000 person-years among veterans in Mississippi and the highest rate in Utah of 33.9 deaths/100,000 person-years, using 2001 to 2009 data.⁵ These data can be compared with a crude general population overdose death rate of 10.6 deaths per 100,000 person-years in Mississippi and 18.4 deaths per 100,000 person-years in the general Utah population during that same period.⁶

Overdose deaths in the U.S. occur most often in persons aged 25 to 54 years.⁷ Older age has been associated with iatrogenic opioid overdose in hospitalized patients.⁸ Pulmonary, cardiovascular, and psychiatric disorders, including past or present substance use, have been associated with an increased risk of opioid overdose.⁹ However, veterans with substance use disorders are less likely to be prescribed opioids than are nonveterans with substance use disorders.¹⁰ Also, concomitant use of sedating medications, such as benzodiazepines (BZDs), can increase mortality from opioid overdose.¹¹ Patients prescribed opioids for chronic pain conditions often take BZDs for various reasons.¹² Veterans seem more likely to receive opioids to treat chronic pain but at lower average daily doses than the doses that nonveterans receive.¹⁰

Emergency management of life-threatening opioid overdose includes prompt administration of naloxone.¹³ Naloxone is FDA approved for complete or partial reversal of opioid-induced clinical effects, most critically respiratory depression.^14,15 Naloxone administration in the emergency department (ED) may serve as a surrogate for an overdose event. During the study period, naloxone take-home kits were not available in the VA setting.

A 2010 ED study described demographic information and comorbidities in opioid overdose, but the study did not include veterans.¹⁶ The clinical characteristics of veterans treated for opioid overdose have not been published. Because identifying characteristics of veterans who overdose may help tailor overdose prevention efforts, the objective of this study is to describe clinical characteristics of veterans treated for opioid overdose.

Methods

A retrospective chart review and archived data study was approved by the University of Utah and VA institutional review boards, and conducted at the George E. Wahlen VAMC in Salt Lake City, Utah. This chart review included veterans who were admitted to the ED and treated with naloxone between January 1, 2009 and January 1, 2013.

The authors used the Pharmacy Benefits Management Data Manager to extract data from the VA Data Warehouse and verified the data by open chart review (Table). The following data were collected: ED visit date (overdose date); demographic information, including age, gender, and race; evidence of next-of-kin or other contact at the same address as the veteran; diagnoses based on ICD-9 codes, including sleep apnea, obesitycardiac disease, pulmonary disease, mental health diagnoses (ICD-9 codes 290-302 [wild card characters (*) included many subdiagnoses]),
cancer, and substance use disorders and/or dependencies (SUDD); tobacco use; VA-issued prescription opioid and BZD availability, including dose, fill dates, quantities dispensed, and day supplies; specialty of opioid prescriber; urine drug screening (UDS) results; and outcome of the overdose.

No standardized research criteria identify overdose in medical chart review.¹⁷ For each identified patient, the authors reviewed provider and nursing notes charted during an ED visit that included naloxone administration. The event was included as an opioid overdose when notes indicated that the veteran was unresponsive and given naloxone, which resulted in increased respirations or increased responsiveness. Cases were excluded if the reason for naloxone administration was anything other than opioid overdose.

Medical, mental health, and SUDD diagnoses were included only if the veteran had more than 3 patient care encounters (PCE) with ICD-9 codes for a specific diagnosis entered by providers. A PCE used in the electronic medical record (EMR) helps collect, manage, and display outpatient encounter data, including providers, procedure codes, and diagnostic codes. Tobacco use was extracted from health factors documented during primary care visit screenings. (Health factors help capture data entered in note templates in the EMR and can be used to query trends.) A diagnosis of obesity was based on a calculated body mass index of > 30 kg/m² on the day of the ED visit date or the most recently charted height and weight. The type of SUDD was stratified into opioids (ICD-9 codes 304.0*), sedatives (ICD-9 code 304.1*), alcohol (ICD-9 code 303.*), and other (ICD-9 codes 304.2-305.9).

The dosage of opioids and BZDs available to a veteran was determined by using methods similar to those described by Gomes and colleagues: the dose of opioids and BZDs available based on prescriptions dispensed during the 120 days prior to the ED visit date and the dose available on the day of the ED visit date if prescription instructions were being followed.¹⁸ Prescription opioids and BZDs were converted to daily morphine equivalent dose (MED) and daily lorazepam-equivalent dose (LED), using established methods.^19,20

Veterans were stratified into 4 groups based on prescribed medication availability: opioids only, BZDs only, opioids and BZDs, and neither opioids nor BZDs. The specialty of the opioid prescribers was categorized as primary care, pain specialist, surgeon, emergency specialist, or hospitalist (discharge prescription). Veteran EMRs contain a list of medications obtained outside the VA facility, referred to as non-VA prescriptions. These medications werenot included in the analysis because accuracy could not be verified.

A study author reviewed the results of any UDS performed up to 120 days before the ED visit date to determine whether the result reflected the currently prescribed prescription medications. If the UDS was positive for the prescribed opioids and/or BZDs and for any nonprescribed drug, including alcohol, the UDS was classified as not reflective. If the prescribed BZD was alprazolam, clonazepam, or lorazepam, a BZD-positive UDS was not required for the UDS to be considered reflective because of the sensitivity of the UDS BZD immunoassay
used at the George E. Wahlen VAMC clinical laboratory.²¹

Outcomes of the overdose were categorized as discharged, hospitalized, or deceased. Descriptive statistical analyses were performed using Microsoft Excel. Group comparisons were performed using Pearson chi-square or Student t test.

Results

The ED at the George E. Wahlen VAMC averages 64 visits per day, almost 94,000 visits within the study period. One hundred seventy ED visits between January 1, 2009 and January 1, 2013, involved naloxone administration. Ninety-two visits met the inclusion criteria of opioid overdose, representing about 0.002% of all ED visits at this facility (Figure 1). Six veterans had multiple ED visits within the study period, including 4 veterans who were in the opioid-only group.

The majority of veterans in this study were non-Hispanic white (n = 83, 90%), male (n = 88, 96%), with a mean age of 63 years. Less than 40% listed a next-of-kin or contact person living at their address.

Based on prescriptions available within 120 days before the overdose, 67 veterans (73%) possessed opioid and/or BZD prescriptions. In this group, the MED available on the day of the ED visit ranged from 7.5 mg to 830 mg. The MED was ≤ 200 mg in 71.6% and ≤ 50 mg in 34.3% of these cases. Veterans prescribed both opioids and BZDs had higher MED (average, 259 mg) available within 120 days of the ED visit than did those prescribed opioids only (average, 118 mg) (P = .015; SD, 132.9). The LED ranged from 1 mg to 12 mg for veterans with available BZDs.

Based on prescriptions available on the day of opioid overdose, 53 veterans (58%) had opioid prescriptions. The ranges of MED and LED available on the day of overdose were the same as the 120-day availability period. The average MED was 183 mg in veterans prescribed both opioids and BZDs and 126 mg in those prescribed opioids only (P = .283; SD, 168.65; Figure 2). The time between the last opioid fill date and the overdose visit date averaged 20 days (range, 0 to 28 days) in veterans prescribed opioids.

All veterans had at least 1 diagnosis that in previous studies was associated with increased risk of overdose.^9,15 The most common diagnoses included cardiovascular diseases, mental health disorders, pulmonary diseases, and cancer. Other SUDDs not including tobacco use were documented in at least half the veterans with prescribed opioids and/or BZDs. No veteran in the sample had a documented history of opioid SUDD.

Hydrocodone products were available in > 50% of cases. None of the veterans were prescribed buprenorphine products; other opioids, including tramadol, comprised the remainder (Figure 3). Primary care providers prescribed 72% of opioid prescriptions, with pain specialists, discharge physicians, ED providers, and surgeons prescribing the rest. When both opioids and BZDs were available, combinations of a hydrocodone product plus clonazepam or lorazepam were most common. The time between the last opioid fill date and the overdose visit date averaged 20 days (range, 0 to 28 days) in veterans prescribed opioids.

Overall, 64% of the sample had UDS results prior to the ED visit. Of veterans prescribed opioids and/or BZDs, 53% of UDSs reflected prescribed regimens.

On the day of the ED visit, 1 death occurred. Ninety-one veterans (99%) survived the overdose; 79 veterans (86%) were hospitalized, most for < 24 hours.

Discussion

This retrospective review identified 92 veterans who were treated with naloxone in the ED for opioid overdose during a 4-year period at the George E. Wahlen VAMC. Seventy-eight cases were excluded because the reason entered in charts for naloxone administration was itching, constipation, altered mental status, or unclear documentation.

Veterans in this study were older on average than the overdose fatalities in the U.S. Opioid overdose deaths in the U.S. and in Utah occur most frequently in non-Hispanic white men aged between 35 and 54 years.^7,22,23 In the 2010 Nationwide Emergency Department Sample of 136,000 opioid overdoses, of which 98% survived, most were aged 18 to 54 years.¹⁶ The older age in this study most likely reflects the age range of veterans served in the VHA; however, as more young veterans enter the VHA, the age range of overdose victims may more closely resemble the age ranges found in previous studies. Post hoc analysis showed 8 veterans (9%) with probable intentional opioid overdose based on chart review, whereas the incidence of intentional prescription drug overdose in the U.S. is 17.1%.²⁴

In Utah, almost 93% of fatal overdoses occur at a residential location.²² Less than half the veterans in this study had a contact or next-of-kin listed as living at the same address. Although veterans may not have identified someone living with them, in many cases, it is likely another person witnessed the overdose. Relying on EMRs to identify who should receive prevention education, in addition to the veteran, may result in missed opportunities to include another person likely to witness an overdose.²⁵ Prescribers should make a conscious effort to ask veterans to identify someone who may be able to assist with rescue efforts in the event of an overdose.

Diagnoses associated with increased risk of opioid overdose death include sleep apnea, morbid obesity, pulmonary or cardiovascular diseases, and/or a history of psychiatric disorders and SUDD.^8,9,16 In a large sample of older veterans, only 64% had at least 1 medical or psychiatric diagnosis.²⁶ Less than half the 18,000 VA primary care patients in 5 VA centers had any psychiatric condition, and < 65% had cardiovascular disease, pulmonary disease, or cancer.²⁷ All veterans in this study had medical and psychiatric comorbidity.

In contrast, a large ED sample described by Yokell and colleagues found chronic mental conditions in 33.9%, circulatory disorders in 29.1%, and respiratory conditions in 25.6% of their sample.¹⁶ Bohnert and associates found a significantly elevated hazard ratio (HR) for any psychiatric disorder in a sample of nearly 4,500 veterans. There was variation in the HR when individual psychiatric diagnoses were broken out, with bipolar disorder having the largest HR and schizophrenia having the lowest but still elevated HR.⁹ In this study, individual diagnoses were not broken out because the smaller sample size could diminish the clinical significance of any apparent differences.

Edlund and colleagues found that < 8% of veterans treated with opioids for chronic noncancer pain had nonopioid SUDD.¹⁰ Bohnert and colleagues found an HR of 21.95 for overdose death among those with opioid-use disorders.⁹ The sample in this study had a much higher incidence of nonopioid SUDD compared with that ub the study by Edlund and colleagues, but none of the veterans in this study had a documented history of opioid use disorder. The absence of opioid use disorders in this sample is unexpected and points to a need for providers to screen for opioid use disorder whenever opioids are prescribed or renewed. If prevention practices were directed only to those with opioid SUDDs, none of the veterans in this study would have been included in those efforts. Non-SUDD providers should address the risks of opioid overdose in veterans with sleep apnea, morbid obesity, pulmonary or cardiovascular diseases, and/or a history of psychiatric disorders.

Gomes and colleagues found that > 100 mg MED available on the day of overdose doubled the risk of opioid-related mortality.¹⁸ The VA/DoD Clinical Practice Guideline for Management of Opioid Therapy for Chronic Pain identifies 200 mg MED as a threshold to define high-dose opioid therapy.²⁸ Fulton-Kehoe and colleagues found that 28% of overdose victims were prescribed < 50 mg MED.²⁹ In this study, the average dose available to veterans was > 100 mg MED; however, one-third of all study veterans had < 50 mg MED available. Using a threshold dose of 50 mg MED to target prevention efforts would capture only two-thirds of those who experienced overdose; a 200 mg MED threshold would exclude the majority, based on the average MED in each group in this study. Overdose education should be provided to veterans with access to any dose of opioids.

Use of BZDs with opioids may result in greater central nervous system (CNS) depression, pharmacokinetic interactions, or pharmacodynamic interactions at the µ opioid receptor.^30-32 About one-third of veterans in this study were prescribed opioids and BZDs concurrently, a combination noted in about 33% of opioid overdose deaths reported by the CDC.²⁴ Individuals taking methadone combined with BZDs have been found to have severe medical outcomes.³³ If preventive efforts are targeted to those receiving opioids and other CNS depressants, such as BZDs, about half (42%) the veterans in this study would not receive a potentially life-saving message about preventing overdoses. All veterans with opioids should be educated about the additional risk of overdose posed by drug interactions with other CNS depressants.

The time since the last fill of opioid prescription ranged from 0 to 28 days. This time frame indicates that some overdoses may have occurred on the day an opioid was filled but most occurred near the end of the expected days’ supply. Because information about adherence or use of the opioid was not studied, it cannot be assumed that medication misuse is the primary reason for the overdose. Delivering prevention efforts only at the time of medication dispensing would be insufficient. Clinicians should review local and remote prescription data, including via their states’ prescription drug monitoring program when discussing the risk of overdose with veterans.

Most veterans had at least 1 UDS result in the chart. Although half the UDSs obtained reflected prescribed medications, the possibility of aberrant behaviors, which increases the risk of overdose, cannot be ruled out with the methods used in this study.³⁴ Medication management agreements that require UDSs for veterans with chronic pain were not mandatory at the George E. Wahlen VAMC during the study period, and those used did not mandate discontinuation of opioid therapy if suspected aberrant behaviors were present.

A Utah study based on interviews of overdose victims’ next-of-kin found that 76% were concerned about victims’ aberrant behaviors, such as medication misuse, prior to the death.²² In contrast, a study of commercial and Medicaid recipients estimated medication misuse rates in
≤ 30% of the sample.³⁵ Urine drug screening results not reflective of the prescribed regimens have been found in up to 50% of patients receiving chronic opioid therapy.

The UDS findings in this study were determined by the authors and did not capture clinical decisions or interpretations made after results were available or whether these decisions resulted in overdose prevention strategies, such as targeted education or changes in prescription availability. Targeting preventive efforts toward veterans only with UDS results suggesting medication misuse would have missed more than half the veterans in this study. Urine drug screening should be used as a clinical monitoring tool whenever opioids, BZDs, or other substances are used or prescribed.

The VA now has a nationwide program, Opioid Overdose Education and Naloxone Distribution (OEND) promoting overdose education and take-home naloxone distribution for providers and patients to prevent opioid-related overdose deaths. A national SharePoint site has been created within the VA that lists resources to support this effort.

Almost all veterans in this review survived the overdose and were hospitalized following the ED visit. Other investigators also have found that the majority (51% to 98%) of overdose victims reaching the ED survived, but fewer patients (3% to 51%) in those studies were hospitalized.^16,36 It is unknown whether there are differences in risk factors associated with survived or fatal overdoses.

Limitations

Although Utah ranked third for drug overdose death rates in 2008 and had the highest death rate among veterans from 2001 to 2009, this review captured only overdoses among veterans treated during the study period at the George E. Wahlen VAMC ED.^5,6 The number and characteristics of veterans during this same period who were treated for overdose in other community EDs or urgent care centers throughout Utah is unknown.

The definition of opioid and BZD dose available in this study may not represent actual use of opioids or BZDs because it was based on chart review of prescription dispensing information and UDS procedures at the George E. Wahlen VAMC, and medication misuse cannot be ruled out. This study did not evaluate specific aberrant behaviors.

Conclusion

Current overdose prevention screening efforts primarily identify patients on high-dose opioids and those with SUDD. Many veterans in this study were older than the average U.S. victims’ age, did not have SUDD, were prescribed opioid doses not considered high risk by current guidelines, were nearer the end of their medication supply, and had UDS reflective of prescribed medications. This study suggests that any veteran with access to opioids, whether prescribed or not, is at risk for an opioid overdose. Established risk factors may aid in developing overdose prevention programs, but prevention should not be limited to veterans with prescribed opioids and known risk factors. Prescribers should screen for opioid use disorder whenever opioids are prescribed and continue to screen throughout therapy. Broader screening for overdose risk is needed to avoid missing important opportunities for overdose prevention.

Acknowledgments
Gale Anderson, VISN 19 PBM Data Manager, performed initial data query for the study.

Overdose deaths remain epidemic throughout the U.S. The rates of unintentional overdose deaths, increasing by 137% between 2000 and 2014, have been driven by a 4-fold increase in prescription opioid overdoses during that period.^1-3

Veterans died of accidental overdose at a rate of 19.85 deaths/ 100,000 people compared with a rate of 10.49 deaths in the general population, based on 2005 data.⁴ There is wide state-by-state variation with the lowest age-adjusted opioid overdose death rate of 1.9 deaths/100,000 person-years among veterans in Mississippi and the highest rate in Utah of 33.9 deaths/100,000 person-years, using 2001 to 2009 data.⁵ These data can be compared with a crude general population overdose death rate of 10.6 deaths per 100,000 person-years in Mississippi and 18.4 deaths per 100,000 person-years in the general Utah population during that same period.⁶

Overdose deaths in the U.S. occur most often in persons aged 25 to 54 years.⁷ Older age has been associated with iatrogenic opioid overdose in hospitalized patients.⁸ Pulmonary, cardiovascular, and psychiatric disorders, including past or present substance use, have been associated with an increased risk of opioid overdose.⁹ However, veterans with substance use disorders are less likely to be prescribed opioids than are nonveterans with substance use disorders.¹⁰ Also, concomitant use of sedating medications, such as benzodiazepines (BZDs), can increase mortality from opioid overdose.¹¹ Patients prescribed opioids for chronic pain conditions often take BZDs for various reasons.¹² Veterans seem more likely to receive opioids to treat chronic pain but at lower average daily doses than the doses that nonveterans receive.¹⁰

Emergency management of life-threatening opioid overdose includes prompt administration of naloxone.¹³ Naloxone is FDA approved for complete or partial reversal of opioid-induced clinical effects, most critically respiratory depression.^14,15 Naloxone administration in the emergency department (ED) may serve as a surrogate for an overdose event. During the study period, naloxone take-home kits were not available in the VA setting.

A 2010 ED study described demographic information and comorbidities in opioid overdose, but the study did not include veterans.¹⁶ The clinical characteristics of veterans treated for opioid overdose have not been published. Because identifying characteristics of veterans who overdose may help tailor overdose prevention efforts, the objective of this study is to describe clinical characteristics of veterans treated for opioid overdose.

Methods

A retrospective chart review and archived data study was approved by the University of Utah and VA institutional review boards, and conducted at the George E. Wahlen VAMC in Salt Lake City, Utah. This chart review included veterans who were admitted to the ED and treated with naloxone between January 1, 2009 and January 1, 2013.

The authors used the Pharmacy Benefits Management Data Manager to extract data from the VA Data Warehouse and verified the data by open chart review (Table). The following data were collected: ED visit date (overdose date); demographic information, including age, gender, and race; evidence of next-of-kin or other contact at the same address as the veteran; diagnoses based on ICD-9 codes, including sleep apnea, obesitycardiac disease, pulmonary disease, mental health diagnoses (ICD-9 codes 290-302 [wild card characters (*) included many subdiagnoses]),
cancer, and substance use disorders and/or dependencies (SUDD); tobacco use; VA-issued prescription opioid and BZD availability, including dose, fill dates, quantities dispensed, and day supplies; specialty of opioid prescriber; urine drug screening (UDS) results; and outcome of the overdose.

No standardized research criteria identify overdose in medical chart review.¹⁷ For each identified patient, the authors reviewed provider and nursing notes charted during an ED visit that included naloxone administration. The event was included as an opioid overdose when notes indicated that the veteran was unresponsive and given naloxone, which resulted in increased respirations or increased responsiveness. Cases were excluded if the reason for naloxone administration was anything other than opioid overdose.

Medical, mental health, and SUDD diagnoses were included only if the veteran had more than 3 patient care encounters (PCE) with ICD-9 codes for a specific diagnosis entered by providers. A PCE used in the electronic medical record (EMR) helps collect, manage, and display outpatient encounter data, including providers, procedure codes, and diagnostic codes. Tobacco use was extracted from health factors documented during primary care visit screenings. (Health factors help capture data entered in note templates in the EMR and can be used to query trends.) A diagnosis of obesity was based on a calculated body mass index of > 30 kg/m² on the day of the ED visit date or the most recently charted height and weight. The type of SUDD was stratified into opioids (ICD-9 codes 304.0*), sedatives (ICD-9 code 304.1*), alcohol (ICD-9 code 303.*), and other (ICD-9 codes 304.2-305.9).

The dosage of opioids and BZDs available to a veteran was determined by using methods similar to those described by Gomes and colleagues: the dose of opioids and BZDs available based on prescriptions dispensed during the 120 days prior to the ED visit date and the dose available on the day of the ED visit date if prescription instructions were being followed.¹⁸ Prescription opioids and BZDs were converted to daily morphine equivalent dose (MED) and daily lorazepam-equivalent dose (LED), using established methods.^19,20

Veterans were stratified into 4 groups based on prescribed medication availability: opioids only, BZDs only, opioids and BZDs, and neither opioids nor BZDs. The specialty of the opioid prescribers was categorized as primary care, pain specialist, surgeon, emergency specialist, or hospitalist (discharge prescription). Veteran EMRs contain a list of medications obtained outside the VA facility, referred to as non-VA prescriptions. These medications werenot included in the analysis because accuracy could not be verified.

A study author reviewed the results of any UDS performed up to 120 days before the ED visit date to determine whether the result reflected the currently prescribed prescription medications. If the UDS was positive for the prescribed opioids and/or BZDs and for any nonprescribed drug, including alcohol, the UDS was classified as not reflective. If the prescribed BZD was alprazolam, clonazepam, or lorazepam, a BZD-positive UDS was not required for the UDS to be considered reflective because of the sensitivity of the UDS BZD immunoassay
used at the George E. Wahlen VAMC clinical laboratory.²¹

Outcomes of the overdose were categorized as discharged, hospitalized, or deceased. Descriptive statistical analyses were performed using Microsoft Excel. Group comparisons were performed using Pearson chi-square or Student t test.

Results

The ED at the George E. Wahlen VAMC averages 64 visits per day, almost 94,000 visits within the study period. One hundred seventy ED visits between January 1, 2009 and January 1, 2013, involved naloxone administration. Ninety-two visits met the inclusion criteria of opioid overdose, representing about 0.002% of all ED visits at this facility (Figure 1). Six veterans had multiple ED visits within the study period, including 4 veterans who were in the opioid-only group.

The majority of veterans in this study were non-Hispanic white (n = 83, 90%), male (n = 88, 96%), with a mean age of 63 years. Less than 40% listed a next-of-kin or contact person living at their address.

Based on prescriptions available within 120 days before the overdose, 67 veterans (73%) possessed opioid and/or BZD prescriptions. In this group, the MED available on the day of the ED visit ranged from 7.5 mg to 830 mg. The MED was ≤ 200 mg in 71.6% and ≤ 50 mg in 34.3% of these cases. Veterans prescribed both opioids and BZDs had higher MED (average, 259 mg) available within 120 days of the ED visit than did those prescribed opioids only (average, 118 mg) (P = .015; SD, 132.9). The LED ranged from 1 mg to 12 mg for veterans with available BZDs.

Based on prescriptions available on the day of opioid overdose, 53 veterans (58%) had opioid prescriptions. The ranges of MED and LED available on the day of overdose were the same as the 120-day availability period. The average MED was 183 mg in veterans prescribed both opioids and BZDs and 126 mg in those prescribed opioids only (P = .283; SD, 168.65; Figure 2). The time between the last opioid fill date and the overdose visit date averaged 20 days (range, 0 to 28 days) in veterans prescribed opioids.

All veterans had at least 1 diagnosis that in previous studies was associated with increased risk of overdose.^9,15 The most common diagnoses included cardiovascular diseases, mental health disorders, pulmonary diseases, and cancer. Other SUDDs not including tobacco use were documented in at least half the veterans with prescribed opioids and/or BZDs. No veteran in the sample had a documented history of opioid SUDD.

Hydrocodone products were available in > 50% of cases. None of the veterans were prescribed buprenorphine products; other opioids, including tramadol, comprised the remainder (Figure 3). Primary care providers prescribed 72% of opioid prescriptions, with pain specialists, discharge physicians, ED providers, and surgeons prescribing the rest. When both opioids and BZDs were available, combinations of a hydrocodone product plus clonazepam or lorazepam were most common. The time between the last opioid fill date and the overdose visit date averaged 20 days (range, 0 to 28 days) in veterans prescribed opioids.

Overall, 64% of the sample had UDS results prior to the ED visit. Of veterans prescribed opioids and/or BZDs, 53% of UDSs reflected prescribed regimens.

On the day of the ED visit, 1 death occurred. Ninety-one veterans (99%) survived the overdose; 79 veterans (86%) were hospitalized, most for < 24 hours.

Discussion

This retrospective review identified 92 veterans who were treated with naloxone in the ED for opioid overdose during a 4-year period at the George E. Wahlen VAMC. Seventy-eight cases were excluded because the reason entered in charts for naloxone administration was itching, constipation, altered mental status, or unclear documentation.

Veterans in this study were older on average than the overdose fatalities in the U.S. Opioid overdose deaths in the U.S. and in Utah occur most frequently in non-Hispanic white men aged between 35 and 54 years.^7,22,23 In the 2010 Nationwide Emergency Department Sample of 136,000 opioid overdoses, of which 98% survived, most were aged 18 to 54 years.¹⁶ The older age in this study most likely reflects the age range of veterans served in the VHA; however, as more young veterans enter the VHA, the age range of overdose victims may more closely resemble the age ranges found in previous studies. Post hoc analysis showed 8 veterans (9%) with probable intentional opioid overdose based on chart review, whereas the incidence of intentional prescription drug overdose in the U.S. is 17.1%.²⁴

In Utah, almost 93% of fatal overdoses occur at a residential location.²² Less than half the veterans in this study had a contact or next-of-kin listed as living at the same address. Although veterans may not have identified someone living with them, in many cases, it is likely another person witnessed the overdose. Relying on EMRs to identify who should receive prevention education, in addition to the veteran, may result in missed opportunities to include another person likely to witness an overdose.²⁵ Prescribers should make a conscious effort to ask veterans to identify someone who may be able to assist with rescue efforts in the event of an overdose.

Diagnoses associated with increased risk of opioid overdose death include sleep apnea, morbid obesity, pulmonary or cardiovascular diseases, and/or a history of psychiatric disorders and SUDD.^8,9,16 In a large sample of older veterans, only 64% had at least 1 medical or psychiatric diagnosis.²⁶ Less than half the 18,000 VA primary care patients in 5 VA centers had any psychiatric condition, and < 65% had cardiovascular disease, pulmonary disease, or cancer.²⁷ All veterans in this study had medical and psychiatric comorbidity.

In contrast, a large ED sample described by Yokell and colleagues found chronic mental conditions in 33.9%, circulatory disorders in 29.1%, and respiratory conditions in 25.6% of their sample.¹⁶ Bohnert and associates found a significantly elevated hazard ratio (HR) for any psychiatric disorder in a sample of nearly 4,500 veterans. There was variation in the HR when individual psychiatric diagnoses were broken out, with bipolar disorder having the largest HR and schizophrenia having the lowest but still elevated HR.⁹ In this study, individual diagnoses were not broken out because the smaller sample size could diminish the clinical significance of any apparent differences.

Edlund and colleagues found that < 8% of veterans treated with opioids for chronic noncancer pain had nonopioid SUDD.¹⁰ Bohnert and colleagues found an HR of 21.95 for overdose death among those with opioid-use disorders.⁹ The sample in this study had a much higher incidence of nonopioid SUDD compared with that ub the study by Edlund and colleagues, but none of the veterans in this study had a documented history of opioid use disorder. The absence of opioid use disorders in this sample is unexpected and points to a need for providers to screen for opioid use disorder whenever opioids are prescribed or renewed. If prevention practices were directed only to those with opioid SUDDs, none of the veterans in this study would have been included in those efforts. Non-SUDD providers should address the risks of opioid overdose in veterans with sleep apnea, morbid obesity, pulmonary or cardiovascular diseases, and/or a history of psychiatric disorders.

Gomes and colleagues found that > 100 mg MED available on the day of overdose doubled the risk of opioid-related mortality.¹⁸ The VA/DoD Clinical Practice Guideline for Management of Opioid Therapy for Chronic Pain identifies 200 mg MED as a threshold to define high-dose opioid therapy.²⁸ Fulton-Kehoe and colleagues found that 28% of overdose victims were prescribed < 50 mg MED.²⁹ In this study, the average dose available to veterans was > 100 mg MED; however, one-third of all study veterans had < 50 mg MED available. Using a threshold dose of 50 mg MED to target prevention efforts would capture only two-thirds of those who experienced overdose; a 200 mg MED threshold would exclude the majority, based on the average MED in each group in this study. Overdose education should be provided to veterans with access to any dose of opioids.

Use of BZDs with opioids may result in greater central nervous system (CNS) depression, pharmacokinetic interactions, or pharmacodynamic interactions at the µ opioid receptor.^30-32 About one-third of veterans in this study were prescribed opioids and BZDs concurrently, a combination noted in about 33% of opioid overdose deaths reported by the CDC.²⁴ Individuals taking methadone combined with BZDs have been found to have severe medical outcomes.³³ If preventive efforts are targeted to those receiving opioids and other CNS depressants, such as BZDs, about half (42%) the veterans in this study would not receive a potentially life-saving message about preventing overdoses. All veterans with opioids should be educated about the additional risk of overdose posed by drug interactions with other CNS depressants.

The time since the last fill of opioid prescription ranged from 0 to 28 days. This time frame indicates that some overdoses may have occurred on the day an opioid was filled but most occurred near the end of the expected days’ supply. Because information about adherence or use of the opioid was not studied, it cannot be assumed that medication misuse is the primary reason for the overdose. Delivering prevention efforts only at the time of medication dispensing would be insufficient. Clinicians should review local and remote prescription data, including via their states’ prescription drug monitoring program when discussing the risk of overdose with veterans.

Most veterans had at least 1 UDS result in the chart. Although half the UDSs obtained reflected prescribed medications, the possibility of aberrant behaviors, which increases the risk of overdose, cannot be ruled out with the methods used in this study.³⁴ Medication management agreements that require UDSs for veterans with chronic pain were not mandatory at the George E. Wahlen VAMC during the study period, and those used did not mandate discontinuation of opioid therapy if suspected aberrant behaviors were present.

A Utah study based on interviews of overdose victims’ next-of-kin found that 76% were concerned about victims’ aberrant behaviors, such as medication misuse, prior to the death.²² In contrast, a study of commercial and Medicaid recipients estimated medication misuse rates in
≤ 30% of the sample.³⁵ Urine drug screening results not reflective of the prescribed regimens have been found in up to 50% of patients receiving chronic opioid therapy.

The UDS findings in this study were determined by the authors and did not capture clinical decisions or interpretations made after results were available or whether these decisions resulted in overdose prevention strategies, such as targeted education or changes in prescription availability. Targeting preventive efforts toward veterans only with UDS results suggesting medication misuse would have missed more than half the veterans in this study. Urine drug screening should be used as a clinical monitoring tool whenever opioids, BZDs, or other substances are used or prescribed.

The VA now has a nationwide program, Opioid Overdose Education and Naloxone Distribution (OEND) promoting overdose education and take-home naloxone distribution for providers and patients to prevent opioid-related overdose deaths. A national SharePoint site has been created within the VA that lists resources to support this effort.

Almost all veterans in this review survived the overdose and were hospitalized following the ED visit. Other investigators also have found that the majority (51% to 98%) of overdose victims reaching the ED survived, but fewer patients (3% to 51%) in those studies were hospitalized.^16,36 It is unknown whether there are differences in risk factors associated with survived or fatal overdoses.

Limitations

Although Utah ranked third for drug overdose death rates in 2008 and had the highest death rate among veterans from 2001 to 2009, this review captured only overdoses among veterans treated during the study period at the George E. Wahlen VAMC ED.^5,6 The number and characteristics of veterans during this same period who were treated for overdose in other community EDs or urgent care centers throughout Utah is unknown.

The definition of opioid and BZD dose available in this study may not represent actual use of opioids or BZDs because it was based on chart review of prescription dispensing information and UDS procedures at the George E. Wahlen VAMC, and medication misuse cannot be ruled out. This study did not evaluate specific aberrant behaviors.

Conclusion

Current overdose prevention screening efforts primarily identify patients on high-dose opioids and those with SUDD. Many veterans in this study were older than the average U.S. victims’ age, did not have SUDD, were prescribed opioid doses not considered high risk by current guidelines, were nearer the end of their medication supply, and had UDS reflective of prescribed medications. This study suggests that any veteran with access to opioids, whether prescribed or not, is at risk for an opioid overdose. Established risk factors may aid in developing overdose prevention programs, but prevention should not be limited to veterans with prescribed opioids and known risk factors. Prescribers should screen for opioid use disorder whenever opioids are prescribed and continue to screen throughout therapy. Broader screening for overdose risk is needed to avoid missing important opportunities for overdose prevention.

Acknowledgments
Gale Anderson, VISN 19 PBM Data Manager, performed initial data query for the study.

Blood for transfusion

Photo by Elise Amendola

There is no association between sex-discordant blood transfusions and the risk of death after cardiac surgery, according to research published in Circulation.

Two previous studies suggested that patients who received red blood cells (RBCs) from a donor of the opposite sex had an increased risk of death after cardiac surgery.

However, the current study showed no significant difference between same-sex and opposite-sex donor-recipient pairs.

The researchers said the reason for the difference between the new and older studies is that, in the new study, the team “carefully adjusted” for the number of transfusions performed and allowed for the effect of RBC transfusions on mortality to differ between men and women.

“The consequences of the findings from [the earlier studies], if proved true, would have been immense and necessitated radical changes to how blood transfusions are managed around the world,” said Martin Holzmann, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.

“Our results clearly show that there is no real connection between sex-discordant blood transfusions and the risk of death.”

Therefore, Dr Holzmann and his colleagues believe there is no need to consider donor sex when allocating RBC units for transfusion.

To come to this conclusion, the researchers analyzed data on 45,090 patients who underwent cardiac surgery and received at least 1 RBC transfusion.

All patients were adults who had undergone isolated coronary artery bypass grafting, isolated valve repair/replacement surgery, or a combination of these procedures between 1997 and 2012.

The researchers estimated the relative hazard of death in relation to exposure to sex-discordant transfusions, adjusting their analyses for potential confounding factors, such as patient sex, age, blood group, and number of transfusions.

Results

The researchers found that women were more likely to receive sex-discordant transfusions than same-sex transfusions—45.3% and 19.8%, respectively. And patients who received sex-discordant transfusions tended to receive more transfusions—a mean of 4.2 vs 2.0 for same-sex transfusions.

However, there were no other significant differences between the sex-discordant and same-sex groups.

The researchers noted that, during the 30-day follow-up period, there were more deaths among patients who received sex-discordant transfusions than those who did not—1701 (4.9%) and 205 (1.9%), respectively.

However, when the team adjusted for potential confounding factors, the relative risk of death was similar for patients who received at least 1 unit of sex-discordant blood and those who did not. The hazard ratio was 0.97 at 30 days of follow-up, 0.97 at the 2-year mark, and 0.98 at 10 years of follow-up.

The risk of death did increase as the number of sex-discordant units transfused increased. However, the increase was not statistically significant.

Blood for transfusion

Photo by Elise Amendola

There is no association between sex-discordant blood transfusions and the risk of death after cardiac surgery, according to research published in Circulation.

Two previous studies suggested that patients who received red blood cells (RBCs) from a donor of the opposite sex had an increased risk of death after cardiac surgery.

However, the current study showed no significant difference between same-sex and opposite-sex donor-recipient pairs.

The researchers said the reason for the difference between the new and older studies is that, in the new study, the team “carefully adjusted” for the number of transfusions performed and allowed for the effect of RBC transfusions on mortality to differ between men and women.

“The consequences of the findings from [the earlier studies], if proved true, would have been immense and necessitated radical changes to how blood transfusions are managed around the world,” said Martin Holzmann, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.

“Our results clearly show that there is no real connection between sex-discordant blood transfusions and the risk of death.”

Therefore, Dr Holzmann and his colleagues believe there is no need to consider donor sex when allocating RBC units for transfusion.

To come to this conclusion, the researchers analyzed data on 45,090 patients who underwent cardiac surgery and received at least 1 RBC transfusion.

All patients were adults who had undergone isolated coronary artery bypass grafting, isolated valve repair/replacement surgery, or a combination of these procedures between 1997 and 2012.

The researchers estimated the relative hazard of death in relation to exposure to sex-discordant transfusions, adjusting their analyses for potential confounding factors, such as patient sex, age, blood group, and number of transfusions.

Results

The researchers found that women were more likely to receive sex-discordant transfusions than same-sex transfusions—45.3% and 19.8%, respectively. And patients who received sex-discordant transfusions tended to receive more transfusions—a mean of 4.2 vs 2.0 for same-sex transfusions.

However, there were no other significant differences between the sex-discordant and same-sex groups.

The researchers noted that, during the 30-day follow-up period, there were more deaths among patients who received sex-discordant transfusions than those who did not—1701 (4.9%) and 205 (1.9%), respectively.

However, when the team adjusted for potential confounding factors, the relative risk of death was similar for patients who received at least 1 unit of sex-discordant blood and those who did not. The hazard ratio was 0.97 at 30 days of follow-up, 0.97 at the 2-year mark, and 0.98 at 10 years of follow-up.

The risk of death did increase as the number of sex-discordant units transfused increased. However, the increase was not statistically significant.

Blood for transfusion

Photo by Elise Amendola

There is no association between sex-discordant blood transfusions and the risk of death after cardiac surgery, according to research published in Circulation.

Two previous studies suggested that patients who received red blood cells (RBCs) from a donor of the opposite sex had an increased risk of death after cardiac surgery.

However, the current study showed no significant difference between same-sex and opposite-sex donor-recipient pairs.

The researchers said the reason for the difference between the new and older studies is that, in the new study, the team “carefully adjusted” for the number of transfusions performed and allowed for the effect of RBC transfusions on mortality to differ between men and women.

“The consequences of the findings from [the earlier studies], if proved true, would have been immense and necessitated radical changes to how blood transfusions are managed around the world,” said Martin Holzmann, MD, PhD, of Karolinska Institutet in Stockholm, Sweden.

“Our results clearly show that there is no real connection between sex-discordant blood transfusions and the risk of death.”

Therefore, Dr Holzmann and his colleagues believe there is no need to consider donor sex when allocating RBC units for transfusion.

To come to this conclusion, the researchers analyzed data on 45,090 patients who underwent cardiac surgery and received at least 1 RBC transfusion.

All patients were adults who had undergone isolated coronary artery bypass grafting, isolated valve repair/replacement surgery, or a combination of these procedures between 1997 and 2012.

The researchers estimated the relative hazard of death in relation to exposure to sex-discordant transfusions, adjusting their analyses for potential confounding factors, such as patient sex, age, blood group, and number of transfusions.

Results

The researchers found that women were more likely to receive sex-discordant transfusions than same-sex transfusions—45.3% and 19.8%, respectively. And patients who received sex-discordant transfusions tended to receive more transfusions—a mean of 4.2 vs 2.0 for same-sex transfusions.

However, there were no other significant differences between the sex-discordant and same-sex groups.

The researchers noted that, during the 30-day follow-up period, there were more deaths among patients who received sex-discordant transfusions than those who did not—1701 (4.9%) and 205 (1.9%), respectively.

However, when the team adjusted for potential confounding factors, the relative risk of death was similar for patients who received at least 1 unit of sex-discordant blood and those who did not. The hazard ratio was 0.97 at 30 days of follow-up, 0.97 at the 2-year mark, and 0.98 at 10 years of follow-up.

The risk of death did increase as the number of sex-discordant units transfused increased. However, the increase was not statistically significant.

Red blood cells

The European Commission (EC) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

RA101495 is a synthetic macrocyclic peptide inhibitor of complement component C5.

Ra Pharmaceuticals is developing RA101495 as a self-administered, subcutaneous injection for the treatment of PNH, refractory generalized myasthenia gravis, and lupus nephritis.

RA101495 binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.

RA101495 also directly binds to C5b, disrupting the interaction between C5b and C6 and preventing assembly of the membrane attack complex.

According to Ra Pharmaceuticals, repeat dosing of RA101495 in vivo has demonstrated “sustained and predictable” inhibition of complement activity with an “excellent” safety profile.

The company also said phase 1 data have suggested that RA101495 is potent inhibitor of C5-mediated hemolysis with a favorable safety profile.

Preclinical research involving RA101495 was presented at the 2015 ASH Annual Meeting, and phase 1 data were presented at the 21st Congress of the European Hematology Association earlier this year.

RA101495’s orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

In situations where there is already an approved standard of care—such as with PNH, where the monoclonal antibody eculizumab (Soliris) is currently available—the EC requires companies developing a potential orphan drug to provide evidence that the drug is expected to provide significant benefits over the standard of care.

In the case of RA101495, the decision to grant orphan designation was based on the potential for improved patient convenience with subcutaneous self-administration, as well as the potential to treat patients who do not respond to eculizumab.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Red blood cells

The European Commission (EC) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

RA101495 is a synthetic macrocyclic peptide inhibitor of complement component C5.

Ra Pharmaceuticals is developing RA101495 as a self-administered, subcutaneous injection for the treatment of PNH, refractory generalized myasthenia gravis, and lupus nephritis.

RA101495 binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.

RA101495 also directly binds to C5b, disrupting the interaction between C5b and C6 and preventing assembly of the membrane attack complex.

According to Ra Pharmaceuticals, repeat dosing of RA101495 in vivo has demonstrated “sustained and predictable” inhibition of complement activity with an “excellent” safety profile.

The company also said phase 1 data have suggested that RA101495 is potent inhibitor of C5-mediated hemolysis with a favorable safety profile.

Preclinical research involving RA101495 was presented at the 2015 ASH Annual Meeting, and phase 1 data were presented at the 21st Congress of the European Hematology Association earlier this year.

RA101495’s orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

In situations where there is already an approved standard of care—such as with PNH, where the monoclonal antibody eculizumab (Soliris) is currently available—the EC requires companies developing a potential orphan drug to provide evidence that the drug is expected to provide significant benefits over the standard of care.

In the case of RA101495, the decision to grant orphan designation was based on the potential for improved patient convenience with subcutaneous self-administration, as well as the potential to treat patients who do not respond to eculizumab.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Red blood cells

The European Commission (EC) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

RA101495 is a synthetic macrocyclic peptide inhibitor of complement component C5.

Ra Pharmaceuticals is developing RA101495 as a self-administered, subcutaneous injection for the treatment of PNH, refractory generalized myasthenia gravis, and lupus nephritis.

RA101495 binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.

RA101495 also directly binds to C5b, disrupting the interaction between C5b and C6 and preventing assembly of the membrane attack complex.

According to Ra Pharmaceuticals, repeat dosing of RA101495 in vivo has demonstrated “sustained and predictable” inhibition of complement activity with an “excellent” safety profile.

The company also said phase 1 data have suggested that RA101495 is potent inhibitor of C5-mediated hemolysis with a favorable safety profile.

Preclinical research involving RA101495 was presented at the 2015 ASH Annual Meeting, and phase 1 data were presented at the 21st Congress of the European Hematology Association earlier this year.

RA101495’s orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

In situations where there is already an approved standard of care—such as with PNH, where the monoclonal antibody eculizumab (Soliris) is currently available—the EC requires companies developing a potential orphan drug to provide evidence that the drug is expected to provide significant benefits over the standard of care.

In the case of RA101495, the decision to grant orphan designation was based on the potential for improved patient convenience with subcutaneous self-administration, as well as the potential to treat patients who do not respond to eculizumab.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Unicompartmental knee arthroplasty (UKA) is considered a less invasive approach for the treatment of unicompartmental knee arthritis when compared with total knee arthroplasty (TKA), with optimal preservation of kinematics.¹ Despite excellent functional outcomes, conversion to TKA may be necessary if the UKA fails, or in patients with progressive knee arthritis. Some studies have found UKA conversion to TKA to be comparable with primary TKA,^2,3 whereas others have found that conversion often requires bone graft, augments, and stemmed components and has increased complications and inferior results compared to primary TKA.^4-7 While some studies report that <10% of UKA conversions to TKA require augments,² others have found that as many as 76% require augments.^4-8

Schwarzkopf and colleagues⁹ recently demonstrated that UKA conversion to TKA is comparable with primary TKA when a conservative tibial resection is performed during the index procedure. However, they reported increased complexity when greater tibial resection was performed and thicker polyethylene inserts were used at the time of the index UKA. The odds ratio of needing an augment or stem during the conversion to TKA was 26.8 (95% confidence interval, 3.71-194) when an aggressive tibial resection was performed during the UKA.⁹ Tibial resection thickness may thus be predictive of anticipated complexity of UKA revision to TKA and may aid in preoperative planning.

Robotic assistance has been shown to enhance the accuracy of bone preparation, implant component alignment, and soft tissue balance in UKA.^10-15 It has yet to be determined whether this improved accuracy translates to improved clinical performance or longevity of the UKA implant. However, the enhanced accuracy of robotic technology may result in more conservative tibial resection when compared to conventional UKA and may be advantageous if conversion to TKA becomes necessary.

The purpose of this study was to compare the distribution of polyethylene insert sizes implanted during conventional and robotic-assisted UKA. We hypothesized that robotic assistance would demonstrate more conservative tibial resection compared to conventional methods of bone preparation.

Methods

We retrospectively compared the distribution of polyethylene insert sizes implanted during consecutive conventional and robotic-assisted UKA procedures. Several manufacturers were queried to provide a listing of the polyethylene insert sizes utilized, ranging from 8 mm to 14 mm. The analysis included 8421 robotic-assisted UKA cases and 27,989 conventional UKA cases. Data were provided by Zimmer Biomet and Smith & Nephew regarding conventional cases, as well as Blue Belt Technologies (now part of Smith & Nephew) and MAKO Surgical (now part of Stryker) regarding robotic-assisted cases. (Dr. Lonner has an ongoing relationship as a consultant with Blue Belt Technologies, whose data was utilized in this study.) Using tibial insert thickness as a surrogate measure of the extent of tibial resection, an insert size of ≥10 mm was defined as aggressive while <10 mm was considered conservative. This cutoff was established based on its corresponding resection level with primary TKA and the anticipated need for augments. Statistical analysis was performed using a Mann-Whitney-Wilcoxon test. Significance was set at P < .05.

Results

Tibial resection thickness was found to be most commonly conservative in nature, with sizes 8-mm and 9-mm polyethylene inserts utilized in the majority of both robotic-assisted and conventional UKA cases. However, statistically more 8-mm and 9-mm polyethylene inserts were used in the robotic group (93.6%) than in the conventional group (84.5%) (P < .0001; Figure). Aggressive tibial resection, requiring tibial inserts ≥10 mm, was performed in 6.4% of robotic-assisted cases and 15.5% of conventional cases.

Discussion

Robotic assistance enhances the accuracy of bone preparation, implant component alignment, and soft tissue balance in UKA.^10-15 It has yet to be determined whether this improved accuracy translates to improved clinical performance or longevity of the UKA implant. However, we demonstrate that the enhanced accuracy of robotic technology results in more conservative tibial resection when compared to conventional techniques with a potential benefit suggested in the literature upon conversion to TKA.

The findings of this study have important implications for patients undergoing conversion of UKA to TKA, potentially optimizing the ease of revision and clinical outcomes. The outcomes of UKA conversion to TKA are often considered inferior to those of primary TKA, compromised by bone loss, need for augmentation, and challenges of restoring the joint line and rotation.^9,16-22 Barrett and Scott¹⁸ reported only 66% of patients had good or excellent results at an average of 4.6 years of follow-up after UKA conversion to TKA. Over 50% required stemmed implants and bone graft or bone cement augmentation to address osseous insufficiency. The authors suggested that the primary determinant of the complexity of the conversion to TKA was the surgical technique used in the index procedure. They concluded that UKA conversion to TKA can be as successful as a primary TKA and primary TKA implants can be used without bone augmentation or stems during the revision procedure if minimal tibial bone is resected at the time of the index UKA.¹⁸ Schwarzkopf and colleagues⁹ supported this conclusion when they found that aggressive tibial resection during UKA resulted in the need for bone graft, stem, wedge, or augment in 70% of cases when converted to TKA. Similarly, Khan and colleagues²³ found that 26% of patients required bone grafting and 26% required some form of augmentation, and Springer and colleagues³ reported that 68% required a graft, augment, or stem.^3,22 Using data from the New Zealand Joint Registry, Pearse and colleagues⁵ reported that revision TKA components were necessary in 28% of patients and concluded that converting a UKA to TKA gives a less reliable result than primary TKA, and with functional results that are not significantly better than a revision from a TKA.

Conservative tibial resection during UKA minimizes the complexity and concerns of bone loss upon conversion to TKA. Schwarzkopf and colleagues⁹ found 96.6% of patients with conservative tibial resection received a primary TKA implant, without augments or stems. Furthermore, patients with a primary TKA implant showed improved tibial survivorship, with revision as an end point, compared with patients who received a TKA implant that required stems and augments or bone graft for support.⁹ Also emphasizing the importance of minimal tibial resection, O’Donnell and colleagues⁸ compared a cohort of patients undergoing conversion of a minimal resection resurfacing onlay-type UKA to TKA with a cohort of patients undergoing primary TKA. They found that 40% of patients required bone grafting for contained defects, 3.6% required metal augments, and 1.8% required stems.⁸ There was no significant difference between the groups in terms of range of motion, functional outcome, or radiologic outcomes. The authors concluded that revision of minimal resection resurfacing implants to TKA is associated with similar results to primary TKA and is superior to revision of UKA with greater bone loss. Prior studies have shown that one of the advantages of robotic-assisted UKA is the accuracy and precision of bone resection. The present study supports this premise by showing that tibial resection is significantly more conservative using robotic-assisted techniques when using tibial component thickness as a surrogate for extent of bone resection. While our study did not address implant durability or the impact of conservative resection on conversion to TKA, studies referenced above suggest that the conservative nature of bone preparation would have a relevant impact on the revision of the implant to TKA.

Our study is a retrospective case series that reports tibial component thickness as a surrogate for volume of tibial resection during UKA. While the implication is that more conservative tibial resection may optimize durability and ease of conversion to TKA, future study will be needed to compare robotic-assisted and conventional cases of UKA upon conversion to TKA in order to ascertain whether the more conventional resections of robotic-assisted UKA in fact lead to revision that is comparable with primary TKA in terms of bone loss at the time of revision, components utilized, the need for bone graft, augments, or stems, and clinical outcomes. Given the method of data collection in this study, we could not control for clinical deformity, selection bias, surgeon experience, or medial vs lateral knee compartments. These potential confounders represent weaknesses of this study.

In conclusion, conversion of UKA to TKA may be associated with significant osseous insufficiency, which may compromise patient outcomes in comparison to primary TKA. Studies have shown that UKA conversion to TKA is comparable to primary TKA when minimal tibial resection is performed during the UKA, and the need for augmentation, grafting or stems is increased with more aggressive tibial resection. This study has shown that when robotic assistance is utilized, tibial resection is more precise, less variable, and more conservative compared to conventional techniques.

Am J Orthop. 2016;45(7):E465-E468. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Unicompartmental knee arthroplasty (UKA) is considered a less invasive approach for the treatment of unicompartmental knee arthritis when compared with total knee arthroplasty (TKA), with optimal preservation of kinematics.¹ Despite excellent functional outcomes, conversion to TKA may be necessary if the UKA fails, or in patients with progressive knee arthritis. Some studies have found UKA conversion to TKA to be comparable with primary TKA,^2,3 whereas others have found that conversion often requires bone graft, augments, and stemmed components and has increased complications and inferior results compared to primary TKA.^4-7 While some studies report that <10% of UKA conversions to TKA require augments,² others have found that as many as 76% require augments.^4-8

Schwarzkopf and colleagues⁹ recently demonstrated that UKA conversion to TKA is comparable with primary TKA when a conservative tibial resection is performed during the index procedure. However, they reported increased complexity when greater tibial resection was performed and thicker polyethylene inserts were used at the time of the index UKA. The odds ratio of needing an augment or stem during the conversion to TKA was 26.8 (95% confidence interval, 3.71-194) when an aggressive tibial resection was performed during the UKA.⁹ Tibial resection thickness may thus be predictive of anticipated complexity of UKA revision to TKA and may aid in preoperative planning.

Robotic assistance has been shown to enhance the accuracy of bone preparation, implant component alignment, and soft tissue balance in UKA.^10-15 It has yet to be determined whether this improved accuracy translates to improved clinical performance or longevity of the UKA implant. However, the enhanced accuracy of robotic technology may result in more conservative tibial resection when compared to conventional UKA and may be advantageous if conversion to TKA becomes necessary.

The purpose of this study was to compare the distribution of polyethylene insert sizes implanted during conventional and robotic-assisted UKA. We hypothesized that robotic assistance would demonstrate more conservative tibial resection compared to conventional methods of bone preparation.

Methods

We retrospectively compared the distribution of polyethylene insert sizes implanted during consecutive conventional and robotic-assisted UKA procedures. Several manufacturers were queried to provide a listing of the polyethylene insert sizes utilized, ranging from 8 mm to 14 mm. The analysis included 8421 robotic-assisted UKA cases and 27,989 conventional UKA cases. Data were provided by Zimmer Biomet and Smith & Nephew regarding conventional cases, as well as Blue Belt Technologies (now part of Smith & Nephew) and MAKO Surgical (now part of Stryker) regarding robotic-assisted cases. (Dr. Lonner has an ongoing relationship as a consultant with Blue Belt Technologies, whose data was utilized in this study.) Using tibial insert thickness as a surrogate measure of the extent of tibial resection, an insert size of ≥10 mm was defined as aggressive while <10 mm was considered conservative. This cutoff was established based on its corresponding resection level with primary TKA and the anticipated need for augments. Statistical analysis was performed using a Mann-Whitney-Wilcoxon test. Significance was set at P < .05.

Results

Tibial resection thickness was found to be most commonly conservative in nature, with sizes 8-mm and 9-mm polyethylene inserts utilized in the majority of both robotic-assisted and conventional UKA cases. However, statistically more 8-mm and 9-mm polyethylene inserts were used in the robotic group (93.6%) than in the conventional group (84.5%) (P < .0001; Figure). Aggressive tibial resection, requiring tibial inserts ≥10 mm, was performed in 6.4% of robotic-assisted cases and 15.5% of conventional cases.

Discussion

Robotic assistance enhances the accuracy of bone preparation, implant component alignment, and soft tissue balance in UKA.^10-15 It has yet to be determined whether this improved accuracy translates to improved clinical performance or longevity of the UKA implant. However, we demonstrate that the enhanced accuracy of robotic technology results in more conservative tibial resection when compared to conventional techniques with a potential benefit suggested in the literature upon conversion to TKA.

The findings of this study have important implications for patients undergoing conversion of UKA to TKA, potentially optimizing the ease of revision and clinical outcomes. The outcomes of UKA conversion to TKA are often considered inferior to those of primary TKA, compromised by bone loss, need for augmentation, and challenges of restoring the joint line and rotation.^9,16-22 Barrett and Scott¹⁸ reported only 66% of patients had good or excellent results at an average of 4.6 years of follow-up after UKA conversion to TKA. Over 50% required stemmed implants and bone graft or bone cement augmentation to address osseous insufficiency. The authors suggested that the primary determinant of the complexity of the conversion to TKA was the surgical technique used in the index procedure. They concluded that UKA conversion to TKA can be as successful as a primary TKA and primary TKA implants can be used without bone augmentation or stems during the revision procedure if minimal tibial bone is resected at the time of the index UKA.¹⁸ Schwarzkopf and colleagues⁹ supported this conclusion when they found that aggressive tibial resection during UKA resulted in the need for bone graft, stem, wedge, or augment in 70% of cases when converted to TKA. Similarly, Khan and colleagues²³ found that 26% of patients required bone grafting and 26% required some form of augmentation, and Springer and colleagues³ reported that 68% required a graft, augment, or stem.^3,22 Using data from the New Zealand Joint Registry, Pearse and colleagues⁵ reported that revision TKA components were necessary in 28% of patients and concluded that converting a UKA to TKA gives a less reliable result than primary TKA, and with functional results that are not significantly better than a revision from a TKA.

Conservative tibial resection during UKA minimizes the complexity and concerns of bone loss upon conversion to TKA. Schwarzkopf and colleagues⁹ found 96.6% of patients with conservative tibial resection received a primary TKA implant, without augments or stems. Furthermore, patients with a primary TKA implant showed improved tibial survivorship, with revision as an end point, compared with patients who received a TKA implant that required stems and augments or bone graft for support.⁹ Also emphasizing the importance of minimal tibial resection, O’Donnell and colleagues⁸ compared a cohort of patients undergoing conversion of a minimal resection resurfacing onlay-type UKA to TKA with a cohort of patients undergoing primary TKA. They found that 40% of patients required bone grafting for contained defects, 3.6% required metal augments, and 1.8% required stems.⁸ There was no significant difference between the groups in terms of range of motion, functional outcome, or radiologic outcomes. The authors concluded that revision of minimal resection resurfacing implants to TKA is associated with similar results to primary TKA and is superior to revision of UKA with greater bone loss. Prior studies have shown that one of the advantages of robotic-assisted UKA is the accuracy and precision of bone resection. The present study supports this premise by showing that tibial resection is significantly more conservative using robotic-assisted techniques when using tibial component thickness as a surrogate for extent of bone resection. While our study did not address implant durability or the impact of conservative resection on conversion to TKA, studies referenced above suggest that the conservative nature of bone preparation would have a relevant impact on the revision of the implant to TKA.

Our study is a retrospective case series that reports tibial component thickness as a surrogate for volume of tibial resection during UKA. While the implication is that more conservative tibial resection may optimize durability and ease of conversion to TKA, future study will be needed to compare robotic-assisted and conventional cases of UKA upon conversion to TKA in order to ascertain whether the more conventional resections of robotic-assisted UKA in fact lead to revision that is comparable with primary TKA in terms of bone loss at the time of revision, components utilized, the need for bone graft, augments, or stems, and clinical outcomes. Given the method of data collection in this study, we could not control for clinical deformity, selection bias, surgeon experience, or medial vs lateral knee compartments. These potential confounders represent weaknesses of this study.

In conclusion, conversion of UKA to TKA may be associated with significant osseous insufficiency, which may compromise patient outcomes in comparison to primary TKA. Studies have shown that UKA conversion to TKA is comparable to primary TKA when minimal tibial resection is performed during the UKA, and the need for augmentation, grafting or stems is increased with more aggressive tibial resection. This study has shown that when robotic assistance is utilized, tibial resection is more precise, less variable, and more conservative compared to conventional techniques.

Am J Orthop. 2016;45(7):E465-E468. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Unicompartmental knee arthroplasty (UKA) is considered a less invasive approach for the treatment of unicompartmental knee arthritis when compared with total knee arthroplasty (TKA), with optimal preservation of kinematics.¹ Despite excellent functional outcomes, conversion to TKA may be necessary if the UKA fails, or in patients with progressive knee arthritis. Some studies have found UKA conversion to TKA to be comparable with primary TKA,^2,3 whereas others have found that conversion often requires bone graft, augments, and stemmed components and has increased complications and inferior results compared to primary TKA.^4-7 While some studies report that <10% of UKA conversions to TKA require augments,² others have found that as many as 76% require augments.^4-8

Schwarzkopf and colleagues⁹ recently demonstrated that UKA conversion to TKA is comparable with primary TKA when a conservative tibial resection is performed during the index procedure. However, they reported increased complexity when greater tibial resection was performed and thicker polyethylene inserts were used at the time of the index UKA. The odds ratio of needing an augment or stem during the conversion to TKA was 26.8 (95% confidence interval, 3.71-194) when an aggressive tibial resection was performed during the UKA.⁹ Tibial resection thickness may thus be predictive of anticipated complexity of UKA revision to TKA and may aid in preoperative planning.

Robotic assistance has been shown to enhance the accuracy of bone preparation, implant component alignment, and soft tissue balance in UKA.^10-15 It has yet to be determined whether this improved accuracy translates to improved clinical performance or longevity of the UKA implant. However, the enhanced accuracy of robotic technology may result in more conservative tibial resection when compared to conventional UKA and may be advantageous if conversion to TKA becomes necessary.

The purpose of this study was to compare the distribution of polyethylene insert sizes implanted during conventional and robotic-assisted UKA. We hypothesized that robotic assistance would demonstrate more conservative tibial resection compared to conventional methods of bone preparation.

Methods

We retrospectively compared the distribution of polyethylene insert sizes implanted during consecutive conventional and robotic-assisted UKA procedures. Several manufacturers were queried to provide a listing of the polyethylene insert sizes utilized, ranging from 8 mm to 14 mm. The analysis included 8421 robotic-assisted UKA cases and 27,989 conventional UKA cases. Data were provided by Zimmer Biomet and Smith & Nephew regarding conventional cases, as well as Blue Belt Technologies (now part of Smith & Nephew) and MAKO Surgical (now part of Stryker) regarding robotic-assisted cases. (Dr. Lonner has an ongoing relationship as a consultant with Blue Belt Technologies, whose data was utilized in this study.) Using tibial insert thickness as a surrogate measure of the extent of tibial resection, an insert size of ≥10 mm was defined as aggressive while <10 mm was considered conservative. This cutoff was established based on its corresponding resection level with primary TKA and the anticipated need for augments. Statistical analysis was performed using a Mann-Whitney-Wilcoxon test. Significance was set at P < .05.

Results

Tibial resection thickness was found to be most commonly conservative in nature, with sizes 8-mm and 9-mm polyethylene inserts utilized in the majority of both robotic-assisted and conventional UKA cases. However, statistically more 8-mm and 9-mm polyethylene inserts were used in the robotic group (93.6%) than in the conventional group (84.5%) (P < .0001; Figure). Aggressive tibial resection, requiring tibial inserts ≥10 mm, was performed in 6.4% of robotic-assisted cases and 15.5% of conventional cases.

Discussion

Robotic assistance enhances the accuracy of bone preparation, implant component alignment, and soft tissue balance in UKA.^10-15 It has yet to be determined whether this improved accuracy translates to improved clinical performance or longevity of the UKA implant. However, we demonstrate that the enhanced accuracy of robotic technology results in more conservative tibial resection when compared to conventional techniques with a potential benefit suggested in the literature upon conversion to TKA.

The findings of this study have important implications for patients undergoing conversion of UKA to TKA, potentially optimizing the ease of revision and clinical outcomes. The outcomes of UKA conversion to TKA are often considered inferior to those of primary TKA, compromised by bone loss, need for augmentation, and challenges of restoring the joint line and rotation.^9,16-22 Barrett and Scott¹⁸ reported only 66% of patients had good or excellent results at an average of 4.6 years of follow-up after UKA conversion to TKA. Over 50% required stemmed implants and bone graft or bone cement augmentation to address osseous insufficiency. The authors suggested that the primary determinant of the complexity of the conversion to TKA was the surgical technique used in the index procedure. They concluded that UKA conversion to TKA can be as successful as a primary TKA and primary TKA implants can be used without bone augmentation or stems during the revision procedure if minimal tibial bone is resected at the time of the index UKA.¹⁸ Schwarzkopf and colleagues⁹ supported this conclusion when they found that aggressive tibial resection during UKA resulted in the need for bone graft, stem, wedge, or augment in 70% of cases when converted to TKA. Similarly, Khan and colleagues²³ found that 26% of patients required bone grafting and 26% required some form of augmentation, and Springer and colleagues³ reported that 68% required a graft, augment, or stem.^3,22 Using data from the New Zealand Joint Registry, Pearse and colleagues⁵ reported that revision TKA components were necessary in 28% of patients and concluded that converting a UKA to TKA gives a less reliable result than primary TKA, and with functional results that are not significantly better than a revision from a TKA.

Conservative tibial resection during UKA minimizes the complexity and concerns of bone loss upon conversion to TKA. Schwarzkopf and colleagues⁹ found 96.6% of patients with conservative tibial resection received a primary TKA implant, without augments or stems. Furthermore, patients with a primary TKA implant showed improved tibial survivorship, with revision as an end point, compared with patients who received a TKA implant that required stems and augments or bone graft for support.⁹ Also emphasizing the importance of minimal tibial resection, O’Donnell and colleagues⁸ compared a cohort of patients undergoing conversion of a minimal resection resurfacing onlay-type UKA to TKA with a cohort of patients undergoing primary TKA. They found that 40% of patients required bone grafting for contained defects, 3.6% required metal augments, and 1.8% required stems.⁸ There was no significant difference between the groups in terms of range of motion, functional outcome, or radiologic outcomes. The authors concluded that revision of minimal resection resurfacing implants to TKA is associated with similar results to primary TKA and is superior to revision of UKA with greater bone loss. Prior studies have shown that one of the advantages of robotic-assisted UKA is the accuracy and precision of bone resection. The present study supports this premise by showing that tibial resection is significantly more conservative using robotic-assisted techniques when using tibial component thickness as a surrogate for extent of bone resection. While our study did not address implant durability or the impact of conservative resection on conversion to TKA, studies referenced above suggest that the conservative nature of bone preparation would have a relevant impact on the revision of the implant to TKA.

Our study is a retrospective case series that reports tibial component thickness as a surrogate for volume of tibial resection during UKA. While the implication is that more conservative tibial resection may optimize durability and ease of conversion to TKA, future study will be needed to compare robotic-assisted and conventional cases of UKA upon conversion to TKA in order to ascertain whether the more conventional resections of robotic-assisted UKA in fact lead to revision that is comparable with primary TKA in terms of bone loss at the time of revision, components utilized, the need for bone graft, augments, or stems, and clinical outcomes. Given the method of data collection in this study, we could not control for clinical deformity, selection bias, surgeon experience, or medial vs lateral knee compartments. These potential confounders represent weaknesses of this study.

In conclusion, conversion of UKA to TKA may be associated with significant osseous insufficiency, which may compromise patient outcomes in comparison to primary TKA. Studies have shown that UKA conversion to TKA is comparable to primary TKA when minimal tibial resection is performed during the UKA, and the need for augmentation, grafting or stems is increased with more aggressive tibial resection. This study has shown that when robotic assistance is utilized, tibial resection is more precise, less variable, and more conservative compared to conventional techniques.

Am J Orthop. 2016;45(7):E465-E468. Copyright Frontline Medical Communications Inc. 2016. All rights reserved.

Tracy Gulling-Leftwich, DO, remembers Chewy very well. He was a 70-pound English bulldog she was caring for last year on behalf of the Rescue Ohio English Bulldogs, an English bulldog rescue group.

She soon learned that Chewy was anemic and suffered from bone cancer of the jaw. Ironically, considering his name, he could barely chew, so Dr. Gulling-Leftwich and her husband, Samuel Leftwich, pureed his food, spoon-fed the animal, and administered around-the-clock pain medications for roughly two weeks. But his pain grew too intense, and Chewy had to be euthanized.

For many people, that would end their experience with an animal organization. People typically compare the heartbreaking experience to losing a beloved family member or friend. But as an animal lover and hospitalist at the Cleveland Clinic, Dr. Gulling-Leftwich has no intentions of looking the other way whenever an animal—or human—is in need. Ever since she was in college, she has been rescuing lab rats and dogs, trying to keep them happy, healthy, and loved throughout their relatively short lives.

Underground Railroad

Dr. Gulling-Leftwich graduated from the Lake Erie College of Osteopathic Medicine in Erie, Penn., in 2007. The following year, she pursued an osteopathic rotating internship at the University of Connecticut. While attending the same university from 2008 to 2010, she completed a traditional, categorical, allopathic medicine residency.

After completing her medical education, she held several positions. She worked as a teaching hospitalist at the Hartford Hospital for one year, served as a primary-care physician for the next three years at The Hospital of Central Connecticut, and then joined the Cleveland Clinic as a hospitalist in 2014.

Her involvement in animal rescue began many years earlier while attending undergraduate school at Westminster College in New Wilmington, Penn. She tells the story how one student at the college kidnapped a rat from the school’s neuroscience lab just before Christmas break.

Since the student’s mother would not allow her to bring a rat home over the six-week holiday, Dr. Gulling-Leftwich babysat him until she returned. However, the student intended on releasing him into the wild. Fearing the worst, that the rat could not fend for itself since it had been caged and fed for many months, Dr. Gulling-Leftwich convinced the student to relinquish custody of the rat to her.

That’s how it all began. Dr. Gulling-Leftwich named the rat Templeton. She suspects he died of a pituitary tumor four years later; still, that’s a long life for a rat. Most live just two years. Just shows what a little love can do.

Since then, she has rescued approximately 21 rats from Kentucky and Connecticut. Years ago, she says, there were multiple Yahoo chat groups of people involved in an underground railroad of sorts for rescued lab rats. People would often drive the rats to different cities, even across state borders, so these rats could enjoy a permanent home.

While she has never broken into a research lab, her opinion is torn on animal research. She believes it is not necessary for consumer products, such as makeup, but can see its value in other fields of science like the development of new medications.

“What I can hope for is that we work toward finding a way of not requiring animals for research in the future,” she says.

Full House

After getting married in 2013, Dr. Gulling-Leftwich told her husband she wanted a dog. But because of their hectic schedules, no one would be home to care for the animal, so the couple waited another two years to adopt a rescue animal.

In 2015, they had purchased a house in Cleveland when they adopted Boomer, a pug and beagle designer breed, as their family pet.

“I had really wanted an English bulldog. They’re just cute, their face is squishy,” she says, adding she had been monitoring English bulldog rescue websites. “I won’t buy a puppy. I will only get a dog that needs a home.”

In September that year, the rescue organization emailed a desperate plea to its followers. Can anyone rescue an English bulldog named Chewy? Dr. Gulling-Leftwich immediately filled out the paperwork and adopted him. But Chewy only stayed with them for two weeks before he was euthanized. She brought him to the vet after he attacked Boomer.

“Chewy wasn’t being a jerk,” she says. “His attacking behavior had to do with his pain and discomfort. He had blood everywhere around his mouth. We had a hard time letting him go.”

One month later, another English bulldog named Olive joined their family. She’s roughly two years old and weighs only 30 pounds mainly because of her disease: congenital cardiomyopathy. They plan to care for Olive until she dies.

She says Olive takes six pills a day for her condition and occasionally receives nitroglycerin when she overexerts herself and passes out.

Meanwhile, Dr. Gulling-Leftwich and her husband care for one rat named Harvey and a cat called Lily in addition to the two dogs. Boomer doesn’t like Olive. Olive doesn’t like the cat. And both dogs and the cat pay no attention to the rat.

“My husband says rescuing animals and taking care of people is one of my more endearing qualities,” she says. “Then he follows it up with, ‘No, you can’t have that bunny that needs a home.’”

She believes caring for these animals balances her work in hospital medicine. While hospital patients often are in pain, act grouchy, and appear unappreciative, she says her four-legged family members are always excited to see her and routinely demonstrate unconditional love.

“You definitely have to be open-minded because you never know what you’ll be walking into when you rescue an animal,” she says, adding that rescue groups tend to pay for vet bills and medicine. “You have to be prepared for what potentially could be the worst.”

Carol Patton is a freelance writer in Las Vegas.

Tracy Gulling-Leftwich, DO, remembers Chewy very well. He was a 70-pound English bulldog she was caring for last year on behalf of the Rescue Ohio English Bulldogs, an English bulldog rescue group.

She soon learned that Chewy was anemic and suffered from bone cancer of the jaw. Ironically, considering his name, he could barely chew, so Dr. Gulling-Leftwich and her husband, Samuel Leftwich, pureed his food, spoon-fed the animal, and administered around-the-clock pain medications for roughly two weeks. But his pain grew too intense, and Chewy had to be euthanized.

For many people, that would end their experience with an animal organization. People typically compare the heartbreaking experience to losing a beloved family member or friend. But as an animal lover and hospitalist at the Cleveland Clinic, Dr. Gulling-Leftwich has no intentions of looking the other way whenever an animal—or human—is in need. Ever since she was in college, she has been rescuing lab rats and dogs, trying to keep them happy, healthy, and loved throughout their relatively short lives.

Underground Railroad

Dr. Gulling-Leftwich graduated from the Lake Erie College of Osteopathic Medicine in Erie, Penn., in 2007. The following year, she pursued an osteopathic rotating internship at the University of Connecticut. While attending the same university from 2008 to 2010, she completed a traditional, categorical, allopathic medicine residency.

After completing her medical education, she held several positions. She worked as a teaching hospitalist at the Hartford Hospital for one year, served as a primary-care physician for the next three years at The Hospital of Central Connecticut, and then joined the Cleveland Clinic as a hospitalist in 2014.

Her involvement in animal rescue began many years earlier while attending undergraduate school at Westminster College in New Wilmington, Penn. She tells the story how one student at the college kidnapped a rat from the school’s neuroscience lab just before Christmas break.

Since the student’s mother would not allow her to bring a rat home over the six-week holiday, Dr. Gulling-Leftwich babysat him until she returned. However, the student intended on releasing him into the wild. Fearing the worst, that the rat could not fend for itself since it had been caged and fed for many months, Dr. Gulling-Leftwich convinced the student to relinquish custody of the rat to her.

That’s how it all began. Dr. Gulling-Leftwich named the rat Templeton. She suspects he died of a pituitary tumor four years later; still, that’s a long life for a rat. Most live just two years. Just shows what a little love can do.

Since then, she has rescued approximately 21 rats from Kentucky and Connecticut. Years ago, she says, there were multiple Yahoo chat groups of people involved in an underground railroad of sorts for rescued lab rats. People would often drive the rats to different cities, even across state borders, so these rats could enjoy a permanent home.

While she has never broken into a research lab, her opinion is torn on animal research. She believes it is not necessary for consumer products, such as makeup, but can see its value in other fields of science like the development of new medications.

“What I can hope for is that we work toward finding a way of not requiring animals for research in the future,” she says.

Full House

After getting married in 2013, Dr. Gulling-Leftwich told her husband she wanted a dog. But because of their hectic schedules, no one would be home to care for the animal, so the couple waited another two years to adopt a rescue animal.

In 2015, they had purchased a house in Cleveland when they adopted Boomer, a pug and beagle designer breed, as their family pet.

“I had really wanted an English bulldog. They’re just cute, their face is squishy,” she says, adding she had been monitoring English bulldog rescue websites. “I won’t buy a puppy. I will only get a dog that needs a home.”

In September that year, the rescue organization emailed a desperate plea to its followers. Can anyone rescue an English bulldog named Chewy? Dr. Gulling-Leftwich immediately filled out the paperwork and adopted him. But Chewy only stayed with them for two weeks before he was euthanized. She brought him to the vet after he attacked Boomer.

“Chewy wasn’t being a jerk,” she says. “His attacking behavior had to do with his pain and discomfort. He had blood everywhere around his mouth. We had a hard time letting him go.”

One month later, another English bulldog named Olive joined their family. She’s roughly two years old and weighs only 30 pounds mainly because of her disease: congenital cardiomyopathy. They plan to care for Olive until she dies.

She says Olive takes six pills a day for her condition and occasionally receives nitroglycerin when she overexerts herself and passes out.

Meanwhile, Dr. Gulling-Leftwich and her husband care for one rat named Harvey and a cat called Lily in addition to the two dogs. Boomer doesn’t like Olive. Olive doesn’t like the cat. And both dogs and the cat pay no attention to the rat.

“My husband says rescuing animals and taking care of people is one of my more endearing qualities,” she says. “Then he follows it up with, ‘No, you can’t have that bunny that needs a home.’”

She believes caring for these animals balances her work in hospital medicine. While hospital patients often are in pain, act grouchy, and appear unappreciative, she says her four-legged family members are always excited to see her and routinely demonstrate unconditional love.

“You definitely have to be open-minded because you never know what you’ll be walking into when you rescue an animal,” she says, adding that rescue groups tend to pay for vet bills and medicine. “You have to be prepared for what potentially could be the worst.”

Carol Patton is a freelance writer in Las Vegas.

Tracy Gulling-Leftwich, DO, remembers Chewy very well. He was a 70-pound English bulldog she was caring for last year on behalf of the Rescue Ohio English Bulldogs, an English bulldog rescue group.

She soon learned that Chewy was anemic and suffered from bone cancer of the jaw. Ironically, considering his name, he could barely chew, so Dr. Gulling-Leftwich and her husband, Samuel Leftwich, pureed his food, spoon-fed the animal, and administered around-the-clock pain medications for roughly two weeks. But his pain grew too intense, and Chewy had to be euthanized.

For many people, that would end their experience with an animal organization. People typically compare the heartbreaking experience to losing a beloved family member or friend. But as an animal lover and hospitalist at the Cleveland Clinic, Dr. Gulling-Leftwich has no intentions of looking the other way whenever an animal—or human—is in need. Ever since she was in college, she has been rescuing lab rats and dogs, trying to keep them happy, healthy, and loved throughout their relatively short lives.

Underground Railroad

Dr. Gulling-Leftwich graduated from the Lake Erie College of Osteopathic Medicine in Erie, Penn., in 2007. The following year, she pursued an osteopathic rotating internship at the University of Connecticut. While attending the same university from 2008 to 2010, she completed a traditional, categorical, allopathic medicine residency.

After completing her medical education, she held several positions. She worked as a teaching hospitalist at the Hartford Hospital for one year, served as a primary-care physician for the next three years at The Hospital of Central Connecticut, and then joined the Cleveland Clinic as a hospitalist in 2014.

Her involvement in animal rescue began many years earlier while attending undergraduate school at Westminster College in New Wilmington, Penn. She tells the story how one student at the college kidnapped a rat from the school’s neuroscience lab just before Christmas break.

Since the student’s mother would not allow her to bring a rat home over the six-week holiday, Dr. Gulling-Leftwich babysat him until she returned. However, the student intended on releasing him into the wild. Fearing the worst, that the rat could not fend for itself since it had been caged and fed for many months, Dr. Gulling-Leftwich convinced the student to relinquish custody of the rat to her.

That’s how it all began. Dr. Gulling-Leftwich named the rat Templeton. She suspects he died of a pituitary tumor four years later; still, that’s a long life for a rat. Most live just two years. Just shows what a little love can do.

Since then, she has rescued approximately 21 rats from Kentucky and Connecticut. Years ago, she says, there were multiple Yahoo chat groups of people involved in an underground railroad of sorts for rescued lab rats. People would often drive the rats to different cities, even across state borders, so these rats could enjoy a permanent home.

While she has never broken into a research lab, her opinion is torn on animal research. She believes it is not necessary for consumer products, such as makeup, but can see its value in other fields of science like the development of new medications.

“What I can hope for is that we work toward finding a way of not requiring animals for research in the future,” she says.

Full House

After getting married in 2013, Dr. Gulling-Leftwich told her husband she wanted a dog. But because of their hectic schedules, no one would be home to care for the animal, so the couple waited another two years to adopt a rescue animal.

In 2015, they had purchased a house in Cleveland when they adopted Boomer, a pug and beagle designer breed, as their family pet.

“I had really wanted an English bulldog. They’re just cute, their face is squishy,” she says, adding she had been monitoring English bulldog rescue websites. “I won’t buy a puppy. I will only get a dog that needs a home.”

In September that year, the rescue organization emailed a desperate plea to its followers. Can anyone rescue an English bulldog named Chewy? Dr. Gulling-Leftwich immediately filled out the paperwork and adopted him. But Chewy only stayed with them for two weeks before he was euthanized. She brought him to the vet after he attacked Boomer.

“Chewy wasn’t being a jerk,” she says. “His attacking behavior had to do with his pain and discomfort. He had blood everywhere around his mouth. We had a hard time letting him go.”

One month later, another English bulldog named Olive joined their family. She’s roughly two years old and weighs only 30 pounds mainly because of her disease: congenital cardiomyopathy. They plan to care for Olive until she dies.

She says Olive takes six pills a day for her condition and occasionally receives nitroglycerin when she overexerts herself and passes out.

Meanwhile, Dr. Gulling-Leftwich and her husband care for one rat named Harvey and a cat called Lily in addition to the two dogs. Boomer doesn’t like Olive. Olive doesn’t like the cat. And both dogs and the cat pay no attention to the rat.

“My husband says rescuing animals and taking care of people is one of my more endearing qualities,” she says. “Then he follows it up with, ‘No, you can’t have that bunny that needs a home.’”

She believes caring for these animals balances her work in hospital medicine. While hospital patients often are in pain, act grouchy, and appear unappreciative, she says her four-legged family members are always excited to see her and routinely demonstrate unconditional love.

“You definitely have to be open-minded because you never know what you’ll be walking into when you rescue an animal,” she says, adding that rescue groups tend to pay for vet bills and medicine. “You have to be prepared for what potentially could be the worst.”

Carol Patton is a freelance writer in Las Vegas.

Image from NIAID

Once again, the phase 2 ROCKET trial has been placed on clinical hold due to patient deaths.

In this trial, researchers are testing the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

Juno Therapeutics, Inc. voluntarily put the trial on hold after 2 more patients suffered cerebral edema and died.

A total of 5 patients have died of cerebral edema in this trial.

Juno has notified the US Food and Drug Administration (FDA) of the latest clinical hold on the ROCKET trial and is working with the agency and the company’s data and safety monitoring board to determine next steps.

The ROCKET trial was previously placed on clinical hold in July, after 3 patients died of cerebral edema. The FDA lifted the hold less than a week later, allowing the trial to continue with a revised protocol.

Juno had theorized the deaths were likely a result of adding fludarabine to the conditioning regimen.

Patients enrolled in ROCKET initially received conditioning with cyclophosphamide alone, but researchers later decided to add fludarabine in the hopes of increasing efficacy. Previous trials of 2 other CAR T-cell therapies, JCAR014 and JCAR017, had suggested that adding fludarabine to conditioning could increase efficacy.

However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.

Juno said that, although other factors may have contributed to the deaths, fludarabine was the most likely culprit. So the company revised the trial protocol, and the FDA allowed ROCKET to continue with a conditioning regimen consisting of cyclophosphamide alone.

Since that time, 12 patients have been treated on the ROCKET trial. Two patients who were treated the week of November 14 developed cerebral edema and died on November 22 and 23, respectively.

In a conference call, Juno’s Chief Medical Officer Mark Gilbert, MD, said the etiology of cerebral edema is multi-factorial, and Juno will need more time to draw even preliminary conclusions about what factors contributed to the cases of cerebral edema in ROCKET.

Right now, the company is assessing data from the cases and the trial and is evaluating its options regarding the JCAR015 program.

Juno’s President and CEO Hans Bishop said the options for JCAR015 going forward include continuing the ROCKET trial with a modified protocol, beginning a new study of JCAR015, and terminating the JCAR015 development program.

Bishop said the company expects to provide an update on the status of ROCKET and JCAR015 in the next few weeks.

Juno’s other trials and plans for its other CD19-directed CAR T-cell product candidates are not affected by the issues with ROCKET and JCAR015.

ROCKET is not the first trial of JCAR015 to be placed on hold. The phase 1 trial of the therapy was placed on clinical hold in 2014, after 2 patients died of cytokine release syndrome.

That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.

Image from NIAID

Once again, the phase 2 ROCKET trial has been placed on clinical hold due to patient deaths.

In this trial, researchers are testing the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

Juno Therapeutics, Inc. voluntarily put the trial on hold after 2 more patients suffered cerebral edema and died.

A total of 5 patients have died of cerebral edema in this trial.

Juno has notified the US Food and Drug Administration (FDA) of the latest clinical hold on the ROCKET trial and is working with the agency and the company’s data and safety monitoring board to determine next steps.

The ROCKET trial was previously placed on clinical hold in July, after 3 patients died of cerebral edema. The FDA lifted the hold less than a week later, allowing the trial to continue with a revised protocol.

Juno had theorized the deaths were likely a result of adding fludarabine to the conditioning regimen.

Patients enrolled in ROCKET initially received conditioning with cyclophosphamide alone, but researchers later decided to add fludarabine in the hopes of increasing efficacy. Previous trials of 2 other CAR T-cell therapies, JCAR014 and JCAR017, had suggested that adding fludarabine to conditioning could increase efficacy.

However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.

Juno said that, although other factors may have contributed to the deaths, fludarabine was the most likely culprit. So the company revised the trial protocol, and the FDA allowed ROCKET to continue with a conditioning regimen consisting of cyclophosphamide alone.

Since that time, 12 patients have been treated on the ROCKET trial. Two patients who were treated the week of November 14 developed cerebral edema and died on November 22 and 23, respectively.

In a conference call, Juno’s Chief Medical Officer Mark Gilbert, MD, said the etiology of cerebral edema is multi-factorial, and Juno will need more time to draw even preliminary conclusions about what factors contributed to the cases of cerebral edema in ROCKET.

Right now, the company is assessing data from the cases and the trial and is evaluating its options regarding the JCAR015 program.

Juno’s President and CEO Hans Bishop said the options for JCAR015 going forward include continuing the ROCKET trial with a modified protocol, beginning a new study of JCAR015, and terminating the JCAR015 development program.

Bishop said the company expects to provide an update on the status of ROCKET and JCAR015 in the next few weeks.

Juno’s other trials and plans for its other CD19-directed CAR T-cell product candidates are not affected by the issues with ROCKET and JCAR015.

ROCKET is not the first trial of JCAR015 to be placed on hold. The phase 1 trial of the therapy was placed on clinical hold in 2014, after 2 patients died of cytokine release syndrome.

That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.

Image from NIAID

Once again, the phase 2 ROCKET trial has been placed on clinical hold due to patient deaths.

In this trial, researchers are testing the chimeric antigen receptor (CAR) T-cell therapy JCAR015 in adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

Juno Therapeutics, Inc. voluntarily put the trial on hold after 2 more patients suffered cerebral edema and died.

A total of 5 patients have died of cerebral edema in this trial.

Juno has notified the US Food and Drug Administration (FDA) of the latest clinical hold on the ROCKET trial and is working with the agency and the company’s data and safety monitoring board to determine next steps.

The ROCKET trial was previously placed on clinical hold in July, after 3 patients died of cerebral edema. The FDA lifted the hold less than a week later, allowing the trial to continue with a revised protocol.

Juno had theorized the deaths were likely a result of adding fludarabine to the conditioning regimen.

Patients enrolled in ROCKET initially received conditioning with cyclophosphamide alone, but researchers later decided to add fludarabine in the hopes of increasing efficacy. Previous trials of 2 other CAR T-cell therapies, JCAR014 and JCAR017, had suggested that adding fludarabine to conditioning could increase efficacy.

However, in the ROCKET trial, the addition of fludarabine was associated with an increase in the incidence of severe neurotoxicity and the 3 deaths from cerebral edema.

Juno said that, although other factors may have contributed to the deaths, fludarabine was the most likely culprit. So the company revised the trial protocol, and the FDA allowed ROCKET to continue with a conditioning regimen consisting of cyclophosphamide alone.

Since that time, 12 patients have been treated on the ROCKET trial. Two patients who were treated the week of November 14 developed cerebral edema and died on November 22 and 23, respectively.

In a conference call, Juno’s Chief Medical Officer Mark Gilbert, MD, said the etiology of cerebral edema is multi-factorial, and Juno will need more time to draw even preliminary conclusions about what factors contributed to the cases of cerebral edema in ROCKET.

Right now, the company is assessing data from the cases and the trial and is evaluating its options regarding the JCAR015 program.

Juno’s President and CEO Hans Bishop said the options for JCAR015 going forward include continuing the ROCKET trial with a modified protocol, beginning a new study of JCAR015, and terminating the JCAR015 development program.

Bishop said the company expects to provide an update on the status of ROCKET and JCAR015 in the next few weeks.

Juno’s other trials and plans for its other CD19-directed CAR T-cell product candidates are not affected by the issues with ROCKET and JCAR015.

ROCKET is not the first trial of JCAR015 to be placed on hold. The phase 1 trial of the therapy was placed on clinical hold in 2014, after 2 patients died of cytokine release syndrome.

That hold was lifted following changes to enrollment criteria and dosing. Results from this trial were presented at ASCO 2015 and ASCO 2016.

Micrograph showing AML

The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.

Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.

Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.

About orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Micrograph showing AML

The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.

Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.

Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.

About orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Micrograph showing AML

The European Commission (EC) has granted orphan drug designation to crenolanib for the treatment of acute myeloid leukemia (AML) and soft tissue sarcoma.

Crenolanib is a benzimidazole type I kinase inhibitor that selectively inhibits signaling of wild-type and mutant isoforms of FLT3 and PDGFRα/β.

The drug is under investigation as a treatment for multiple cancers. It is being developed by Arog Pharmaceuticals, Inc.

Results from a phase 2 trial of crenolanib in relapsed/refractory, FLT3+ AML were presented at the 2016 ASCO Annual Meeting.

About orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides companies developing such drugs with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

Chronic pain, defined as pain lasting longer than 3 to 6 months in duration, affects about 100 million Americans.¹ The use of opioids in the management of chronic nonmalignant pain is common in primary care. The U.S., with only 5% of the global population, nevertheless is the world’s leading opioid consumer.² For example, it is estimated that the U.S. consumes 56% of the global supply of morphine, 99% of hydrocodone, and 83% of oxycodone; this consumption is a growing problem in the use of chronic opioid therapy in managing chronic nonmalignant pain.^2,3 The high rates of use of opioids continues, despite a lack of solid evidence on the long-term effectiveness of opioids for managing chronic nonmalignant pain and on the associated risks of opioid addiction, abuse, and misuse.^3,4 Among veterans, the prevalence of opioid abuse and misuse has been reported to be about 30%, a nearly 7-fold occurrence compared with that in the general population.^5,6

Due to the pervasiveness of opioid abuse and misuse among veterans, a project was initiated to develop, implement, and evaluate an Opioid Monitoring Clinic (OMC) as a clinical referral system within the primary care service of the VA Southern Nevada Healthcare System (VASNHS) in North Las Vegas. A health care provider (HCP) needs assessment was conducted at the facility, resulting in recommendations to improve adherence to evidence-based clinical practice guidelines in opioid management and regular monitoring of veterans on chronic opioid therapy for the identification of opioid abuse and misuse. Based on the results, an advanced practice registered nurse (APRN) in consultation with the chief of primary care at VASNHS and teamlet support (a registered nurse, licensed practical nurse, and medical support assistant) started the OMC. The OMC was developed consistent with the 2010 VA/DoD clinical practice guidelines for managing opioid therapy for chronic pain.⁷

After 6 months of OMC operation, the project also was evaluated for efficacy. First, a retrospective chart review of participants was conducted to identify the use of opioid pain agreements, prescription drug monitoring programs (PDMP) for controlled substance use review, and urine drug screens (UDSs). The chart review also included the average daily morphine equivalent dose (MED) for patients and OMC retention rates. Second, an online survey of primary care providers (PCPs) assessed their adherence to evidence-based guidelines in opioid management and satisfaction of the OMC services.

Background

In 1997, the average sales and distribution of opioids in the U.S. was 96 mg MED per individual, which increased to 710 mg per individual in 2010.^8,9 The MED is a standardized daily dose measure for all opioids.¹⁰ At VASNHS North Las Vegas, there were 5,881 patients on opioid therapy in 2013 with about 13% of patients on opioid therapy using about 100 mg MED/d. The potential for abuse and misuse was great. Almost 30% of patients on chronic opioid therapy for chronic nonmalignant pain abuse their opioid prescriptions.^5,7 Subsequently, opioid analgesics were responsible for nearly 60% of overdose deaths in 2010.¹¹

In 2010, there were about 12 million people in the U.S. who abused or misused prescription opioids, using them for nonmedical reasons; annually, the prevalence rate of Americans who abuse and misuse opioids is about 2 million people.¹² The 5-year prevalence rate of opioid abuse among veterans is at least 3%.⁶ This results in health care expenditures with an average excess medical cost of $20,546 per year for patients who misuse opioids compared with those who do not.¹³ The economic burden among veterans is even higher. Baser and colleagues reported that the annual economic cost for veterans who abused their opioid prescriptions was nearly $29,000.⁶

Unfortunately, injudicious opioid prescribing by HCPs is often cited as a contributor to the growing problem of opioid abuse and misuse in the U.S.¹⁴ Health care provider education on the proper and judicious use of opioids and adherence to clinical practice guidelines in the management of chronic pain is a crucial factor in reducing the complications of chron

Method

This project evaluated the APRN-led OMC with both quantitative and qualitative data from patients and PCPs. The OMC was implemented at VASNHS North Las Vegas, which serves almost 60,000 veterans. Patients referred to the OMC who were eligible for admission were veterans aged ≥ 18 years, who had chronic nonmalignant pain for at least 3 months, were receiving chronic opioid therapy, and were considered high risk for abuse or misuse of opioids. Patients were considered high risk if they had documented aberrant behaviors, such as multiple early refill requests, history of lost medications, drug screens not showing prescribed opioid(s), positive drug screens for controlled substance not prescribed, nonadherence with plan of care, or a history of substance abuse, including alcohol, cocaine, heroin, and marijuana. Veterans found to be suicidal or homicidal were excluded from the OMC and instead were referred to appropriate specialty care for further evaluation. A total of 61 veteran participants were successfully recruited.

Primary care physicians, physician assistants, and APRNs working at VASNHS on a full-time and part-time basis were eligible for participation as PCPs in this project. Thirty of 42 eligible PCPs participated and responded to the secure online provider survey (71% response rate).

Risks and benefits were discussed, and a written informed consent was obtained for each participant. There were no apparent risks or adverse effects encountered during project implementation and evaluation. Prior to data collection, permission for the study was obtained from the VA facility. An institutional review board application through the University of Nevada, Las Vegas’ Office of Research Integrity-Human Subjects was also submitted and approved through an expedited review.

Results

Table 1 details patient data, including demographics on the veteran participants. The av

Review of PDMPs revealed that 20% of the participants received controlled substances from other HCPs. Consequently, all OMC patients completed and had reinforced OPAs that served 2 purposes. First, the content in the agreement provided patient education regarding the potential hazards of opioid use. Second, the content provided specific expectations from the patient if opioid therapy is continued, including opioid risk reduction strategies (ie, random UDSs and pill counts, PDMP for controlled substance utilization review), and the consequences of lack of adherence to opioid management.

The majority of patients remained as patients and continued to be monitored after 6 months at the OMC (Table 2). However, only 64% were retained in the OMC, in large part because 36% had their opioids discontinued due to discovery of active illicit substance use, opioi

The mean MED/d among OMC participants was 54 mg/d before admission, which decreased gradually to 22 mg/d after 6 months of OMC care; this represented a 59% MED reduction (Table 3). Using the exact single-tailed Wilcoxon signed rank

Primary Care Providers

Based on the survey of PCPs, 40% of respondents referred at least 1 patient to the OMC. The majority (90%) acknowledged following the VA/DoD guidelines for opioid management, with 80% using an OPA more than usual since the implementation of the OMC, and 54% routinely accessing a PDMP for controlled substance utilization review. Moreover, 93% of PCPs routinely ordered a UDS when indicated.

For 3 months prior to opening the OMC in 2013, 1,606 UDSs were ordered at VASNHS. The UDS number steadily increased, and 6 months after opening the OMC, UDSs increased to 2,293 from months 4 to 6, representing a 30% increase. This was an expected outcome from the OMC—more PCPs now were following the VA/DoD clinical practice guidelines regarding the monitoring of patients on chronic opioid therapy.

A survey assessed the level of satisfaction among PCPs who had referred their patients to the OMC. Although only 11 PCPs responded to this question, a large majority found the OMC to have a positive effect on primary care services; many noted receiving fewer complaints regarding pain medications and fewer walk-ins. The majority recognized the advantage of the OMC in facilitating more PCP time for managing other medical problems beyond opioid use, which tends to be challenging and time consuming. Overall, 100% were satisfied with the OMC service.

Finally, 82% of PCPs reported that the OMC referral process did not need improvement. Two PCPs (18%) left positive feedback, reporting that the OMC was “simple, easy and accessible” and that the referral process “so far, it is great.” Another PCP noted, “I want patients who are suicidal but still need pain control with narcotics to be addressed.”

Discussion

The OMC has shown great promise in identifying abuse and misuse of opioids through evidence-based guidelines and risk-mitigation strategies. In the past, VA clinics specifically focused on opioid renewal have been implemented. In 2002, the Philadelphia VAMC opened an opioid renewal clinic (ORC) to assist PCPs in the management of patients with chronic pain on chronic opioid therapy.¹⁵ The Philadelphia VAMC ORC was operated collaboratively by PCPs and Pharmacy Service. They reported that 51% of their patients initially had documented aberrant behaviors, and 45% of these patients resolved their aberrant behaviors through intensive opioid monitoring using random UDSs.¹⁴ Thirteen percent of their patients were found to have an opioid addiction disorder and eventually were referred to addiction treatment; and 4% were weaned off opioids due to consistently negative UDSs.¹⁴

In the same manner, the OMC has effectively identified patients who abused and misused their opioids and consequently referred these patients for pain interventional management or to the VASNHS alcohol and drug treatment program as appropriate, which falls under the VASNHS Mental Health Care line, a service that is vital for veterans who are suicidal and homicidal. The importance of mental health care cannot be understated, as many patients with chronic pain also experience mental health challenges.

The Malcom Randall VAMC in Gainesville, Florida, structured a nurse-led, multidisciplinary ORC in 2003.¹⁶ A retrospective review of their program showed that 33% of patients had a positive UDS for marijuana, cocaine, or alcohol. The ORC had increased patient involvement in substance abuse treatment, resulting in some patients taking lower opioid dosages than before.

The New York Harbor VAMC reduced opioid cost by effectively switching veterans on expensive long-acting opioids, such as oxycodone and fentanyl, to less expensive alternatives, such a long-acting morphine.¹⁷ A secondary purpose of the New York initiative was to reduce the potential for inappropriate use of expensive long-acting opioids. Accordingly, the initiative reduced the number of expensive long-acting and potentially inappropriate opioids from 165 to 69 prescriptions in less than 6 months (November 2007 through March 2008). Similarly, after 6 months of operation, the OMC significantly reduced opioid prescription from 54 mg to 22 MED/d. This reduction represents a significant pharmacy cost savings. The combination of the discontinuation of opioids for patients found to be abusing and misusing opioids coupled with the decrease in pill burden resulting from changes from short-acting to long-acting opioids also resulted in significant savings for VA facilities.

The impact of the OMC on PCP adherence to opioid management guidelines as well as PCP satisfaction with the OMC services was significant. Similarly, Wiedemer and colleagues found significant PCP satisfaction with the ORC.¹⁵ The ability to spend more time with patients on other medical problems while allowing the OMC to focus on opioid and pain management was found to be beneficial. Buy-in among PCPs coupled with their concerns for chronic opioid therapy for high-risk patients facilitated the success of the OMC. The commitment of the VASNHS leadership to the OMC and their support for the APRN in leading this initiative were important facilitators in the success of the OMC.

Limitations

Long-term evaluation of the OMC with a larger sample is needed to fully evaluate its impact on decreasing opioid misuse and abuse. This project was limited by a small sample size, although the results are promising. Pharmacy costs, emergency department visits, as well as patient satisfaction, physical and emotional function, and pain levels are outcomes that need to be considered over the long term. Incorporating mental health counseling, cognitive behavior therapy, self-management programs, and group educational sessions have the potential to be important OMC services. The continued success and cost-effectiveness of the OMC can be a potentially significant model for this type of service that can be applied to clinics outside the VA system.

Implications

Possible implications to practice settings that are considering an OMC or ORC include the chance that patients will want to be discharged from such a clinic and return to the PCP for opioid management. Collaborative relationships and communication between PCPs and OMC providers are important to facilitate adherence and consistency with pain care. Collaboration and effective communication can be facilitated by electronic recording and reporting. For example, the VA Computerized Patient Record System can alert PCPs to patient discharges from the OMC along with OMC provider recommendations for patient care. Another challenge for the OMC would be a lack of referrals for patients who are at high risk for opioid abuse or misuse. These challenges can be mitigated by providing in-services, educational flyers, and advertisement promotions regarding OMC services. With the high prevalence of opioid abuse and misuse as well as the subsequent exorbitant health-related costs and deaths associated with opioids, OMCs and ORCs are viable options for improving opioid management in the treatment of patients with nonmalignant chronic pain.

Conclusion

The OMC effectively reduced the MED of patients referred to the clinic by 59%. The significant reduction in the opioid dose of patients referred to the OMC resulted from the implementation of evidence-based strategies that were used to identify abuse of prescription opioids, the use of illicit substances that can cause opioid-related complications, and the discovery of doctor shopping, coupled with gradual dose reductions for patients when appropriate. Provider satisfaction and increased use of evidence-based guidelines in opioid management and risk mitigation strategies, such as OPAs, PDMP databases, and UDS were evident. These results suggest that an OMC can be an effective program to help identify abuse and misuse of prescription opioids among high-risk patients and can improve patient safety and provider satisfaction.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the VA Southern Nevada Healthcare System.

Chronic pain, defined as pain lasting longer than 3 to 6 months in duration, affects about 100 million Americans.¹ The use of opioids in the management of chronic nonmalignant pain is common in primary care. The U.S., with only 5% of the global population, nevertheless is the world’s leading opioid consumer.² For example, it is estimated that the U.S. consumes 56% of the global supply of morphine, 99% of hydrocodone, and 83% of oxycodone; this consumption is a growing problem in the use of chronic opioid therapy in managing chronic nonmalignant pain.^2,3 The high rates of use of opioids continues, despite a lack of solid evidence on the long-term effectiveness of opioids for managing chronic nonmalignant pain and on the associated risks of opioid addiction, abuse, and misuse.^3,4 Among veterans, the prevalence of opioid abuse and misuse has been reported to be about 30%, a nearly 7-fold occurrence compared with that in the general population.^5,6

Due to the pervasiveness of opioid abuse and misuse among veterans, a project was initiated to develop, implement, and evaluate an Opioid Monitoring Clinic (OMC) as a clinical referral system within the primary care service of the VA Southern Nevada Healthcare System (VASNHS) in North Las Vegas. A health care provider (HCP) needs assessment was conducted at the facility, resulting in recommendations to improve adherence to evidence-based clinical practice guidelines in opioid management and regular monitoring of veterans on chronic opioid therapy for the identification of opioid abuse and misuse. Based on the results, an advanced practice registered nurse (APRN) in consultation with the chief of primary care at VASNHS and teamlet support (a registered nurse, licensed practical nurse, and medical support assistant) started the OMC. The OMC was developed consistent with the 2010 VA/DoD clinical practice guidelines for managing opioid therapy for chronic pain.⁷

After 6 months of OMC operation, the project also was evaluated for efficacy. First, a retrospective chart review of participants was conducted to identify the use of opioid pain agreements, prescription drug monitoring programs (PDMP) for controlled substance use review, and urine drug screens (UDSs). The chart review also included the average daily morphine equivalent dose (MED) for patients and OMC retention rates. Second, an online survey of primary care providers (PCPs) assessed their adherence to evidence-based guidelines in opioid management and satisfaction of the OMC services.

Background

In 1997, the average sales and distribution of opioids in the U.S. was 96 mg MED per individual, which increased to 710 mg per individual in 2010.^8,9 The MED is a standardized daily dose measure for all opioids.¹⁰ At VASNHS North Las Vegas, there were 5,881 patients on opioid therapy in 2013 with about 13% of patients on opioid therapy using about 100 mg MED/d. The potential for abuse and misuse was great. Almost 30% of patients on chronic opioid therapy for chronic nonmalignant pain abuse their opioid prescriptions.^5,7 Subsequently, opioid analgesics were responsible for nearly 60% of overdose deaths in 2010.¹¹

In 2010, there were about 12 million people in the U.S. who abused or misused prescription opioids, using them for nonmedical reasons; annually, the prevalence rate of Americans who abuse and misuse opioids is about 2 million people.¹² The 5-year prevalence rate of opioid abuse among veterans is at least 3%.⁶ This results in health care expenditures with an average excess medical cost of $20,546 per year for patients who misuse opioids compared with those who do not.¹³ The economic burden among veterans is even higher. Baser and colleagues reported that the annual economic cost for veterans who abused their opioid prescriptions was nearly $29,000.⁶

Unfortunately, injudicious opioid prescribing by HCPs is often cited as a contributor to the growing problem of opioid abuse and misuse in the U.S.¹⁴ Health care provider education on the proper and judicious use of opioids and adherence to clinical practice guidelines in the management of chronic pain is a crucial factor in reducing the complications of chron

Method

This project evaluated the APRN-led OMC with both quantitative and qualitative data from patients and PCPs. The OMC was implemented at VASNHS North Las Vegas, which serves almost 60,000 veterans. Patients referred to the OMC who were eligible for admission were veterans aged ≥ 18 years, who had chronic nonmalignant pain for at least 3 months, were receiving chronic opioid therapy, and were considered high risk for abuse or misuse of opioids. Patients were considered high risk if they had documented aberrant behaviors, such as multiple early refill requests, history of lost medications, drug screens not showing prescribed opioid(s), positive drug screens for controlled substance not prescribed, nonadherence with plan of care, or a history of substance abuse, including alcohol, cocaine, heroin, and marijuana. Veterans found to be suicidal or homicidal were excluded from the OMC and instead were referred to appropriate specialty care for further evaluation. A total of 61 veteran participants were successfully recruited.

Primary care physicians, physician assistants, and APRNs working at VASNHS on a full-time and part-time basis were eligible for participation as PCPs in this project. Thirty of 42 eligible PCPs participated and responded to the secure online provider survey (71% response rate).

Risks and benefits were discussed, and a written informed consent was obtained for each participant. There were no apparent risks or adverse effects encountered during project implementation and evaluation. Prior to data collection, permission for the study was obtained from the VA facility. An institutional review board application through the University of Nevada, Las Vegas’ Office of Research Integrity-Human Subjects was also submitted and approved through an expedited review.

Results

Table 1 details patient data, including demographics on the veteran participants. The av

Review of PDMPs revealed that 20% of the participants received controlled substances from other HCPs. Consequently, all OMC patients completed and had reinforced OPAs that served 2 purposes. First, the content in the agreement provided patient education regarding the potential hazards of opioid use. Second, the content provided specific expectations from the patient if opioid therapy is continued, including opioid risk reduction strategies (ie, random UDSs and pill counts, PDMP for controlled substance utilization review), and the consequences of lack of adherence to opioid management.

The majority of patients remained as patients and continued to be monitored after 6 months at the OMC (Table 2). However, only 64% were retained in the OMC, in large part because 36% had their opioids discontinued due to discovery of active illicit substance use, opioi

The mean MED/d among OMC participants was 54 mg/d before admission, which decreased gradually to 22 mg/d after 6 months of OMC care; this represented a 59% MED reduction (Table 3). Using the exact single-tailed Wilcoxon signed rank

Primary Care Providers

Based on the survey of PCPs, 40% of respondents referred at least 1 patient to the OMC. The majority (90%) acknowledged following the VA/DoD guidelines for opioid management, with 80% using an OPA more than usual since the implementation of the OMC, and 54% routinely accessing a PDMP for controlled substance utilization review. Moreover, 93% of PCPs routinely ordered a UDS when indicated.

For 3 months prior to opening the OMC in 2013, 1,606 UDSs were ordered at VASNHS. The UDS number steadily increased, and 6 months after opening the OMC, UDSs increased to 2,293 from months 4 to 6, representing a 30% increase. This was an expected outcome from the OMC—more PCPs now were following the VA/DoD clinical practice guidelines regarding the monitoring of patients on chronic opioid therapy.

A survey assessed the level of satisfaction among PCPs who had referred their patients to the OMC. Although only 11 PCPs responded to this question, a large majority found the OMC to have a positive effect on primary care services; many noted receiving fewer complaints regarding pain medications and fewer walk-ins. The majority recognized the advantage of the OMC in facilitating more PCP time for managing other medical problems beyond opioid use, which tends to be challenging and time consuming. Overall, 100% were satisfied with the OMC service.

Finally, 82% of PCPs reported that the OMC referral process did not need improvement. Two PCPs (18%) left positive feedback, reporting that the OMC was “simple, easy and accessible” and that the referral process “so far, it is great.” Another PCP noted, “I want patients who are suicidal but still need pain control with narcotics to be addressed.”

Discussion

The OMC has shown great promise in identifying abuse and misuse of opioids through evidence-based guidelines and risk-mitigation strategies. In the past, VA clinics specifically focused on opioid renewal have been implemented. In 2002, the Philadelphia VAMC opened an opioid renewal clinic (ORC) to assist PCPs in the management of patients with chronic pain on chronic opioid therapy.¹⁵ The Philadelphia VAMC ORC was operated collaboratively by PCPs and Pharmacy Service. They reported that 51% of their patients initially had documented aberrant behaviors, and 45% of these patients resolved their aberrant behaviors through intensive opioid monitoring using random UDSs.¹⁴ Thirteen percent of their patients were found to have an opioid addiction disorder and eventually were referred to addiction treatment; and 4% were weaned off opioids due to consistently negative UDSs.¹⁴

In the same manner, the OMC has effectively identified patients who abused and misused their opioids and consequently referred these patients for pain interventional management or to the VASNHS alcohol and drug treatment program as appropriate, which falls under the VASNHS Mental Health Care line, a service that is vital for veterans who are suicidal and homicidal. The importance of mental health care cannot be understated, as many patients with chronic pain also experience mental health challenges.

The Malcom Randall VAMC in Gainesville, Florida, structured a nurse-led, multidisciplinary ORC in 2003.¹⁶ A retrospective review of their program showed that 33% of patients had a positive UDS for marijuana, cocaine, or alcohol. The ORC had increased patient involvement in substance abuse treatment, resulting in some patients taking lower opioid dosages than before.

The New York Harbor VAMC reduced opioid cost by effectively switching veterans on expensive long-acting opioids, such as oxycodone and fentanyl, to less expensive alternatives, such a long-acting morphine.¹⁷ A secondary purpose of the New York initiative was to reduce the potential for inappropriate use of expensive long-acting opioids. Accordingly, the initiative reduced the number of expensive long-acting and potentially inappropriate opioids from 165 to 69 prescriptions in less than 6 months (November 2007 through March 2008). Similarly, after 6 months of operation, the OMC significantly reduced opioid prescription from 54 mg to 22 MED/d. This reduction represents a significant pharmacy cost savings. The combination of the discontinuation of opioids for patients found to be abusing and misusing opioids coupled with the decrease in pill burden resulting from changes from short-acting to long-acting opioids also resulted in significant savings for VA facilities.

The impact of the OMC on PCP adherence to opioid management guidelines as well as PCP satisfaction with the OMC services was significant. Similarly, Wiedemer and colleagues found significant PCP satisfaction with the ORC.¹⁵ The ability to spend more time with patients on other medical problems while allowing the OMC to focus on opioid and pain management was found to be beneficial. Buy-in among PCPs coupled with their concerns for chronic opioid therapy for high-risk patients facilitated the success of the OMC. The commitment of the VASNHS leadership to the OMC and their support for the APRN in leading this initiative were important facilitators in the success of the OMC.

Limitations

Long-term evaluation of the OMC with a larger sample is needed to fully evaluate its impact on decreasing opioid misuse and abuse. This project was limited by a small sample size, although the results are promising. Pharmacy costs, emergency department visits, as well as patient satisfaction, physical and emotional function, and pain levels are outcomes that need to be considered over the long term. Incorporating mental health counseling, cognitive behavior therapy, self-management programs, and group educational sessions have the potential to be important OMC services. The continued success and cost-effectiveness of the OMC can be a potentially significant model for this type of service that can be applied to clinics outside the VA system.

Implications

Possible implications to practice settings that are considering an OMC or ORC include the chance that patients will want to be discharged from such a clinic and return to the PCP for opioid management. Collaborative relationships and communication between PCPs and OMC providers are important to facilitate adherence and consistency with pain care. Collaboration and effective communication can be facilitated by electronic recording and reporting. For example, the VA Computerized Patient Record System can alert PCPs to patient discharges from the OMC along with OMC provider recommendations for patient care. Another challenge for the OMC would be a lack of referrals for patients who are at high risk for opioid abuse or misuse. These challenges can be mitigated by providing in-services, educational flyers, and advertisement promotions regarding OMC services. With the high prevalence of opioid abuse and misuse as well as the subsequent exorbitant health-related costs and deaths associated with opioids, OMCs and ORCs are viable options for improving opioid management in the treatment of patients with nonmalignant chronic pain.

Conclusion

The OMC effectively reduced the MED of patients referred to the clinic by 59%. The significant reduction in the opioid dose of patients referred to the OMC resulted from the implementation of evidence-based strategies that were used to identify abuse of prescription opioids, the use of illicit substances that can cause opioid-related complications, and the discovery of doctor shopping, coupled with gradual dose reductions for patients when appropriate. Provider satisfaction and increased use of evidence-based guidelines in opioid management and risk mitigation strategies, such as OPAs, PDMP databases, and UDS were evident. These results suggest that an OMC can be an effective program to help identify abuse and misuse of prescription opioids among high-risk patients and can improve patient safety and provider satisfaction.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the VA Southern Nevada Healthcare System.

Chronic pain, defined as pain lasting longer than 3 to 6 months in duration, affects about 100 million Americans.¹ The use of opioids in the management of chronic nonmalignant pain is common in primary care. The U.S., with only 5% of the global population, nevertheless is the world’s leading opioid consumer.² For example, it is estimated that the U.S. consumes 56% of the global supply of morphine, 99% of hydrocodone, and 83% of oxycodone; this consumption is a growing problem in the use of chronic opioid therapy in managing chronic nonmalignant pain.^2,3 The high rates of use of opioids continues, despite a lack of solid evidence on the long-term effectiveness of opioids for managing chronic nonmalignant pain and on the associated risks of opioid addiction, abuse, and misuse.^3,4 Among veterans, the prevalence of opioid abuse and misuse has been reported to be about 30%, a nearly 7-fold occurrence compared with that in the general population.^5,6

Due to the pervasiveness of opioid abuse and misuse among veterans, a project was initiated to develop, implement, and evaluate an Opioid Monitoring Clinic (OMC) as a clinical referral system within the primary care service of the VA Southern Nevada Healthcare System (VASNHS) in North Las Vegas. A health care provider (HCP) needs assessment was conducted at the facility, resulting in recommendations to improve adherence to evidence-based clinical practice guidelines in opioid management and regular monitoring of veterans on chronic opioid therapy for the identification of opioid abuse and misuse. Based on the results, an advanced practice registered nurse (APRN) in consultation with the chief of primary care at VASNHS and teamlet support (a registered nurse, licensed practical nurse, and medical support assistant) started the OMC. The OMC was developed consistent with the 2010 VA/DoD clinical practice guidelines for managing opioid therapy for chronic pain.⁷

After 6 months of OMC operation, the project also was evaluated for efficacy. First, a retrospective chart review of participants was conducted to identify the use of opioid pain agreements, prescription drug monitoring programs (PDMP) for controlled substance use review, and urine drug screens (UDSs). The chart review also included the average daily morphine equivalent dose (MED) for patients and OMC retention rates. Second, an online survey of primary care providers (PCPs) assessed their adherence to evidence-based guidelines in opioid management and satisfaction of the OMC services.

Background

In 1997, the average sales and distribution of opioids in the U.S. was 96 mg MED per individual, which increased to 710 mg per individual in 2010.^8,9 The MED is a standardized daily dose measure for all opioids.¹⁰ At VASNHS North Las Vegas, there were 5,881 patients on opioid therapy in 2013 with about 13% of patients on opioid therapy using about 100 mg MED/d. The potential for abuse and misuse was great. Almost 30% of patients on chronic opioid therapy for chronic nonmalignant pain abuse their opioid prescriptions.^5,7 Subsequently, opioid analgesics were responsible for nearly 60% of overdose deaths in 2010.¹¹

In 2010, there were about 12 million people in the U.S. who abused or misused prescription opioids, using them for nonmedical reasons; annually, the prevalence rate of Americans who abuse and misuse opioids is about 2 million people.¹² The 5-year prevalence rate of opioid abuse among veterans is at least 3%.⁶ This results in health care expenditures with an average excess medical cost of $20,546 per year for patients who misuse opioids compared with those who do not.¹³ The economic burden among veterans is even higher. Baser and colleagues reported that the annual economic cost for veterans who abused their opioid prescriptions was nearly $29,000.⁶

Unfortunately, injudicious opioid prescribing by HCPs is often cited as a contributor to the growing problem of opioid abuse and misuse in the U.S.¹⁴ Health care provider education on the proper and judicious use of opioids and adherence to clinical practice guidelines in the management of chronic pain is a crucial factor in reducing the complications of chron

Method

This project evaluated the APRN-led OMC with both quantitative and qualitative data from patients and PCPs. The OMC was implemented at VASNHS North Las Vegas, which serves almost 60,000 veterans. Patients referred to the OMC who were eligible for admission were veterans aged ≥ 18 years, who had chronic nonmalignant pain for at least 3 months, were receiving chronic opioid therapy, and were considered high risk for abuse or misuse of opioids. Patients were considered high risk if they had documented aberrant behaviors, such as multiple early refill requests, history of lost medications, drug screens not showing prescribed opioid(s), positive drug screens for controlled substance not prescribed, nonadherence with plan of care, or a history of substance abuse, including alcohol, cocaine, heroin, and marijuana. Veterans found to be suicidal or homicidal were excluded from the OMC and instead were referred to appropriate specialty care for further evaluation. A total of 61 veteran participants were successfully recruited.

Primary care physicians, physician assistants, and APRNs working at VASNHS on a full-time and part-time basis were eligible for participation as PCPs in this project. Thirty of 42 eligible PCPs participated and responded to the secure online provider survey (71% response rate).

Risks and benefits were discussed, and a written informed consent was obtained for each participant. There were no apparent risks or adverse effects encountered during project implementation and evaluation. Prior to data collection, permission for the study was obtained from the VA facility. An institutional review board application through the University of Nevada, Las Vegas’ Office of Research Integrity-Human Subjects was also submitted and approved through an expedited review.

Results

Table 1 details patient data, including demographics on the veteran participants. The av

Review of PDMPs revealed that 20% of the participants received controlled substances from other HCPs. Consequently, all OMC patients completed and had reinforced OPAs that served 2 purposes. First, the content in the agreement provided patient education regarding the potential hazards of opioid use. Second, the content provided specific expectations from the patient if opioid therapy is continued, including opioid risk reduction strategies (ie, random UDSs and pill counts, PDMP for controlled substance utilization review), and the consequences of lack of adherence to opioid management.

The majority of patients remained as patients and continued to be monitored after 6 months at the OMC (Table 2). However, only 64% were retained in the OMC, in large part because 36% had their opioids discontinued due to discovery of active illicit substance use, opioi

The mean MED/d among OMC participants was 54 mg/d before admission, which decreased gradually to 22 mg/d after 6 months of OMC care; this represented a 59% MED reduction (Table 3). Using the exact single-tailed Wilcoxon signed rank

Primary Care Providers

Based on the survey of PCPs, 40% of respondents referred at least 1 patient to the OMC. The majority (90%) acknowledged following the VA/DoD guidelines for opioid management, with 80% using an OPA more than usual since the implementation of the OMC, and 54% routinely accessing a PDMP for controlled substance utilization review. Moreover, 93% of PCPs routinely ordered a UDS when indicated.

For 3 months prior to opening the OMC in 2013, 1,606 UDSs were ordered at VASNHS. The UDS number steadily increased, and 6 months after opening the OMC, UDSs increased to 2,293 from months 4 to 6, representing a 30% increase. This was an expected outcome from the OMC—more PCPs now were following the VA/DoD clinical practice guidelines regarding the monitoring of patients on chronic opioid therapy.

A survey assessed the level of satisfaction among PCPs who had referred their patients to the OMC. Although only 11 PCPs responded to this question, a large majority found the OMC to have a positive effect on primary care services; many noted receiving fewer complaints regarding pain medications and fewer walk-ins. The majority recognized the advantage of the OMC in facilitating more PCP time for managing other medical problems beyond opioid use, which tends to be challenging and time consuming. Overall, 100% were satisfied with the OMC service.

Finally, 82% of PCPs reported that the OMC referral process did not need improvement. Two PCPs (18%) left positive feedback, reporting that the OMC was “simple, easy and accessible” and that the referral process “so far, it is great.” Another PCP noted, “I want patients who are suicidal but still need pain control with narcotics to be addressed.”

Discussion

The OMC has shown great promise in identifying abuse and misuse of opioids through evidence-based guidelines and risk-mitigation strategies. In the past, VA clinics specifically focused on opioid renewal have been implemented. In 2002, the Philadelphia VAMC opened an opioid renewal clinic (ORC) to assist PCPs in the management of patients with chronic pain on chronic opioid therapy.¹⁵ The Philadelphia VAMC ORC was operated collaboratively by PCPs and Pharmacy Service. They reported that 51% of their patients initially had documented aberrant behaviors, and 45% of these patients resolved their aberrant behaviors through intensive opioid monitoring using random UDSs.¹⁴ Thirteen percent of their patients were found to have an opioid addiction disorder and eventually were referred to addiction treatment; and 4% were weaned off opioids due to consistently negative UDSs.¹⁴

In the same manner, the OMC has effectively identified patients who abused and misused their opioids and consequently referred these patients for pain interventional management or to the VASNHS alcohol and drug treatment program as appropriate, which falls under the VASNHS Mental Health Care line, a service that is vital for veterans who are suicidal and homicidal. The importance of mental health care cannot be understated, as many patients with chronic pain also experience mental health challenges.

The Malcom Randall VAMC in Gainesville, Florida, structured a nurse-led, multidisciplinary ORC in 2003.¹⁶ A retrospective review of their program showed that 33% of patients had a positive UDS for marijuana, cocaine, or alcohol. The ORC had increased patient involvement in substance abuse treatment, resulting in some patients taking lower opioid dosages than before.

The New York Harbor VAMC reduced opioid cost by effectively switching veterans on expensive long-acting opioids, such as oxycodone and fentanyl, to less expensive alternatives, such a long-acting morphine.¹⁷ A secondary purpose of the New York initiative was to reduce the potential for inappropriate use of expensive long-acting opioids. Accordingly, the initiative reduced the number of expensive long-acting and potentially inappropriate opioids from 165 to 69 prescriptions in less than 6 months (November 2007 through March 2008). Similarly, after 6 months of operation, the OMC significantly reduced opioid prescription from 54 mg to 22 MED/d. This reduction represents a significant pharmacy cost savings. The combination of the discontinuation of opioids for patients found to be abusing and misusing opioids coupled with the decrease in pill burden resulting from changes from short-acting to long-acting opioids also resulted in significant savings for VA facilities.

The impact of the OMC on PCP adherence to opioid management guidelines as well as PCP satisfaction with the OMC services was significant. Similarly, Wiedemer and colleagues found significant PCP satisfaction with the ORC.¹⁵ The ability to spend more time with patients on other medical problems while allowing the OMC to focus on opioid and pain management was found to be beneficial. Buy-in among PCPs coupled with their concerns for chronic opioid therapy for high-risk patients facilitated the success of the OMC. The commitment of the VASNHS leadership to the OMC and their support for the APRN in leading this initiative were important facilitators in the success of the OMC.

Limitations

Long-term evaluation of the OMC with a larger sample is needed to fully evaluate its impact on decreasing opioid misuse and abuse. This project was limited by a small sample size, although the results are promising. Pharmacy costs, emergency department visits, as well as patient satisfaction, physical and emotional function, and pain levels are outcomes that need to be considered over the long term. Incorporating mental health counseling, cognitive behavior therapy, self-management programs, and group educational sessions have the potential to be important OMC services. The continued success and cost-effectiveness of the OMC can be a potentially significant model for this type of service that can be applied to clinics outside the VA system.

Implications

Possible implications to practice settings that are considering an OMC or ORC include the chance that patients will want to be discharged from such a clinic and return to the PCP for opioid management. Collaborative relationships and communication between PCPs and OMC providers are important to facilitate adherence and consistency with pain care. Collaboration and effective communication can be facilitated by electronic recording and reporting. For example, the VA Computerized Patient Record System can alert PCPs to patient discharges from the OMC along with OMC provider recommendations for patient care. Another challenge for the OMC would be a lack of referrals for patients who are at high risk for opioid abuse or misuse. These challenges can be mitigated by providing in-services, educational flyers, and advertisement promotions regarding OMC services. With the high prevalence of opioid abuse and misuse as well as the subsequent exorbitant health-related costs and deaths associated with opioids, OMCs and ORCs are viable options for improving opioid management in the treatment of patients with nonmalignant chronic pain.

Conclusion

The OMC effectively reduced the MED of patients referred to the clinic by 59%. The significant reduction in the opioid dose of patients referred to the OMC resulted from the implementation of evidence-based strategies that were used to identify abuse of prescription opioids, the use of illicit substances that can cause opioid-related complications, and the discovery of doctor shopping, coupled with gradual dose reductions for patients when appropriate. Provider satisfaction and increased use of evidence-based guidelines in opioid management and risk mitigation strategies, such as OPAs, PDMP databases, and UDS were evident. These results suggest that an OMC can be an effective program to help identify abuse and misuse of prescription opioids among high-risk patients and can improve patient safety and provider satisfaction.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the VA Southern Nevada Healthcare System.

Single-agent therapy with decitabine elicited favorable responses in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who had cytogenetic abnormalities associated with an unfavorable risk profile, a study showed.

Even though the responses were not long lasting, the overall survival rates were similar to those of AML patients who had an intermediate-risk cytogenetic profile and who had received the same treatment regimen.

Adult AML patients with karyotypes associated with unfavorable risk and older patients with AML (aged 60 or older) generally have poor outcomes, with a median survival in the range of 1 year. Those with AML and TP53 mutations tend to be older (median age, 61-67 years), and nearly all patients have karyotypes associated with unfavorable risk. These patients have particularly dismal outcomes, with median survival in the range of 4-6 months, if they receive cytotoxic chemotherapy.

In their study, John S Welch, MD, of Washington University, St Louis, and his colleagues evaluated somatic mutations and their relationships to clinical responses in 84 adult patients with AML or MDS who received treatment with decitabine as monotherapy.

Decitabine was administered at a dose of 20 mg/m² of body surface area per day for 10 consecutive days in monthly cycles. An extension cohort that included 32 additional patients also were treated with decitabine but in different protocols.

Of the entire cohort of 116 patients, 15 patients (13%) achieved a complete remission, and 38 patients had bone marrow blast clearance with less than 5% blasts (complete remission with incomplete count recovery or morphologic complete remission). The overall response rate was 46%. In addition, 9 patients (8%), achieved a partial response, stable disease was observed in 23 patients (20%), and progressive disease was seen in 19 patients (16%).

Clinical responses were strongly correlated with karyotypes associated with unfavorable risk and the presence of TP53 mutations. Bone marrow blast clearance (complete remission, complete remission with incomplete count recovery, or morphologic complete remission) occurred in 29 of 43 patients with karyotypes associated with unfavorable risk (67%), compared with 24 of 71 patients with karyotypes associated with intermediate or favorable risk (34%). The same pattern was observed in all patients with TP53 mutations (100%) versus 32 of 78 patients with wildtype TP53 mutations (41%).

“Additional studies will be required to determine whether these differences in survival are truly due to improved responses associated with decitabine or whether conventional chemotherapy with an anthracycline and cytarabine actually decreases the rate of survival among patients with unfavorable-risk cytogenetic profiles,” wrote Dr. Welch and his colleagues.

The study was supported by the Specialized Program of Research Excellence in AML of the National Cancer Institute and the Genomics of AML Program Project. Dr. Welch had no disclosures, and several of his coauthors reported relationships with industry.

Single-agent therapy with decitabine elicited favorable responses in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who had cytogenetic abnormalities associated with an unfavorable risk profile, a study showed.

Even though the responses were not long lasting, the overall survival rates were similar to those of AML patients who had an intermediate-risk cytogenetic profile and who had received the same treatment regimen.

Adult AML patients with karyotypes associated with unfavorable risk and older patients with AML (aged 60 or older) generally have poor outcomes, with a median survival in the range of 1 year. Those with AML and TP53 mutations tend to be older (median age, 61-67 years), and nearly all patients have karyotypes associated with unfavorable risk. These patients have particularly dismal outcomes, with median survival in the range of 4-6 months, if they receive cytotoxic chemotherapy.

In their study, John S Welch, MD, of Washington University, St Louis, and his colleagues evaluated somatic mutations and their relationships to clinical responses in 84 adult patients with AML or MDS who received treatment with decitabine as monotherapy.

Decitabine was administered at a dose of 20 mg/m² of body surface area per day for 10 consecutive days in monthly cycles. An extension cohort that included 32 additional patients also were treated with decitabine but in different protocols.

Of the entire cohort of 116 patients, 15 patients (13%) achieved a complete remission, and 38 patients had bone marrow blast clearance with less than 5% blasts (complete remission with incomplete count recovery or morphologic complete remission). The overall response rate was 46%. In addition, 9 patients (8%), achieved a partial response, stable disease was observed in 23 patients (20%), and progressive disease was seen in 19 patients (16%).

Clinical responses were strongly correlated with karyotypes associated with unfavorable risk and the presence of TP53 mutations. Bone marrow blast clearance (complete remission, complete remission with incomplete count recovery, or morphologic complete remission) occurred in 29 of 43 patients with karyotypes associated with unfavorable risk (67%), compared with 24 of 71 patients with karyotypes associated with intermediate or favorable risk (34%). The same pattern was observed in all patients with TP53 mutations (100%) versus 32 of 78 patients with wildtype TP53 mutations (41%).

“Additional studies will be required to determine whether these differences in survival are truly due to improved responses associated with decitabine or whether conventional chemotherapy with an anthracycline and cytarabine actually decreases the rate of survival among patients with unfavorable-risk cytogenetic profiles,” wrote Dr. Welch and his colleagues.

The study was supported by the Specialized Program of Research Excellence in AML of the National Cancer Institute and the Genomics of AML Program Project. Dr. Welch had no disclosures, and several of his coauthors reported relationships with industry.

Single-agent therapy with decitabine elicited favorable responses in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who had cytogenetic abnormalities associated with an unfavorable risk profile, a study showed.

Even though the responses were not long lasting, the overall survival rates were similar to those of AML patients who had an intermediate-risk cytogenetic profile and who had received the same treatment regimen.

Adult AML patients with karyotypes associated with unfavorable risk and older patients with AML (aged 60 or older) generally have poor outcomes, with a median survival in the range of 1 year. Those with AML and TP53 mutations tend to be older (median age, 61-67 years), and nearly all patients have karyotypes associated with unfavorable risk. These patients have particularly dismal outcomes, with median survival in the range of 4-6 months, if they receive cytotoxic chemotherapy.

In their study, John S Welch, MD, of Washington University, St Louis, and his colleagues evaluated somatic mutations and their relationships to clinical responses in 84 adult patients with AML or MDS who received treatment with decitabine as monotherapy.

Decitabine was administered at a dose of 20 mg/m² of body surface area per day for 10 consecutive days in monthly cycles. An extension cohort that included 32 additional patients also were treated with decitabine but in different protocols.

Of the entire cohort of 116 patients, 15 patients (13%) achieved a complete remission, and 38 patients had bone marrow blast clearance with less than 5% blasts (complete remission with incomplete count recovery or morphologic complete remission). The overall response rate was 46%. In addition, 9 patients (8%), achieved a partial response, stable disease was observed in 23 patients (20%), and progressive disease was seen in 19 patients (16%).

Clinical responses were strongly correlated with karyotypes associated with unfavorable risk and the presence of TP53 mutations. Bone marrow blast clearance (complete remission, complete remission with incomplete count recovery, or morphologic complete remission) occurred in 29 of 43 patients with karyotypes associated with unfavorable risk (67%), compared with 24 of 71 patients with karyotypes associated with intermediate or favorable risk (34%). The same pattern was observed in all patients with TP53 mutations (100%) versus 32 of 78 patients with wildtype TP53 mutations (41%).

“Additional studies will be required to determine whether these differences in survival are truly due to improved responses associated with decitabine or whether conventional chemotherapy with an anthracycline and cytarabine actually decreases the rate of survival among patients with unfavorable-risk cytogenetic profiles,” wrote Dr. Welch and his colleagues.

The study was supported by the Specialized Program of Research Excellence in AML of the National Cancer Institute and the Genomics of AML Program Project. Dr. Welch had no disclosures, and several of his coauthors reported relationships with industry.