NEW ORLEANS – Prepregnancy overweight and obesity are associated with increased incidence and severity of depressive symptoms during pregnancy, independent of preeclampsia and other hypertensive pregnancy disorders or gestational diabetes, Satu Kumpulainen reported at Obesity Week 2016.

The implications of this novel finding are clear: “Prepregnancy interventions targeting overweight and obesity and mental health will not only benefit the pregnant mother’s health but will also provide optimal odds for healthy development of the fetus as well,” said Ms. Kumpulainen, a doctoral student at the University of Helsinki Institute of Behavioral Sciences.

Bruce Jancin/Frontline Medical News

kzenon/ThinkStock

[email protected]


 

NEW ORLEANS – Prepregnancy overweight and obesity are associated with increased incidence and severity of depressive symptoms during pregnancy, independent of preeclampsia and other hypertensive pregnancy disorders or gestational diabetes, Satu Kumpulainen reported at Obesity Week 2016.

The implications of this novel finding are clear: “Prepregnancy interventions targeting overweight and obesity and mental health will not only benefit the pregnant mother’s health but will also provide optimal odds for healthy development of the fetus as well,” said Ms. Kumpulainen, a doctoral student at the University of Helsinki Institute of Behavioral Sciences.

Bruce Jancin/Frontline Medical News

kzenon/ThinkStock

[email protected]


 

NEW ORLEANS – Prepregnancy overweight and obesity are associated with increased incidence and severity of depressive symptoms during pregnancy, independent of preeclampsia and other hypertensive pregnancy disorders or gestational diabetes, Satu Kumpulainen reported at Obesity Week 2016.

The implications of this novel finding are clear: “Prepregnancy interventions targeting overweight and obesity and mental health will not only benefit the pregnant mother’s health but will also provide optimal odds for healthy development of the fetus as well,” said Ms. Kumpulainen, a doctoral student at the University of Helsinki Institute of Behavioral Sciences.

Bruce Jancin/Frontline Medical News

kzenon/ThinkStock

[email protected]


 

Empagliflozin (Jardiance) and liraglutide (Victoza) should be considered in type 2 diabetes patients with documented cardiovascular disease to reduce the risk of CV death, according to the American Diabetes Association 2017 Standards of Medical Care.

ADA updates it standards annually based on new information and research; like its predecessors, the 2017 guidance is comprehensive, addressing mental, social, and other challenges faced by patients with diabetes, along with clinical care (Diabetes Care. 2017 Jan;40(Suppl 1):S4-S5).

The 2017 guidance contains a great deal of new information. At 135 pages, there are 22 more pages than in 2016. “They did a really nice job. This guide is useful for anyone helping patients with diabetes,” including diabetologists, dietitians, educators, psychologists, and social workers, Richard Hellman, MD, a clinical endocrinologist in North Kansas City, Mo., said in an interview.

[email protected]

Empagliflozin (Jardiance) and liraglutide (Victoza) should be considered in type 2 diabetes patients with documented cardiovascular disease to reduce the risk of CV death, according to the American Diabetes Association 2017 Standards of Medical Care.

ADA updates it standards annually based on new information and research; like its predecessors, the 2017 guidance is comprehensive, addressing mental, social, and other challenges faced by patients with diabetes, along with clinical care (Diabetes Care. 2017 Jan;40(Suppl 1):S4-S5).

The 2017 guidance contains a great deal of new information. At 135 pages, there are 22 more pages than in 2016. “They did a really nice job. This guide is useful for anyone helping patients with diabetes,” including diabetologists, dietitians, educators, psychologists, and social workers, Richard Hellman, MD, a clinical endocrinologist in North Kansas City, Mo., said in an interview.

[email protected]

Empagliflozin (Jardiance) and liraglutide (Victoza) should be considered in type 2 diabetes patients with documented cardiovascular disease to reduce the risk of CV death, according to the American Diabetes Association 2017 Standards of Medical Care.

ADA updates it standards annually based on new information and research; like its predecessors, the 2017 guidance is comprehensive, addressing mental, social, and other challenges faced by patients with diabetes, along with clinical care (Diabetes Care. 2017 Jan;40(Suppl 1):S4-S5).

The 2017 guidance contains a great deal of new information. At 135 pages, there are 22 more pages than in 2016. “They did a really nice job. This guide is useful for anyone helping patients with diabetes,” including diabetologists, dietitians, educators, psychologists, and social workers, Richard Hellman, MD, a clinical endocrinologist in North Kansas City, Mo., said in an interview.

[email protected]

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been a welcome addition to the armamentarium for treating depressive disorders, neuropathic pain, and anxiety disorders. Despite the more favorable side-effect profile compared with tricyclic antidepressants and monoamine oxidase inhibitors, these serotonergic agents have been associated with bleeding disorders, purpura, thrombocytopenia, and, in extreme cases, death.^1-4

We describe a case of purpura associated with different classes of antidepressants, including the non-serotonergic agent bupropion, as well as a family history of similar adverse effects to antidepressants.

CASE Purpura resolves when drug is stopped

Ms. R, age 70, presents with major depressive disorder and fibromyalgia and is receiving duloxetine, 20 mg/d, which is gradually increased to 60 mg. She also has a history of chronic obstructive pulmonary disease (COPD), for which she is taking albuterol and a steroid inhaler. Ms. R responds well to treatment; however, she develops blue–purple purpura on her arms each measuring 1 to 2 inches. Laboratory test results including platelet count and prothrombin time/international normalized ratio are within normal ranges. Duloxetine is stopped, and purpura resolves in 1 to 2 weeks. To avoid serotonergic antidepressants, Ms. R receives bupropion XL, 150 mg; however, similar purpura develops, then resolves when the medication is discontinued. She is lost to follow up for approximately 6 months, but returns requesting a rechallenge with duloxetine for her depression, which has worsened. Duloxetine is restarted with similar results and is then discontinued. Because she has developed neuropathy, Ms. R is started on nortriptyline, 25 mg/d, increased to 50 mg/d, but purpura develops again, which resolves when medication is discontinued. Ms. R’s daughter reports she also developed a similar reaction with several antidepressants, which resolved with medication discontinuation.

Bleeding risk with antidepressants

The role of serotonin reuptake inhibitors (SRIs) in inducing bleeding has emerged as a safety concern,^5,6 which have been documented in case reports.^7-11 Mechanisms of action that have been thought to affect platelet aggregation include:

• depletion of serotonin in platelets
• increase in capillary fragility
• modification of platelet plug formation
• responsiveness of peptide-induced activation of platelets through stimulation of the thrombin receptor.^7,8,12,13

The severity of bleeding varies with patient-related factors, such as a history of gastritis, peptic ulcer disease, and heavy bleeding during menses; use of gastrotoxic drugs, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), also have been shown to increase this risk.^14,15 For patients taking SRIs and gastrotoxic drugs (eg, NSAIDs), use of acid-suppressing agents have been shown to limit the risk of bleeding.¹⁶

Studies evaluating relative bleeding risks among classes of antidepressants have not shown increased risk with tricyclic antidepressants compared with SSRIs.¹⁷ Adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) are signaling molecules in the vascular system and are important in the thromboregulatory system. Studies in rats reported significant inhibition of ATP, ADP, and AMP hydrolysis with chronic treatment with fluoxetine and nortriptyline, and suggested that both medications changed the nucleotide catabolism, which means that homeostasis of the vascular system can be altered by antidepressant treatments.¹⁸ This is one possible pathway in the role these medications play in the etiology of dysregulation of the thromboregulatory system.

We did not anticipate that our patient would develop similar purpura with bupropion because the bleeding risk associated with antidepressants has been attributed to the effect of serotonin on platelets. Studies observing the effect of SSRIs, SNRIs, and bupropion on platelets and bleeding have not shown significant risk with bupropion.¹⁹ Bleeding associated with bupropion is atypical and needs to be further studied. Although this medication is centrally selective in its action on dopamine receptors, it might have possible peripheral effect on other neurotransmitters, including serotonin.

Ms. R had no personal or family history of purpura or a bleeding disorder. Significant improvement in her physical signs after discontinuing medications and recurrence of pupura with rechallenge indicate that this reaction was triggered by 3 different classes of antidepressants. Family history of similar reaction further suggests a genetic predisposition to platelet dysfunction to antidepressant treatment in a select group of patients.

Limitations include the possibility of senile purpura, which cannot be ruled out despite strong indications that antidepressants were the cause. The possibility of drug interactions needs be considered as well. Ms. R was taking albuterol and a steroid inhaler for her COPD at the time of the initial medication trials, which did not interact with duloxetine or bupropion. During the trials with duloxetine and then nortriptyline, she was taking acetaminophen/hydrocodone in addition to her inhalers, and no significant interactions with the antidepressants were identified. Interactions with unreported or over-the-counter medications or supplements are a possibility.

Before prescribing an antidepressant, we suggest taking a careful history including a family history of bleeding disorders and adverse effects of antidepressants, especially in patients who have risk factors (eg, concomitant use of gastrotoxic medications). Use of gastric acid-suppressing medications could be considered if antidepressants are used. Further investigations into the incidence, risk factors, mechanism of action, and treatment of this adverse effect are indicated.

Drug Brand Names
Acetaminophen/hydrocodone • Lorcet, Norco, Vicodin
Albuterol • Proventil
Bupropion • Wellbutrin
Duloxetine • Cymbalta
Nortriptyline • Pamelor, Aventyl

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been a welcome addition to the armamentarium for treating depressive disorders, neuropathic pain, and anxiety disorders. Despite the more favorable side-effect profile compared with tricyclic antidepressants and monoamine oxidase inhibitors, these serotonergic agents have been associated with bleeding disorders, purpura, thrombocytopenia, and, in extreme cases, death.^1-4

We describe a case of purpura associated with different classes of antidepressants, including the non-serotonergic agent bupropion, as well as a family history of similar adverse effects to antidepressants.

CASE Purpura resolves when drug is stopped

Ms. R, age 70, presents with major depressive disorder and fibromyalgia and is receiving duloxetine, 20 mg/d, which is gradually increased to 60 mg. She also has a history of chronic obstructive pulmonary disease (COPD), for which she is taking albuterol and a steroid inhaler. Ms. R responds well to treatment; however, she develops blue–purple purpura on her arms each measuring 1 to 2 inches. Laboratory test results including platelet count and prothrombin time/international normalized ratio are within normal ranges. Duloxetine is stopped, and purpura resolves in 1 to 2 weeks. To avoid serotonergic antidepressants, Ms. R receives bupropion XL, 150 mg; however, similar purpura develops, then resolves when the medication is discontinued. She is lost to follow up for approximately 6 months, but returns requesting a rechallenge with duloxetine for her depression, which has worsened. Duloxetine is restarted with similar results and is then discontinued. Because she has developed neuropathy, Ms. R is started on nortriptyline, 25 mg/d, increased to 50 mg/d, but purpura develops again, which resolves when medication is discontinued. Ms. R’s daughter reports she also developed a similar reaction with several antidepressants, which resolved with medication discontinuation.

Bleeding risk with antidepressants

The role of serotonin reuptake inhibitors (SRIs) in inducing bleeding has emerged as a safety concern,^5,6 which have been documented in case reports.^7-11 Mechanisms of action that have been thought to affect platelet aggregation include:

• depletion of serotonin in platelets
• increase in capillary fragility
• modification of platelet plug formation
• responsiveness of peptide-induced activation of platelets through stimulation of the thrombin receptor.^7,8,12,13

The severity of bleeding varies with patient-related factors, such as a history of gastritis, peptic ulcer disease, and heavy bleeding during menses; use of gastrotoxic drugs, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), also have been shown to increase this risk.^14,15 For patients taking SRIs and gastrotoxic drugs (eg, NSAIDs), use of acid-suppressing agents have been shown to limit the risk of bleeding.¹⁶

Studies evaluating relative bleeding risks among classes of antidepressants have not shown increased risk with tricyclic antidepressants compared with SSRIs.¹⁷ Adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) are signaling molecules in the vascular system and are important in the thromboregulatory system. Studies in rats reported significant inhibition of ATP, ADP, and AMP hydrolysis with chronic treatment with fluoxetine and nortriptyline, and suggested that both medications changed the nucleotide catabolism, which means that homeostasis of the vascular system can be altered by antidepressant treatments.¹⁸ This is one possible pathway in the role these medications play in the etiology of dysregulation of the thromboregulatory system.

We did not anticipate that our patient would develop similar purpura with bupropion because the bleeding risk associated with antidepressants has been attributed to the effect of serotonin on platelets. Studies observing the effect of SSRIs, SNRIs, and bupropion on platelets and bleeding have not shown significant risk with bupropion.¹⁹ Bleeding associated with bupropion is atypical and needs to be further studied. Although this medication is centrally selective in its action on dopamine receptors, it might have possible peripheral effect on other neurotransmitters, including serotonin.

Ms. R had no personal or family history of purpura or a bleeding disorder. Significant improvement in her physical signs after discontinuing medications and recurrence of pupura with rechallenge indicate that this reaction was triggered by 3 different classes of antidepressants. Family history of similar reaction further suggests a genetic predisposition to platelet dysfunction to antidepressant treatment in a select group of patients.

Limitations include the possibility of senile purpura, which cannot be ruled out despite strong indications that antidepressants were the cause. The possibility of drug interactions needs be considered as well. Ms. R was taking albuterol and a steroid inhaler for her COPD at the time of the initial medication trials, which did not interact with duloxetine or bupropion. During the trials with duloxetine and then nortriptyline, she was taking acetaminophen/hydrocodone in addition to her inhalers, and no significant interactions with the antidepressants were identified. Interactions with unreported or over-the-counter medications or supplements are a possibility.

Before prescribing an antidepressant, we suggest taking a careful history including a family history of bleeding disorders and adverse effects of antidepressants, especially in patients who have risk factors (eg, concomitant use of gastrotoxic medications). Use of gastric acid-suppressing medications could be considered if antidepressants are used. Further investigations into the incidence, risk factors, mechanism of action, and treatment of this adverse effect are indicated.

Drug Brand Names
Acetaminophen/hydrocodone • Lorcet, Norco, Vicodin
Albuterol • Proventil
Bupropion • Wellbutrin
Duloxetine • Cymbalta
Nortriptyline • Pamelor, Aventyl

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been a welcome addition to the armamentarium for treating depressive disorders, neuropathic pain, and anxiety disorders. Despite the more favorable side-effect profile compared with tricyclic antidepressants and monoamine oxidase inhibitors, these serotonergic agents have been associated with bleeding disorders, purpura, thrombocytopenia, and, in extreme cases, death.^1-4

We describe a case of purpura associated with different classes of antidepressants, including the non-serotonergic agent bupropion, as well as a family history of similar adverse effects to antidepressants.

CASE Purpura resolves when drug is stopped

Ms. R, age 70, presents with major depressive disorder and fibromyalgia and is receiving duloxetine, 20 mg/d, which is gradually increased to 60 mg. She also has a history of chronic obstructive pulmonary disease (COPD), for which she is taking albuterol and a steroid inhaler. Ms. R responds well to treatment; however, she develops blue–purple purpura on her arms each measuring 1 to 2 inches. Laboratory test results including platelet count and prothrombin time/international normalized ratio are within normal ranges. Duloxetine is stopped, and purpura resolves in 1 to 2 weeks. To avoid serotonergic antidepressants, Ms. R receives bupropion XL, 150 mg; however, similar purpura develops, then resolves when the medication is discontinued. She is lost to follow up for approximately 6 months, but returns requesting a rechallenge with duloxetine for her depression, which has worsened. Duloxetine is restarted with similar results and is then discontinued. Because she has developed neuropathy, Ms. R is started on nortriptyline, 25 mg/d, increased to 50 mg/d, but purpura develops again, which resolves when medication is discontinued. Ms. R’s daughter reports she also developed a similar reaction with several antidepressants, which resolved with medication discontinuation.

Bleeding risk with antidepressants

The role of serotonin reuptake inhibitors (SRIs) in inducing bleeding has emerged as a safety concern,^5,6 which have been documented in case reports.^7-11 Mechanisms of action that have been thought to affect platelet aggregation include:

• depletion of serotonin in platelets
• increase in capillary fragility
• modification of platelet plug formation
• responsiveness of peptide-induced activation of platelets through stimulation of the thrombin receptor.^7,8,12,13

The severity of bleeding varies with patient-related factors, such as a history of gastritis, peptic ulcer disease, and heavy bleeding during menses; use of gastrotoxic drugs, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), also have been shown to increase this risk.^14,15 For patients taking SRIs and gastrotoxic drugs (eg, NSAIDs), use of acid-suppressing agents have been shown to limit the risk of bleeding.¹⁶

Studies evaluating relative bleeding risks among classes of antidepressants have not shown increased risk with tricyclic antidepressants compared with SSRIs.¹⁷ Adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) are signaling molecules in the vascular system and are important in the thromboregulatory system. Studies in rats reported significant inhibition of ATP, ADP, and AMP hydrolysis with chronic treatment with fluoxetine and nortriptyline, and suggested that both medications changed the nucleotide catabolism, which means that homeostasis of the vascular system can be altered by antidepressant treatments.¹⁸ This is one possible pathway in the role these medications play in the etiology of dysregulation of the thromboregulatory system.

We did not anticipate that our patient would develop similar purpura with bupropion because the bleeding risk associated with antidepressants has been attributed to the effect of serotonin on platelets. Studies observing the effect of SSRIs, SNRIs, and bupropion on platelets and bleeding have not shown significant risk with bupropion.¹⁹ Bleeding associated with bupropion is atypical and needs to be further studied. Although this medication is centrally selective in its action on dopamine receptors, it might have possible peripheral effect on other neurotransmitters, including serotonin.

Ms. R had no personal or family history of purpura or a bleeding disorder. Significant improvement in her physical signs after discontinuing medications and recurrence of pupura with rechallenge indicate that this reaction was triggered by 3 different classes of antidepressants. Family history of similar reaction further suggests a genetic predisposition to platelet dysfunction to antidepressant treatment in a select group of patients.

Limitations include the possibility of senile purpura, which cannot be ruled out despite strong indications that antidepressants were the cause. The possibility of drug interactions needs be considered as well. Ms. R was taking albuterol and a steroid inhaler for her COPD at the time of the initial medication trials, which did not interact with duloxetine or bupropion. During the trials with duloxetine and then nortriptyline, she was taking acetaminophen/hydrocodone in addition to her inhalers, and no significant interactions with the antidepressants were identified. Interactions with unreported or over-the-counter medications or supplements are a possibility.

Before prescribing an antidepressant, we suggest taking a careful history including a family history of bleeding disorders and adverse effects of antidepressants, especially in patients who have risk factors (eg, concomitant use of gastrotoxic medications). Use of gastric acid-suppressing medications could be considered if antidepressants are used. Further investigations into the incidence, risk factors, mechanism of action, and treatment of this adverse effect are indicated.

Drug Brand Names
Acetaminophen/hydrocodone • Lorcet, Norco, Vicodin
Albuterol • Proventil
Bupropion • Wellbutrin
Duloxetine • Cymbalta
Nortriptyline • Pamelor, Aventyl

High doses of radiation are often followed by infection. HHS is preparing for emergencies by buying 2 colony-stimulating factor (CSF) products to reduce infection and risk of death in radiologic or nuclear incidents.
Related: Emergency Test for Absorbed Radiation

HHS is purchasing Neulasta (Amgen USA, Inc) and Leukine (Sanofi-Aventis US), under agreements totaling about $37.7 million and 37.6 million, respectively. Neulasta already is FDA approved to treat cancer patients exposed to high levels of radiation that damage bone marrow. Leukine is undergoing studies needed for approval.

The Biomedical Advanced Research and Development Authority had earlier sponsored advanced development and purchase of Neupogen, another leukocyte growth factor product approved for treating adults and children exposed to radiation that damages bone marrow.

Related: HHS Hails Big Ideas

The deal for Neulasta and Leukine thus increases the number of CSF factor doses available for use in an emergency. It also increases operational capability, HHS says, since treatments with Neulasta are given once weekly, whereas treatment with Neupogen is daily.

High doses of radiation are often followed by infection. HHS is preparing for emergencies by buying 2 colony-stimulating factor (CSF) products to reduce infection and risk of death in radiologic or nuclear incidents.
Related: Emergency Test for Absorbed Radiation

HHS is purchasing Neulasta (Amgen USA, Inc) and Leukine (Sanofi-Aventis US), under agreements totaling about $37.7 million and 37.6 million, respectively. Neulasta already is FDA approved to treat cancer patients exposed to high levels of radiation that damage bone marrow. Leukine is undergoing studies needed for approval.

The Biomedical Advanced Research and Development Authority had earlier sponsored advanced development and purchase of Neupogen, another leukocyte growth factor product approved for treating adults and children exposed to radiation that damages bone marrow.

Related: HHS Hails Big Ideas

The deal for Neulasta and Leukine thus increases the number of CSF factor doses available for use in an emergency. It also increases operational capability, HHS says, since treatments with Neulasta are given once weekly, whereas treatment with Neupogen is daily.

High doses of radiation are often followed by infection. HHS is preparing for emergencies by buying 2 colony-stimulating factor (CSF) products to reduce infection and risk of death in radiologic or nuclear incidents.
Related: Emergency Test for Absorbed Radiation

HHS is purchasing Neulasta (Amgen USA, Inc) and Leukine (Sanofi-Aventis US), under agreements totaling about $37.7 million and 37.6 million, respectively. Neulasta already is FDA approved to treat cancer patients exposed to high levels of radiation that damage bone marrow. Leukine is undergoing studies needed for approval.

The Biomedical Advanced Research and Development Authority had earlier sponsored advanced development and purchase of Neupogen, another leukocyte growth factor product approved for treating adults and children exposed to radiation that damages bone marrow.

Related: HHS Hails Big Ideas

The deal for Neulasta and Leukine thus increases the number of CSF factor doses available for use in an emergency. It also increases operational capability, HHS says, since treatments with Neulasta are given once weekly, whereas treatment with Neupogen is daily.

Christoph Driessen, MD, PhD

SAN DIEGO—An antiretroviral drug used to treat the human immunodeficiency virus (HIV) may find a role in the treatment of multiple myeloma (MM) patients who are proteasome inhibitor (PI)-refractory.

According to investigators, nelfinavir may sensitize refractory patients so that PI-based treatments become an option for them.

In a phase 2 study of 34 patients, nelfinavir in combination with bortezomib and dexamethasone produced an objective response rate of 65%, which investigators called an “exceptional” response in this heavily pretreated, mostly dual-refractory patient population.

Christoph Driessen, MD, PhD, of Kantonsspital St Gallen in Switzerland, discussed the findings of this study, known as SAKK 39/13, at the 2016 ASH Annual Meeting as abstract 487.

Dr Driessen explained that downregulation of IRE1/XBP1 produces PI resistance, and this downregulation occurs in PI-refractory MM patients.

High expression of IRE1/XBP1 correlates with bortezomib sensitivity, and pharmacologic upregulation of IRE1/XBP1 re-sensitizes myeloma cells to PI treatment.

Nelfinavir, which overcomes PI resistance in vitro, is approved for oral HIV therapy.

“It’s an old drug, it’s a generic drug,” Dr Driessen said, and it’s approved at a dose of 2 x 1250 mg daily.

So the SAKK investigators undertook a phase 1 trial of nelfinavir in MM patients.

In an exploratory extension cohort, they found that 5 of 6 MM patients double-refractory to bortezomib and lenalidomide experienced clinical benefit from nelfinavir at the recommended phase 2 dose (2 x 2500 mg daily) in addition to standard treatment with bortezomib and dexamethasone.

Three patients achieved a partial response (PR) and 3 a minor response (MR).

The investigators’ objective in the phase 2 study was to determine whether the addition of nelfinavir to approved bortezomib-dexamethasone therapy is sufficiently active to merit further investigation in a randomized trial.

Study design

Patients in this prospective, single-arm, multicenter, open-label trial received the following treatment:

• Nelfinavir at 2 x 2500 mg orally on days 1–14
• Bortezomib at 1.3 mg/m² intravenously or subcutaneously on days 1, 4, 8, and 11
• Dexamethasone at 20 mg orally on days 1-2, 4-5, 8-9, and 11-12 of each 21-day cycle.

Trial therapy lasted for a maximum of 6 cycles (18 weeks).

Dr Driessen explained that the trial “was a truly academic trial, without any finances from industry or drug support from industry. So we actually had to get a grant to buy commercial drugs for the study on the commercial drug market, and that limited the duration of treatment in this trial.”

The primary endpoint of the trial was response rate—best response of PR or better by IMWG criteria.

Investigators considered a 30% or higher response rate promising.

Secondary endpoints included adverse events, time to next new anti-myeloma therapy or death, progressive disease under trial treatment, duration of response, progression-free survival, and time to progression.

Patients were eligible to enroll if they had been exposed to or could not tolerate an immunomodulatory drug, were refractory to their most recent PI-containing regimen, had a performance status of 3 or less, had creatinine clearance of 15 mL/minute or greater, had a platelet count of 50,000/μL or more, and had a hemoglobin level of 8.0 g/dL or higher.

Patients were excluded if they had uncontrolled, clinically significant, active concurrent disease, concomitant additional systemic cancer treatment, concomitant radiotherapy, or significant neuropathy of grades 3-4 or grade 2 with pain.

Patient population

Thirty-four patients enrolled on the trial. They were a median age of 67 (range, 42–82), 62% were male, 91% had a performance status of 0 or 1, and 76% had a prior autologous stem cell transplant.

They had a median of 5 prior systemic therapies (range, 2–10), and 38% had poor-risk cytogenetics.

The time from last dose of prior therapy to enrollment on the study was a median of 27 days.

“So [it was] a truly progressive, highly refractory myeloma population,” Dr Driessen emphasized.

All 34 patients were refractory to bortezomib. All patients were also exposed to lenalidomide, and 79% were refractory to it.

Forty-four percent were refractory to pomalidomide, and 6% were refractory to carfilzomib. One patient was refractory to all 4 agents.

“Very few patients were exposed to carfilzomib because it wasn’t available in Switzerland at that time,” Dr Driessen explained.

Efficacy

Patients received a median of 4.5 cycles of therapy (range, 1–6), and the best response of PR or greater was achieved by 22 patients (65%).

Five patients (15%) achieved a very good partial response (VGPR), 17 (50%) PR, 3 (9%) MR, and 4 (12%) stable disease.

Twenty-five patients (74%) achieved a clinical benefit (VGPR+PR+MR).

Ten of the 13 patients (77%) with poor-risk cytogenetics achieved a best response of PR or greater.

Patients had a median of 16 weeks (range, 13–24) time to a new anti-myeloma therapy or death, and 13 patients (38%) had confirmed progressive disease while on trial therapy.

In 32 patients, all but 4 had a decrease from baseline in serum M protein or serum free light chain concentration.

Efficacy by prior therapy

Twenty-two of 34 patients (65%) refractory to bortezomib had a best response of PR or greater.

For patients refractory to bortezomib and lenalidomide, 70% achieved a best response of PR or greater.

For patients refractory to bortezomib, lenalidomide, and pomalidomide, 60% achieved a best response of PR or greater.

And for patients who were refractory to bortezomib, lenalidomide, and carfilzomib, 50% achieved a best response of PR or greater.

Adverse events

“The hematologic toxicity was essentially what you would expect from this heavily pretreated population,” Dr Driessen said.

“We did, however, experience 4 deaths on the trial therapy from infectious complications of sepsis and neutropenia, and we don’t know whether this is a true signal or whether this is due to the low numbers. We did not mandate antibiotic prophylaxis on the trial.”

Grade 3 or higher adverse events (AEs) occurring in 2 or more patients were anemia (n=10), febrile neutropenia (n=4, including 1 grade 5), thrombocytopenia (n=15), lung infection (n=8), sepsis (n=3, all grade 5), fatigue (n=5), peripheral sensory neuropathy (n=3), hypertension (n=6), increased creatinine (n=4), hyperglycemia (n=6) hypokalemia (n=3), and hyponatremia (n=5).

Dr Driessen indicated that with a future generic version of bortezomib, nelfinavir plus bortezomib and dexamethasone “has the potential to become a fully generic, affordable, active therapy option for PI-refractory patients.”

The investigators believe the results of their study call for further development of nelfinavir as a sensitizing drug for PI-based treatments and as a promising new agent for MM therapy.

Christoph Driessen, MD, PhD

SAN DIEGO—An antiretroviral drug used to treat the human immunodeficiency virus (HIV) may find a role in the treatment of multiple myeloma (MM) patients who are proteasome inhibitor (PI)-refractory.

According to investigators, nelfinavir may sensitize refractory patients so that PI-based treatments become an option for them.

In a phase 2 study of 34 patients, nelfinavir in combination with bortezomib and dexamethasone produced an objective response rate of 65%, which investigators called an “exceptional” response in this heavily pretreated, mostly dual-refractory patient population.

Christoph Driessen, MD, PhD, of Kantonsspital St Gallen in Switzerland, discussed the findings of this study, known as SAKK 39/13, at the 2016 ASH Annual Meeting as abstract 487.

Dr Driessen explained that downregulation of IRE1/XBP1 produces PI resistance, and this downregulation occurs in PI-refractory MM patients.

High expression of IRE1/XBP1 correlates with bortezomib sensitivity, and pharmacologic upregulation of IRE1/XBP1 re-sensitizes myeloma cells to PI treatment.

Nelfinavir, which overcomes PI resistance in vitro, is approved for oral HIV therapy.

“It’s an old drug, it’s a generic drug,” Dr Driessen said, and it’s approved at a dose of 2 x 1250 mg daily.

So the SAKK investigators undertook a phase 1 trial of nelfinavir in MM patients.

In an exploratory extension cohort, they found that 5 of 6 MM patients double-refractory to bortezomib and lenalidomide experienced clinical benefit from nelfinavir at the recommended phase 2 dose (2 x 2500 mg daily) in addition to standard treatment with bortezomib and dexamethasone.

Three patients achieved a partial response (PR) and 3 a minor response (MR).

The investigators’ objective in the phase 2 study was to determine whether the addition of nelfinavir to approved bortezomib-dexamethasone therapy is sufficiently active to merit further investigation in a randomized trial.

Study design

Patients in this prospective, single-arm, multicenter, open-label trial received the following treatment:

• Nelfinavir at 2 x 2500 mg orally on days 1–14
• Bortezomib at 1.3 mg/m² intravenously or subcutaneously on days 1, 4, 8, and 11
• Dexamethasone at 20 mg orally on days 1-2, 4-5, 8-9, and 11-12 of each 21-day cycle.

Trial therapy lasted for a maximum of 6 cycles (18 weeks).

Dr Driessen explained that the trial “was a truly academic trial, without any finances from industry or drug support from industry. So we actually had to get a grant to buy commercial drugs for the study on the commercial drug market, and that limited the duration of treatment in this trial.”

The primary endpoint of the trial was response rate—best response of PR or better by IMWG criteria.

Investigators considered a 30% or higher response rate promising.

Secondary endpoints included adverse events, time to next new anti-myeloma therapy or death, progressive disease under trial treatment, duration of response, progression-free survival, and time to progression.

Patients were eligible to enroll if they had been exposed to or could not tolerate an immunomodulatory drug, were refractory to their most recent PI-containing regimen, had a performance status of 3 or less, had creatinine clearance of 15 mL/minute or greater, had a platelet count of 50,000/μL or more, and had a hemoglobin level of 8.0 g/dL or higher.

Patients were excluded if they had uncontrolled, clinically significant, active concurrent disease, concomitant additional systemic cancer treatment, concomitant radiotherapy, or significant neuropathy of grades 3-4 or grade 2 with pain.

Patient population

Thirty-four patients enrolled on the trial. They were a median age of 67 (range, 42–82), 62% were male, 91% had a performance status of 0 or 1, and 76% had a prior autologous stem cell transplant.

They had a median of 5 prior systemic therapies (range, 2–10), and 38% had poor-risk cytogenetics.

The time from last dose of prior therapy to enrollment on the study was a median of 27 days.

“So [it was] a truly progressive, highly refractory myeloma population,” Dr Driessen emphasized.

All 34 patients were refractory to bortezomib. All patients were also exposed to lenalidomide, and 79% were refractory to it.

Forty-four percent were refractory to pomalidomide, and 6% were refractory to carfilzomib. One patient was refractory to all 4 agents.

“Very few patients were exposed to carfilzomib because it wasn’t available in Switzerland at that time,” Dr Driessen explained.

Efficacy

Patients received a median of 4.5 cycles of therapy (range, 1–6), and the best response of PR or greater was achieved by 22 patients (65%).

Five patients (15%) achieved a very good partial response (VGPR), 17 (50%) PR, 3 (9%) MR, and 4 (12%) stable disease.

Twenty-five patients (74%) achieved a clinical benefit (VGPR+PR+MR).

Ten of the 13 patients (77%) with poor-risk cytogenetics achieved a best response of PR or greater.

Patients had a median of 16 weeks (range, 13–24) time to a new anti-myeloma therapy or death, and 13 patients (38%) had confirmed progressive disease while on trial therapy.

In 32 patients, all but 4 had a decrease from baseline in serum M protein or serum free light chain concentration.

Efficacy by prior therapy

Twenty-two of 34 patients (65%) refractory to bortezomib had a best response of PR or greater.

For patients refractory to bortezomib and lenalidomide, 70% achieved a best response of PR or greater.

For patients refractory to bortezomib, lenalidomide, and pomalidomide, 60% achieved a best response of PR or greater.

And for patients who were refractory to bortezomib, lenalidomide, and carfilzomib, 50% achieved a best response of PR or greater.

Adverse events

“The hematologic toxicity was essentially what you would expect from this heavily pretreated population,” Dr Driessen said.

“We did, however, experience 4 deaths on the trial therapy from infectious complications of sepsis and neutropenia, and we don’t know whether this is a true signal or whether this is due to the low numbers. We did not mandate antibiotic prophylaxis on the trial.”

Grade 3 or higher adverse events (AEs) occurring in 2 or more patients were anemia (n=10), febrile neutropenia (n=4, including 1 grade 5), thrombocytopenia (n=15), lung infection (n=8), sepsis (n=3, all grade 5), fatigue (n=5), peripheral sensory neuropathy (n=3), hypertension (n=6), increased creatinine (n=4), hyperglycemia (n=6) hypokalemia (n=3), and hyponatremia (n=5).

Dr Driessen indicated that with a future generic version of bortezomib, nelfinavir plus bortezomib and dexamethasone “has the potential to become a fully generic, affordable, active therapy option for PI-refractory patients.”

The investigators believe the results of their study call for further development of nelfinavir as a sensitizing drug for PI-based treatments and as a promising new agent for MM therapy.

Christoph Driessen, MD, PhD

SAN DIEGO—An antiretroviral drug used to treat the human immunodeficiency virus (HIV) may find a role in the treatment of multiple myeloma (MM) patients who are proteasome inhibitor (PI)-refractory.

According to investigators, nelfinavir may sensitize refractory patients so that PI-based treatments become an option for them.

In a phase 2 study of 34 patients, nelfinavir in combination with bortezomib and dexamethasone produced an objective response rate of 65%, which investigators called an “exceptional” response in this heavily pretreated, mostly dual-refractory patient population.

Christoph Driessen, MD, PhD, of Kantonsspital St Gallen in Switzerland, discussed the findings of this study, known as SAKK 39/13, at the 2016 ASH Annual Meeting as abstract 487.

Dr Driessen explained that downregulation of IRE1/XBP1 produces PI resistance, and this downregulation occurs in PI-refractory MM patients.

High expression of IRE1/XBP1 correlates with bortezomib sensitivity, and pharmacologic upregulation of IRE1/XBP1 re-sensitizes myeloma cells to PI treatment.

Nelfinavir, which overcomes PI resistance in vitro, is approved for oral HIV therapy.

“It’s an old drug, it’s a generic drug,” Dr Driessen said, and it’s approved at a dose of 2 x 1250 mg daily.

So the SAKK investigators undertook a phase 1 trial of nelfinavir in MM patients.

In an exploratory extension cohort, they found that 5 of 6 MM patients double-refractory to bortezomib and lenalidomide experienced clinical benefit from nelfinavir at the recommended phase 2 dose (2 x 2500 mg daily) in addition to standard treatment with bortezomib and dexamethasone.

Three patients achieved a partial response (PR) and 3 a minor response (MR).

The investigators’ objective in the phase 2 study was to determine whether the addition of nelfinavir to approved bortezomib-dexamethasone therapy is sufficiently active to merit further investigation in a randomized trial.

Study design

Patients in this prospective, single-arm, multicenter, open-label trial received the following treatment:

• Nelfinavir at 2 x 2500 mg orally on days 1–14
• Bortezomib at 1.3 mg/m² intravenously or subcutaneously on days 1, 4, 8, and 11
• Dexamethasone at 20 mg orally on days 1-2, 4-5, 8-9, and 11-12 of each 21-day cycle.

Trial therapy lasted for a maximum of 6 cycles (18 weeks).

Dr Driessen explained that the trial “was a truly academic trial, without any finances from industry or drug support from industry. So we actually had to get a grant to buy commercial drugs for the study on the commercial drug market, and that limited the duration of treatment in this trial.”

The primary endpoint of the trial was response rate—best response of PR or better by IMWG criteria.

Investigators considered a 30% or higher response rate promising.

Secondary endpoints included adverse events, time to next new anti-myeloma therapy or death, progressive disease under trial treatment, duration of response, progression-free survival, and time to progression.

Patients were eligible to enroll if they had been exposed to or could not tolerate an immunomodulatory drug, were refractory to their most recent PI-containing regimen, had a performance status of 3 or less, had creatinine clearance of 15 mL/minute or greater, had a platelet count of 50,000/μL or more, and had a hemoglobin level of 8.0 g/dL or higher.

Patients were excluded if they had uncontrolled, clinically significant, active concurrent disease, concomitant additional systemic cancer treatment, concomitant radiotherapy, or significant neuropathy of grades 3-4 or grade 2 with pain.

Patient population

Thirty-four patients enrolled on the trial. They were a median age of 67 (range, 42–82), 62% were male, 91% had a performance status of 0 or 1, and 76% had a prior autologous stem cell transplant.

They had a median of 5 prior systemic therapies (range, 2–10), and 38% had poor-risk cytogenetics.

The time from last dose of prior therapy to enrollment on the study was a median of 27 days.

“So [it was] a truly progressive, highly refractory myeloma population,” Dr Driessen emphasized.

All 34 patients were refractory to bortezomib. All patients were also exposed to lenalidomide, and 79% were refractory to it.

Forty-four percent were refractory to pomalidomide, and 6% were refractory to carfilzomib. One patient was refractory to all 4 agents.

“Very few patients were exposed to carfilzomib because it wasn’t available in Switzerland at that time,” Dr Driessen explained.

Efficacy

Patients received a median of 4.5 cycles of therapy (range, 1–6), and the best response of PR or greater was achieved by 22 patients (65%).

Five patients (15%) achieved a very good partial response (VGPR), 17 (50%) PR, 3 (9%) MR, and 4 (12%) stable disease.

Twenty-five patients (74%) achieved a clinical benefit (VGPR+PR+MR).

Ten of the 13 patients (77%) with poor-risk cytogenetics achieved a best response of PR or greater.

Patients had a median of 16 weeks (range, 13–24) time to a new anti-myeloma therapy or death, and 13 patients (38%) had confirmed progressive disease while on trial therapy.

In 32 patients, all but 4 had a decrease from baseline in serum M protein or serum free light chain concentration.

Efficacy by prior therapy

Twenty-two of 34 patients (65%) refractory to bortezomib had a best response of PR or greater.

For patients refractory to bortezomib and lenalidomide, 70% achieved a best response of PR or greater.

For patients refractory to bortezomib, lenalidomide, and pomalidomide, 60% achieved a best response of PR or greater.

And for patients who were refractory to bortezomib, lenalidomide, and carfilzomib, 50% achieved a best response of PR or greater.

Adverse events

“The hematologic toxicity was essentially what you would expect from this heavily pretreated population,” Dr Driessen said.

“We did, however, experience 4 deaths on the trial therapy from infectious complications of sepsis and neutropenia, and we don’t know whether this is a true signal or whether this is due to the low numbers. We did not mandate antibiotic prophylaxis on the trial.”

Grade 3 or higher adverse events (AEs) occurring in 2 or more patients were anemia (n=10), febrile neutropenia (n=4, including 1 grade 5), thrombocytopenia (n=15), lung infection (n=8), sepsis (n=3, all grade 5), fatigue (n=5), peripheral sensory neuropathy (n=3), hypertension (n=6), increased creatinine (n=4), hyperglycemia (n=6) hypokalemia (n=3), and hyponatremia (n=5).

Dr Driessen indicated that with a future generic version of bortezomib, nelfinavir plus bortezomib and dexamethasone “has the potential to become a fully generic, affordable, active therapy option for PI-refractory patients.”

The investigators believe the results of their study call for further development of nelfinavir as a sensitizing drug for PI-based treatments and as a promising new agent for MM therapy.

The Primary Care Chronic Pain Program (PC-CPP) of the Women’s Primary Care Clinics at the VA Salt Lake City Health Care System (VASLCHCS) in Utah was the first VA primary care clinical service to incorporate patient participation in obtaining chronic opioid medications in the treatment of chronic noncancer pain. In addition, the program used a multimodality approach for chronic pain treatment and veteran education about the relationship between physical and mental health issues.

Treatment Complexity

Chronic, noncancer pain is a complex issue in the primary care setting. Diagnosis is difficult, patient education is time consuming, goals and expectations are often unclear, and the experience can be unsatisfying for the patient and the provider.¹ These issues, combined with an estimated prevalence rate of 71% for moderate pain among veterans seen in primary care, present a unique challenge for the primary care provider (PCP), given the limited time available to spend with these complex patients.² Comorbidity rates with mental health issues (eg, depression, anxiety, substance use disorders, etc), which range from 18% to 44%, add to the management challenges for PCPs.³

Veterans also pose unique challenges in pain care as they have a 2-fold greater risk of death from opioid overdose compared with that of the general population, and Utah has been shown to have the highest rate of veteran overdoses.⁴ Developing programs to help PCPs efficiently manage patients with chronic noncancer pain and mental health comorbidities was vital at VASLCHCS.

Before VASLCHCS established the PC-CPP, the treatment for chronic noncancer pain and related mental health comorbidities followed a biomedical model that separated physical and mental health with the treatment focus on pharmacologic management of symptoms by separate services. Consistent with the biomedical model, management of chronic noncancer pain commonly included long-term use of opioids.

Over the past 2 decades, the use of opioids for treating chronic noncancer pain has significantly increased, with more than 62 million opioid prescriptions dispensed in 2012.⁵ There are no longitudinal follow-up studies, however, beyond 16 weeks on the use of opioids.⁶ Further, patients who are prescribed increased opioids continue to report high levels of pain, poor quality of life, and functional disability.⁷ High-dose opioids also are associated with overdose deaths.

Likewise, PCPs in the Women’s Primary Care Clinics at the VASLCHCS struggled with decreasing opioid use, often because other interventions for managing pain and related mental health conditions in primary care were not readily available. Although the VASLCHCS has an effective specialty pain service caring for patients with complex pain issues, opioid morphine equivalent doses > 200 mg/d, and palliative care, patients with chronic noncancer pain treated in the primary care setting did not have a consistent treatment approach.

A chart review of women veterans seen in Women’s Primary Care Clinic (N = 122) revealed that the majority of patients lacked timely urine drug screening, state database queries, signed medication management agreements, and documentation consistent with state and national guidelines. Additionally, many patients lacked provider follow-through regarding alternative and adjunctive therapy consults, which were often discontinued after failed contact attempts or no-shows to scheduled appointments.

There also was a general consensus among the Women’s Primary Care Clinic PCPs that caring for patients with chronic noncancer pain was exhausting, time consuming, ineffective, and often straining on the patient-provider relationship, as evidenced in many patients’ request to change providers secondary to pain management. The PC-CPP was developed to help systematically facilitate safe opioid prescribing, manage chronic pain issues, and document evidence-based care among women veterans receiving treatment for chronic noncancer pain at the Women’s Primary Care Clinics at VASLCHCS while coordinating and following through with nonpharmacologic interventions.

Program Development

National, state, VA, and professional licensure guidelines for chronic noncancer pain treatment standards were reviewed with the goal of creating a program that was evidence based, would benefit the patient in terms of opioid prescribing and pain control, and improve function while identifying key elements of care and documentation that adequately covered the prescriber of retribution.^1,8-10

Concurrent to a review of the guidelines was a review of the literature with the goal of identifying useful patient education and alternative interventions and chronic pain programs that were already established and might meet the clinic’s needs.^10,11 These reviews provided direction for a generalized approach to caring for patients with chronic nonmalignant pain. They also clarified that although pain education programs existed nationally, a program that offered a holistic, reproducible, adherence-driven yet patient-centered approach to the patient prescribed opioids chronically in a primary care setting was lacking.

• Patient education about chronic pain and opioids
• Evaluation of pain, function, opioid misuse risk at least twice yearly
• Patient-centered and driven treatment plans
• A holistic approach to chronic pain interventions
• Review of treatment plan efficacy at least twice yearly
• Enzyme multiplied immunoassay technique urine drug screening (UDS) 2 times per year
• State prescription monitoring program query annually
• Signed iMedConsent for treatment of chronic pain
• Plan for safe discontinuation of opioids
• Documentation that the above has been performed with patient understanding

The literature suggested a multimodality approach to chronic nonmalignant pain by minimizing the use of opioids over time while emphasizing nonpharmacologic therapies, such as cognitive behavioral therapy (CBT), mindfulness, meditation, yoga, and spiritual growth, to name a few.^10,11 These findings are based on several studies, which suggested that passive coping strategies (eg, use of medication for immediate relief, depending on others, restricting medications) result in an increase in subjective pain among chronic nonmalignant pain patients.¹² Helping patients reduce frequent use of passive coping strategies is believed to decrease pain.¹² Active coping strategies (eg, engaging in therapies, staying busy or active, distracting attention from pain) have been found to decrease pain.¹² The PC-CPP program shifted health care outcomes and responsibilities away from the hierarchal PCP-patient relationship toward a collaborative relationship that encourages patient-driven, patient-centered care outcomes and shared responsibilities.

Program Overview

The PC-CPP was shaped by the following hypotheses: (1) Transparent expectations and consequences would increase functional scores and decrease chronic opioid doses; (2) Treatment plans consisting of chronic opioid prescriptions linked with interactive nonpharmacologic interventions led to decreased pain and increased functional scores; (3) Transparent expectations combined with a streamlined approach to the chronic nonmalignant pain patient would improve patient and PCP satisfaction scores.

The PC-CPP was developed to provide an efficient, effective, and evidence-based approach to managing chronic nonmalignant pain and opioid therapy issues in the primary care setting. Referred patients attend 1 shared medical appointment (SMA) every 6 months with up to 19 other female veterans also referred to the PC-CPP. The group was composed of only female veterans as the pilot study for this SMA occurred in the Women’s Clinic. At each 6-month SMA, patients received education from the Taking Opioids Responsibly for Your Safety and the Safety of Others (TORYSSO) guide¹³ and signed the corresponding long-term opioid therapy for pain informed consent form (iMedConsent).

The patient and a staff member developed a treatment plan that was patient driven and included at least 1 nonpharmacologic treatment option. The 1-hour nonpharmacologic sessions were either group or individual and occurred weekly for 6 to 8 weeks. These options included CBT for chronic pain, Living Well With Chronic Conditions, trauma-sensitive yoga, smoking cessation, mindfulness for stress and anxiety, MOVE! weight management, Walk With Ease, and a self-help option (VA-issued Manage Stress Workbook, 2014). The workbook was included as an option for those who lived far away, were limited by work schedules, or were unable to afford the copays for a 6- to 8-session program.

Inclusion and Exclusion Criteria

Any female veteran patient enrolled in the VASLCHCS with a chronic nonmalignant pain diagnosis who received daily opioids for 3 or more consecutive months from a PCP was included. Excluded individuals were those with cognitive decline/dementia, serious mental illness, psychosis, active suicidality, disruptive behavior flag, or those excluded by PCP discretion if it was determined that the patient would do better in a one-on-one setting with the PCP (Table 1). Patients taking > 200 MED/d of opioids who were seen in the VASLCHCS specialty pain clinic were also excluded.

Patient and PCP Responsibilities

The patient was responsible for timely attendance and full participation in all SMA group classes as determined in the veteran’s Treatment Plan Agreement (TPA). In addition, the patient had to provide UDS when requested (a minimum of twice yearly) and communicate with the PCP if having a procedure requiring additional opioids. This was in line with the current standards set forth by the VA Opioid Safety Initiative (OSI) Taskforce.¹²

The PC-CPP provided education, evaluation, documentation, and referral and follow-up with the nonpharmacologic treatment options discussed but did not provide prescription medications. The PCP reviewed the medical documents completed in the PC-CPP, and the PCP was strongly encouraged to follow its recommendations. The expectation was that the PCP would support the PC-CPP when the care recommendation was for a pharmacist-guided opioid taper.

Lack of attendance was defined as a no-show or a reschedule. Patients were considered adherent if they missed fewer than 2 SMA appointments and 2 nonpharmacologic treatment appointments every 6 months. The patient was required to attend the SMA and nonpharmacologic treatment on the third appointment to remain adherent with PC-CPP expectations and agreements. Adherence was acknowledged after 12 and 24 months by a reduction in PC-CPP requirements.

Shared Medical Appointment

Patients referred to the program and who met inclusion criteria received letters explaining the importance of SMA attendance and follow-up reminder calls. At least 30 minutes before the SMA, the patient provided an UDS sample at the laboratory. Next, the patient received an individualized program packet that included the TORYSSO guide, iMedConsent, a TPA specific to the program, a brief pain inventory (BPI) and opioid risk tool, a list of medication disposal sites, and short descriptions of available nonpharmacologic therapies.

Each SMA began with a presentation delivered by a pharmacist, a psychologist, and a medical provider, discussing TORYSSO, program expectations, and holistic approaches to pain. Each SMA also included a rotating chronic pain information topic (eg, nutrition and pain, the physiology of addiction, and the value of multiple modalities in pain treatment). Together, the staff and patients reviewed and completed the blank forms enclosed in the individualized

Each visit was entered into a Computerized Patient Record System (CPRS) template, which included a pain diagnosis, Opioid Risk Tool score, pain and functional scores, opioid fill history, last comprehensive metabolic panel, last electrocardiogram if on methadone, dates of signed agreements, patient adherence with SMA and optional therapies, and follow-up (eFigure).

Every patient enrolled in the PC-CPP had to attend a SMA every 6 months. Patients continued this indefinitely while receiving opioids, and requirements were lessened for patients who had a history of meeting program requirements. For those fully adherent after the first year, only 1 nonpharmacologic intervention was needed (instead of 1 every 6 months) yearly. After 2 years of full adherence, nonpharmacologic interventions were no longer necessary as the expectation was that the patient would continue to use the strategies that they had learned over the previous 2 years. Patients left the PC-CPP if they chose to discontinue opioids, met any of the exclusion criteria, or were nonadherent. Tapering opioid medication was recommended for patients who missed a SMA meeting or 2 nonpharmacologic treatment meetings in a 6-month period; received opioids from more than 1 provider; test positive on a UDS for substances that should not be present; consistently testing negative on a UDS for substances that should be present (indicating diversion); or exhibiting other aberrant behavior (frequent requests for early refills, medications often lost/stolen, etc).

Program Barriers

The PC-CPP took about 2 years to set up, and several barriers were encountered. A thorough understanding of the following factors is necessary for establishing a similar program.

Initially, consults were placed by a designee (someone other than the PCP currently caring for the patient). The designee was usually a member of the PC-CPP who placed consults for all patients who had opioids listed on the CPRS profile. Further, patients who had any opioids within the past 3 months were initially included as were patients who wanted pain education but were not taking opioids. After 12 months, it became apparent that the focus of the PC-CPP should center on patients taking opioids for a minimum of 3 months consecutively. Patients who wanted only education could attend other hospital education opportunities, which helped keep the patient load manageable for PC-CPP staff. Further, to lessen patient confusion and improve adherence, the PCP placed the consult and discussed the program with the patient. Class sizes of 5 to 10 patients seemed to be ideal for patient participation and provider workload.

Patient Education

Initially, the SMA did not follow a standard curriculum, but the current format is more consistent, reproducible, streamlined, and organized. This adjustment improved SMA attendance as well as patient satisfaction, as the class started and finished on time. The SMA also started with numerous handouts, including brochures for nonpharmacologic programs offered at this facility. This led to patients feeling overwhelmed, missing the important forms, and wasted paper. Handouts were simplified to 2 color-coded forms (TPA and BPI).

The take-home assessment was streamlined to a single general assessment. This assessment consisted of 2 questions that asked patients to write a summary of what they learned and then write a summary of how they applied what they learned to their pain management. The VA Manage Stress Workbook also was added to the take-home materials. There are currently 5 different take-home options, which are necessary for those who live more than 50 miles from any VA facility or for those who have transportation issues.

Patient Distress

The SMA could be stressful for patients who felt they were being “punished” or who showed up more than 15 minutes late and had to reschedule the SMA. Having a mental health provider available was crucial for these situations.

Therapeutic Option Development

A cornerstone of the program was getting patients to participate in nonpharmacologic treatment options, which required a robust selection of programs. The VASLCHCS was fortunate to have many programs already available (Table 2), but this was not always the case for the VA community-based outpatient clinics (CBOCs).

Stakeholder Support

Before its start, PC-CPP was presented to the Pentad (a group of 5 individuals in the local facility who hold executive leadership positions) for approval. Tapering opioids can lead to feelings of hostility, frustration, or sadness for patients, so having the Pentad support for the program was crucial to address complaints made to patient advocates or senators. Provider support also was important to reinforce program rules. The PC-CPP inclusion criteria included only those patients whose PCP was agreeable to a taper when the patient did not comply with program expectations. This strategy helped to improve patient adherence with the PC-CPP and decrease patient arguments with clinic staff, as all patients are held to the same standards.

Staff

Finding willing staff can be a challenge. It is estimated that each site needed a program leader who can champion the program objectives and drive organization of staff, space, documentation, and consistency for the patients consulted to the PC-CPP. The goal is that the consistent, reproducible expectations for both the PCP and the patient will reduce overall workload for a clinic. Patients may test the firmness and conviction of the staff to the PC-CPP. Having staff who are able and willing to be firm on relaying information for adherence to the patient is vital.

Administrative Support

At a minimum, a medical support assistant was required to help with scheduling, reminder calls and letters, CPRS check-in/check-out, ensuring necessary forms are ready for the SMA, tracking adherence, and following-up on no-shows and rescheduling.

Documentation

The CPRS consult and note template titles required the approval of the template committee. Although the template is helpful, there is still a great deal that needs to be manually entered in the note, such as BPI scores, opioid risk scores, and chosen nonpharmacologic interventions scores of pain, function, and opioid risk as well individual comorbidities, diagnosis, and follow-up dates. Documentation is geared toward easy review for the PCP who should scan the document prior to renewing opioid medications. The PC-CPP consult became a message board. Once the patient attends the SMA, the designated staff will add a comment to the message board, identifying all dates attended, complete history of the patient’s intervention choices and rate of adherence, as well a follow-up SMA date and whether the patient should bring materials such as take-home tests.

Time Commitment

Program development carries a heavy time burden. One full-time equivalent clinician for 6 weeks for program development is needed. Time allotment is estimated to be the following:

• Medical provider—30 minutes per patient (chart review, documentation, consult resolution). With training, these duties could be completed by support staff
• Pharmacist—30 minutes per patient (chart review, UDS, Utah Division of Occupational and Professional Licensing, fill history). Additional time is needed for writing opioid tapers for qualifying patients
• Primary care mental health integration—a PhD spent 1 to 2 hours per SMA visit assisting patients who became distressed during the visit. Only once has a patient needed to be escorted to the emergency department for active suicidality. A PhD also spent 10+ hours per week running and managing the CBT for Chronic Pain Group
• Support staff—a registered nurse spent 4 hours each month preparing for the SMA (entering consults, ordering EMITs, purchasing snacks)

Conclusion

In this descriptive report, the authors presented an overview of a newly developed program to manage chronic nonmalignant pain and safe opioid prescribing in a primary care setting. A final report is pending. The intent with this interim report was to describe the PC-CPP at the VASLCHCS, its methods and protocols, and logistic considerations for other providers who are working with patients with chronic pain in a primary care model. Standard operating procedure and inclusion/exclusion criteria were included to help with clinical decision making for patients chronic pain for whom aberrant opioid-related behavior presents a problem.

The authors expect that the PC-CPP will provide more comprehensive assisted care, lending to decreased complications associated with accidental overdose, because since patients have been educated about risks for accidental overdose from chronic opioids and have the responsibility for their outcomes. The authors also anticipated that functional scores (as measured by the BPI) will increase despite lowering opioid doses because patients will use ancillary treatments for pain. The desired outcome is that patients will come to understand that pain control is best approached holistically rather than through opioid monotherapy.

There have been several recent initiatives within the VA to decrease opioid prescribing and increase patient safety. With this in mind, continued expansion of this program to CBOCs and male patients could be useful to providers. Also, this program was conducted in a small setting (Women’s Clinic), and there are many challenges with rolling out such a program in a larger clinic (eg, greater chance for provider disagreement, greater need for administrative staff support). Nonetheless, the benefits of close monitoring of prescription opioids and active encouragement to engage in nonpharmacologic therapies are substantial and deserve further advancement.

The Primary Care Chronic Pain Program (PC-CPP) of the Women’s Primary Care Clinics at the VA Salt Lake City Health Care System (VASLCHCS) in Utah was the first VA primary care clinical service to incorporate patient participation in obtaining chronic opioid medications in the treatment of chronic noncancer pain. In addition, the program used a multimodality approach for chronic pain treatment and veteran education about the relationship between physical and mental health issues.

Treatment Complexity

Chronic, noncancer pain is a complex issue in the primary care setting. Diagnosis is difficult, patient education is time consuming, goals and expectations are often unclear, and the experience can be unsatisfying for the patient and the provider.¹ These issues, combined with an estimated prevalence rate of 71% for moderate pain among veterans seen in primary care, present a unique challenge for the primary care provider (PCP), given the limited time available to spend with these complex patients.² Comorbidity rates with mental health issues (eg, depression, anxiety, substance use disorders, etc), which range from 18% to 44%, add to the management challenges for PCPs.³

Veterans also pose unique challenges in pain care as they have a 2-fold greater risk of death from opioid overdose compared with that of the general population, and Utah has been shown to have the highest rate of veteran overdoses.⁴ Developing programs to help PCPs efficiently manage patients with chronic noncancer pain and mental health comorbidities was vital at VASLCHCS.

Before VASLCHCS established the PC-CPP, the treatment for chronic noncancer pain and related mental health comorbidities followed a biomedical model that separated physical and mental health with the treatment focus on pharmacologic management of symptoms by separate services. Consistent with the biomedical model, management of chronic noncancer pain commonly included long-term use of opioids.

Over the past 2 decades, the use of opioids for treating chronic noncancer pain has significantly increased, with more than 62 million opioid prescriptions dispensed in 2012.⁵ There are no longitudinal follow-up studies, however, beyond 16 weeks on the use of opioids.⁶ Further, patients who are prescribed increased opioids continue to report high levels of pain, poor quality of life, and functional disability.⁷ High-dose opioids also are associated with overdose deaths.

Likewise, PCPs in the Women’s Primary Care Clinics at the VASLCHCS struggled with decreasing opioid use, often because other interventions for managing pain and related mental health conditions in primary care were not readily available. Although the VASLCHCS has an effective specialty pain service caring for patients with complex pain issues, opioid morphine equivalent doses > 200 mg/d, and palliative care, patients with chronic noncancer pain treated in the primary care setting did not have a consistent treatment approach.

A chart review of women veterans seen in Women’s Primary Care Clinic (N = 122) revealed that the majority of patients lacked timely urine drug screening, state database queries, signed medication management agreements, and documentation consistent with state and national guidelines. Additionally, many patients lacked provider follow-through regarding alternative and adjunctive therapy consults, which were often discontinued after failed contact attempts or no-shows to scheduled appointments.

There also was a general consensus among the Women’s Primary Care Clinic PCPs that caring for patients with chronic noncancer pain was exhausting, time consuming, ineffective, and often straining on the patient-provider relationship, as evidenced in many patients’ request to change providers secondary to pain management. The PC-CPP was developed to help systematically facilitate safe opioid prescribing, manage chronic pain issues, and document evidence-based care among women veterans receiving treatment for chronic noncancer pain at the Women’s Primary Care Clinics at VASLCHCS while coordinating and following through with nonpharmacologic interventions.

Program Development

National, state, VA, and professional licensure guidelines for chronic noncancer pain treatment standards were reviewed with the goal of creating a program that was evidence based, would benefit the patient in terms of opioid prescribing and pain control, and improve function while identifying key elements of care and documentation that adequately covered the prescriber of retribution.^1,8-10

Concurrent to a review of the guidelines was a review of the literature with the goal of identifying useful patient education and alternative interventions and chronic pain programs that were already established and might meet the clinic’s needs.^10,11 These reviews provided direction for a generalized approach to caring for patients with chronic nonmalignant pain. They also clarified that although pain education programs existed nationally, a program that offered a holistic, reproducible, adherence-driven yet patient-centered approach to the patient prescribed opioids chronically in a primary care setting was lacking.

• Patient education about chronic pain and opioids
• Evaluation of pain, function, opioid misuse risk at least twice yearly
• Patient-centered and driven treatment plans
• A holistic approach to chronic pain interventions
• Review of treatment plan efficacy at least twice yearly
• Enzyme multiplied immunoassay technique urine drug screening (UDS) 2 times per year
• State prescription monitoring program query annually
• Signed iMedConsent for treatment of chronic pain
• Plan for safe discontinuation of opioids
• Documentation that the above has been performed with patient understanding

The literature suggested a multimodality approach to chronic nonmalignant pain by minimizing the use of opioids over time while emphasizing nonpharmacologic therapies, such as cognitive behavioral therapy (CBT), mindfulness, meditation, yoga, and spiritual growth, to name a few.^10,11 These findings are based on several studies, which suggested that passive coping strategies (eg, use of medication for immediate relief, depending on others, restricting medications) result in an increase in subjective pain among chronic nonmalignant pain patients.¹² Helping patients reduce frequent use of passive coping strategies is believed to decrease pain.¹² Active coping strategies (eg, engaging in therapies, staying busy or active, distracting attention from pain) have been found to decrease pain.¹² The PC-CPP program shifted health care outcomes and responsibilities away from the hierarchal PCP-patient relationship toward a collaborative relationship that encourages patient-driven, patient-centered care outcomes and shared responsibilities.

Program Overview

The PC-CPP was shaped by the following hypotheses: (1) Transparent expectations and consequences would increase functional scores and decrease chronic opioid doses; (2) Treatment plans consisting of chronic opioid prescriptions linked with interactive nonpharmacologic interventions led to decreased pain and increased functional scores; (3) Transparent expectations combined with a streamlined approach to the chronic nonmalignant pain patient would improve patient and PCP satisfaction scores.

The PC-CPP was developed to provide an efficient, effective, and evidence-based approach to managing chronic nonmalignant pain and opioid therapy issues in the primary care setting. Referred patients attend 1 shared medical appointment (SMA) every 6 months with up to 19 other female veterans also referred to the PC-CPP. The group was composed of only female veterans as the pilot study for this SMA occurred in the Women’s Clinic. At each 6-month SMA, patients received education from the Taking Opioids Responsibly for Your Safety and the Safety of Others (TORYSSO) guide¹³ and signed the corresponding long-term opioid therapy for pain informed consent form (iMedConsent).

The patient and a staff member developed a treatment plan that was patient driven and included at least 1 nonpharmacologic treatment option. The 1-hour nonpharmacologic sessions were either group or individual and occurred weekly for 6 to 8 weeks. These options included CBT for chronic pain, Living Well With Chronic Conditions, trauma-sensitive yoga, smoking cessation, mindfulness for stress and anxiety, MOVE! weight management, Walk With Ease, and a self-help option (VA-issued Manage Stress Workbook, 2014). The workbook was included as an option for those who lived far away, were limited by work schedules, or were unable to afford the copays for a 6- to 8-session program.

Inclusion and Exclusion Criteria

Any female veteran patient enrolled in the VASLCHCS with a chronic nonmalignant pain diagnosis who received daily opioids for 3 or more consecutive months from a PCP was included. Excluded individuals were those with cognitive decline/dementia, serious mental illness, psychosis, active suicidality, disruptive behavior flag, or those excluded by PCP discretion if it was determined that the patient would do better in a one-on-one setting with the PCP (Table 1). Patients taking > 200 MED/d of opioids who were seen in the VASLCHCS specialty pain clinic were also excluded.

Patient and PCP Responsibilities

The patient was responsible for timely attendance and full participation in all SMA group classes as determined in the veteran’s Treatment Plan Agreement (TPA). In addition, the patient had to provide UDS when requested (a minimum of twice yearly) and communicate with the PCP if having a procedure requiring additional opioids. This was in line with the current standards set forth by the VA Opioid Safety Initiative (OSI) Taskforce.¹²

The PC-CPP provided education, evaluation, documentation, and referral and follow-up with the nonpharmacologic treatment options discussed but did not provide prescription medications. The PCP reviewed the medical documents completed in the PC-CPP, and the PCP was strongly encouraged to follow its recommendations. The expectation was that the PCP would support the PC-CPP when the care recommendation was for a pharmacist-guided opioid taper.

Lack of attendance was defined as a no-show or a reschedule. Patients were considered adherent if they missed fewer than 2 SMA appointments and 2 nonpharmacologic treatment appointments every 6 months. The patient was required to attend the SMA and nonpharmacologic treatment on the third appointment to remain adherent with PC-CPP expectations and agreements. Adherence was acknowledged after 12 and 24 months by a reduction in PC-CPP requirements.

Shared Medical Appointment

Patients referred to the program and who met inclusion criteria received letters explaining the importance of SMA attendance and follow-up reminder calls. At least 30 minutes before the SMA, the patient provided an UDS sample at the laboratory. Next, the patient received an individualized program packet that included the TORYSSO guide, iMedConsent, a TPA specific to the program, a brief pain inventory (BPI) and opioid risk tool, a list of medication disposal sites, and short descriptions of available nonpharmacologic therapies.

Each SMA began with a presentation delivered by a pharmacist, a psychologist, and a medical provider, discussing TORYSSO, program expectations, and holistic approaches to pain. Each SMA also included a rotating chronic pain information topic (eg, nutrition and pain, the physiology of addiction, and the value of multiple modalities in pain treatment). Together, the staff and patients reviewed and completed the blank forms enclosed in the individualized

Each visit was entered into a Computerized Patient Record System (CPRS) template, which included a pain diagnosis, Opioid Risk Tool score, pain and functional scores, opioid fill history, last comprehensive metabolic panel, last electrocardiogram if on methadone, dates of signed agreements, patient adherence with SMA and optional therapies, and follow-up (eFigure).

Every patient enrolled in the PC-CPP had to attend a SMA every 6 months. Patients continued this indefinitely while receiving opioids, and requirements were lessened for patients who had a history of meeting program requirements. For those fully adherent after the first year, only 1 nonpharmacologic intervention was needed (instead of 1 every 6 months) yearly. After 2 years of full adherence, nonpharmacologic interventions were no longer necessary as the expectation was that the patient would continue to use the strategies that they had learned over the previous 2 years. Patients left the PC-CPP if they chose to discontinue opioids, met any of the exclusion criteria, or were nonadherent. Tapering opioid medication was recommended for patients who missed a SMA meeting or 2 nonpharmacologic treatment meetings in a 6-month period; received opioids from more than 1 provider; test positive on a UDS for substances that should not be present; consistently testing negative on a UDS for substances that should be present (indicating diversion); or exhibiting other aberrant behavior (frequent requests for early refills, medications often lost/stolen, etc).

Program Barriers

The PC-CPP took about 2 years to set up, and several barriers were encountered. A thorough understanding of the following factors is necessary for establishing a similar program.

Initially, consults were placed by a designee (someone other than the PCP currently caring for the patient). The designee was usually a member of the PC-CPP who placed consults for all patients who had opioids listed on the CPRS profile. Further, patients who had any opioids within the past 3 months were initially included as were patients who wanted pain education but were not taking opioids. After 12 months, it became apparent that the focus of the PC-CPP should center on patients taking opioids for a minimum of 3 months consecutively. Patients who wanted only education could attend other hospital education opportunities, which helped keep the patient load manageable for PC-CPP staff. Further, to lessen patient confusion and improve adherence, the PCP placed the consult and discussed the program with the patient. Class sizes of 5 to 10 patients seemed to be ideal for patient participation and provider workload.

Patient Education

Initially, the SMA did not follow a standard curriculum, but the current format is more consistent, reproducible, streamlined, and organized. This adjustment improved SMA attendance as well as patient satisfaction, as the class started and finished on time. The SMA also started with numerous handouts, including brochures for nonpharmacologic programs offered at this facility. This led to patients feeling overwhelmed, missing the important forms, and wasted paper. Handouts were simplified to 2 color-coded forms (TPA and BPI).

The take-home assessment was streamlined to a single general assessment. This assessment consisted of 2 questions that asked patients to write a summary of what they learned and then write a summary of how they applied what they learned to their pain management. The VA Manage Stress Workbook also was added to the take-home materials. There are currently 5 different take-home options, which are necessary for those who live more than 50 miles from any VA facility or for those who have transportation issues.

Patient Distress

The SMA could be stressful for patients who felt they were being “punished” or who showed up more than 15 minutes late and had to reschedule the SMA. Having a mental health provider available was crucial for these situations.

Therapeutic Option Development

A cornerstone of the program was getting patients to participate in nonpharmacologic treatment options, which required a robust selection of programs. The VASLCHCS was fortunate to have many programs already available (Table 2), but this was not always the case for the VA community-based outpatient clinics (CBOCs).

Stakeholder Support

Before its start, PC-CPP was presented to the Pentad (a group of 5 individuals in the local facility who hold executive leadership positions) for approval. Tapering opioids can lead to feelings of hostility, frustration, or sadness for patients, so having the Pentad support for the program was crucial to address complaints made to patient advocates or senators. Provider support also was important to reinforce program rules. The PC-CPP inclusion criteria included only those patients whose PCP was agreeable to a taper when the patient did not comply with program expectations. This strategy helped to improve patient adherence with the PC-CPP and decrease patient arguments with clinic staff, as all patients are held to the same standards.

Staff

Finding willing staff can be a challenge. It is estimated that each site needed a program leader who can champion the program objectives and drive organization of staff, space, documentation, and consistency for the patients consulted to the PC-CPP. The goal is that the consistent, reproducible expectations for both the PCP and the patient will reduce overall workload for a clinic. Patients may test the firmness and conviction of the staff to the PC-CPP. Having staff who are able and willing to be firm on relaying information for adherence to the patient is vital.

Administrative Support

At a minimum, a medical support assistant was required to help with scheduling, reminder calls and letters, CPRS check-in/check-out, ensuring necessary forms are ready for the SMA, tracking adherence, and following-up on no-shows and rescheduling.

Documentation

The CPRS consult and note template titles required the approval of the template committee. Although the template is helpful, there is still a great deal that needs to be manually entered in the note, such as BPI scores, opioid risk scores, and chosen nonpharmacologic interventions scores of pain, function, and opioid risk as well individual comorbidities, diagnosis, and follow-up dates. Documentation is geared toward easy review for the PCP who should scan the document prior to renewing opioid medications. The PC-CPP consult became a message board. Once the patient attends the SMA, the designated staff will add a comment to the message board, identifying all dates attended, complete history of the patient’s intervention choices and rate of adherence, as well a follow-up SMA date and whether the patient should bring materials such as take-home tests.

Time Commitment

Program development carries a heavy time burden. One full-time equivalent clinician for 6 weeks for program development is needed. Time allotment is estimated to be the following:

• Medical provider—30 minutes per patient (chart review, documentation, consult resolution). With training, these duties could be completed by support staff
• Pharmacist—30 minutes per patient (chart review, UDS, Utah Division of Occupational and Professional Licensing, fill history). Additional time is needed for writing opioid tapers for qualifying patients
• Primary care mental health integration—a PhD spent 1 to 2 hours per SMA visit assisting patients who became distressed during the visit. Only once has a patient needed to be escorted to the emergency department for active suicidality. A PhD also spent 10+ hours per week running and managing the CBT for Chronic Pain Group
• Support staff—a registered nurse spent 4 hours each month preparing for the SMA (entering consults, ordering EMITs, purchasing snacks)

Conclusion

In this descriptive report, the authors presented an overview of a newly developed program to manage chronic nonmalignant pain and safe opioid prescribing in a primary care setting. A final report is pending. The intent with this interim report was to describe the PC-CPP at the VASLCHCS, its methods and protocols, and logistic considerations for other providers who are working with patients with chronic pain in a primary care model. Standard operating procedure and inclusion/exclusion criteria were included to help with clinical decision making for patients chronic pain for whom aberrant opioid-related behavior presents a problem.

The authors expect that the PC-CPP will provide more comprehensive assisted care, lending to decreased complications associated with accidental overdose, because since patients have been educated about risks for accidental overdose from chronic opioids and have the responsibility for their outcomes. The authors also anticipated that functional scores (as measured by the BPI) will increase despite lowering opioid doses because patients will use ancillary treatments for pain. The desired outcome is that patients will come to understand that pain control is best approached holistically rather than through opioid monotherapy.

There have been several recent initiatives within the VA to decrease opioid prescribing and increase patient safety. With this in mind, continued expansion of this program to CBOCs and male patients could be useful to providers. Also, this program was conducted in a small setting (Women’s Clinic), and there are many challenges with rolling out such a program in a larger clinic (eg, greater chance for provider disagreement, greater need for administrative staff support). Nonetheless, the benefits of close monitoring of prescription opioids and active encouragement to engage in nonpharmacologic therapies are substantial and deserve further advancement.

The Primary Care Chronic Pain Program (PC-CPP) of the Women’s Primary Care Clinics at the VA Salt Lake City Health Care System (VASLCHCS) in Utah was the first VA primary care clinical service to incorporate patient participation in obtaining chronic opioid medications in the treatment of chronic noncancer pain. In addition, the program used a multimodality approach for chronic pain treatment and veteran education about the relationship between physical and mental health issues.

Treatment Complexity

Chronic, noncancer pain is a complex issue in the primary care setting. Diagnosis is difficult, patient education is time consuming, goals and expectations are often unclear, and the experience can be unsatisfying for the patient and the provider.¹ These issues, combined with an estimated prevalence rate of 71% for moderate pain among veterans seen in primary care, present a unique challenge for the primary care provider (PCP), given the limited time available to spend with these complex patients.² Comorbidity rates with mental health issues (eg, depression, anxiety, substance use disorders, etc), which range from 18% to 44%, add to the management challenges for PCPs.³

Veterans also pose unique challenges in pain care as they have a 2-fold greater risk of death from opioid overdose compared with that of the general population, and Utah has been shown to have the highest rate of veteran overdoses.⁴ Developing programs to help PCPs efficiently manage patients with chronic noncancer pain and mental health comorbidities was vital at VASLCHCS.

Before VASLCHCS established the PC-CPP, the treatment for chronic noncancer pain and related mental health comorbidities followed a biomedical model that separated physical and mental health with the treatment focus on pharmacologic management of symptoms by separate services. Consistent with the biomedical model, management of chronic noncancer pain commonly included long-term use of opioids.

Over the past 2 decades, the use of opioids for treating chronic noncancer pain has significantly increased, with more than 62 million opioid prescriptions dispensed in 2012.⁵ There are no longitudinal follow-up studies, however, beyond 16 weeks on the use of opioids.⁶ Further, patients who are prescribed increased opioids continue to report high levels of pain, poor quality of life, and functional disability.⁷ High-dose opioids also are associated with overdose deaths.

Likewise, PCPs in the Women’s Primary Care Clinics at the VASLCHCS struggled with decreasing opioid use, often because other interventions for managing pain and related mental health conditions in primary care were not readily available. Although the VASLCHCS has an effective specialty pain service caring for patients with complex pain issues, opioid morphine equivalent doses > 200 mg/d, and palliative care, patients with chronic noncancer pain treated in the primary care setting did not have a consistent treatment approach.

A chart review of women veterans seen in Women’s Primary Care Clinic (N = 122) revealed that the majority of patients lacked timely urine drug screening, state database queries, signed medication management agreements, and documentation consistent with state and national guidelines. Additionally, many patients lacked provider follow-through regarding alternative and adjunctive therapy consults, which were often discontinued after failed contact attempts or no-shows to scheduled appointments.

There also was a general consensus among the Women’s Primary Care Clinic PCPs that caring for patients with chronic noncancer pain was exhausting, time consuming, ineffective, and often straining on the patient-provider relationship, as evidenced in many patients’ request to change providers secondary to pain management. The PC-CPP was developed to help systematically facilitate safe opioid prescribing, manage chronic pain issues, and document evidence-based care among women veterans receiving treatment for chronic noncancer pain at the Women’s Primary Care Clinics at VASLCHCS while coordinating and following through with nonpharmacologic interventions.

Program Development

National, state, VA, and professional licensure guidelines for chronic noncancer pain treatment standards were reviewed with the goal of creating a program that was evidence based, would benefit the patient in terms of opioid prescribing and pain control, and improve function while identifying key elements of care and documentation that adequately covered the prescriber of retribution.^1,8-10

Concurrent to a review of the guidelines was a review of the literature with the goal of identifying useful patient education and alternative interventions and chronic pain programs that were already established and might meet the clinic’s needs.^10,11 These reviews provided direction for a generalized approach to caring for patients with chronic nonmalignant pain. They also clarified that although pain education programs existed nationally, a program that offered a holistic, reproducible, adherence-driven yet patient-centered approach to the patient prescribed opioids chronically in a primary care setting was lacking.

• Patient education about chronic pain and opioids
• Evaluation of pain, function, opioid misuse risk at least twice yearly
• Patient-centered and driven treatment plans
• A holistic approach to chronic pain interventions
• Review of treatment plan efficacy at least twice yearly
• Enzyme multiplied immunoassay technique urine drug screening (UDS) 2 times per year
• State prescription monitoring program query annually
• Signed iMedConsent for treatment of chronic pain
• Plan for safe discontinuation of opioids
• Documentation that the above has been performed with patient understanding

The literature suggested a multimodality approach to chronic nonmalignant pain by minimizing the use of opioids over time while emphasizing nonpharmacologic therapies, such as cognitive behavioral therapy (CBT), mindfulness, meditation, yoga, and spiritual growth, to name a few.^10,11 These findings are based on several studies, which suggested that passive coping strategies (eg, use of medication for immediate relief, depending on others, restricting medications) result in an increase in subjective pain among chronic nonmalignant pain patients.¹² Helping patients reduce frequent use of passive coping strategies is believed to decrease pain.¹² Active coping strategies (eg, engaging in therapies, staying busy or active, distracting attention from pain) have been found to decrease pain.¹² The PC-CPP program shifted health care outcomes and responsibilities away from the hierarchal PCP-patient relationship toward a collaborative relationship that encourages patient-driven, patient-centered care outcomes and shared responsibilities.

Program Overview

The PC-CPP was shaped by the following hypotheses: (1) Transparent expectations and consequences would increase functional scores and decrease chronic opioid doses; (2) Treatment plans consisting of chronic opioid prescriptions linked with interactive nonpharmacologic interventions led to decreased pain and increased functional scores; (3) Transparent expectations combined with a streamlined approach to the chronic nonmalignant pain patient would improve patient and PCP satisfaction scores.

The PC-CPP was developed to provide an efficient, effective, and evidence-based approach to managing chronic nonmalignant pain and opioid therapy issues in the primary care setting. Referred patients attend 1 shared medical appointment (SMA) every 6 months with up to 19 other female veterans also referred to the PC-CPP. The group was composed of only female veterans as the pilot study for this SMA occurred in the Women’s Clinic. At each 6-month SMA, patients received education from the Taking Opioids Responsibly for Your Safety and the Safety of Others (TORYSSO) guide¹³ and signed the corresponding long-term opioid therapy for pain informed consent form (iMedConsent).

The patient and a staff member developed a treatment plan that was patient driven and included at least 1 nonpharmacologic treatment option. The 1-hour nonpharmacologic sessions were either group or individual and occurred weekly for 6 to 8 weeks. These options included CBT for chronic pain, Living Well With Chronic Conditions, trauma-sensitive yoga, smoking cessation, mindfulness for stress and anxiety, MOVE! weight management, Walk With Ease, and a self-help option (VA-issued Manage Stress Workbook, 2014). The workbook was included as an option for those who lived far away, were limited by work schedules, or were unable to afford the copays for a 6- to 8-session program.

Inclusion and Exclusion Criteria

Any female veteran patient enrolled in the VASLCHCS with a chronic nonmalignant pain diagnosis who received daily opioids for 3 or more consecutive months from a PCP was included. Excluded individuals were those with cognitive decline/dementia, serious mental illness, psychosis, active suicidality, disruptive behavior flag, or those excluded by PCP discretion if it was determined that the patient would do better in a one-on-one setting with the PCP (Table 1). Patients taking > 200 MED/d of opioids who were seen in the VASLCHCS specialty pain clinic were also excluded.

Patient and PCP Responsibilities

The patient was responsible for timely attendance and full participation in all SMA group classes as determined in the veteran’s Treatment Plan Agreement (TPA). In addition, the patient had to provide UDS when requested (a minimum of twice yearly) and communicate with the PCP if having a procedure requiring additional opioids. This was in line with the current standards set forth by the VA Opioid Safety Initiative (OSI) Taskforce.¹²

The PC-CPP provided education, evaluation, documentation, and referral and follow-up with the nonpharmacologic treatment options discussed but did not provide prescription medications. The PCP reviewed the medical documents completed in the PC-CPP, and the PCP was strongly encouraged to follow its recommendations. The expectation was that the PCP would support the PC-CPP when the care recommendation was for a pharmacist-guided opioid taper.

Lack of attendance was defined as a no-show or a reschedule. Patients were considered adherent if they missed fewer than 2 SMA appointments and 2 nonpharmacologic treatment appointments every 6 months. The patient was required to attend the SMA and nonpharmacologic treatment on the third appointment to remain adherent with PC-CPP expectations and agreements. Adherence was acknowledged after 12 and 24 months by a reduction in PC-CPP requirements.

Shared Medical Appointment

Patients referred to the program and who met inclusion criteria received letters explaining the importance of SMA attendance and follow-up reminder calls. At least 30 minutes before the SMA, the patient provided an UDS sample at the laboratory. Next, the patient received an individualized program packet that included the TORYSSO guide, iMedConsent, a TPA specific to the program, a brief pain inventory (BPI) and opioid risk tool, a list of medication disposal sites, and short descriptions of available nonpharmacologic therapies.

Each SMA began with a presentation delivered by a pharmacist, a psychologist, and a medical provider, discussing TORYSSO, program expectations, and holistic approaches to pain. Each SMA also included a rotating chronic pain information topic (eg, nutrition and pain, the physiology of addiction, and the value of multiple modalities in pain treatment). Together, the staff and patients reviewed and completed the blank forms enclosed in the individualized

Each visit was entered into a Computerized Patient Record System (CPRS) template, which included a pain diagnosis, Opioid Risk Tool score, pain and functional scores, opioid fill history, last comprehensive metabolic panel, last electrocardiogram if on methadone, dates of signed agreements, patient adherence with SMA and optional therapies, and follow-up (eFigure).

Every patient enrolled in the PC-CPP had to attend a SMA every 6 months. Patients continued this indefinitely while receiving opioids, and requirements were lessened for patients who had a history of meeting program requirements. For those fully adherent after the first year, only 1 nonpharmacologic intervention was needed (instead of 1 every 6 months) yearly. After 2 years of full adherence, nonpharmacologic interventions were no longer necessary as the expectation was that the patient would continue to use the strategies that they had learned over the previous 2 years. Patients left the PC-CPP if they chose to discontinue opioids, met any of the exclusion criteria, or were nonadherent. Tapering opioid medication was recommended for patients who missed a SMA meeting or 2 nonpharmacologic treatment meetings in a 6-month period; received opioids from more than 1 provider; test positive on a UDS for substances that should not be present; consistently testing negative on a UDS for substances that should be present (indicating diversion); or exhibiting other aberrant behavior (frequent requests for early refills, medications often lost/stolen, etc).

Program Barriers

The PC-CPP took about 2 years to set up, and several barriers were encountered. A thorough understanding of the following factors is necessary for establishing a similar program.

Initially, consults were placed by a designee (someone other than the PCP currently caring for the patient). The designee was usually a member of the PC-CPP who placed consults for all patients who had opioids listed on the CPRS profile. Further, patients who had any opioids within the past 3 months were initially included as were patients who wanted pain education but were not taking opioids. After 12 months, it became apparent that the focus of the PC-CPP should center on patients taking opioids for a minimum of 3 months consecutively. Patients who wanted only education could attend other hospital education opportunities, which helped keep the patient load manageable for PC-CPP staff. Further, to lessen patient confusion and improve adherence, the PCP placed the consult and discussed the program with the patient. Class sizes of 5 to 10 patients seemed to be ideal for patient participation and provider workload.

Patient Education

Initially, the SMA did not follow a standard curriculum, but the current format is more consistent, reproducible, streamlined, and organized. This adjustment improved SMA attendance as well as patient satisfaction, as the class started and finished on time. The SMA also started with numerous handouts, including brochures for nonpharmacologic programs offered at this facility. This led to patients feeling overwhelmed, missing the important forms, and wasted paper. Handouts were simplified to 2 color-coded forms (TPA and BPI).

The take-home assessment was streamlined to a single general assessment. This assessment consisted of 2 questions that asked patients to write a summary of what they learned and then write a summary of how they applied what they learned to their pain management. The VA Manage Stress Workbook also was added to the take-home materials. There are currently 5 different take-home options, which are necessary for those who live more than 50 miles from any VA facility or for those who have transportation issues.

Patient Distress

The SMA could be stressful for patients who felt they were being “punished” or who showed up more than 15 minutes late and had to reschedule the SMA. Having a mental health provider available was crucial for these situations.

Therapeutic Option Development

A cornerstone of the program was getting patients to participate in nonpharmacologic treatment options, which required a robust selection of programs. The VASLCHCS was fortunate to have many programs already available (Table 2), but this was not always the case for the VA community-based outpatient clinics (CBOCs).

Stakeholder Support

Before its start, PC-CPP was presented to the Pentad (a group of 5 individuals in the local facility who hold executive leadership positions) for approval. Tapering opioids can lead to feelings of hostility, frustration, or sadness for patients, so having the Pentad support for the program was crucial to address complaints made to patient advocates or senators. Provider support also was important to reinforce program rules. The PC-CPP inclusion criteria included only those patients whose PCP was agreeable to a taper when the patient did not comply with program expectations. This strategy helped to improve patient adherence with the PC-CPP and decrease patient arguments with clinic staff, as all patients are held to the same standards.

Staff

Finding willing staff can be a challenge. It is estimated that each site needed a program leader who can champion the program objectives and drive organization of staff, space, documentation, and consistency for the patients consulted to the PC-CPP. The goal is that the consistent, reproducible expectations for both the PCP and the patient will reduce overall workload for a clinic. Patients may test the firmness and conviction of the staff to the PC-CPP. Having staff who are able and willing to be firm on relaying information for adherence to the patient is vital.

Administrative Support

At a minimum, a medical support assistant was required to help with scheduling, reminder calls and letters, CPRS check-in/check-out, ensuring necessary forms are ready for the SMA, tracking adherence, and following-up on no-shows and rescheduling.

Documentation

The CPRS consult and note template titles required the approval of the template committee. Although the template is helpful, there is still a great deal that needs to be manually entered in the note, such as BPI scores, opioid risk scores, and chosen nonpharmacologic interventions scores of pain, function, and opioid risk as well individual comorbidities, diagnosis, and follow-up dates. Documentation is geared toward easy review for the PCP who should scan the document prior to renewing opioid medications. The PC-CPP consult became a message board. Once the patient attends the SMA, the designated staff will add a comment to the message board, identifying all dates attended, complete history of the patient’s intervention choices and rate of adherence, as well a follow-up SMA date and whether the patient should bring materials such as take-home tests.

Time Commitment

Program development carries a heavy time burden. One full-time equivalent clinician for 6 weeks for program development is needed. Time allotment is estimated to be the following:

• Medical provider—30 minutes per patient (chart review, documentation, consult resolution). With training, these duties could be completed by support staff
• Pharmacist—30 minutes per patient (chart review, UDS, Utah Division of Occupational and Professional Licensing, fill history). Additional time is needed for writing opioid tapers for qualifying patients
• Primary care mental health integration—a PhD spent 1 to 2 hours per SMA visit assisting patients who became distressed during the visit. Only once has a patient needed to be escorted to the emergency department for active suicidality. A PhD also spent 10+ hours per week running and managing the CBT for Chronic Pain Group
• Support staff—a registered nurse spent 4 hours each month preparing for the SMA (entering consults, ordering EMITs, purchasing snacks)

Conclusion

In this descriptive report, the authors presented an overview of a newly developed program to manage chronic nonmalignant pain and safe opioid prescribing in a primary care setting. A final report is pending. The intent with this interim report was to describe the PC-CPP at the VASLCHCS, its methods and protocols, and logistic considerations for other providers who are working with patients with chronic pain in a primary care model. Standard operating procedure and inclusion/exclusion criteria were included to help with clinical decision making for patients chronic pain for whom aberrant opioid-related behavior presents a problem.

The authors expect that the PC-CPP will provide more comprehensive assisted care, lending to decreased complications associated with accidental overdose, because since patients have been educated about risks for accidental overdose from chronic opioids and have the responsibility for their outcomes. The authors also anticipated that functional scores (as measured by the BPI) will increase despite lowering opioid doses because patients will use ancillary treatments for pain. The desired outcome is that patients will come to understand that pain control is best approached holistically rather than through opioid monotherapy.

There have been several recent initiatives within the VA to decrease opioid prescribing and increase patient safety. With this in mind, continued expansion of this program to CBOCs and male patients could be useful to providers. Also, this program was conducted in a small setting (Women’s Clinic), and there are many challenges with rolling out such a program in a larger clinic (eg, greater chance for provider disagreement, greater need for administrative staff support). Nonetheless, the benefits of close monitoring of prescription opioids and active encouragement to engage in nonpharmacologic therapies are substantial and deserve further advancement.

Thrombus

Image by Andre E.X. Brown

The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for betrixaban, an oral factor Xa inhibitor, for extended-duration prophylaxis of venous thromboembolism (VTE) in acute medically ill patients with risk factors for VTE.

A priority review shortens the FDA review timeline to 6 months from the standard review period of 10 months.

The application for betrixaban has been given a Prescription Drug User Fee Act action date of June 24, 2017.  (Betrixaban also has fast track designation from the FDA.)

Meanwhile, the European Medicines Agency (EMA) is reviewing a marketing authorization application (MAA) for betrixaban for extended-duration prophylaxis of VTE in adults with acute medical illness and risk factors for VTE.

However, the EMA’s Committee for Medicinal Products for Human Use is reviewing the application under a standard 210-day review period.

“With the filing of the betrixaban NDA and the MAA validation, we now look forward to working with the FDA and EMA to bring this drug to market,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, Inc., the company developing betrixaban.

The NDA and MAA for betrixaban are supported by data from Portola’s phase 3 APEX study, which enrolled 7513 patients at more than 450 clinical sites worldwide.

In this study, researchers compared extended-duration anticoagulation with oral betrixaban for 35-42 days to standard-duration enoxaparin for 10±4 days in preventing VTE in high-risk acute medically ill patients.

Patients who received betrixaban had a significantly lower incidence of VTE than those who received enoxaparin, and there was no significant difference in major bleeding between the treatment groups.

Full results from this study were presented at the 62nd Annual International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Meeting and published in NEJM in May 2016.

Thrombus

Image by Andre E.X. Brown

The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for betrixaban, an oral factor Xa inhibitor, for extended-duration prophylaxis of venous thromboembolism (VTE) in acute medically ill patients with risk factors for VTE.

A priority review shortens the FDA review timeline to 6 months from the standard review period of 10 months.

The application for betrixaban has been given a Prescription Drug User Fee Act action date of June 24, 2017.  (Betrixaban also has fast track designation from the FDA.)

Meanwhile, the European Medicines Agency (EMA) is reviewing a marketing authorization application (MAA) for betrixaban for extended-duration prophylaxis of VTE in adults with acute medical illness and risk factors for VTE.

However, the EMA’s Committee for Medicinal Products for Human Use is reviewing the application under a standard 210-day review period.

“With the filing of the betrixaban NDA and the MAA validation, we now look forward to working with the FDA and EMA to bring this drug to market,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, Inc., the company developing betrixaban.

The NDA and MAA for betrixaban are supported by data from Portola’s phase 3 APEX study, which enrolled 7513 patients at more than 450 clinical sites worldwide.

In this study, researchers compared extended-duration anticoagulation with oral betrixaban for 35-42 days to standard-duration enoxaparin for 10±4 days in preventing VTE in high-risk acute medically ill patients.

Patients who received betrixaban had a significantly lower incidence of VTE than those who received enoxaparin, and there was no significant difference in major bleeding between the treatment groups.

Full results from this study were presented at the 62nd Annual International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Meeting and published in NEJM in May 2016.

Thrombus

Image by Andre E.X. Brown

The US Food and Drug Administration (FDA) has granted priority review to the new drug application (NDA) for betrixaban, an oral factor Xa inhibitor, for extended-duration prophylaxis of venous thromboembolism (VTE) in acute medically ill patients with risk factors for VTE.

A priority review shortens the FDA review timeline to 6 months from the standard review period of 10 months.

The application for betrixaban has been given a Prescription Drug User Fee Act action date of June 24, 2017.  (Betrixaban also has fast track designation from the FDA.)

Meanwhile, the European Medicines Agency (EMA) is reviewing a marketing authorization application (MAA) for betrixaban for extended-duration prophylaxis of VTE in adults with acute medical illness and risk factors for VTE.

However, the EMA’s Committee for Medicinal Products for Human Use is reviewing the application under a standard 210-day review period.

“With the filing of the betrixaban NDA and the MAA validation, we now look forward to working with the FDA and EMA to bring this drug to market,” said Bill Lis, chief executive officer of Portola Pharmaceuticals, Inc., the company developing betrixaban.

The NDA and MAA for betrixaban are supported by data from Portola’s phase 3 APEX study, which enrolled 7513 patients at more than 450 clinical sites worldwide.

In this study, researchers compared extended-duration anticoagulation with oral betrixaban for 35-42 days to standard-duration enoxaparin for 10±4 days in preventing VTE in high-risk acute medically ill patients.

Patients who received betrixaban had a significantly lower incidence of VTE than those who received enoxaparin, and there was no significant difference in major bleeding between the treatment groups.

Full results from this study were presented at the 62nd Annual International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Meeting and published in NEJM in May 2016.

A postlicensure safety study of a meningococcal conjugate vaccine in Southern California has shown that the vaccine may be associated with an increase in the risk of Bell’s palsy, but only if the vaccine is taken concomitantly with another vaccine.

Researchers set out to evaluate the safety of one quadrivalent meningococcal conjugate vaccine, MenACWY-CRM. Two MenACWY vaccines are currently licensed in the United States; MenACWY-D is the other. The vaccines underwent studies on the road to approval, but researchers saw an absence of data about how the vaccine was faring in routine clinical use.

copyright DesignPics/Thinkstock

[email protected]

A postlicensure safety study of a meningococcal conjugate vaccine in Southern California has shown that the vaccine may be associated with an increase in the risk of Bell’s palsy, but only if the vaccine is taken concomitantly with another vaccine.

Researchers set out to evaluate the safety of one quadrivalent meningococcal conjugate vaccine, MenACWY-CRM. Two MenACWY vaccines are currently licensed in the United States; MenACWY-D is the other. The vaccines underwent studies on the road to approval, but researchers saw an absence of data about how the vaccine was faring in routine clinical use.

copyright DesignPics/Thinkstock

[email protected]

A postlicensure safety study of a meningococcal conjugate vaccine in Southern California has shown that the vaccine may be associated with an increase in the risk of Bell’s palsy, but only if the vaccine is taken concomitantly with another vaccine.

Researchers set out to evaluate the safety of one quadrivalent meningococcal conjugate vaccine, MenACWY-CRM. Two MenACWY vaccines are currently licensed in the United States; MenACWY-D is the other. The vaccines underwent studies on the road to approval, but researchers saw an absence of data about how the vaccine was faring in routine clinical use.

copyright DesignPics/Thinkstock

[email protected]

Micrograph showing CLL

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”

Micrograph showing CLL

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”

Micrograph showing CLL

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”