Mixed Topics

What happens to grief when those around you don’t understand it? Where does it go? How do you process it?

Disenfranchised grief, when someone or society more generally doesn’t see a loss as worthy of mourning, can deprive people of experiencing or processing their sadness. This grief, which may be triggered by the death of an ex-spouse, a pet, a failed adoption, can be painful and long-lasting.

Here, we reflect as physicians on our own experiences and memories of this phenomenon.
 

Suzanne Cole, MD: ‘I didn’t feel the right to grieve’

During the COVID-19 pandemic, my little sister unexpectedly died. Though she was not one of the nearly 7 million people who died of the virus, in 2021 she became another type of statistic: one of the 109,699 people in the United State who died from a drug overdose. Hers was from fentanyl laced with methamphetamines.

Her death unraveled me. I felt deep guilt that I could not pull her from the sweeping current that had wrenched her from mainstream society into the underbelly of sex work and toward the solace of mind-altering drugs.

But I did not feel the right to grieve for her as I have grieved for other loved ones who were not blamed for their exit from this world. My sister was living a sordid life on the fringes of society. My grief felt invalid, undeserved. Yet, in the eyes of other “upstanding citizens,” her life was not as worth grieving – or so I thought. I tucked my sorrow into a small corner of my soul so no one would see, and I carried on.

To this day, the shame I feel robbed me of the ability to freely talk about her or share the searing pain I feel. Tears still prick my eyes when I think of her, but I have become adept at swallowing them, shaking off the waves of grief as though nothing happened. Even now, I cannot shake the pervasive feeling that my silent tears don’t deserve to be wept.
 

Don S. Dizon, MD: Working through tragedy

As a medical student, I worked with an outpatient physician as part of a third-year rotation. When we met, the first thing that struck me was how disheveled he looked. His clothes were wrinkled, and his pants were baggy. He took cigarette breaks, which I found disturbing.

But I quickly came to admire him. Despite my first impression, he was the type of doctor I aspired to be. He didn’t need to look at a patient’s chart to recall who they were. He just knew them. He greeted patients warmly, asked about their family. He even remembered the special occasions his patients had mentioned since their past visit. He epitomized empathy and connectedness.

Spending one day in clinic brought to light the challenges of forming such bonds with patients. A man came into the cancer clinic reporting chest pain and was triaged to an exam room. Soon after, the patient was found unresponsive on the floor. Nurses were yelling for help, and the doctor ran in and started CPR while minutes ticked by waiting for an ambulance that could take him to the ED.

By the time help arrived, the patient was blue.

He had died in the clinic in the middle of the day, as the waiting room filled. After the body was taken away, the doctor went into the bathroom. About 20 minutes later, he came out, eyes bloodshot, and continued with the rest of his day, ensuring each patient was seen and cared for.

As a medical student, it hit me how hard it must be to see something so tragic like the end of a life and then continue with your day as if nothing had happened. This is an experience of grief I later came to know well after nearly 30 years treating patients with advanced cancers: compartmentalizing it and carrying on.
 

A space for grieving: The Schwartz Center Rounds

Disenfranchised grief, the grief that is hard to share and often seems wrong to feel in the first place, can be triggered in many situations. Losing a person others don’t believe deserve to be grieved, such as an abusive partner or someone who committed a crime; losing someone you cared for in a professional role; a loss experienced in a breakup or same-sex partnership, if that relationship was not accepted by one’s family; loss from infertility, miscarriage, stillbirth, or failed adoption; loss that may be taboo or stigmatized, such as deaths via suicide or abortion; and loss of a job, home, or possession that you treasure.

Many of us have had similar situations or will, and the feeling that no one understands the need to mourn can be paralyzing and alienating. In the early days, intense, crushing feelings can cause intrusive, distracting thoughts, and over time, that grief can linger and find a permanent place in our minds.

More and more, though, we are being given opportunities to reflect on these sad moments.

The Schwartz Rounds are an example of such an opportunity. In these rounds, we gather to talk about the experience of caring for people, not the science of medicine.

During one particularly powerful rounds, I spoke to my colleagues about my initial meeting with a patient who was very sick. I detailed the experience of telling her children and her at that initial consult how I thought she was dying and that I did not recommend therapy. I remember how they cried. And I remembered how powerless I felt.

As I recalled that memory during Schwartz Rounds, I could not stop from crying. The unfairness of being a physician meeting someone for the first time and having to tell them such bad news overwhelmed me.

Even more poignant, I had the chance to reconnect with this woman’s children, who were present that day, not as audience members but as participants. Their presence may have brought my emotions to the surface more strongly. In that moment, I could show them the feelings I had bottled up for the sake of professionalism. Ultimately, I felt relieved, freer somehow, as if this burden my soul was carrying had been lifted.

Although we are both grateful for forums like this, these opportunities to share and express the grief we may have hidden away are not as common as they should be.

As physicians, we may express grief by shedding tears at the bedside of a patient nearing the end of life or through the anxiety we feel when our patient suffers a severe reaction to treatment. But we tend to put it away, to go on with our day, because there are others to be seen and cared for and more work to be done. Somehow, we move forward, shedding tears in one room and celebrating victories in another.

We need to create more spaces to express and feel grief, so we don’t get lost in it. Because understanding how grief impacts us, as people and as providers, is one of the most important realizations we can make as we go about our time-honored profession as healers.

Dr. Dizon is the director of women’s cancers at Lifespan Cancer Institute, director of medical oncology at Rhode Island Hospital, and a professor of medicine at Brown University, all in Providence. He reported conflicts of interest with Regeneron, AstraZeneca, Clovis, Bristol-Myers Squibb, and Kazia.

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

What happens to grief when those around you don’t understand it? Where does it go? How do you process it?

Disenfranchised grief, when someone or society more generally doesn’t see a loss as worthy of mourning, can deprive people of experiencing or processing their sadness. This grief, which may be triggered by the death of an ex-spouse, a pet, a failed adoption, can be painful and long-lasting.

Here, we reflect as physicians on our own experiences and memories of this phenomenon.
 

Suzanne Cole, MD: ‘I didn’t feel the right to grieve’

During the COVID-19 pandemic, my little sister unexpectedly died. Though she was not one of the nearly 7 million people who died of the virus, in 2021 she became another type of statistic: one of the 109,699 people in the United State who died from a drug overdose. Hers was from fentanyl laced with methamphetamines.

Her death unraveled me. I felt deep guilt that I could not pull her from the sweeping current that had wrenched her from mainstream society into the underbelly of sex work and toward the solace of mind-altering drugs.

But I did not feel the right to grieve for her as I have grieved for other loved ones who were not blamed for their exit from this world. My sister was living a sordid life on the fringes of society. My grief felt invalid, undeserved. Yet, in the eyes of other “upstanding citizens,” her life was not as worth grieving – or so I thought. I tucked my sorrow into a small corner of my soul so no one would see, and I carried on.

To this day, the shame I feel robbed me of the ability to freely talk about her or share the searing pain I feel. Tears still prick my eyes when I think of her, but I have become adept at swallowing them, shaking off the waves of grief as though nothing happened. Even now, I cannot shake the pervasive feeling that my silent tears don’t deserve to be wept.
 

Don S. Dizon, MD: Working through tragedy

As a medical student, I worked with an outpatient physician as part of a third-year rotation. When we met, the first thing that struck me was how disheveled he looked. His clothes were wrinkled, and his pants were baggy. He took cigarette breaks, which I found disturbing.

But I quickly came to admire him. Despite my first impression, he was the type of doctor I aspired to be. He didn’t need to look at a patient’s chart to recall who they were. He just knew them. He greeted patients warmly, asked about their family. He even remembered the special occasions his patients had mentioned since their past visit. He epitomized empathy and connectedness.

Spending one day in clinic brought to light the challenges of forming such bonds with patients. A man came into the cancer clinic reporting chest pain and was triaged to an exam room. Soon after, the patient was found unresponsive on the floor. Nurses were yelling for help, and the doctor ran in and started CPR while minutes ticked by waiting for an ambulance that could take him to the ED.

By the time help arrived, the patient was blue.

He had died in the clinic in the middle of the day, as the waiting room filled. After the body was taken away, the doctor went into the bathroom. About 20 minutes later, he came out, eyes bloodshot, and continued with the rest of his day, ensuring each patient was seen and cared for.

As a medical student, it hit me how hard it must be to see something so tragic like the end of a life and then continue with your day as if nothing had happened. This is an experience of grief I later came to know well after nearly 30 years treating patients with advanced cancers: compartmentalizing it and carrying on.
 

A space for grieving: The Schwartz Center Rounds

Disenfranchised grief, the grief that is hard to share and often seems wrong to feel in the first place, can be triggered in many situations. Losing a person others don’t believe deserve to be grieved, such as an abusive partner or someone who committed a crime; losing someone you cared for in a professional role; a loss experienced in a breakup or same-sex partnership, if that relationship was not accepted by one’s family; loss from infertility, miscarriage, stillbirth, or failed adoption; loss that may be taboo or stigmatized, such as deaths via suicide or abortion; and loss of a job, home, or possession that you treasure.

Many of us have had similar situations or will, and the feeling that no one understands the need to mourn can be paralyzing and alienating. In the early days, intense, crushing feelings can cause intrusive, distracting thoughts, and over time, that grief can linger and find a permanent place in our minds.

More and more, though, we are being given opportunities to reflect on these sad moments.

The Schwartz Rounds are an example of such an opportunity. In these rounds, we gather to talk about the experience of caring for people, not the science of medicine.

During one particularly powerful rounds, I spoke to my colleagues about my initial meeting with a patient who was very sick. I detailed the experience of telling her children and her at that initial consult how I thought she was dying and that I did not recommend therapy. I remember how they cried. And I remembered how powerless I felt.

As I recalled that memory during Schwartz Rounds, I could not stop from crying. The unfairness of being a physician meeting someone for the first time and having to tell them such bad news overwhelmed me.

Even more poignant, I had the chance to reconnect with this woman’s children, who were present that day, not as audience members but as participants. Their presence may have brought my emotions to the surface more strongly. In that moment, I could show them the feelings I had bottled up for the sake of professionalism. Ultimately, I felt relieved, freer somehow, as if this burden my soul was carrying had been lifted.

Although we are both grateful for forums like this, these opportunities to share and express the grief we may have hidden away are not as common as they should be.

As physicians, we may express grief by shedding tears at the bedside of a patient nearing the end of life or through the anxiety we feel when our patient suffers a severe reaction to treatment. But we tend to put it away, to go on with our day, because there are others to be seen and cared for and more work to be done. Somehow, we move forward, shedding tears in one room and celebrating victories in another.

We need to create more spaces to express and feel grief, so we don’t get lost in it. Because understanding how grief impacts us, as people and as providers, is one of the most important realizations we can make as we go about our time-honored profession as healers.

Dr. Dizon is the director of women’s cancers at Lifespan Cancer Institute, director of medical oncology at Rhode Island Hospital, and a professor of medicine at Brown University, all in Providence. He reported conflicts of interest with Regeneron, AstraZeneca, Clovis, Bristol-Myers Squibb, and Kazia.

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

What happens to grief when those around you don’t understand it? Where does it go? How do you process it?

Disenfranchised grief, when someone or society more generally doesn’t see a loss as worthy of mourning, can deprive people of experiencing or processing their sadness. This grief, which may be triggered by the death of an ex-spouse, a pet, a failed adoption, can be painful and long-lasting.

Here, we reflect as physicians on our own experiences and memories of this phenomenon.
 

Suzanne Cole, MD: ‘I didn’t feel the right to grieve’

During the COVID-19 pandemic, my little sister unexpectedly died. Though she was not one of the nearly 7 million people who died of the virus, in 2021 she became another type of statistic: one of the 109,699 people in the United State who died from a drug overdose. Hers was from fentanyl laced with methamphetamines.

Her death unraveled me. I felt deep guilt that I could not pull her from the sweeping current that had wrenched her from mainstream society into the underbelly of sex work and toward the solace of mind-altering drugs.

But I did not feel the right to grieve for her as I have grieved for other loved ones who were not blamed for their exit from this world. My sister was living a sordid life on the fringes of society. My grief felt invalid, undeserved. Yet, in the eyes of other “upstanding citizens,” her life was not as worth grieving – or so I thought. I tucked my sorrow into a small corner of my soul so no one would see, and I carried on.

To this day, the shame I feel robbed me of the ability to freely talk about her or share the searing pain I feel. Tears still prick my eyes when I think of her, but I have become adept at swallowing them, shaking off the waves of grief as though nothing happened. Even now, I cannot shake the pervasive feeling that my silent tears don’t deserve to be wept.
 

Don S. Dizon, MD: Working through tragedy

As a medical student, I worked with an outpatient physician as part of a third-year rotation. When we met, the first thing that struck me was how disheveled he looked. His clothes were wrinkled, and his pants were baggy. He took cigarette breaks, which I found disturbing.

But I quickly came to admire him. Despite my first impression, he was the type of doctor I aspired to be. He didn’t need to look at a patient’s chart to recall who they were. He just knew them. He greeted patients warmly, asked about their family. He even remembered the special occasions his patients had mentioned since their past visit. He epitomized empathy and connectedness.

Spending one day in clinic brought to light the challenges of forming such bonds with patients. A man came into the cancer clinic reporting chest pain and was triaged to an exam room. Soon after, the patient was found unresponsive on the floor. Nurses were yelling for help, and the doctor ran in and started CPR while minutes ticked by waiting for an ambulance that could take him to the ED.

By the time help arrived, the patient was blue.

He had died in the clinic in the middle of the day, as the waiting room filled. After the body was taken away, the doctor went into the bathroom. About 20 minutes later, he came out, eyes bloodshot, and continued with the rest of his day, ensuring each patient was seen and cared for.

As a medical student, it hit me how hard it must be to see something so tragic like the end of a life and then continue with your day as if nothing had happened. This is an experience of grief I later came to know well after nearly 30 years treating patients with advanced cancers: compartmentalizing it and carrying on.
 

A space for grieving: The Schwartz Center Rounds

Disenfranchised grief, the grief that is hard to share and often seems wrong to feel in the first place, can be triggered in many situations. Losing a person others don’t believe deserve to be grieved, such as an abusive partner or someone who committed a crime; losing someone you cared for in a professional role; a loss experienced in a breakup or same-sex partnership, if that relationship was not accepted by one’s family; loss from infertility, miscarriage, stillbirth, or failed adoption; loss that may be taboo or stigmatized, such as deaths via suicide or abortion; and loss of a job, home, or possession that you treasure.

Many of us have had similar situations or will, and the feeling that no one understands the need to mourn can be paralyzing and alienating. In the early days, intense, crushing feelings can cause intrusive, distracting thoughts, and over time, that grief can linger and find a permanent place in our minds.

More and more, though, we are being given opportunities to reflect on these sad moments.

The Schwartz Rounds are an example of such an opportunity. In these rounds, we gather to talk about the experience of caring for people, not the science of medicine.

During one particularly powerful rounds, I spoke to my colleagues about my initial meeting with a patient who was very sick. I detailed the experience of telling her children and her at that initial consult how I thought she was dying and that I did not recommend therapy. I remember how they cried. And I remembered how powerless I felt.

As I recalled that memory during Schwartz Rounds, I could not stop from crying. The unfairness of being a physician meeting someone for the first time and having to tell them such bad news overwhelmed me.

Even more poignant, I had the chance to reconnect with this woman’s children, who were present that day, not as audience members but as participants. Their presence may have brought my emotions to the surface more strongly. In that moment, I could show them the feelings I had bottled up for the sake of professionalism. Ultimately, I felt relieved, freer somehow, as if this burden my soul was carrying had been lifted.

Although we are both grateful for forums like this, these opportunities to share and express the grief we may have hidden away are not as common as they should be.

As physicians, we may express grief by shedding tears at the bedside of a patient nearing the end of life or through the anxiety we feel when our patient suffers a severe reaction to treatment. But we tend to put it away, to go on with our day, because there are others to be seen and cared for and more work to be done. Somehow, we move forward, shedding tears in one room and celebrating victories in another.

We need to create more spaces to express and feel grief, so we don’t get lost in it. Because understanding how grief impacts us, as people and as providers, is one of the most important realizations we can make as we go about our time-honored profession as healers.

Dr. Dizon is the director of women’s cancers at Lifespan Cancer Institute, director of medical oncology at Rhode Island Hospital, and a professor of medicine at Brown University, all in Providence. He reported conflicts of interest with Regeneron, AstraZeneca, Clovis, Bristol-Myers Squibb, and Kazia.

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

THE CASE

A 24-year-old woman with a history of type 1 diabetes, seizure disorder, and migraines presented to a rural Federally Qualified Health Center (FQHC) with progressive and severe symmetric large joint arthralgias of several weeks’ duration. The patient’s existing medications included etonogestrel 68 mg subdermal implant, levetiracetam 1500 mg bid, insulin glargine 26 units subcutaneously nightly, and insulin lispro 20 units subcutaneously tid (before meals).

An examination revealed symmetrically edematous elbows, wrists, and fingers. Subsequent serologic analyses and a telemedicine consultation with a rheumatologist confirmed a diagnosis of rheumatoid arthritis (RA). The patient’s lab work was positive for antinuclear antibody titers (1:40), rheumatoid factor (513 IU/mL), and anticyclic citrullinated peptide antibodies (248 units/mL). Treatment was started with prednisone 60 mg PO daily, methotrexate 20 mg PO weekly, and hydroxychloroquine 400 mg PO daily. (The benefits of prednisone in treating this patient’s severe arthralgias outweighed concerns over its use in a patient with diabetes.)

After 2 months of receiving RA therapy, the patient underwent further work-up to assess its effectiveness. Liver function testing was performed, and she tested positive for hepatitis C virus (HCV) antibodies. Viral polymerase chain reaction confirmed active HCV infection. Lab work revealed a viral load of 15,000,000 IU/mL; transaminase, 173 U/L (normal range, 4-36 U/L); and aspartate aminotransferase, 246 U/L (normal range, 8-33 U/L). A liver sonogram demonstrated no findings of cirrhosis or fibrosis.

Upon receiving a diagnosis of active hepatitis C, the patient acknowledged that she’d had unprotected heterosexual intercourse and shared used insulin syringes with friends.

THE DIAGNOSIS

Consideration was given to a diagnosis of HCV arthropathy, which can present as an RA-like arthritis in HCV-infected individuals, in the differential diagnosis.¹ A cohort study found HCV-associated arthropathy occurred in 6.8% of those with chronic HCV infection.²

However, the symmetrical involvement of shoulders and knees as the patient’s primary arthralgias, and a rheumatologic work-up showing the presence of anticyclic citrullinated peptide antibody levels, confirmed the diagnosis of RA with coexisting HCV.

DISCUSSION

Delivering interdisciplinary care in a rural area

Although evidence-based guidelines and online HCV Treatment Path programs guided the initial evaluation of potential treatments for this patient, her multiple comorbidities prompted us to seek out additional, interdisciplinary advice through a resource for underserved communities called Project Extension for Community Healthcare Outcomes (ECHO; see “What is Project ECHO?^3,4”). The patient’s case was presented virtually, without identifying information, to a multidisciplinary HCV team. Two treatment options were suggested:

• sofosbuvir/velpatasvir (400 mg/100 mg) for 12 weeks or
• glecaprevir/pibrentasvir (100 mg/40 mg) for 8 weeks.

Both are evidence-based and recommended treatment options according to the HCV treatment guidelines issued jointly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.⁵

In most patients with HCV, treatment is guided by a number of factors, including pill burden, access to care, duration of therapy, drug interactions, and patient-specific needs. After analyzing all aspects of this patient’s case, 2 major concerns guided our shared decision-making process on treatment.

The best treatment is what works for the patient

Owing to the patient’s multiple comorbidities and prescribed medications for chronic diseases, concerns about possible medication interactions with the HCV treatment options were a factor in her HCV treatment plan. Additionally, the patient had significant social determinants of health barriers that made continued treatment and follow-up challenging.

The potential interaction of HCV infection treatment with the patient’s current methotrexate therapy for her RA was a primary concern. To determine the risk for interactions, the team used the University of Liverpool HEP/HIV Drug Interactions Checker, which helps identify possible interactions with these disease-specific medication therapies.⁶

Both sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir have a potential interaction with methotrexate and are driven by a similar mechanism. Methotrexate is a substrate of the Breast Cancer Resistance Protein efflux transporter (BCRP), and the components of both sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are inhibitors of BCRP.⁷ The inhibition of this efflux transporter can lead to an increased concentration of methotrexate, increasing the risk for methotrexate toxicity.⁷

Since no quantitative data exist regarding the degree of inhibition that these HCV drugs exert on BCRP, the team considered ­sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir to have equal risk with regard to potential for drug interactions.

The patient’s barriers to treatment were another area of concern that directed our therapy decision. The patient had multiple barriers, including poor access to health care because of transportation issues, multiple children requiring care, a variety of chronic diseases, and other life stressors. Shared decision­-making ensured our patient’s autonomy in choosing a specific treatment.

This case shines a light on the multiple challenges that could have come between our patient and proper treatment—but ultimately, did not.

The patient’s social situation and preference narrowed the team’s basis for medication choice primarily down to the duration of therapy: 8 weeks of glecaprevir/pibrentasvir vs 12 weeks of sofosbuvir/velpatasvir. The patient mentioned multiple transportation challenges for follow-up visits to the clinic and therefore wanted to utilize the shorter treatment duration. Follow-up is needed every 4 weeks, so the patient was able to go from 3 to 2 visits.

For problems, there are solutions. Following careful consideration of these patient-specific factors and preferences, the team decided to begin therapy with glecaprevir/pibrentasvir. The patient worked with an outreach specialist at the FQHC to coordinate care and complete paperwork for the Project ECHO consultation. The outreach specialist also assisted the patient in completing paperwork for the Patient Assistance Program for HCV treatment. Because the patient is being cared for at an FQHC, the clinic’s in-house pharmacy was able to utilize the 340B Federal Drug Pricing Program, which makes otherwise out-of-reach medicines affordable for patients such as ours.

Our patient has had no issues with treatment adherence, adverse effects, or follow­-up appointments. The patient’s RA symptoms have improved significantly without any discernable worsening of her HCV infection.

THE TAKEAWAY

This case shines a light on the multiple challenges (clinical, geographic, and financial) that could have come between our patient and proper treatment—but ultimately, did not. The Project ECHO model of care remains a viable way to provide patients who live in rural and underserved communities and who have active HCV and other underlying chronic conditions with interdisciplinary care that can improve health outcomes.

THE CASE

A 24-year-old woman with a history of type 1 diabetes, seizure disorder, and migraines presented to a rural Federally Qualified Health Center (FQHC) with progressive and severe symmetric large joint arthralgias of several weeks’ duration. The patient’s existing medications included etonogestrel 68 mg subdermal implant, levetiracetam 1500 mg bid, insulin glargine 26 units subcutaneously nightly, and insulin lispro 20 units subcutaneously tid (before meals).

An examination revealed symmetrically edematous elbows, wrists, and fingers. Subsequent serologic analyses and a telemedicine consultation with a rheumatologist confirmed a diagnosis of rheumatoid arthritis (RA). The patient’s lab work was positive for antinuclear antibody titers (1:40), rheumatoid factor (513 IU/mL), and anticyclic citrullinated peptide antibodies (248 units/mL). Treatment was started with prednisone 60 mg PO daily, methotrexate 20 mg PO weekly, and hydroxychloroquine 400 mg PO daily. (The benefits of prednisone in treating this patient’s severe arthralgias outweighed concerns over its use in a patient with diabetes.)

After 2 months of receiving RA therapy, the patient underwent further work-up to assess its effectiveness. Liver function testing was performed, and she tested positive for hepatitis C virus (HCV) antibodies. Viral polymerase chain reaction confirmed active HCV infection. Lab work revealed a viral load of 15,000,000 IU/mL; transaminase, 173 U/L (normal range, 4-36 U/L); and aspartate aminotransferase, 246 U/L (normal range, 8-33 U/L). A liver sonogram demonstrated no findings of cirrhosis or fibrosis.

Upon receiving a diagnosis of active hepatitis C, the patient acknowledged that she’d had unprotected heterosexual intercourse and shared used insulin syringes with friends.

THE DIAGNOSIS

Consideration was given to a diagnosis of HCV arthropathy, which can present as an RA-like arthritis in HCV-infected individuals, in the differential diagnosis.¹ A cohort study found HCV-associated arthropathy occurred in 6.8% of those with chronic HCV infection.²

However, the symmetrical involvement of shoulders and knees as the patient’s primary arthralgias, and a rheumatologic work-up showing the presence of anticyclic citrullinated peptide antibody levels, confirmed the diagnosis of RA with coexisting HCV.

DISCUSSION

Delivering interdisciplinary care in a rural area

Although evidence-based guidelines and online HCV Treatment Path programs guided the initial evaluation of potential treatments for this patient, her multiple comorbidities prompted us to seek out additional, interdisciplinary advice through a resource for underserved communities called Project Extension for Community Healthcare Outcomes (ECHO; see “What is Project ECHO?^3,4”). The patient’s case was presented virtually, without identifying information, to a multidisciplinary HCV team. Two treatment options were suggested:

• sofosbuvir/velpatasvir (400 mg/100 mg) for 12 weeks or
• glecaprevir/pibrentasvir (100 mg/40 mg) for 8 weeks.

Both are evidence-based and recommended treatment options according to the HCV treatment guidelines issued jointly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.⁵

In most patients with HCV, treatment is guided by a number of factors, including pill burden, access to care, duration of therapy, drug interactions, and patient-specific needs. After analyzing all aspects of this patient’s case, 2 major concerns guided our shared decision-making process on treatment.

The best treatment is what works for the patient

Owing to the patient’s multiple comorbidities and prescribed medications for chronic diseases, concerns about possible medication interactions with the HCV treatment options were a factor in her HCV treatment plan. Additionally, the patient had significant social determinants of health barriers that made continued treatment and follow-up challenging.

The potential interaction of HCV infection treatment with the patient’s current methotrexate therapy for her RA was a primary concern. To determine the risk for interactions, the team used the University of Liverpool HEP/HIV Drug Interactions Checker, which helps identify possible interactions with these disease-specific medication therapies.⁶

Both sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir have a potential interaction with methotrexate and are driven by a similar mechanism. Methotrexate is a substrate of the Breast Cancer Resistance Protein efflux transporter (BCRP), and the components of both sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are inhibitors of BCRP.⁷ The inhibition of this efflux transporter can lead to an increased concentration of methotrexate, increasing the risk for methotrexate toxicity.⁷

Since no quantitative data exist regarding the degree of inhibition that these HCV drugs exert on BCRP, the team considered ­sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir to have equal risk with regard to potential for drug interactions.

The patient’s barriers to treatment were another area of concern that directed our therapy decision. The patient had multiple barriers, including poor access to health care because of transportation issues, multiple children requiring care, a variety of chronic diseases, and other life stressors. Shared decision­-making ensured our patient’s autonomy in choosing a specific treatment.

This case shines a light on the multiple challenges that could have come between our patient and proper treatment—but ultimately, did not.

The patient’s social situation and preference narrowed the team’s basis for medication choice primarily down to the duration of therapy: 8 weeks of glecaprevir/pibrentasvir vs 12 weeks of sofosbuvir/velpatasvir. The patient mentioned multiple transportation challenges for follow-up visits to the clinic and therefore wanted to utilize the shorter treatment duration. Follow-up is needed every 4 weeks, so the patient was able to go from 3 to 2 visits.

For problems, there are solutions. Following careful consideration of these patient-specific factors and preferences, the team decided to begin therapy with glecaprevir/pibrentasvir. The patient worked with an outreach specialist at the FQHC to coordinate care and complete paperwork for the Project ECHO consultation. The outreach specialist also assisted the patient in completing paperwork for the Patient Assistance Program for HCV treatment. Because the patient is being cared for at an FQHC, the clinic’s in-house pharmacy was able to utilize the 340B Federal Drug Pricing Program, which makes otherwise out-of-reach medicines affordable for patients such as ours.

Our patient has had no issues with treatment adherence, adverse effects, or follow­-up appointments. The patient’s RA symptoms have improved significantly without any discernable worsening of her HCV infection.

THE TAKEAWAY

This case shines a light on the multiple challenges (clinical, geographic, and financial) that could have come between our patient and proper treatment—but ultimately, did not. The Project ECHO model of care remains a viable way to provide patients who live in rural and underserved communities and who have active HCV and other underlying chronic conditions with interdisciplinary care that can improve health outcomes.

THE CASE

A 24-year-old woman with a history of type 1 diabetes, seizure disorder, and migraines presented to a rural Federally Qualified Health Center (FQHC) with progressive and severe symmetric large joint arthralgias of several weeks’ duration. The patient’s existing medications included etonogestrel 68 mg subdermal implant, levetiracetam 1500 mg bid, insulin glargine 26 units subcutaneously nightly, and insulin lispro 20 units subcutaneously tid (before meals).

An examination revealed symmetrically edematous elbows, wrists, and fingers. Subsequent serologic analyses and a telemedicine consultation with a rheumatologist confirmed a diagnosis of rheumatoid arthritis (RA). The patient’s lab work was positive for antinuclear antibody titers (1:40), rheumatoid factor (513 IU/mL), and anticyclic citrullinated peptide antibodies (248 units/mL). Treatment was started with prednisone 60 mg PO daily, methotrexate 20 mg PO weekly, and hydroxychloroquine 400 mg PO daily. (The benefits of prednisone in treating this patient’s severe arthralgias outweighed concerns over its use in a patient with diabetes.)

After 2 months of receiving RA therapy, the patient underwent further work-up to assess its effectiveness. Liver function testing was performed, and she tested positive for hepatitis C virus (HCV) antibodies. Viral polymerase chain reaction confirmed active HCV infection. Lab work revealed a viral load of 15,000,000 IU/mL; transaminase, 173 U/L (normal range, 4-36 U/L); and aspartate aminotransferase, 246 U/L (normal range, 8-33 U/L). A liver sonogram demonstrated no findings of cirrhosis or fibrosis.

Upon receiving a diagnosis of active hepatitis C, the patient acknowledged that she’d had unprotected heterosexual intercourse and shared used insulin syringes with friends.

THE DIAGNOSIS

Consideration was given to a diagnosis of HCV arthropathy, which can present as an RA-like arthritis in HCV-infected individuals, in the differential diagnosis.¹ A cohort study found HCV-associated arthropathy occurred in 6.8% of those with chronic HCV infection.²

However, the symmetrical involvement of shoulders and knees as the patient’s primary arthralgias, and a rheumatologic work-up showing the presence of anticyclic citrullinated peptide antibody levels, confirmed the diagnosis of RA with coexisting HCV.

DISCUSSION

Delivering interdisciplinary care in a rural area

Although evidence-based guidelines and online HCV Treatment Path programs guided the initial evaluation of potential treatments for this patient, her multiple comorbidities prompted us to seek out additional, interdisciplinary advice through a resource for underserved communities called Project Extension for Community Healthcare Outcomes (ECHO; see “What is Project ECHO?^3,4”). The patient’s case was presented virtually, without identifying information, to a multidisciplinary HCV team. Two treatment options were suggested:

• sofosbuvir/velpatasvir (400 mg/100 mg) for 12 weeks or
• glecaprevir/pibrentasvir (100 mg/40 mg) for 8 weeks.

Both are evidence-based and recommended treatment options according to the HCV treatment guidelines issued jointly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.⁵

In most patients with HCV, treatment is guided by a number of factors, including pill burden, access to care, duration of therapy, drug interactions, and patient-specific needs. After analyzing all aspects of this patient’s case, 2 major concerns guided our shared decision-making process on treatment.

The best treatment is what works for the patient

Owing to the patient’s multiple comorbidities and prescribed medications for chronic diseases, concerns about possible medication interactions with the HCV treatment options were a factor in her HCV treatment plan. Additionally, the patient had significant social determinants of health barriers that made continued treatment and follow-up challenging.

The potential interaction of HCV infection treatment with the patient’s current methotrexate therapy for her RA was a primary concern. To determine the risk for interactions, the team used the University of Liverpool HEP/HIV Drug Interactions Checker, which helps identify possible interactions with these disease-specific medication therapies.⁶

Both sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir have a potential interaction with methotrexate and are driven by a similar mechanism. Methotrexate is a substrate of the Breast Cancer Resistance Protein efflux transporter (BCRP), and the components of both sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are inhibitors of BCRP.⁷ The inhibition of this efflux transporter can lead to an increased concentration of methotrexate, increasing the risk for methotrexate toxicity.⁷

Since no quantitative data exist regarding the degree of inhibition that these HCV drugs exert on BCRP, the team considered ­sofosbuvir/velpatasvir and glecaprevir/­pibrentasvir to have equal risk with regard to potential for drug interactions.

The patient’s barriers to treatment were another area of concern that directed our therapy decision. The patient had multiple barriers, including poor access to health care because of transportation issues, multiple children requiring care, a variety of chronic diseases, and other life stressors. Shared decision­-making ensured our patient’s autonomy in choosing a specific treatment.

This case shines a light on the multiple challenges that could have come between our patient and proper treatment—but ultimately, did not.

The patient’s social situation and preference narrowed the team’s basis for medication choice primarily down to the duration of therapy: 8 weeks of glecaprevir/pibrentasvir vs 12 weeks of sofosbuvir/velpatasvir. The patient mentioned multiple transportation challenges for follow-up visits to the clinic and therefore wanted to utilize the shorter treatment duration. Follow-up is needed every 4 weeks, so the patient was able to go from 3 to 2 visits.

For problems, there are solutions. Following careful consideration of these patient-specific factors and preferences, the team decided to begin therapy with glecaprevir/pibrentasvir. The patient worked with an outreach specialist at the FQHC to coordinate care and complete paperwork for the Project ECHO consultation. The outreach specialist also assisted the patient in completing paperwork for the Patient Assistance Program for HCV treatment. Because the patient is being cared for at an FQHC, the clinic’s in-house pharmacy was able to utilize the 340B Federal Drug Pricing Program, which makes otherwise out-of-reach medicines affordable for patients such as ours.

Our patient has had no issues with treatment adherence, adverse effects, or follow­-up appointments. The patient’s RA symptoms have improved significantly without any discernable worsening of her HCV infection.

THE TAKEAWAY

This case shines a light on the multiple challenges (clinical, geographic, and financial) that could have come between our patient and proper treatment—but ultimately, did not. The Project ECHO model of care remains a viable way to provide patients who live in rural and underserved communities and who have active HCV and other underlying chronic conditions with interdisciplinary care that can improve health outcomes.

THE CASE

A 49-year-old woman was hospitalized with a headache and neck pain that radiated to her ears and eyes in the context of severe hypertension (270/150 mm Hg). Her medical history was significant for heterozygous factor V Leiden mutation, longstanding untreated hypertension, and multiple severe episodes of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome during pregnancy.

After receiving antihypertensive treatment at a community hospital, her blood pressure gradually improved to 160/100 mm Hg with the addition of a third medication. However, on Day 3 of her stay, her systolic blood pressure rose to more than 200 mm Hg and was accompanied by somnolence, emesis, and paleness. She was transferred to a tertiary care center.

THE DIAGNOSIS

On admission, the patient had left-side hemiparesis and facial droop with dysarthria, resulting in a National Institutes of Health Stroke Scale (NIHSS) score of 7 (out of 42) and a Glasgow Coma Scale (GCS) score of 13 (out of 15). Noncontrast computed tomography (CT) and CT angiography of the head and neck were ordered and showed occlusion of both intracranial vertebral arteries. There were also signs of multifocal infarction in her occipital lobes, thus systemic recombinant human-tissue plasminogen activator (tPA) could not be administered.

The patient was next taken to the angiography suite, where a digital subtraction angiography confirmed the presence of bilateral vertebral artery occlusions (FIGURE 1A). A thrombectomy was performed to open the left occluded segment, resulting in recanalization; however, a high-grade stenosis remained in the intracranial left vertebral artery (FIGURE 1B). The right vertebral artery had a severe extracranial origin stenosis, and balloon angioplasty was performed in order to reach the intracranial circulation; however, the occlusion of the intracranial right vertebral artery segment could not be catheterized. Subsequent magnetic resonance imaging (MRI) with a time-of-flight magnetic resonance angiography showed that the intracranial left vertebral artery with high-grade stenosis had closed down again; thus, there was occlusion of both intracranial vertebral arteries and absent flow signal in the basilar artery (FIGURE 2). There were scattered small acute strokes within the cerebellum, brainstem, and occipital lobes.

Unfortunately, within 48 hours, the patient’s NIHSS score increased from 7 to 29. She developed tetraplegia, was significantly less responsive (GCS score, 3/15), and required intubation and mechanical ventilation. Reopening the stenosis and keeping it open with a stent would be an aggressive procedure with poor odds for success and would require antithrombotic medications with the associated risk for intracranial hemorrhage in the setting of demarcated strokes. Thus, no further intervention was pursued.

Further standard stroke work-up (echocardiography, extracranial ultrasound of the cerebral circulation, and vasculitis screening) was unremarkable. In the intensive care unit, intravenous therapeutic heparin was initiated because of the potential prothrombotic effect of the factor V Leiden mutation but was subsequently switched to dual anti-­aggregation therapy (aspirin 100 mg/d and clopidogrel 75 mg/d) as secondary stroke prevention given the final diagnosis of severe atherosclerosis. Nevertheless, the patient remained tetraplegic with a partial locked-in syndrome when she was discharged, after 2 weeks in the tertiary care center, to a rehabilitation center.

DISCUSSION

Posterior circulation strokes account for 20% to 25% of all ischemic strokes^1,2 and are associated with infarction within the vertebrobasilar arterial system. Common etiologies of these infarctions include atherosclerosis (as seen in our patient), embolism, small-artery penetrating disease, and arterial dissection.² Although the estimated overall mortality of these strokes is low (3.6% to 11%),² basilar occlusion syndrome, in particular, is a life-threatening condition with a high mortality rate of 80% to 90%.³

Continue to: Diagnosis can be particularly challenging...

Diagnosis can be particularly challenging due to the anatomic variations of posterior arterial circulation, as well as the fluctuating nonfocal or multifocal symptoms.² Specific symptoms include vertigo, ataxia, unilateral motor weakness, dysarthria, and oculomotor dysfunction. However, nonspecific symptoms such as headache, nausea, dizziness, hoarseness, falls, and Horner syndrome may be the only presenting signs of a posterior circulation stroke—as was the case with our patient.² Her radiating neck pain could have been interpreted as a pointer to vertebral artery dissection within the context of severe hypertension.⁴ Unfortunately, the diagnosis was delayed and head imaging was obtained only after her mental status deteriorated.

Immediate neuroimaging is necessary to guide treatment in patients with suspected acute posterior circulation stroke,^1,5,6 although it is not always definitive. While CT is pivotal in stroke work-up and may reliably exclude intracranial hemorrhage, its ability to detect acute posterior circulation ischemic strokes is limited given its poor visualization of the posterior fossa (as low as 16% sensitivity).⁵ Fortunately, CT angiography has a high sensitivity (nearing 100%) for large-vessel occlusion and high predictive values for dissection (65%-100% positive predictive value and 70%-98% negative predictive value).^5,7 ­Diffusion-weighted MRI (when available in the emergency setting) has the highest sensitivity for detecting acute infarcts, although posterior circulation infarcts still can be missed (19% false-negative rate).^5,8 Thus, correlative vessel imaging with magnetic resonance or CT angiography is very important, along with a high index of suspicion. In some instances, repeat MRI may be necessary to detect small strokes.

A patient-specific approach to management is key for individuals with suspected posterior circulation stroke.⁵ Because specific data for the appropriate management of posterior circulation ischemic stroke are lacking, current American Heart ­Association/American Stroke Association (AHA/ASA) guidelines apply to anterior and ­posterior circulation strokes.⁶ For eligible ­patients without multifocal disease, intravenous tPA is the first-line therapy and should be initiated according to guidelines within 4.5 hours of stroke onset⁹; it is important to note that these guidelines are based on studies that ­focused more on anterior circulation strokes than posterior circulation strokes.^6,9-13 This can be done in combination with ­endovascular therapy, which consists of ­mechanical thrombectomy, intra-arterial thrombolysis, or a combination of revascularization ­techniques.^3,5,6

Nonspecific symptoms such as headache, nausea, and dizziness may be the only presenting signs of a posterior circulation stroke.

Mechanical thrombectomy specifically has high proven recanalization rates for all target vessels.^3-6 The latest AHA/ASA guidelines recommend mechanical thrombectomy be performed within 6 hours of stroke onset.⁶ However, there is emerging evidence that suggests this timeframe should be ­extended—even beyond 24 hours—given the poor prognosis of posterior circulation strokes.^5,6,14 More data on the management of posterior circulation strokes are urgently needed to better understand which therapeutic approach is most efficient.

In patients such as ours, who have evidence of multifocal disease, treatment may be limited to endovascular therapy. Intracranial stenting of symptomatic lesions in particular has been controversial since the publication of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis trial, which found that aggressive medical management was superior to stenting in patients who recently had a transient ischemic attack or stroke attributed to stenosis.¹⁵ Although additional studies have been performed, there are no definitive data on the topic—and certainly no data in the emergency setting.¹⁶ Further challenges are raised in patients with bilateral disease, as was the case with this patient.

When our patient was admitted to the rehabilitation clinic, she had a GCS score of 10 to 11/15. After 9 months of rehabilitation, she was discharged home with a GCS score of 15/15 and persistent left-side hemiparesis.

THE TAKEAWAY

Posterior circulation stroke is a life-­threatening disease that may manifest with a variety of symptoms and be difficult to identify on emergent imaging. Thus, a high degree of clinical suspicion and additional follow-up are paramount to ensure prompt diagnosis and a patient-tailored treatment strategy.

CORRESPONDENCE
Kristine A. Blackham, MD, Associate Professor, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; kristine.blackham@gmail.com Orcid no: 0000-0002-1620-1144 (Dr. Blackham); 0000-0002- 5225-5414 (Dr. Saleh)

THE CASE

A 49-year-old woman was hospitalized with a headache and neck pain that radiated to her ears and eyes in the context of severe hypertension (270/150 mm Hg). Her medical history was significant for heterozygous factor V Leiden mutation, longstanding untreated hypertension, and multiple severe episodes of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome during pregnancy.

After receiving antihypertensive treatment at a community hospital, her blood pressure gradually improved to 160/100 mm Hg with the addition of a third medication. However, on Day 3 of her stay, her systolic blood pressure rose to more than 200 mm Hg and was accompanied by somnolence, emesis, and paleness. She was transferred to a tertiary care center.

THE DIAGNOSIS

On admission, the patient had left-side hemiparesis and facial droop with dysarthria, resulting in a National Institutes of Health Stroke Scale (NIHSS) score of 7 (out of 42) and a Glasgow Coma Scale (GCS) score of 13 (out of 15). Noncontrast computed tomography (CT) and CT angiography of the head and neck were ordered and showed occlusion of both intracranial vertebral arteries. There were also signs of multifocal infarction in her occipital lobes, thus systemic recombinant human-tissue plasminogen activator (tPA) could not be administered.

The patient was next taken to the angiography suite, where a digital subtraction angiography confirmed the presence of bilateral vertebral artery occlusions (FIGURE 1A). A thrombectomy was performed to open the left occluded segment, resulting in recanalization; however, a high-grade stenosis remained in the intracranial left vertebral artery (FIGURE 1B). The right vertebral artery had a severe extracranial origin stenosis, and balloon angioplasty was performed in order to reach the intracranial circulation; however, the occlusion of the intracranial right vertebral artery segment could not be catheterized. Subsequent magnetic resonance imaging (MRI) with a time-of-flight magnetic resonance angiography showed that the intracranial left vertebral artery with high-grade stenosis had closed down again; thus, there was occlusion of both intracranial vertebral arteries and absent flow signal in the basilar artery (FIGURE 2). There were scattered small acute strokes within the cerebellum, brainstem, and occipital lobes.

Unfortunately, within 48 hours, the patient’s NIHSS score increased from 7 to 29. She developed tetraplegia, was significantly less responsive (GCS score, 3/15), and required intubation and mechanical ventilation. Reopening the stenosis and keeping it open with a stent would be an aggressive procedure with poor odds for success and would require antithrombotic medications with the associated risk for intracranial hemorrhage in the setting of demarcated strokes. Thus, no further intervention was pursued.

Further standard stroke work-up (echocardiography, extracranial ultrasound of the cerebral circulation, and vasculitis screening) was unremarkable. In the intensive care unit, intravenous therapeutic heparin was initiated because of the potential prothrombotic effect of the factor V Leiden mutation but was subsequently switched to dual anti-­aggregation therapy (aspirin 100 mg/d and clopidogrel 75 mg/d) as secondary stroke prevention given the final diagnosis of severe atherosclerosis. Nevertheless, the patient remained tetraplegic with a partial locked-in syndrome when she was discharged, after 2 weeks in the tertiary care center, to a rehabilitation center.

DISCUSSION

Posterior circulation strokes account for 20% to 25% of all ischemic strokes^1,2 and are associated with infarction within the vertebrobasilar arterial system. Common etiologies of these infarctions include atherosclerosis (as seen in our patient), embolism, small-artery penetrating disease, and arterial dissection.² Although the estimated overall mortality of these strokes is low (3.6% to 11%),² basilar occlusion syndrome, in particular, is a life-threatening condition with a high mortality rate of 80% to 90%.³

Continue to: Diagnosis can be particularly challenging...

Diagnosis can be particularly challenging due to the anatomic variations of posterior arterial circulation, as well as the fluctuating nonfocal or multifocal symptoms.² Specific symptoms include vertigo, ataxia, unilateral motor weakness, dysarthria, and oculomotor dysfunction. However, nonspecific symptoms such as headache, nausea, dizziness, hoarseness, falls, and Horner syndrome may be the only presenting signs of a posterior circulation stroke—as was the case with our patient.² Her radiating neck pain could have been interpreted as a pointer to vertebral artery dissection within the context of severe hypertension.⁴ Unfortunately, the diagnosis was delayed and head imaging was obtained only after her mental status deteriorated.

Immediate neuroimaging is necessary to guide treatment in patients with suspected acute posterior circulation stroke,^1,5,6 although it is not always definitive. While CT is pivotal in stroke work-up and may reliably exclude intracranial hemorrhage, its ability to detect acute posterior circulation ischemic strokes is limited given its poor visualization of the posterior fossa (as low as 16% sensitivity).⁵ Fortunately, CT angiography has a high sensitivity (nearing 100%) for large-vessel occlusion and high predictive values for dissection (65%-100% positive predictive value and 70%-98% negative predictive value).^5,7 ­Diffusion-weighted MRI (when available in the emergency setting) has the highest sensitivity for detecting acute infarcts, although posterior circulation infarcts still can be missed (19% false-negative rate).^5,8 Thus, correlative vessel imaging with magnetic resonance or CT angiography is very important, along with a high index of suspicion. In some instances, repeat MRI may be necessary to detect small strokes.

A patient-specific approach to management is key for individuals with suspected posterior circulation stroke.⁵ Because specific data for the appropriate management of posterior circulation ischemic stroke are lacking, current American Heart ­Association/American Stroke Association (AHA/ASA) guidelines apply to anterior and ­posterior circulation strokes.⁶ For eligible ­patients without multifocal disease, intravenous tPA is the first-line therapy and should be initiated according to guidelines within 4.5 hours of stroke onset⁹; it is important to note that these guidelines are based on studies that ­focused more on anterior circulation strokes than posterior circulation strokes.^6,9-13 This can be done in combination with ­endovascular therapy, which consists of ­mechanical thrombectomy, intra-arterial thrombolysis, or a combination of revascularization ­techniques.^3,5,6

Nonspecific symptoms such as headache, nausea, and dizziness may be the only presenting signs of a posterior circulation stroke.

Mechanical thrombectomy specifically has high proven recanalization rates for all target vessels.^3-6 The latest AHA/ASA guidelines recommend mechanical thrombectomy be performed within 6 hours of stroke onset.⁶ However, there is emerging evidence that suggests this timeframe should be ­extended—even beyond 24 hours—given the poor prognosis of posterior circulation strokes.^5,6,14 More data on the management of posterior circulation strokes are urgently needed to better understand which therapeutic approach is most efficient.

In patients such as ours, who have evidence of multifocal disease, treatment may be limited to endovascular therapy. Intracranial stenting of symptomatic lesions in particular has been controversial since the publication of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis trial, which found that aggressive medical management was superior to stenting in patients who recently had a transient ischemic attack or stroke attributed to stenosis.¹⁵ Although additional studies have been performed, there are no definitive data on the topic—and certainly no data in the emergency setting.¹⁶ Further challenges are raised in patients with bilateral disease, as was the case with this patient.

When our patient was admitted to the rehabilitation clinic, she had a GCS score of 10 to 11/15. After 9 months of rehabilitation, she was discharged home with a GCS score of 15/15 and persistent left-side hemiparesis.

THE TAKEAWAY

Posterior circulation stroke is a life-­threatening disease that may manifest with a variety of symptoms and be difficult to identify on emergent imaging. Thus, a high degree of clinical suspicion and additional follow-up are paramount to ensure prompt diagnosis and a patient-tailored treatment strategy.

CORRESPONDENCE
Kristine A. Blackham, MD, Associate Professor, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; kristine.blackham@gmail.com Orcid no: 0000-0002-1620-1144 (Dr. Blackham); 0000-0002- 5225-5414 (Dr. Saleh)

THE CASE

A 49-year-old woman was hospitalized with a headache and neck pain that radiated to her ears and eyes in the context of severe hypertension (270/150 mm Hg). Her medical history was significant for heterozygous factor V Leiden mutation, longstanding untreated hypertension, and multiple severe episodes of HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome during pregnancy.

After receiving antihypertensive treatment at a community hospital, her blood pressure gradually improved to 160/100 mm Hg with the addition of a third medication. However, on Day 3 of her stay, her systolic blood pressure rose to more than 200 mm Hg and was accompanied by somnolence, emesis, and paleness. She was transferred to a tertiary care center.

THE DIAGNOSIS

On admission, the patient had left-side hemiparesis and facial droop with dysarthria, resulting in a National Institutes of Health Stroke Scale (NIHSS) score of 7 (out of 42) and a Glasgow Coma Scale (GCS) score of 13 (out of 15). Noncontrast computed tomography (CT) and CT angiography of the head and neck were ordered and showed occlusion of both intracranial vertebral arteries. There were also signs of multifocal infarction in her occipital lobes, thus systemic recombinant human-tissue plasminogen activator (tPA) could not be administered.

The patient was next taken to the angiography suite, where a digital subtraction angiography confirmed the presence of bilateral vertebral artery occlusions (FIGURE 1A). A thrombectomy was performed to open the left occluded segment, resulting in recanalization; however, a high-grade stenosis remained in the intracranial left vertebral artery (FIGURE 1B). The right vertebral artery had a severe extracranial origin stenosis, and balloon angioplasty was performed in order to reach the intracranial circulation; however, the occlusion of the intracranial right vertebral artery segment could not be catheterized. Subsequent magnetic resonance imaging (MRI) with a time-of-flight magnetic resonance angiography showed that the intracranial left vertebral artery with high-grade stenosis had closed down again; thus, there was occlusion of both intracranial vertebral arteries and absent flow signal in the basilar artery (FIGURE 2). There were scattered small acute strokes within the cerebellum, brainstem, and occipital lobes.

Unfortunately, within 48 hours, the patient’s NIHSS score increased from 7 to 29. She developed tetraplegia, was significantly less responsive (GCS score, 3/15), and required intubation and mechanical ventilation. Reopening the stenosis and keeping it open with a stent would be an aggressive procedure with poor odds for success and would require antithrombotic medications with the associated risk for intracranial hemorrhage in the setting of demarcated strokes. Thus, no further intervention was pursued.

Further standard stroke work-up (echocardiography, extracranial ultrasound of the cerebral circulation, and vasculitis screening) was unremarkable. In the intensive care unit, intravenous therapeutic heparin was initiated because of the potential prothrombotic effect of the factor V Leiden mutation but was subsequently switched to dual anti-­aggregation therapy (aspirin 100 mg/d and clopidogrel 75 mg/d) as secondary stroke prevention given the final diagnosis of severe atherosclerosis. Nevertheless, the patient remained tetraplegic with a partial locked-in syndrome when she was discharged, after 2 weeks in the tertiary care center, to a rehabilitation center.

DISCUSSION

Posterior circulation strokes account for 20% to 25% of all ischemic strokes^1,2 and are associated with infarction within the vertebrobasilar arterial system. Common etiologies of these infarctions include atherosclerosis (as seen in our patient), embolism, small-artery penetrating disease, and arterial dissection.² Although the estimated overall mortality of these strokes is low (3.6% to 11%),² basilar occlusion syndrome, in particular, is a life-threatening condition with a high mortality rate of 80% to 90%.³

Continue to: Diagnosis can be particularly challenging...

Diagnosis can be particularly challenging due to the anatomic variations of posterior arterial circulation, as well as the fluctuating nonfocal or multifocal symptoms.² Specific symptoms include vertigo, ataxia, unilateral motor weakness, dysarthria, and oculomotor dysfunction. However, nonspecific symptoms such as headache, nausea, dizziness, hoarseness, falls, and Horner syndrome may be the only presenting signs of a posterior circulation stroke—as was the case with our patient.² Her radiating neck pain could have been interpreted as a pointer to vertebral artery dissection within the context of severe hypertension.⁴ Unfortunately, the diagnosis was delayed and head imaging was obtained only after her mental status deteriorated.

Immediate neuroimaging is necessary to guide treatment in patients with suspected acute posterior circulation stroke,^1,5,6 although it is not always definitive. While CT is pivotal in stroke work-up and may reliably exclude intracranial hemorrhage, its ability to detect acute posterior circulation ischemic strokes is limited given its poor visualization of the posterior fossa (as low as 16% sensitivity).⁵ Fortunately, CT angiography has a high sensitivity (nearing 100%) for large-vessel occlusion and high predictive values for dissection (65%-100% positive predictive value and 70%-98% negative predictive value).^5,7 ­Diffusion-weighted MRI (when available in the emergency setting) has the highest sensitivity for detecting acute infarcts, although posterior circulation infarcts still can be missed (19% false-negative rate).^5,8 Thus, correlative vessel imaging with magnetic resonance or CT angiography is very important, along with a high index of suspicion. In some instances, repeat MRI may be necessary to detect small strokes.

A patient-specific approach to management is key for individuals with suspected posterior circulation stroke.⁵ Because specific data for the appropriate management of posterior circulation ischemic stroke are lacking, current American Heart ­Association/American Stroke Association (AHA/ASA) guidelines apply to anterior and ­posterior circulation strokes.⁶ For eligible ­patients without multifocal disease, intravenous tPA is the first-line therapy and should be initiated according to guidelines within 4.5 hours of stroke onset⁹; it is important to note that these guidelines are based on studies that ­focused more on anterior circulation strokes than posterior circulation strokes.^6,9-13 This can be done in combination with ­endovascular therapy, which consists of ­mechanical thrombectomy, intra-arterial thrombolysis, or a combination of revascularization ­techniques.^3,5,6

Nonspecific symptoms such as headache, nausea, and dizziness may be the only presenting signs of a posterior circulation stroke.

Mechanical thrombectomy specifically has high proven recanalization rates for all target vessels.^3-6 The latest AHA/ASA guidelines recommend mechanical thrombectomy be performed within 6 hours of stroke onset.⁶ However, there is emerging evidence that suggests this timeframe should be ­extended—even beyond 24 hours—given the poor prognosis of posterior circulation strokes.^5,6,14 More data on the management of posterior circulation strokes are urgently needed to better understand which therapeutic approach is most efficient.

In patients such as ours, who have evidence of multifocal disease, treatment may be limited to endovascular therapy. Intracranial stenting of symptomatic lesions in particular has been controversial since the publication of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis trial, which found that aggressive medical management was superior to stenting in patients who recently had a transient ischemic attack or stroke attributed to stenosis.¹⁵ Although additional studies have been performed, there are no definitive data on the topic—and certainly no data in the emergency setting.¹⁶ Further challenges are raised in patients with bilateral disease, as was the case with this patient.

When our patient was admitted to the rehabilitation clinic, she had a GCS score of 10 to 11/15. After 9 months of rehabilitation, she was discharged home with a GCS score of 15/15 and persistent left-side hemiparesis.

THE TAKEAWAY

Posterior circulation stroke is a life-­threatening disease that may manifest with a variety of symptoms and be difficult to identify on emergent imaging. Thus, a high degree of clinical suspicion and additional follow-up are paramount to ensure prompt diagnosis and a patient-tailored treatment strategy.

CORRESPONDENCE
Kristine A. Blackham, MD, Associate Professor, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland; kristine.blackham@gmail.com Orcid no: 0000-0002-1620-1144 (Dr. Blackham); 0000-0002- 5225-5414 (Dr. Saleh)

Changing behavior is hard. And at nearly every clinical encounter, we counsel/encourage/remind/help (choose a verb) our patients to make a change—to do something hard. We tell them they need to increase their physical activity, get more sleep, or alter their eating habits. We know that if they make the needed changes, they can improve their health and possibly lengthen their lives. But we also know (from the systematic reviews the US Preventive Services Task Force [USPSTF] uses to make its recommendations) that brief counseling in our offices is largely ineffective unless we connect patients to resources to support the recommended change.

As examples, the USPSTF currently recommends the following (both grade “B”):

• offer or refer adults with cardiovascular disease risk factors to behavioral counseling interventions to promote a healthy diet and physical activity.¹
• offer or refer adults with a body mass index of 30 or higher to intensive, multicomponent behavioral interventions.²

This 2-step rule is tech-free and can be applied by patients in a few seconds to make healthier food choices.

To support our patients when making recommendations such as these, we might refer them to a dietitian for intensive counseling and meal-planning guidance. The American Diabetes Association says that patients seeking to manage their diabetes and prediabetes “can start by working with a registered dietitian nutritionist … to make an eating plan that works for [them].”³ However, this kind of resource is unavailable to many of our patients.

So what else can we do?

We can help patients decide what to buy in the grocery aisle. Nutrition labels are useful, but they are limited by their complexity and requisite level of health literacy.⁴ Even the concept of “calories” is not so intuitive. This challenge with interpreting calories led me (in some of my prior work) to explore a potentially more useful approach: conveying calorie information as physical activity equivalents.⁵

In this issue of The Journal of Family Practice, Dong and colleagues present their findings on whether a simple equation (the Altman Rule) that uses information on nutrition labels may be a reasonable proxy for an even more difficult concept—­glycemic load.⁶ The idea is that consumers (eg, patients with diabetes) can use this rule to help them in their decision-making at the grocery store (or the convenience store or gas station, for that matter, where the high-glycemic-load carbohydrates may be even more tempting). The 2-step rule is tech-free and can be applied in a few seconds. Their research demonstrated that the rule is a reasonable proxy for glycemic load for packaged carbohydrates (eg, chips, cereals, crackers, granola bars). Caveats acknowledged, foods that meet the rule are likely to be healthier choices.

Looking ahead, I would like to see whether counseling patients about the Altman Rule leads to their use of it, and how that translates into healthier eating, lower A1C, and ideally better health. For now, the Altman Rule is worth learning about. It may serve as another tool that you can use to support your patients when you ask them to do the hard work of making healthier food choices. 

Changing behavior is hard. And at nearly every clinical encounter, we counsel/encourage/remind/help (choose a verb) our patients to make a change—to do something hard. We tell them they need to increase their physical activity, get more sleep, or alter their eating habits. We know that if they make the needed changes, they can improve their health and possibly lengthen their lives. But we also know (from the systematic reviews the US Preventive Services Task Force [USPSTF] uses to make its recommendations) that brief counseling in our offices is largely ineffective unless we connect patients to resources to support the recommended change.

As examples, the USPSTF currently recommends the following (both grade “B”):

• offer or refer adults with cardiovascular disease risk factors to behavioral counseling interventions to promote a healthy diet and physical activity.¹
• offer or refer adults with a body mass index of 30 or higher to intensive, multicomponent behavioral interventions.²

This 2-step rule is tech-free and can be applied by patients in a few seconds to make healthier food choices.

To support our patients when making recommendations such as these, we might refer them to a dietitian for intensive counseling and meal-planning guidance. The American Diabetes Association says that patients seeking to manage their diabetes and prediabetes “can start by working with a registered dietitian nutritionist … to make an eating plan that works for [them].”³ However, this kind of resource is unavailable to many of our patients.

So what else can we do?

We can help patients decide what to buy in the grocery aisle. Nutrition labels are useful, but they are limited by their complexity and requisite level of health literacy.⁴ Even the concept of “calories” is not so intuitive. This challenge with interpreting calories led me (in some of my prior work) to explore a potentially more useful approach: conveying calorie information as physical activity equivalents.⁵

In this issue of The Journal of Family Practice, Dong and colleagues present their findings on whether a simple equation (the Altman Rule) that uses information on nutrition labels may be a reasonable proxy for an even more difficult concept—­glycemic load.⁶ The idea is that consumers (eg, patients with diabetes) can use this rule to help them in their decision-making at the grocery store (or the convenience store or gas station, for that matter, where the high-glycemic-load carbohydrates may be even more tempting). The 2-step rule is tech-free and can be applied in a few seconds. Their research demonstrated that the rule is a reasonable proxy for glycemic load for packaged carbohydrates (eg, chips, cereals, crackers, granola bars). Caveats acknowledged, foods that meet the rule are likely to be healthier choices.

Looking ahead, I would like to see whether counseling patients about the Altman Rule leads to their use of it, and how that translates into healthier eating, lower A1C, and ideally better health. For now, the Altman Rule is worth learning about. It may serve as another tool that you can use to support your patients when you ask them to do the hard work of making healthier food choices. 

Changing behavior is hard. And at nearly every clinical encounter, we counsel/encourage/remind/help (choose a verb) our patients to make a change—to do something hard. We tell them they need to increase their physical activity, get more sleep, or alter their eating habits. We know that if they make the needed changes, they can improve their health and possibly lengthen their lives. But we also know (from the systematic reviews the US Preventive Services Task Force [USPSTF] uses to make its recommendations) that brief counseling in our offices is largely ineffective unless we connect patients to resources to support the recommended change.

As examples, the USPSTF currently recommends the following (both grade “B”):

• offer or refer adults with cardiovascular disease risk factors to behavioral counseling interventions to promote a healthy diet and physical activity.¹
• offer or refer adults with a body mass index of 30 or higher to intensive, multicomponent behavioral interventions.²

This 2-step rule is tech-free and can be applied by patients in a few seconds to make healthier food choices.

To support our patients when making recommendations such as these, we might refer them to a dietitian for intensive counseling and meal-planning guidance. The American Diabetes Association says that patients seeking to manage their diabetes and prediabetes “can start by working with a registered dietitian nutritionist … to make an eating plan that works for [them].”³ However, this kind of resource is unavailable to many of our patients.

So what else can we do?

We can help patients decide what to buy in the grocery aisle. Nutrition labels are useful, but they are limited by their complexity and requisite level of health literacy.⁴ Even the concept of “calories” is not so intuitive. This challenge with interpreting calories led me (in some of my prior work) to explore a potentially more useful approach: conveying calorie information as physical activity equivalents.⁵

In this issue of The Journal of Family Practice, Dong and colleagues present their findings on whether a simple equation (the Altman Rule) that uses information on nutrition labels may be a reasonable proxy for an even more difficult concept—­glycemic load.⁶ The idea is that consumers (eg, patients with diabetes) can use this rule to help them in their decision-making at the grocery store (or the convenience store or gas station, for that matter, where the high-glycemic-load carbohydrates may be even more tempting). The 2-step rule is tech-free and can be applied in a few seconds. Their research demonstrated that the rule is a reasonable proxy for glycemic load for packaged carbohydrates (eg, chips, cereals, crackers, granola bars). Caveats acknowledged, foods that meet the rule are likely to be healthier choices.

Looking ahead, I would like to see whether counseling patients about the Altman Rule leads to their use of it, and how that translates into healthier eating, lower A1C, and ideally better health. For now, the Altman Rule is worth learning about. It may serve as another tool that you can use to support your patients when you ask them to do the hard work of making healthier food choices. 

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.

THE CASE

Juana*, a 10-year-old who identifies as a cisgender, Hispanic female, was referred to our integrated behavioral health program by her primary care physician. Her mother was concerned because Juana had been refusing to attend school due to complaints of gastrointestinal upset. This concern began when Juana was in first grade but had increased in severity over the past few months.

Upon further questioning, the patient reported that she initially did not want to attend school due to academic difficulties and bullying. However, since COVID-19, her fears of attending school had significantly worsened. Juana’s mother’s primary language was Spanish and she had limited English proficiency; she reported difficulty communicating with school personnel about Juana’s poor attendance.

Juana had recently had a complete medical work-up for her gastrointestinal concerns, with negative results. Since the negative work-up, Juana’s mother had told her daughter that she would be punished if she didn’t go to school.

● How would you proceed with this patient?

* The patient’s name has been changed to protect her identity.

School avoidance, also referred to as school refusal, is a symptom of an emotional condition that manifests as a child refusing to go to school or having difficulty going to school or remaining in the classroom for the entire day. School avoidance is not a clinical diagnosis but often is related to an underlying disorder.¹

School avoidance is common, affecting 5% to 28% of youth sometime in their school career.² Available data are not specific to school avoidance but focus on chronic absenteeism (missing ≥ 15 days per school year). Rates of chronic absenteeism are high in elementary and middle school (about 14% each) and tend to increase in high school (about 21%).³ Students with disabilities are 1.5 times more likely to be chronically absent than students without disabilities.³ Compared to White students, American Indian and Pacific Islander students are > 50% more likely, Black students 40% more likely, and Hispanic students 17% more likely to miss ≥ 3 weeks of school.³ Rates of chronic absenteeism are similar (about 16%) for males and females.³

Absenteeism can have immediate and long-term negative effects.⁴ School attendance issues are correlated to negative life outcomes, such as delinquency, teen pregnancy, substance use, and poor academic achievement.⁵ According to the US Department of Education, individuals who chronically miss school are less likely to achieve educational milestones (particularly in younger years) and may be more likely to drop out of school.³

What school avoidance is (and what it isn’t)

It is important to distinguish school avoidance from truancy. Truancy often is associated with antisocial behavior such as lying and stealing, while school avoidance occurs in the absence of significant antisocial disorders.⁶ With truancy, the absence usually is hidden from the parent. In contrast, with school avoidance, the parents usually know where their child is; the child often spends the day secluded in their bedroom. Students who engage in truancy do not demonstrate excessive anxiety about attending school but may have decreased interest in schoolwork and academic performance.⁶ With school avoidance, the child exhibits severe emotional distress about attending school but is willing to complete schoolwork at home.

Why children may avoid school

School avoidance is a biopsychosocial condition with a multitude of underlying causes.⁴ It is associated most commonly with anxiety disorders and neurodevelopmental disorders, including but not limited to learning disabilities and attention-deficit/hyperactivity disorder.¹ Depressive disorders also have been associated with school avoidance.⁷ Social concerns related to changes with school personnel or classes, academic challenges, bullying, health emergencies, and family stressors also can result in symptoms of school avoidance.¹

Continue to: A child seeking to avoid...

A child seeking to avoid school may be motivated by potential negative and/or positive effects of doing so. Kearney and Silverman⁸ identified 4 primary functions of school refusal behaviors:

• avoiding stimuli at school that lend to negative affect (depression, anxiety)
• escaping the social interactions and/or situations for evaluation that occur at school
• gaining more attention from caregivers, and
• obtaining tangible rewards or benefits outside the school environment.

How school avoidance manifests

School avoidance has attributes of internalizing (depression, anxiety, somatic complaints) and externalizing (aggression, tantrums, running away, clinginess) behaviors. It can cause distress for the student, parents and caregivers, and school personnel.

With school avoidance, the child exhibits severe emotional distress about attending school but is willing to complete schoolwork at home.

The avoidance may manifest with behaviors such as crying, hiding, emotional outbursts, and refusing to move prior to the start of the school day. Additionally, the child may beg their parents not to make them go to school or, when at school, they may leave the classroom to go to a safe place such as the nurse’s or counselor’s office.

The avoidance may occur abruptly, such as after a break in the school schedule or a change of school. Or it may be the final result of the student’s gradual inability to cope with the underlying issue.

How to assess for school avoidance

Due to the multifactorial nature of this presenting concern, a comprehensive evaluation is recommended when school avoidance is reported.⁴ Often the child will present with physical symptoms, such as abdominal pain, nausea, vomiting, diarrhea, headaches, shortness of breath, dizziness, chest pain, and palpitations. A thorough medical examination should be performed to rule out a physiological cause. The medical visit should include clinical interviews with the patient and family members or guardians.

Continue to: To identify school avoidance...

To identify school avoidance in pediatric and adolescent populations, medical history and physical ­examination—along with social history to better understand familial, social, and academic concerns—should be a regular part of the medical encounter. The School Refusal Assessment Scale-Revised (SRAS-R) for both parents and their children was developed to assess for school avoidance and can be utilized within the primary care setting. Additional psychiatric history for both the family and patient may be beneficial, due to associations between parental mental health concerns and school avoidance in their children.^9,10

More than onethird of children with behavioral problems, such as school avoidance, have been diagnosed with anxiety.

Assessment for an underlying mental health condition, such as an anxiety or depressive disorder, should be completed when a patient presents with school avoidance.⁴ More than one-third of children with behavioral problems, such as school avoidance, have been diagnosed with anxiety.¹¹ The 2020 National Survey of Children’s Health found that 7.8% of children and adolescents ages 3 to 17 years had a current anxiety disorder, leading the US Preventive Services Task Force to recommend screening for anxiety in children and adolescents ages 8 to 18 years.^12,13 Furthermore, if academic achievement is of concern, then consideration of further assessment for neurodevelopmental disorders is warranted.¹

Treatment is multimodal and multidisciplinary

Treatment for school avoidance is often multimodal and may involve interdisciplinary, team-based care including the medical provider, school system (eg, Child Study Team), family, and mental health care provider.^1,4

Cognitive behavioral therapy (CBT) is the most-studied intervention for school avoidance, with behavioral, exposure-based interventions often central to therapeutic gains in treatment.^1,14,15 The goals of treatment are to increase school attendance while decreasing emotional distress through various strategies, including exposure-based interventions, contingency management with parents and school staff, relaxation training, and/or social skills training.^14,16 Collaborative involvement between the medical provider and the school system is key to successful treatment.

Medication may be considered alone or in combination with CBT when comorbid mental health conditions have been identified. Selective serotonin reuptake inhibitors (SSRIs)—including fluoxetine, sertraline, and escitalopram—are considered first-line treatment for anxiety in children and adolescents.¹⁷ Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and venlafaxine, also have been shown to be effective. Duloxetine is the only medication approved by the US Food and Drug Administration (FDA) for treatment of generalized anxiety disorder in children ages 7 years and older.¹⁷

Continue to: SSRIs and SNRIs have a boxed warning...

SSRIs and SNRIs have a boxed warning from the FDA for increased suicidal thoughts and behaviors in children and adolescents. Although this risk is rare, it should be discussed with the patient and parent/guardian in order to obtain informed consent prior to treatment initiation.

Medication should be started at the lowest possible dose and increased gradually. Patients should remain on the medication for 6 to 12 months after symptom resolution and should be tapered during a nonstressful time, such as the summer break.

THE CASE

Based on the concerns of continued school refusal after negative gastrointestinal work-up, Juana’s physician screened her for anxiety and conducted a clinical interview to better understand any psychosocial concerns. Juana’s score of 10 on the General Anxiety Disorder-7 scale indicated moderate anxiety. She reported symptoms consistent with social anxiety disorder contributing to school avoidance.

The physician consulted with the clinic’s behavioral health consultant (BHC) to confirm the multimodal treatment plan, which was then discussed with Juana and her mother. The physician discussed medication options (SSRIs) and provided documentation (in both English and Spanish) from the visit to Juana’s mother so she could initiate a school-based intervention with the Child Study Team at Juana’s school. A plan for CBT—including a collaborative contingency management plan between the patient and her parent (eg, a reward chart for attending school) and exposure interventions (eg, a graduated plan to participate in school-based activities with the end goal to resume full school attendance)—was developed with the BHC. Biweekly follow-up appointments were scheduled with the BHC and monthly appointments were scheduled with the physician to reinforce the interventions.

CORRESPONDENCE
Meredith L. C. Williamson, PhD, 2900 East 29th Street, Suite 100, Bryan, TX 77840; meredith.williamson@tamu.edu

THE CASE

Juana*, a 10-year-old who identifies as a cisgender, Hispanic female, was referred to our integrated behavioral health program by her primary care physician. Her mother was concerned because Juana had been refusing to attend school due to complaints of gastrointestinal upset. This concern began when Juana was in first grade but had increased in severity over the past few months.

Upon further questioning, the patient reported that she initially did not want to attend school due to academic difficulties and bullying. However, since COVID-19, her fears of attending school had significantly worsened. Juana’s mother’s primary language was Spanish and she had limited English proficiency; she reported difficulty communicating with school personnel about Juana’s poor attendance.

Juana had recently had a complete medical work-up for her gastrointestinal concerns, with negative results. Since the negative work-up, Juana’s mother had told her daughter that she would be punished if she didn’t go to school.

● How would you proceed with this patient?

* The patient’s name has been changed to protect her identity.

School avoidance, also referred to as school refusal, is a symptom of an emotional condition that manifests as a child refusing to go to school or having difficulty going to school or remaining in the classroom for the entire day. School avoidance is not a clinical diagnosis but often is related to an underlying disorder.¹

School avoidance is common, affecting 5% to 28% of youth sometime in their school career.² Available data are not specific to school avoidance but focus on chronic absenteeism (missing ≥ 15 days per school year). Rates of chronic absenteeism are high in elementary and middle school (about 14% each) and tend to increase in high school (about 21%).³ Students with disabilities are 1.5 times more likely to be chronically absent than students without disabilities.³ Compared to White students, American Indian and Pacific Islander students are > 50% more likely, Black students 40% more likely, and Hispanic students 17% more likely to miss ≥ 3 weeks of school.³ Rates of chronic absenteeism are similar (about 16%) for males and females.³

Absenteeism can have immediate and long-term negative effects.⁴ School attendance issues are correlated to negative life outcomes, such as delinquency, teen pregnancy, substance use, and poor academic achievement.⁵ According to the US Department of Education, individuals who chronically miss school are less likely to achieve educational milestones (particularly in younger years) and may be more likely to drop out of school.³

What school avoidance is (and what it isn’t)

It is important to distinguish school avoidance from truancy. Truancy often is associated with antisocial behavior such as lying and stealing, while school avoidance occurs in the absence of significant antisocial disorders.⁶ With truancy, the absence usually is hidden from the parent. In contrast, with school avoidance, the parents usually know where their child is; the child often spends the day secluded in their bedroom. Students who engage in truancy do not demonstrate excessive anxiety about attending school but may have decreased interest in schoolwork and academic performance.⁶ With school avoidance, the child exhibits severe emotional distress about attending school but is willing to complete schoolwork at home.

Why children may avoid school

School avoidance is a biopsychosocial condition with a multitude of underlying causes.⁴ It is associated most commonly with anxiety disorders and neurodevelopmental disorders, including but not limited to learning disabilities and attention-deficit/hyperactivity disorder.¹ Depressive disorders also have been associated with school avoidance.⁷ Social concerns related to changes with school personnel or classes, academic challenges, bullying, health emergencies, and family stressors also can result in symptoms of school avoidance.¹

Continue to: A child seeking to avoid...

A child seeking to avoid school may be motivated by potential negative and/or positive effects of doing so. Kearney and Silverman⁸ identified 4 primary functions of school refusal behaviors:

• avoiding stimuli at school that lend to negative affect (depression, anxiety)
• escaping the social interactions and/or situations for evaluation that occur at school
• gaining more attention from caregivers, and
• obtaining tangible rewards or benefits outside the school environment.

How school avoidance manifests

School avoidance has attributes of internalizing (depression, anxiety, somatic complaints) and externalizing (aggression, tantrums, running away, clinginess) behaviors. It can cause distress for the student, parents and caregivers, and school personnel.

With school avoidance, the child exhibits severe emotional distress about attending school but is willing to complete schoolwork at home.

The avoidance may manifest with behaviors such as crying, hiding, emotional outbursts, and refusing to move prior to the start of the school day. Additionally, the child may beg their parents not to make them go to school or, when at school, they may leave the classroom to go to a safe place such as the nurse’s or counselor’s office.

The avoidance may occur abruptly, such as after a break in the school schedule or a change of school. Or it may be the final result of the student’s gradual inability to cope with the underlying issue.

How to assess for school avoidance

Due to the multifactorial nature of this presenting concern, a comprehensive evaluation is recommended when school avoidance is reported.⁴ Often the child will present with physical symptoms, such as abdominal pain, nausea, vomiting, diarrhea, headaches, shortness of breath, dizziness, chest pain, and palpitations. A thorough medical examination should be performed to rule out a physiological cause. The medical visit should include clinical interviews with the patient and family members or guardians.

Continue to: To identify school avoidance...

To identify school avoidance in pediatric and adolescent populations, medical history and physical ­examination—along with social history to better understand familial, social, and academic concerns—should be a regular part of the medical encounter. The School Refusal Assessment Scale-Revised (SRAS-R) for both parents and their children was developed to assess for school avoidance and can be utilized within the primary care setting. Additional psychiatric history for both the family and patient may be beneficial, due to associations between parental mental health concerns and school avoidance in their children.^9,10

More than onethird of children with behavioral problems, such as school avoidance, have been diagnosed with anxiety.

Assessment for an underlying mental health condition, such as an anxiety or depressive disorder, should be completed when a patient presents with school avoidance.⁴ More than one-third of children with behavioral problems, such as school avoidance, have been diagnosed with anxiety.¹¹ The 2020 National Survey of Children’s Health found that 7.8% of children and adolescents ages 3 to 17 years had a current anxiety disorder, leading the US Preventive Services Task Force to recommend screening for anxiety in children and adolescents ages 8 to 18 years.^12,13 Furthermore, if academic achievement is of concern, then consideration of further assessment for neurodevelopmental disorders is warranted.¹

Treatment is multimodal and multidisciplinary

Treatment for school avoidance is often multimodal and may involve interdisciplinary, team-based care including the medical provider, school system (eg, Child Study Team), family, and mental health care provider.^1,4

Cognitive behavioral therapy (CBT) is the most-studied intervention for school avoidance, with behavioral, exposure-based interventions often central to therapeutic gains in treatment.^1,14,15 The goals of treatment are to increase school attendance while decreasing emotional distress through various strategies, including exposure-based interventions, contingency management with parents and school staff, relaxation training, and/or social skills training.^14,16 Collaborative involvement between the medical provider and the school system is key to successful treatment.

Medication may be considered alone or in combination with CBT when comorbid mental health conditions have been identified. Selective serotonin reuptake inhibitors (SSRIs)—including fluoxetine, sertraline, and escitalopram—are considered first-line treatment for anxiety in children and adolescents.¹⁷ Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and venlafaxine, also have been shown to be effective. Duloxetine is the only medication approved by the US Food and Drug Administration (FDA) for treatment of generalized anxiety disorder in children ages 7 years and older.¹⁷

Continue to: SSRIs and SNRIs have a boxed warning...

SSRIs and SNRIs have a boxed warning from the FDA for increased suicidal thoughts and behaviors in children and adolescents. Although this risk is rare, it should be discussed with the patient and parent/guardian in order to obtain informed consent prior to treatment initiation.

Medication should be started at the lowest possible dose and increased gradually. Patients should remain on the medication for 6 to 12 months after symptom resolution and should be tapered during a nonstressful time, such as the summer break.

THE CASE

Based on the concerns of continued school refusal after negative gastrointestinal work-up, Juana’s physician screened her for anxiety and conducted a clinical interview to better understand any psychosocial concerns. Juana’s score of 10 on the General Anxiety Disorder-7 scale indicated moderate anxiety. She reported symptoms consistent with social anxiety disorder contributing to school avoidance.

The physician consulted with the clinic’s behavioral health consultant (BHC) to confirm the multimodal treatment plan, which was then discussed with Juana and her mother. The physician discussed medication options (SSRIs) and provided documentation (in both English and Spanish) from the visit to Juana’s mother so she could initiate a school-based intervention with the Child Study Team at Juana’s school. A plan for CBT—including a collaborative contingency management plan between the patient and her parent (eg, a reward chart for attending school) and exposure interventions (eg, a graduated plan to participate in school-based activities with the end goal to resume full school attendance)—was developed with the BHC. Biweekly follow-up appointments were scheduled with the BHC and monthly appointments were scheduled with the physician to reinforce the interventions.

CORRESPONDENCE
Meredith L. C. Williamson, PhD, 2900 East 29th Street, Suite 100, Bryan, TX 77840; meredith.williamson@tamu.edu

THE CASE

Juana*, a 10-year-old who identifies as a cisgender, Hispanic female, was referred to our integrated behavioral health program by her primary care physician. Her mother was concerned because Juana had been refusing to attend school due to complaints of gastrointestinal upset. This concern began when Juana was in first grade but had increased in severity over the past few months.

Upon further questioning, the patient reported that she initially did not want to attend school due to academic difficulties and bullying. However, since COVID-19, her fears of attending school had significantly worsened. Juana’s mother’s primary language was Spanish and she had limited English proficiency; she reported difficulty communicating with school personnel about Juana’s poor attendance.

Juana had recently had a complete medical work-up for her gastrointestinal concerns, with negative results. Since the negative work-up, Juana’s mother had told her daughter that she would be punished if she didn’t go to school.

● How would you proceed with this patient?

* The patient’s name has been changed to protect her identity.

School avoidance, also referred to as school refusal, is a symptom of an emotional condition that manifests as a child refusing to go to school or having difficulty going to school or remaining in the classroom for the entire day. School avoidance is not a clinical diagnosis but often is related to an underlying disorder.¹

School avoidance is common, affecting 5% to 28% of youth sometime in their school career.² Available data are not specific to school avoidance but focus on chronic absenteeism (missing ≥ 15 days per school year). Rates of chronic absenteeism are high in elementary and middle school (about 14% each) and tend to increase in high school (about 21%).³ Students with disabilities are 1.5 times more likely to be chronically absent than students without disabilities.³ Compared to White students, American Indian and Pacific Islander students are > 50% more likely, Black students 40% more likely, and Hispanic students 17% more likely to miss ≥ 3 weeks of school.³ Rates of chronic absenteeism are similar (about 16%) for males and females.³

Absenteeism can have immediate and long-term negative effects.⁴ School attendance issues are correlated to negative life outcomes, such as delinquency, teen pregnancy, substance use, and poor academic achievement.⁵ According to the US Department of Education, individuals who chronically miss school are less likely to achieve educational milestones (particularly in younger years) and may be more likely to drop out of school.³

What school avoidance is (and what it isn’t)

It is important to distinguish school avoidance from truancy. Truancy often is associated with antisocial behavior such as lying and stealing, while school avoidance occurs in the absence of significant antisocial disorders.⁶ With truancy, the absence usually is hidden from the parent. In contrast, with school avoidance, the parents usually know where their child is; the child often spends the day secluded in their bedroom. Students who engage in truancy do not demonstrate excessive anxiety about attending school but may have decreased interest in schoolwork and academic performance.⁶ With school avoidance, the child exhibits severe emotional distress about attending school but is willing to complete schoolwork at home.

Why children may avoid school

School avoidance is a biopsychosocial condition with a multitude of underlying causes.⁴ It is associated most commonly with anxiety disorders and neurodevelopmental disorders, including but not limited to learning disabilities and attention-deficit/hyperactivity disorder.¹ Depressive disorders also have been associated with school avoidance.⁷ Social concerns related to changes with school personnel or classes, academic challenges, bullying, health emergencies, and family stressors also can result in symptoms of school avoidance.¹

Continue to: A child seeking to avoid...

A child seeking to avoid school may be motivated by potential negative and/or positive effects of doing so. Kearney and Silverman⁸ identified 4 primary functions of school refusal behaviors:

• avoiding stimuli at school that lend to negative affect (depression, anxiety)
• escaping the social interactions and/or situations for evaluation that occur at school
• gaining more attention from caregivers, and
• obtaining tangible rewards or benefits outside the school environment.

How school avoidance manifests

School avoidance has attributes of internalizing (depression, anxiety, somatic complaints) and externalizing (aggression, tantrums, running away, clinginess) behaviors. It can cause distress for the student, parents and caregivers, and school personnel.

With school avoidance, the child exhibits severe emotional distress about attending school but is willing to complete schoolwork at home.

The avoidance may manifest with behaviors such as crying, hiding, emotional outbursts, and refusing to move prior to the start of the school day. Additionally, the child may beg their parents not to make them go to school or, when at school, they may leave the classroom to go to a safe place such as the nurse’s or counselor’s office.

The avoidance may occur abruptly, such as after a break in the school schedule or a change of school. Or it may be the final result of the student’s gradual inability to cope with the underlying issue.

How to assess for school avoidance

Due to the multifactorial nature of this presenting concern, a comprehensive evaluation is recommended when school avoidance is reported.⁴ Often the child will present with physical symptoms, such as abdominal pain, nausea, vomiting, diarrhea, headaches, shortness of breath, dizziness, chest pain, and palpitations. A thorough medical examination should be performed to rule out a physiological cause. The medical visit should include clinical interviews with the patient and family members or guardians.

Continue to: To identify school avoidance...

To identify school avoidance in pediatric and adolescent populations, medical history and physical ­examination—along with social history to better understand familial, social, and academic concerns—should be a regular part of the medical encounter. The School Refusal Assessment Scale-Revised (SRAS-R) for both parents and their children was developed to assess for school avoidance and can be utilized within the primary care setting. Additional psychiatric history for both the family and patient may be beneficial, due to associations between parental mental health concerns and school avoidance in their children.^9,10

More than onethird of children with behavioral problems, such as school avoidance, have been diagnosed with anxiety.

Assessment for an underlying mental health condition, such as an anxiety or depressive disorder, should be completed when a patient presents with school avoidance.⁴ More than one-third of children with behavioral problems, such as school avoidance, have been diagnosed with anxiety.¹¹ The 2020 National Survey of Children’s Health found that 7.8% of children and adolescents ages 3 to 17 years had a current anxiety disorder, leading the US Preventive Services Task Force to recommend screening for anxiety in children and adolescents ages 8 to 18 years.^12,13 Furthermore, if academic achievement is of concern, then consideration of further assessment for neurodevelopmental disorders is warranted.¹

Treatment is multimodal and multidisciplinary

Treatment for school avoidance is often multimodal and may involve interdisciplinary, team-based care including the medical provider, school system (eg, Child Study Team), family, and mental health care provider.^1,4

Cognitive behavioral therapy (CBT) is the most-studied intervention for school avoidance, with behavioral, exposure-based interventions often central to therapeutic gains in treatment.^1,14,15 The goals of treatment are to increase school attendance while decreasing emotional distress through various strategies, including exposure-based interventions, contingency management with parents and school staff, relaxation training, and/or social skills training.^14,16 Collaborative involvement between the medical provider and the school system is key to successful treatment.

Medication may be considered alone or in combination with CBT when comorbid mental health conditions have been identified. Selective serotonin reuptake inhibitors (SSRIs)—including fluoxetine, sertraline, and escitalopram—are considered first-line treatment for anxiety in children and adolescents.¹⁷ Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and venlafaxine, also have been shown to be effective. Duloxetine is the only medication approved by the US Food and Drug Administration (FDA) for treatment of generalized anxiety disorder in children ages 7 years and older.¹⁷

Continue to: SSRIs and SNRIs have a boxed warning...

SSRIs and SNRIs have a boxed warning from the FDA for increased suicidal thoughts and behaviors in children and adolescents. Although this risk is rare, it should be discussed with the patient and parent/guardian in order to obtain informed consent prior to treatment initiation.

Medication should be started at the lowest possible dose and increased gradually. Patients should remain on the medication for 6 to 12 months after symptom resolution and should be tapered during a nonstressful time, such as the summer break.

THE CASE

Based on the concerns of continued school refusal after negative gastrointestinal work-up, Juana’s physician screened her for anxiety and conducted a clinical interview to better understand any psychosocial concerns. Juana’s score of 10 on the General Anxiety Disorder-7 scale indicated moderate anxiety. She reported symptoms consistent with social anxiety disorder contributing to school avoidance.

The physician consulted with the clinic’s behavioral health consultant (BHC) to confirm the multimodal treatment plan, which was then discussed with Juana and her mother. The physician discussed medication options (SSRIs) and provided documentation (in both English and Spanish) from the visit to Juana’s mother so she could initiate a school-based intervention with the Child Study Team at Juana’s school. A plan for CBT—including a collaborative contingency management plan between the patient and her parent (eg, a reward chart for attending school) and exposure interventions (eg, a graduated plan to participate in school-based activities with the end goal to resume full school attendance)—was developed with the BHC. Biweekly follow-up appointments were scheduled with the BHC and monthly appointments were scheduled with the physician to reinforce the interventions.

CORRESPONDENCE
Meredith L. C. Williamson, PhD, 2900 East 29th Street, Suite 100, Bryan, TX 77840; meredith.williamson@tamu.edu

ABSTRACT

Background: The Altman Rule, a simple tool for consumers seeking to make healthier packaged food choices at the point of sale, applies to packaged carbohydrates. According to the Altman Rule, a food is a healthier option if it has at least 3 g of fiber per serving and the grams of fiber plus the grams of protein exceed the grams of sugar per serving. This study sought to evaluate whether the Altman Rule is a valid proxy for glycemic load (GL).

Methods: We compared the binary outcome of whether a food item meets the Altman Rule with the GL of all foods categorized as cereals, chips, crackers, and granola bars in the Nutrition Data System for Research Database (University of Minnesota, Version 2010). We examined the percentage of foods in low-, medium-, and high-GL categories that met the Altman Rule.

Results: There were 1235 foods (342 cereals, 305 chips, 379 crackers, and 209 granola bars) in this analysis. There was a significant relationship between the GL of foods and the Altman Rule (P < .001) in that most low-GL (68%), almost half of medium-GL (48%), and very few high-GL (7%) foods met the criteria of the rule.

Conclusions: The Altman Rule is a reasonable proxy for GL and can be a useful and accessible tool for consumers interested in buying healthier packaged carbohydrate foods.

Nutrition can be complicated for consumers interested in making healthier choices at the grocery store. Consumers may have difficulty identifying more nutritious options, especially when food labels are adorned with claims such as “Good Source of Fiber” or “Heart Healthy.”¹ In addition, when reading food labels, consumers may find it difficult to decipher which data to prioritize when carbohydrates, total sugars, added sugars, total dietary fiber, soluble fiber, and insoluble fiber are all listed.

The concept of glycemic load (GL) is an important consideration, especially for people with diabetes. GL approximates the blood sugar response to different foods. A food with a high GL is digested quickly, and its carbohydrates are taken into the bloodstream rapidly. This leads to a spike and subsequent drop in blood sugars, which can cause symptoms of hyperglycemia and hypoglycemia in a person with diabetes.^2,3 Despite its usefulness, GL may be too complicated for a consumer to understand, and it does not appear anywhere on the food label. Since GL is calculated using pooled blood sugar response from individuals after the ingestion of the particular food, estimation of the GL is not intuitable.⁴

Point-of-sale tools. People seeking to lose weight, control diabetes, improve dyslipidemia and/or blood pressure, and/or decrease their risk for heart disease may benefit from point-of-sale tools such as the Altman Rule, which simplifies and encourages the selection of more nutritious foods.¹ Other tools—such as Guiding Stars (https://guidingstars.com), NuVal (www.nuval.com), and different variations of traffic lights—have been created to help consumers make more informed and healthier food choices.^5-8 However, Guiding Stars and NuVal are based on complicated algorithms that are not entirely transparent and not accessible to the average consumer.^6,7 Evaluations of these nutrition tools indicate that consumers tend to underrate the healthiness of some foods, such as raw almonds and salmon, and overrate the healthiness of others, such as fruit punch and diet soda, when using traffic light systems.⁶ Furthermore, these nutrition tools are not available in many supermarkets. Previous research suggests that the use of point-of-sale nutrition apps decreases with the time and effort involved in using an app.⁹

Continue to: The Altman Rule

The Altman Rule was developed by a family physician (author WA) to provide a more accessible tool for people interested in choosing healthier prepackaged carbohydrate foods while shopping. Since the user does not need to have a smartphone, and they are not required to download or understand an app for each purchase, the Altman Rule may be more usable compared with more complicated alternatives.

The Altman Rule can be used with nutrition labels that feature serving information and calories in enlarged and bold type, in compliance with the most recent US Food and Drug Administration (FDA) guideline from 2016. Many foods with high fiber also have high amounts of sugar, so the criteria of the Altman Rule includes a 2-step process requiring (1) a minimum of 3 g of total dietary fiber per serving and (2) the sum of the grams of fiber plus the grams of protein per serving to be greater than the total grams of sugar (not grams of added sugar or grams of carbohydrate) per serving (FIGURE 1A). Unlike the relatively complicated formula related to GL, this 2-part rule can be applied in seconds while shopping (FIGURE 1B).

The rule is intended only to be used for packaged carbohydrate products, such as bread, muffins, bagels, pasta, rice, oatmeal, cereals, snack bars, chips, and crackers. It does not apply to whole foods, such as meat, dairy, fruits, or vegetables. These foods are excluded to prevent any consumer confusion related to the nutritional content of whole foods (eg, an apple may have more sugar than fiber and protein combined, but it is still a nutritious option).

Since the user does not need to have a smartphone, the Altman Rule may be more usable compared with more complicated alternatives.

This study aimed to determine if the Altman Rule is a reasonable proxy for the more complicated concept of GL. We calculated the relationship between the GL of commercially available packaged carbohydrate foods and whether those foods met the Altman Rule.

METHODS

The Altman Rule was tested by comparing the binary outcome of the rule (meets/does not meet) with data on all foods categorized as cereals, chips, crackers, and granola bars in the Nutrition Data System for Research (NDSR) Database (University of Minnesota, Version 2010).

Continue to: To account for differences...

To account for differences in serving size, we used the standard of 50 g for each product as 1 serving. We used 50 g (about 1.7 oz) to help compare the different foods and between foods within the same group. Additionally, 50 g is close to 1 serving for most foods in these groups; it is about the size of a typical granola bar, three-quarters to 2 cups of cereal, 10 to 12 crackers, and 15 to 25 chips. We determined the GL for each product by multiplying the number of available carbohydrates (total carbohydrate – dietary fiber) by the product’s glycemic index/100. In general, GL is categorized as low (≤ 10), medium (11-19), or high (≥ 20).

We applied the Altman Rule to categorize each product as meeting or not meeting the rule. We compared the proportion of foods meeting the Altman Rule, stratified by GL and by specific foods, and used chi-square to determine if differences were statistically significant. These data were collected and analyzed in the summer of 2019.

RESULTS

There were 1235 foods (342 breakfast cereals, 305 chips, 379 crackers, and 209 granola bars) used for this analysis. There is a significant relationship between the GL of foods and the Altman Rule in that most low-GL (68%), almost half of medium-GL (48%), and only a few high-GL foods (7%) met the rule (P < .001) (TABLE 1). There was also a significant relationship between “meeting the ­Altman Rule” and GL within each food type (P < .001) (TABLE 2).

The medium-GL foods were the second largest category of foods we calculated; thus we further broke them into binary categories of low-medium GL (values 11-14) and high-medium GL (values 15-19) to explore the results of the Altman Rule. About half of the foods in medium-GL category met the Altman Rule. About eighty-five percent of the foods with low-medium GL passed the Altman Rule, while only 39% of the foods with high-medium GL did.

Foods that met the rule were more likely to be low GL and foods that did not pass the rule were more likely high GL. Within the medium-GL category, foods that met the rule were more likely to be low-medium GL. 

Continue to: The findings within food categories...

The findings within food categories showed that very few cereals, chips, crackers, and granola bars were low GL. For every food category, except granola bars, far more low-GL foods met the Altman Rule than those that did not. At the same time, very few high-GL foods met the Altman Rule. The category with the most individual high-GL food items meeting the Altman Rule was cereal. This was also the subcategory with the largest percentage of high-GL food items meeting the Altman Rule. Thirty-nine cereals that were high GL met the rule, but more than 4 times as many high-GL cereals did not (n = 190).

DISCUSSION

Marketing and nutrition messaging create consumer confusion that makes it challenging to identify packaged food items that are more nutrient dense. The Altman Rule simplifies food choices that have become unnecessarily complex. Our findings suggest this 2-step rule is a reasonable proxy for the more complicated and less accessible GL for packaged carbohydrates, such as cereals, chips, crackers, and snack bars. Foods that meet the rule are likely low or low-medium GL and thus are foods that are likely to be healthier choices.

Our findings suggest this 2-step rule is a reasonable proxy for the more complicated and less accessible glycemic load for packaged carbohydrates.

Of note, only 9% of chips (n = 27) passed the Altman Rule, likely due to their low dietary fiber content, which was typical of chips. If a food item does not have at least 3 grams of total dietary fiber per serving, it does not pass the Altman Rule, regardless of how much protein or sugar is in the product. This may be considered a strength or a weakness of the Altman Rule. Few nutrition-dense foods are low in fiber, but some foods could be nutritious but do not meet the Altman Rule due to having < 3 g of fiber.

With the high prevalence of chronic diseases such as hypertension, diabetes, hyperlipidemia, and cardiovascular disease, it is essential to help consumers prevent chronic disease altogether or manage their chronic disease by providing tools to identify healthier food choices. The tool also has a place in clinical medicine for use by physicians and other health care professionals. Research shows that physicians find both time and lack of ­knowledge/resources to be a barrier to providing nutritional counseling to patients.¹⁰ Since the Altman Rule can be shared and explained with very little time and without extensive nutritional knowledge, it meets these needs.

Limitations

Glycemic load. We acknowledge that the Altman Rule is not foolproof and that assessing this rule based on GL has some limitations. GL is not a perfect or comprehensive way to measure the nutritional value of a food. For example, fruits such as watermelon and grapes are nutritionally dense. However, they contain high amounts of natural sugars—and as such, their GL is relatively high, which could lead a consumer to perceive them as unhealthy. Nevertheless, GL is both a useful and accepted tool and a reasonable way to assess the validity of the rule, specifically when assessing packaged carbohydrates. The simplicity of the Altman Rule and its relationship with GL makes it such that consumers are more likely to make a healthier food choice using it.⁹

Continue to: Specificity and sensitivity

Specificity and sensitivity. There are other limitations to the Altman Rule, given that a small number of high-GL foods meet the rule. For example, some granola bars had high dietary protein, which offset a high sugar content just enough to pass the rule despite a higher GL. As such, concluding that a snack bar is a healthier choice because it meets the Altman Rule when it has high amounts of sugar may not be appropriate. This limitation could be considered a lack of specificity (the rule includes food it ought not to include). Another limitation to consider would be a lack of sensitivity, given that only 68% of low-GL foods passed the Altman Rule. Since GL is associated with carbohydrate content, foods with a low carbohydrate count often have little to no fiber and thus would fall into the category of foods that did not meet the Altman Rule but had low GL. In this case, however, the low amount of fiber may render the Altman Rule a better indicator of a healthier food choice than the GL.

Hidden sugars. Foods with sugar alcohols and artificial sweeteners may be as deleterious as caloric alternatives while not being accounted for when reporting the grams of sugar per serving on the nutrition label.⁷ This may represent an exception to the Altman Rule, as foods that are not healthier choices may pass the rule because the sugar content on the nutrition label is, in a sense, artificially lowered. Future research may investigate the hypothesis that these foods are nutritionally inferior despite meeting the Altman Rule.

The sample. Our study also was limited to working only with foods that were included in the NDSR database up to 2010. This limitation is mitigated by the fact that the sample size was large (> 1000 packaged food items were included in our analyses). The study also could be limited by the food categories that were analyzed; food categories such as bread, rice, pasta, and bagels were not included.

The objective of this research was to investigate the relationship between GL and the Altman Rule, rather than to conduct an exhaustive analysis of the Altman Rule for every possible food category. Studying the relationship between the Altman Rule and GL in other categories of food is an objective for future research. The data so far support a relationship between these entities. The likelihood of the nutrition facts of foods changing without the GL changing (or vice versa) is very low. As such, the Altman Rule still seems to be a reasonable proxy of GL.

CONCLUSIONS

Research indicates that point-of-sale tools, such as Guiding Stars, NuVal, and other stoplight tools, can successfully alter consumers’ behaviors.⁹ These tools can be helpful but are not available in many supermarkets. Despite the limitations, the Altman Rule is a useful decision aid that is accessible to all consumers no matter where they live or shop and is easy to use and remember.

The Altman rule can be used in clinical practice by health care professionals, such as physicians, nurse practitioners, physician assistants, dietitians, and health coaches. It also has the potential to be used in commercial settings, such as grocery stores, to help consumers easily identify healthier convenience foods. This has public health implications, as the rule can both empower consumers and potentially incentivize food manufacturers to upgrade their products nutritionally.

Additional research would be useful to evaluate consumers’ preferences and perceptions about how user-friendly the Altman Rule is at the point of sale with packaged carbohydrate foods. This would help to further understand how the use of information on food packaging can motivate healthier decisions—thereby helping to alleviate the burden of chronic disease.

CORRESPONDENCE
Kimberly R. Dong, DrPH, MS, RDN, Tufts University School of Medicine, Department of Public Health and Community Medicine, 136 Harrison Avenue, MV Building, Boston, MA 02111; kimberly.dong@tufts.edu

ABSTRACT

Background: The Altman Rule, a simple tool for consumers seeking to make healthier packaged food choices at the point of sale, applies to packaged carbohydrates. According to the Altman Rule, a food is a healthier option if it has at least 3 g of fiber per serving and the grams of fiber plus the grams of protein exceed the grams of sugar per serving. This study sought to evaluate whether the Altman Rule is a valid proxy for glycemic load (GL).

Methods: We compared the binary outcome of whether a food item meets the Altman Rule with the GL of all foods categorized as cereals, chips, crackers, and granola bars in the Nutrition Data System for Research Database (University of Minnesota, Version 2010). We examined the percentage of foods in low-, medium-, and high-GL categories that met the Altman Rule.

Results: There were 1235 foods (342 cereals, 305 chips, 379 crackers, and 209 granola bars) in this analysis. There was a significant relationship between the GL of foods and the Altman Rule (P < .001) in that most low-GL (68%), almost half of medium-GL (48%), and very few high-GL (7%) foods met the criteria of the rule.

Conclusions: The Altman Rule is a reasonable proxy for GL and can be a useful and accessible tool for consumers interested in buying healthier packaged carbohydrate foods.

Nutrition can be complicated for consumers interested in making healthier choices at the grocery store. Consumers may have difficulty identifying more nutritious options, especially when food labels are adorned with claims such as “Good Source of Fiber” or “Heart Healthy.”¹ In addition, when reading food labels, consumers may find it difficult to decipher which data to prioritize when carbohydrates, total sugars, added sugars, total dietary fiber, soluble fiber, and insoluble fiber are all listed.

The concept of glycemic load (GL) is an important consideration, especially for people with diabetes. GL approximates the blood sugar response to different foods. A food with a high GL is digested quickly, and its carbohydrates are taken into the bloodstream rapidly. This leads to a spike and subsequent drop in blood sugars, which can cause symptoms of hyperglycemia and hypoglycemia in a person with diabetes.^2,3 Despite its usefulness, GL may be too complicated for a consumer to understand, and it does not appear anywhere on the food label. Since GL is calculated using pooled blood sugar response from individuals after the ingestion of the particular food, estimation of the GL is not intuitable.⁴

Point-of-sale tools. People seeking to lose weight, control diabetes, improve dyslipidemia and/or blood pressure, and/or decrease their risk for heart disease may benefit from point-of-sale tools such as the Altman Rule, which simplifies and encourages the selection of more nutritious foods.¹ Other tools—such as Guiding Stars (https://guidingstars.com), NuVal (www.nuval.com), and different variations of traffic lights—have been created to help consumers make more informed and healthier food choices.^5-8 However, Guiding Stars and NuVal are based on complicated algorithms that are not entirely transparent and not accessible to the average consumer.^6,7 Evaluations of these nutrition tools indicate that consumers tend to underrate the healthiness of some foods, such as raw almonds and salmon, and overrate the healthiness of others, such as fruit punch and diet soda, when using traffic light systems.⁶ Furthermore, these nutrition tools are not available in many supermarkets. Previous research suggests that the use of point-of-sale nutrition apps decreases with the time and effort involved in using an app.⁹

Continue to: The Altman Rule

The Altman Rule was developed by a family physician (author WA) to provide a more accessible tool for people interested in choosing healthier prepackaged carbohydrate foods while shopping. Since the user does not need to have a smartphone, and they are not required to download or understand an app for each purchase, the Altman Rule may be more usable compared with more complicated alternatives.

The Altman Rule can be used with nutrition labels that feature serving information and calories in enlarged and bold type, in compliance with the most recent US Food and Drug Administration (FDA) guideline from 2016. Many foods with high fiber also have high amounts of sugar, so the criteria of the Altman Rule includes a 2-step process requiring (1) a minimum of 3 g of total dietary fiber per serving and (2) the sum of the grams of fiber plus the grams of protein per serving to be greater than the total grams of sugar (not grams of added sugar or grams of carbohydrate) per serving (FIGURE 1A). Unlike the relatively complicated formula related to GL, this 2-part rule can be applied in seconds while shopping (FIGURE 1B).

The rule is intended only to be used for packaged carbohydrate products, such as bread, muffins, bagels, pasta, rice, oatmeal, cereals, snack bars, chips, and crackers. It does not apply to whole foods, such as meat, dairy, fruits, or vegetables. These foods are excluded to prevent any consumer confusion related to the nutritional content of whole foods (eg, an apple may have more sugar than fiber and protein combined, but it is still a nutritious option).

Since the user does not need to have a smartphone, the Altman Rule may be more usable compared with more complicated alternatives.

This study aimed to determine if the Altman Rule is a reasonable proxy for the more complicated concept of GL. We calculated the relationship between the GL of commercially available packaged carbohydrate foods and whether those foods met the Altman Rule.

METHODS

The Altman Rule was tested by comparing the binary outcome of the rule (meets/does not meet) with data on all foods categorized as cereals, chips, crackers, and granola bars in the Nutrition Data System for Research (NDSR) Database (University of Minnesota, Version 2010).

Continue to: To account for differences...

To account for differences in serving size, we used the standard of 50 g for each product as 1 serving. We used 50 g (about 1.7 oz) to help compare the different foods and between foods within the same group. Additionally, 50 g is close to 1 serving for most foods in these groups; it is about the size of a typical granola bar, three-quarters to 2 cups of cereal, 10 to 12 crackers, and 15 to 25 chips. We determined the GL for each product by multiplying the number of available carbohydrates (total carbohydrate – dietary fiber) by the product’s glycemic index/100. In general, GL is categorized as low (≤ 10), medium (11-19), or high (≥ 20).

We applied the Altman Rule to categorize each product as meeting or not meeting the rule. We compared the proportion of foods meeting the Altman Rule, stratified by GL and by specific foods, and used chi-square to determine if differences were statistically significant. These data were collected and analyzed in the summer of 2019.

RESULTS

There were 1235 foods (342 breakfast cereals, 305 chips, 379 crackers, and 209 granola bars) used for this analysis. There is a significant relationship between the GL of foods and the Altman Rule in that most low-GL (68%), almost half of medium-GL (48%), and only a few high-GL foods (7%) met the rule (P < .001) (TABLE 1). There was also a significant relationship between “meeting the ­Altman Rule” and GL within each food type (P < .001) (TABLE 2).

The medium-GL foods were the second largest category of foods we calculated; thus we further broke them into binary categories of low-medium GL (values 11-14) and high-medium GL (values 15-19) to explore the results of the Altman Rule. About half of the foods in medium-GL category met the Altman Rule. About eighty-five percent of the foods with low-medium GL passed the Altman Rule, while only 39% of the foods with high-medium GL did.

Foods that met the rule were more likely to be low GL and foods that did not pass the rule were more likely high GL. Within the medium-GL category, foods that met the rule were more likely to be low-medium GL. 

Continue to: The findings within food categories...

The findings within food categories showed that very few cereals, chips, crackers, and granola bars were low GL. For every food category, except granola bars, far more low-GL foods met the Altman Rule than those that did not. At the same time, very few high-GL foods met the Altman Rule. The category with the most individual high-GL food items meeting the Altman Rule was cereal. This was also the subcategory with the largest percentage of high-GL food items meeting the Altman Rule. Thirty-nine cereals that were high GL met the rule, but more than 4 times as many high-GL cereals did not (n = 190).

DISCUSSION

Marketing and nutrition messaging create consumer confusion that makes it challenging to identify packaged food items that are more nutrient dense. The Altman Rule simplifies food choices that have become unnecessarily complex. Our findings suggest this 2-step rule is a reasonable proxy for the more complicated and less accessible GL for packaged carbohydrates, such as cereals, chips, crackers, and snack bars. Foods that meet the rule are likely low or low-medium GL and thus are foods that are likely to be healthier choices.

Our findings suggest this 2-step rule is a reasonable proxy for the more complicated and less accessible glycemic load for packaged carbohydrates.

Of note, only 9% of chips (n = 27) passed the Altman Rule, likely due to their low dietary fiber content, which was typical of chips. If a food item does not have at least 3 grams of total dietary fiber per serving, it does not pass the Altman Rule, regardless of how much protein or sugar is in the product. This may be considered a strength or a weakness of the Altman Rule. Few nutrition-dense foods are low in fiber, but some foods could be nutritious but do not meet the Altman Rule due to having < 3 g of fiber.

With the high prevalence of chronic diseases such as hypertension, diabetes, hyperlipidemia, and cardiovascular disease, it is essential to help consumers prevent chronic disease altogether or manage their chronic disease by providing tools to identify healthier food choices. The tool also has a place in clinical medicine for use by physicians and other health care professionals. Research shows that physicians find both time and lack of ­knowledge/resources to be a barrier to providing nutritional counseling to patients.¹⁰ Since the Altman Rule can be shared and explained with very little time and without extensive nutritional knowledge, it meets these needs.

Limitations

Glycemic load. We acknowledge that the Altman Rule is not foolproof and that assessing this rule based on GL has some limitations. GL is not a perfect or comprehensive way to measure the nutritional value of a food. For example, fruits such as watermelon and grapes are nutritionally dense. However, they contain high amounts of natural sugars—and as such, their GL is relatively high, which could lead a consumer to perceive them as unhealthy. Nevertheless, GL is both a useful and accepted tool and a reasonable way to assess the validity of the rule, specifically when assessing packaged carbohydrates. The simplicity of the Altman Rule and its relationship with GL makes it such that consumers are more likely to make a healthier food choice using it.⁹

Continue to: Specificity and sensitivity

Specificity and sensitivity. There are other limitations to the Altman Rule, given that a small number of high-GL foods meet the rule. For example, some granola bars had high dietary protein, which offset a high sugar content just enough to pass the rule despite a higher GL. As such, concluding that a snack bar is a healthier choice because it meets the Altman Rule when it has high amounts of sugar may not be appropriate. This limitation could be considered a lack of specificity (the rule includes food it ought not to include). Another limitation to consider would be a lack of sensitivity, given that only 68% of low-GL foods passed the Altman Rule. Since GL is associated with carbohydrate content, foods with a low carbohydrate count often have little to no fiber and thus would fall into the category of foods that did not meet the Altman Rule but had low GL. In this case, however, the low amount of fiber may render the Altman Rule a better indicator of a healthier food choice than the GL.

Hidden sugars. Foods with sugar alcohols and artificial sweeteners may be as deleterious as caloric alternatives while not being accounted for when reporting the grams of sugar per serving on the nutrition label.⁷ This may represent an exception to the Altman Rule, as foods that are not healthier choices may pass the rule because the sugar content on the nutrition label is, in a sense, artificially lowered. Future research may investigate the hypothesis that these foods are nutritionally inferior despite meeting the Altman Rule.

The sample. Our study also was limited to working only with foods that were included in the NDSR database up to 2010. This limitation is mitigated by the fact that the sample size was large (> 1000 packaged food items were included in our analyses). The study also could be limited by the food categories that were analyzed; food categories such as bread, rice, pasta, and bagels were not included.

The objective of this research was to investigate the relationship between GL and the Altman Rule, rather than to conduct an exhaustive analysis of the Altman Rule for every possible food category. Studying the relationship between the Altman Rule and GL in other categories of food is an objective for future research. The data so far support a relationship between these entities. The likelihood of the nutrition facts of foods changing without the GL changing (or vice versa) is very low. As such, the Altman Rule still seems to be a reasonable proxy of GL.

CONCLUSIONS

Research indicates that point-of-sale tools, such as Guiding Stars, NuVal, and other stoplight tools, can successfully alter consumers’ behaviors.⁹ These tools can be helpful but are not available in many supermarkets. Despite the limitations, the Altman Rule is a useful decision aid that is accessible to all consumers no matter where they live or shop and is easy to use and remember.

The Altman rule can be used in clinical practice by health care professionals, such as physicians, nurse practitioners, physician assistants, dietitians, and health coaches. It also has the potential to be used in commercial settings, such as grocery stores, to help consumers easily identify healthier convenience foods. This has public health implications, as the rule can both empower consumers and potentially incentivize food manufacturers to upgrade their products nutritionally.

Additional research would be useful to evaluate consumers’ preferences and perceptions about how user-friendly the Altman Rule is at the point of sale with packaged carbohydrate foods. This would help to further understand how the use of information on food packaging can motivate healthier decisions—thereby helping to alleviate the burden of chronic disease.

CORRESPONDENCE
Kimberly R. Dong, DrPH, MS, RDN, Tufts University School of Medicine, Department of Public Health and Community Medicine, 136 Harrison Avenue, MV Building, Boston, MA 02111; kimberly.dong@tufts.edu

ABSTRACT

Background: The Altman Rule, a simple tool for consumers seeking to make healthier packaged food choices at the point of sale, applies to packaged carbohydrates. According to the Altman Rule, a food is a healthier option if it has at least 3 g of fiber per serving and the grams of fiber plus the grams of protein exceed the grams of sugar per serving. This study sought to evaluate whether the Altman Rule is a valid proxy for glycemic load (GL).

Methods: We compared the binary outcome of whether a food item meets the Altman Rule with the GL of all foods categorized as cereals, chips, crackers, and granola bars in the Nutrition Data System for Research Database (University of Minnesota, Version 2010). We examined the percentage of foods in low-, medium-, and high-GL categories that met the Altman Rule.

Results: There were 1235 foods (342 cereals, 305 chips, 379 crackers, and 209 granola bars) in this analysis. There was a significant relationship between the GL of foods and the Altman Rule (P < .001) in that most low-GL (68%), almost half of medium-GL (48%), and very few high-GL (7%) foods met the criteria of the rule.

Conclusions: The Altman Rule is a reasonable proxy for GL and can be a useful and accessible tool for consumers interested in buying healthier packaged carbohydrate foods.

Nutrition can be complicated for consumers interested in making healthier choices at the grocery store. Consumers may have difficulty identifying more nutritious options, especially when food labels are adorned with claims such as “Good Source of Fiber” or “Heart Healthy.”¹ In addition, when reading food labels, consumers may find it difficult to decipher which data to prioritize when carbohydrates, total sugars, added sugars, total dietary fiber, soluble fiber, and insoluble fiber are all listed.

The concept of glycemic load (GL) is an important consideration, especially for people with diabetes. GL approximates the blood sugar response to different foods. A food with a high GL is digested quickly, and its carbohydrates are taken into the bloodstream rapidly. This leads to a spike and subsequent drop in blood sugars, which can cause symptoms of hyperglycemia and hypoglycemia in a person with diabetes.^2,3 Despite its usefulness, GL may be too complicated for a consumer to understand, and it does not appear anywhere on the food label. Since GL is calculated using pooled blood sugar response from individuals after the ingestion of the particular food, estimation of the GL is not intuitable.⁴

Point-of-sale tools. People seeking to lose weight, control diabetes, improve dyslipidemia and/or blood pressure, and/or decrease their risk for heart disease may benefit from point-of-sale tools such as the Altman Rule, which simplifies and encourages the selection of more nutritious foods.¹ Other tools—such as Guiding Stars (https://guidingstars.com), NuVal (www.nuval.com), and different variations of traffic lights—have been created to help consumers make more informed and healthier food choices.^5-8 However, Guiding Stars and NuVal are based on complicated algorithms that are not entirely transparent and not accessible to the average consumer.^6,7 Evaluations of these nutrition tools indicate that consumers tend to underrate the healthiness of some foods, such as raw almonds and salmon, and overrate the healthiness of others, such as fruit punch and diet soda, when using traffic light systems.⁶ Furthermore, these nutrition tools are not available in many supermarkets. Previous research suggests that the use of point-of-sale nutrition apps decreases with the time and effort involved in using an app.⁹

Continue to: The Altman Rule

The Altman Rule was developed by a family physician (author WA) to provide a more accessible tool for people interested in choosing healthier prepackaged carbohydrate foods while shopping. Since the user does not need to have a smartphone, and they are not required to download or understand an app for each purchase, the Altman Rule may be more usable compared with more complicated alternatives.

The Altman Rule can be used with nutrition labels that feature serving information and calories in enlarged and bold type, in compliance with the most recent US Food and Drug Administration (FDA) guideline from 2016. Many foods with high fiber also have high amounts of sugar, so the criteria of the Altman Rule includes a 2-step process requiring (1) a minimum of 3 g of total dietary fiber per serving and (2) the sum of the grams of fiber plus the grams of protein per serving to be greater than the total grams of sugar (not grams of added sugar or grams of carbohydrate) per serving (FIGURE 1A). Unlike the relatively complicated formula related to GL, this 2-part rule can be applied in seconds while shopping (FIGURE 1B).

The rule is intended only to be used for packaged carbohydrate products, such as bread, muffins, bagels, pasta, rice, oatmeal, cereals, snack bars, chips, and crackers. It does not apply to whole foods, such as meat, dairy, fruits, or vegetables. These foods are excluded to prevent any consumer confusion related to the nutritional content of whole foods (eg, an apple may have more sugar than fiber and protein combined, but it is still a nutritious option).

Since the user does not need to have a smartphone, the Altman Rule may be more usable compared with more complicated alternatives.

This study aimed to determine if the Altman Rule is a reasonable proxy for the more complicated concept of GL. We calculated the relationship between the GL of commercially available packaged carbohydrate foods and whether those foods met the Altman Rule.

METHODS

The Altman Rule was tested by comparing the binary outcome of the rule (meets/does not meet) with data on all foods categorized as cereals, chips, crackers, and granola bars in the Nutrition Data System for Research (NDSR) Database (University of Minnesota, Version 2010).

Continue to: To account for differences...

To account for differences in serving size, we used the standard of 50 g for each product as 1 serving. We used 50 g (about 1.7 oz) to help compare the different foods and between foods within the same group. Additionally, 50 g is close to 1 serving for most foods in these groups; it is about the size of a typical granola bar, three-quarters to 2 cups of cereal, 10 to 12 crackers, and 15 to 25 chips. We determined the GL for each product by multiplying the number of available carbohydrates (total carbohydrate – dietary fiber) by the product’s glycemic index/100. In general, GL is categorized as low (≤ 10), medium (11-19), or high (≥ 20).

We applied the Altman Rule to categorize each product as meeting or not meeting the rule. We compared the proportion of foods meeting the Altman Rule, stratified by GL and by specific foods, and used chi-square to determine if differences were statistically significant. These data were collected and analyzed in the summer of 2019.

RESULTS

There were 1235 foods (342 breakfast cereals, 305 chips, 379 crackers, and 209 granola bars) used for this analysis. There is a significant relationship between the GL of foods and the Altman Rule in that most low-GL (68%), almost half of medium-GL (48%), and only a few high-GL foods (7%) met the rule (P < .001) (TABLE 1). There was also a significant relationship between “meeting the ­Altman Rule” and GL within each food type (P < .001) (TABLE 2).

The medium-GL foods were the second largest category of foods we calculated; thus we further broke them into binary categories of low-medium GL (values 11-14) and high-medium GL (values 15-19) to explore the results of the Altman Rule. About half of the foods in medium-GL category met the Altman Rule. About eighty-five percent of the foods with low-medium GL passed the Altman Rule, while only 39% of the foods with high-medium GL did.

Foods that met the rule were more likely to be low GL and foods that did not pass the rule were more likely high GL. Within the medium-GL category, foods that met the rule were more likely to be low-medium GL. 

Continue to: The findings within food categories...

The findings within food categories showed that very few cereals, chips, crackers, and granola bars were low GL. For every food category, except granola bars, far more low-GL foods met the Altman Rule than those that did not. At the same time, very few high-GL foods met the Altman Rule. The category with the most individual high-GL food items meeting the Altman Rule was cereal. This was also the subcategory with the largest percentage of high-GL food items meeting the Altman Rule. Thirty-nine cereals that were high GL met the rule, but more than 4 times as many high-GL cereals did not (n = 190).

DISCUSSION

Marketing and nutrition messaging create consumer confusion that makes it challenging to identify packaged food items that are more nutrient dense. The Altman Rule simplifies food choices that have become unnecessarily complex. Our findings suggest this 2-step rule is a reasonable proxy for the more complicated and less accessible GL for packaged carbohydrates, such as cereals, chips, crackers, and snack bars. Foods that meet the rule are likely low or low-medium GL and thus are foods that are likely to be healthier choices.

Our findings suggest this 2-step rule is a reasonable proxy for the more complicated and less accessible glycemic load for packaged carbohydrates.

Of note, only 9% of chips (n = 27) passed the Altman Rule, likely due to their low dietary fiber content, which was typical of chips. If a food item does not have at least 3 grams of total dietary fiber per serving, it does not pass the Altman Rule, regardless of how much protein or sugar is in the product. This may be considered a strength or a weakness of the Altman Rule. Few nutrition-dense foods are low in fiber, but some foods could be nutritious but do not meet the Altman Rule due to having < 3 g of fiber.

With the high prevalence of chronic diseases such as hypertension, diabetes, hyperlipidemia, and cardiovascular disease, it is essential to help consumers prevent chronic disease altogether or manage their chronic disease by providing tools to identify healthier food choices. The tool also has a place in clinical medicine for use by physicians and other health care professionals. Research shows that physicians find both time and lack of ­knowledge/resources to be a barrier to providing nutritional counseling to patients.¹⁰ Since the Altman Rule can be shared and explained with very little time and without extensive nutritional knowledge, it meets these needs.

Limitations

Glycemic load. We acknowledge that the Altman Rule is not foolproof and that assessing this rule based on GL has some limitations. GL is not a perfect or comprehensive way to measure the nutritional value of a food. For example, fruits such as watermelon and grapes are nutritionally dense. However, they contain high amounts of natural sugars—and as such, their GL is relatively high, which could lead a consumer to perceive them as unhealthy. Nevertheless, GL is both a useful and accepted tool and a reasonable way to assess the validity of the rule, specifically when assessing packaged carbohydrates. The simplicity of the Altman Rule and its relationship with GL makes it such that consumers are more likely to make a healthier food choice using it.⁹

Continue to: Specificity and sensitivity

Specificity and sensitivity. There are other limitations to the Altman Rule, given that a small number of high-GL foods meet the rule. For example, some granola bars had high dietary protein, which offset a high sugar content just enough to pass the rule despite a higher GL. As such, concluding that a snack bar is a healthier choice because it meets the Altman Rule when it has high amounts of sugar may not be appropriate. This limitation could be considered a lack of specificity (the rule includes food it ought not to include). Another limitation to consider would be a lack of sensitivity, given that only 68% of low-GL foods passed the Altman Rule. Since GL is associated with carbohydrate content, foods with a low carbohydrate count often have little to no fiber and thus would fall into the category of foods that did not meet the Altman Rule but had low GL. In this case, however, the low amount of fiber may render the Altman Rule a better indicator of a healthier food choice than the GL.

Hidden sugars. Foods with sugar alcohols and artificial sweeteners may be as deleterious as caloric alternatives while not being accounted for when reporting the grams of sugar per serving on the nutrition label.⁷ This may represent an exception to the Altman Rule, as foods that are not healthier choices may pass the rule because the sugar content on the nutrition label is, in a sense, artificially lowered. Future research may investigate the hypothesis that these foods are nutritionally inferior despite meeting the Altman Rule.

The sample. Our study also was limited to working only with foods that were included in the NDSR database up to 2010. This limitation is mitigated by the fact that the sample size was large (> 1000 packaged food items were included in our analyses). The study also could be limited by the food categories that were analyzed; food categories such as bread, rice, pasta, and bagels were not included.

The objective of this research was to investigate the relationship between GL and the Altman Rule, rather than to conduct an exhaustive analysis of the Altman Rule for every possible food category. Studying the relationship between the Altman Rule and GL in other categories of food is an objective for future research. The data so far support a relationship between these entities. The likelihood of the nutrition facts of foods changing without the GL changing (or vice versa) is very low. As such, the Altman Rule still seems to be a reasonable proxy of GL.

CONCLUSIONS

Research indicates that point-of-sale tools, such as Guiding Stars, NuVal, and other stoplight tools, can successfully alter consumers’ behaviors.⁹ These tools can be helpful but are not available in many supermarkets. Despite the limitations, the Altman Rule is a useful decision aid that is accessible to all consumers no matter where they live or shop and is easy to use and remember.

The Altman rule can be used in clinical practice by health care professionals, such as physicians, nurse practitioners, physician assistants, dietitians, and health coaches. It also has the potential to be used in commercial settings, such as grocery stores, to help consumers easily identify healthier convenience foods. This has public health implications, as the rule can both empower consumers and potentially incentivize food manufacturers to upgrade their products nutritionally.

Additional research would be useful to evaluate consumers’ preferences and perceptions about how user-friendly the Altman Rule is at the point of sale with packaged carbohydrate foods. This would help to further understand how the use of information on food packaging can motivate healthier decisions—thereby helping to alleviate the burden of chronic disease.

CORRESPONDENCE
Kimberly R. Dong, DrPH, MS, RDN, Tufts University School of Medicine, Department of Public Health and Community Medicine, 136 Harrison Avenue, MV Building, Boston, MA 02111; kimberly.dong@tufts.edu

Migraine is a headache disorder that often causes unilateral pain, photophobia, phonophobia, nausea, and vomiting. More than 70% of office visits for migraine are made to primary care physicians.¹ Recent data suggest migraine may be caused primarily by neuronal dysfunction and only secondarily by vasodilation.² Although there are numerous classes of drugs used for migraine prevention and treatment, their success has been limited by inadequate efficacy, tolerability, and patient adherence.³ The discovery of pro-inflammatory markers such as calcitonin gene-related peptide (CGRP) has led to the development of new medications to prevent and treat migraine.⁴

IMAGE: © SCOTT BODELL

Pathophysiology, Dx and triggers, indications for pharmacotherapy

Pathophysiology. A migraine is thought to be caused by cortical spreading depression (CSD), a depolarization of glial and neuronal cell membranes.⁵ This results in increased cortical excitability, central trigeminal-thalamic sensitization, and defective descending pain modulatory activity.⁶ The activation of the trigeminal sensory pathways, primarily the ophthalmic branch, sends nociceptive signals to second-order neurons mediated by the release of neurotransmitters, such as CGRPs.⁵ This activation explains in part the primary location for a migraine, which is around the eye and the neighboring cranial regions. The pain perceived by the patient is caused by these second-order neurons.

It has been theorized that gepants bind to calcitonin gene-related peptide receptors, resulting in decreased blood flow to the brain, inhibition of neurogenic inflammation, and reduced pain signaling.

Dx and triggers. In 2018, the International Headache Society revised its guidelines for the diagnosis of migraine.⁷ According to the 3rd edition of The International Classification of Headache Disorders (ICHD-3), the diagnosis of migraine is made when a patient has at least 5 headache attacks that last 4 to 72 hours and have at least 2 of the following characteristics: (1) unilateral location, (2) pulsating quality, (3) moderate-to-severe pain intensity, and (4) aggravated by or causing avoidance of routine physical activity.⁷ The headache attacks also should have (1) associated nausea or vomiting or (2) photophobia and phonophobia.⁷ The presence of atypical signs or symptoms as indicated by the SNNOOP10 mnemonic raises concerns for secondary headaches and the need for further investigation into the cause of the headache (TABLE 1).⁸ It is not possible to detect every secondary headache with standard neuroimaging, but the SNNOOP10 red flags can help determine when imaging may be indicated.⁸ Potential triggers for migraine can be found in TABLE 2.⁹

Indications for pharmacotherapy. All patients receiving a diagnosis of migraine should be offered acute pharmacologic treatment. Consider preventive therapy anytime there are ≥ 4 headache days per month, debilitating attacks despite acute therapy, overuse of acute medication (> 2 d/wk), difficulty tolerating acute medication, patient preference, or presence of certain migraine subtypes.^7,10

Acute treatments

Abortive therapies for migraine include analgesics such as nonsteroidal anti-­inflammatory drugs (NSAIDs) and acetaminophen, and ergot alkaloids, triptans, or small-molecule CGRP receptor antagonists (gepants). Prompt administration increases the chance of success with acute therapy. Medications with the highest levels of efficacy based on the 2015 guidelines from the American Headache Society (AHS) are given in TABLE 3.¹¹ Lasmiditan (Reyvow) is not included in the 2015 guidelines, as it was approved after publication of the guidelines.

Non-CGRP first-line therapies

NSAIDs and acetaminophen. NSAIDs such as aspirin, diclofenac, ibuprofen, and naproxen have a high level of evidence to support their use as first-line treatments for mild-to-moderate migraine attacks. Trials consistently demonstrate their superiority to placebo in headache relief and complete pain relief at 2 hours. There is no recommendation for selecting one NSAID over another; however, consider their frequency of dosing and ­adverse effect profiles. The number needed to treat for complete pain relief at 2 hours ranges from 7 to 10 for most NSAIDs.^11,12 In some placebo-controlled studies, acetaminophen was less effective than NSAIDs, but was safer because it did not cause gastric irritation or antiplatelet effects.¹²

Triptans inhibit 5-HT_1B/1D receptors. Consider formulation, route of administration, cost, and pharmacokinetics when selecting a triptan. Patients who do not respond well to one triptan may respond favorably to another. A meta-analysis of the effectiveness of the 7 available agents found that triptans at standard doses provided pain relief within 2 hours in 42% to 76% of patients, and sustained freedom from pain for 2 hours in 18% to 50% of patients.¹³ Lasmiditan is a selective serotonin receptor (5-HT_1F) agonist that lacks vasoconstrictor activity. This is an option for patients with relative contraindications to triptans due to cardiovascular risk factors.¹⁰

Continue to: Second-line therapies

 

 

Second-line therapies

Intranasal dihydroergotamine has a favorable adverse event profile and greater evidence for efficacy compared with ergotamine. Compared with triptans, intranasal dihydroergotamine has a high level of efficacy but causes more adverse effects.¹⁴ Severe nausea is common, and dihydroergotamine often is used in combination with an antiemetic drug. Dihydroergotamine should not be used within 24 hours of taking a triptan, and it is contraindicated for patients who have hypertension or ischemic heart disease or who are pregnant or breastfeeding. There is also the potential for adverse drug interactions.¹⁵

A meta-analysis found that triptans at standard doses provided pain relief within 2 hours in 42% to 76% of patients, and sustained freedom from pain for 2 hours in 18% to 50% of patients.

Antiemetics may be helpful for migraine associated with severe nausea or vomiting. The dopamine antagonists metoclopramide, prochlorperazine, and chlorpromazine have demonstrated benefit in randomized ­placebo-controlled trials.¹¹ Ondansetron has not been studied extensively, but sometimes is used in clinical practice. Nonoral routes of administration may be useful in patients having trouble swallowing medications or in those experiencing significant nausea or vomiting early during migraine attacks.

Due to the high potential for abuse, opioids should not be used routinely for the treatment of migraine.¹² There is no high-quality evidence supporting the efficacy of barbiturates (ie, butalbital-containing compounds) for acute migraine treatment.¹¹ Moreover, use of these agents may increase the likelihood of progression from episodic to chronic migraine.¹⁶

Gepants for acute migraine treatment

Neuropeptide CGRP is released from trigeminal nerves and is a potent dilator of cerebral and dural vessels, playing a key role in regulating blood flow to the brain. Other roles of CGRP include the release of inflammatory agents from mast cells and the transmission of painful stimuli from intracranial vessels.¹⁷ The CGRP receptor or ligand can be targeted by small-molecule receptor antagonists for acute and preventive migraine treatment (and by monoclonal antibodies solely for prevention, discussed later). It has been theorized that gepants bind to CGRP receptors, resulting in decreased blood flow to the brain, inhibition of neurogenic inflammation, and reduced pain signaling.¹⁷ Unlike triptans and ergotamine derivatives, these novel treatments do not constrict blood vessels and may have a unique role in patients with contraindications to triptans.

The 3 gepants approved for acute treatment—ubrogepant (Ubrelvy),¹⁸ rimegepant (Nurtec),¹⁹ and zavegepant (Zavzpret)²⁰—were compared with placebo in clinical trials and were shown to increase the number of patients who were completely pain free at 2 hours, were free of the most bothersome associated symptom (photophobia, phonophobia, or nausea) at 2 hours, and remained pain free at 24 hours (TABLE 4^18-24).

Continue to: Ubrogrepant

Ubrogepant, in 2 Phase 3 trials (ACHIEVE I and ACHIEVE II) demonstrated effectiveness compared with placebo.^21,22 The most common adverse effects reported were nausea and somnolence at very low rates. Pain-relief rates at 2 hours post dose (> 60% of participants) were higher than pain-free rates, and a significantly higher percentage (> 40%) of ubrogepant-treated participants reported ability to function normally on the Functional Disability Scale.²⁵

Rimegepant was also superior to placebo (59% vs 43%) in pain relief at 2 hours post dose and other secondary endpoints.²³ Rimegepant also has potential drug interactions and dose adjustments (TABLE 4^18-24).

Zavegepant, approved in March 2023, is administered once daily as a 10-mg nasal spray. In its Phase 3 trial, zavegepant was significantly superior to placebo at 2 hours post dose in freedom from pain (24% v 15%), and in freedom from the most bothersome symptom (40% v 31%).²⁴ Dosage modifications are not needed with mild-to-moderate renal or hepatic disease.²⁰

Worth noting. The safety of using ubrogepant to treat more than 8 migraine episodes in a 30-day period has not been established. The safety of using more than 18 doses of zavegepant in a 30-day period also has not been established. With ubrogepant and rimegepant, there are dosing modifications for concomitant use with specific drugs (CYP3A4 inhibitors and inducers) due to potential interactions and in patients with hepatic or renal impairment.^18,19

There are no trials comparing efficacy of CGRP antagonists to triptans. Recognizing that these newer medications would be costly, the AHS position statement released in 2019 recommends that gepants be considered for those with contraindications to triptans or for whom at least 2 oral triptans have failed (as determined by a validated patient outcome questionnaire).¹⁰ Step therapy with documentation of previous trials and therapy failures is often required by insurance companies prior to gepant coverage.

Continue to: Preventive therapies

Preventive therapies

Preventive migraine therapies are used to reduce duration, frequency, and severity of attacks, the need for acute treatment, and overall headache disability.²⁶ Medications typically are chosen based on efficacy, adverse effect profile, and patient comorbidities. Barriers to successful use include poor patient adherence and tolerability, the need for slow dose titration, and long-term use (minimum of 2 months) at maximum tolerated or minimum effective doses. Medications with established efficacy (Level A^a) based on the 2012 guidelines from the American Academy of Neurology (AAN) and the AHS are given in TABLE 5.^27-29

Drugs having received the strongest level of evidence for migraine prevention are metoprolol, propranolol, timolol, topiramate, valproate sodium, divalproex sodium, and onabotulinumtoxinA (Botox), and frovatriptan for menstrual migraine prevention. Because these guidelines were last updated in 2012, they did not cover gepants (which will be discussed shortly). The AHS released a position statement in 2019 supporting the use of anti-CGRP monoclonal antibodies (mAbs) in those who cannot tolerate or have had an inadequate response to a 6-week trial of at least 2 AAN/AHA Level A or B^b treatments.¹⁰ No head-to-head trials exist between non-CGRP preventive therapies and the CGRP antagonists.

CGRP-targeted prevention

Four anti-CGRP mAbs and 2 gepants have been approved for migraine prevention in the United States. Differences between products include targets (ligand vs receptor), antibody IgG subtype, bioavailability, route of administration, and frequency of administration.²⁸ As noted in the Phase 3 studies (TABLE 6^19,30-47), these therapies are highly efficacious, safe, and tolerable.

Gepants. Rimegepant, discussed earlier for migraine treatment, is one of the CGRP receptor antagonists approved for prevention. The other is atogepant (Qulipta), approved only for prevention. Ubrogepant is not approved for prevention.

Anti-CGRP mAb is the only medication class specifically created for migraine prevention.^10,26 As already noted, several efficacious non-CGRP treatment options are available for migraine prevention. However, higher doses of those agents, if needed, can lead to intolerable adverse effects for some patients, thereby limiting overall efficacy. ­Anti-CGRP mAbs, a targeted, highly efficacious treatment option, offer efficacy comparable to non-CGRP agents with a more favorable adverse effect profile for those who cannot tolerate or achieve only minimal efficacy with traditional preventive therapies.¹⁰

Continue to: The targeted anti-CGRP approach...

The targeted anti-CGRP approach, which can be used by patients with liver or kidney disease, results in decreased toxicity and minimal drug interactions. Long half-lives allow for monthly or quarterly injections, possibly resulting in increased compliance.²⁸ Dose titration is not needed, allowing for more rapid symptom management. The large molecular size of a mAb limits its transfer across the blood-brain barrier, making central nervous system adverse effects unlikely.²⁸ Despite the compelling mAb pharmacologic properties, their use may be limited by a lack of long-term safety data and the need for parenteral administration. Although ­immunogenicity—the development of neutralizing antibodies—can limit long-term tolerability or efficacy of mAbs generally,^26,28 anti-CGRP mAbs were engineered to minimally activate the immune system and have not been associated with immune suppression, opportunistic infections, malignancies, or decreased efficacy.²⁸

Unlike triptans and ergotamine derivatives, gepants do not constrict blood vessels and may have a unique role in patients with contraindications to triptans.

A pooled meta-analysis including 4 trials (3166 patients) found that CGRP mAbs compared with placebo significantly improved patient response rates, defined as at least a 50% and 75% reduction in monthly ­headache/migraine days from baseline to Weeks 9 to 12.⁴⁸ Another meta-analysis including 8 trials (2292 patients) found a significant reduction from baseline in monthly migraine days and monthly acute migraine medication consumption among patients taking CGRP mAbs compared with those taking placebo.⁴⁹ Open-label extension studies have shown progressive and cumulative benefits in individuals who respond to anti-CGRP mAbs. Therefore, several treatment cycles may be necessary to determine overall efficacy of therapy.^10,28

Cost initially can be a barrier. Insurance companies often require step therapy before agreeing to cover mAb therapy, which aligns with the 2019 AHS position statement.¹⁰ Due to differences in insurance coverage, out-of-pocket expenses can vary greatly. However, options are available through online manufacturer assistance to reduce cost, making it comparable to other migraine treatments. Safety and efficacy studies of anti-CGRP mAbs use in pregnant individuals are limited. At this time, they should not be prescribed for those who are pregnant, planning to become pregnant, or breastfeeding. Counsel nonpregnant patients on appropriate contraception while using a mAb due to possible teratogenicity and negative pregnancy outcomes.^28,50

When combination treatment may be appropriate

Monotherapy is the usual approach to preventing migraine due to advantages of efficacy, simplified regimens, lower cost, and reduced adverse effects.⁵¹ However, if a patient does not benefit from monotherapy even after trying dose titrations as tolerated or switching therapies, trying complementary combination therapy is appropriate. Despite a shortage of clinical trials supporting the use of 2 or more preventive medications with different mechanisms of action, this strategy is used clinically.¹⁰ Consider combination therapy in those with refractory disease, partial responses, or intolerance to recommended doses.⁵² Articles reporting on case study reviews have rationalized the combined use of onabotulinumtoxinA and anti-CGRP mAbs, noting better migraine control.^51,53 The 2019 AHS position statement recommends adding a mAb to an existing preventive treatment regimen with no other changes until mAb effectiveness is determined, as the risk for drug interactions on dual therapy is low.¹⁰ Safety and efficacy also have been demonstrated with the combination of preventive anti-CGRP mAbs and acute treatment with gepants as needed.⁵⁴

Monoclonal antibodies are highly efficacious options for those who cannot tolerate or achieve only minimal efficacy with traditional preventive therapies.

Overall, gepants and mAbs are as effective as traditional acute and preventive treatments for migraine, and they cause fewer adverse effects and often allow a more simplified regimen. Gepants and mAbs are viable options in the primary care setting. Due to limited long-term data and high cost, however, they routinely are used for refractory migraine rather than as first-line agents. These therapies are especially favorable options for patients when traditional migraine therapies yield inadequate efficacy, cause intolerable adverse effects, are contraindicated, or introduce the risk for medication interactions.

CORRESPONDENCE
Emily Peterson, PharmD, BCACP, 3640 Middlebury Road, Iowa City, IA 52242; Emily-a-peterson@uiowa.edu

Migraine is a headache disorder that often causes unilateral pain, photophobia, phonophobia, nausea, and vomiting. More than 70% of office visits for migraine are made to primary care physicians.¹ Recent data suggest migraine may be caused primarily by neuronal dysfunction and only secondarily by vasodilation.² Although there are numerous classes of drugs used for migraine prevention and treatment, their success has been limited by inadequate efficacy, tolerability, and patient adherence.³ The discovery of pro-inflammatory markers such as calcitonin gene-related peptide (CGRP) has led to the development of new medications to prevent and treat migraine.⁴

IMAGE: © SCOTT BODELL

Pathophysiology, Dx and triggers, indications for pharmacotherapy

Pathophysiology. A migraine is thought to be caused by cortical spreading depression (CSD), a depolarization of glial and neuronal cell membranes.⁵ This results in increased cortical excitability, central trigeminal-thalamic sensitization, and defective descending pain modulatory activity.⁶ The activation of the trigeminal sensory pathways, primarily the ophthalmic branch, sends nociceptive signals to second-order neurons mediated by the release of neurotransmitters, such as CGRPs.⁵ This activation explains in part the primary location for a migraine, which is around the eye and the neighboring cranial regions. The pain perceived by the patient is caused by these second-order neurons.

It has been theorized that gepants bind to calcitonin gene-related peptide receptors, resulting in decreased blood flow to the brain, inhibition of neurogenic inflammation, and reduced pain signaling.

Dx and triggers. In 2018, the International Headache Society revised its guidelines for the diagnosis of migraine.⁷ According to the 3rd edition of The International Classification of Headache Disorders (ICHD-3), the diagnosis of migraine is made when a patient has at least 5 headache attacks that last 4 to 72 hours and have at least 2 of the following characteristics: (1) unilateral location, (2) pulsating quality, (3) moderate-to-severe pain intensity, and (4) aggravated by or causing avoidance of routine physical activity.⁷ The headache attacks also should have (1) associated nausea or vomiting or (2) photophobia and phonophobia.⁷ The presence of atypical signs or symptoms as indicated by the SNNOOP10 mnemonic raises concerns for secondary headaches and the need for further investigation into the cause of the headache (TABLE 1).⁸ It is not possible to detect every secondary headache with standard neuroimaging, but the SNNOOP10 red flags can help determine when imaging may be indicated.⁸ Potential triggers for migraine can be found in TABLE 2.⁹

Indications for pharmacotherapy. All patients receiving a diagnosis of migraine should be offered acute pharmacologic treatment. Consider preventive therapy anytime there are ≥ 4 headache days per month, debilitating attacks despite acute therapy, overuse of acute medication (> 2 d/wk), difficulty tolerating acute medication, patient preference, or presence of certain migraine subtypes.^7,10

Acute treatments

Abortive therapies for migraine include analgesics such as nonsteroidal anti-­inflammatory drugs (NSAIDs) and acetaminophen, and ergot alkaloids, triptans, or small-molecule CGRP receptor antagonists (gepants). Prompt administration increases the chance of success with acute therapy. Medications with the highest levels of efficacy based on the 2015 guidelines from the American Headache Society (AHS) are given in TABLE 3.¹¹ Lasmiditan (Reyvow) is not included in the 2015 guidelines, as it was approved after publication of the guidelines.

Non-CGRP first-line therapies

NSAIDs and acetaminophen. NSAIDs such as aspirin, diclofenac, ibuprofen, and naproxen have a high level of evidence to support their use as first-line treatments for mild-to-moderate migraine attacks. Trials consistently demonstrate their superiority to placebo in headache relief and complete pain relief at 2 hours. There is no recommendation for selecting one NSAID over another; however, consider their frequency of dosing and ­adverse effect profiles. The number needed to treat for complete pain relief at 2 hours ranges from 7 to 10 for most NSAIDs.^11,12 In some placebo-controlled studies, acetaminophen was less effective than NSAIDs, but was safer because it did not cause gastric irritation or antiplatelet effects.¹²

Triptans inhibit 5-HT_1B/1D receptors. Consider formulation, route of administration, cost, and pharmacokinetics when selecting a triptan. Patients who do not respond well to one triptan may respond favorably to another. A meta-analysis of the effectiveness of the 7 available agents found that triptans at standard doses provided pain relief within 2 hours in 42% to 76% of patients, and sustained freedom from pain for 2 hours in 18% to 50% of patients.¹³ Lasmiditan is a selective serotonin receptor (5-HT_1F) agonist that lacks vasoconstrictor activity. This is an option for patients with relative contraindications to triptans due to cardiovascular risk factors.¹⁰

Continue to: Second-line therapies

 

 

Second-line therapies

Intranasal dihydroergotamine has a favorable adverse event profile and greater evidence for efficacy compared with ergotamine. Compared with triptans, intranasal dihydroergotamine has a high level of efficacy but causes more adverse effects.¹⁴ Severe nausea is common, and dihydroergotamine often is used in combination with an antiemetic drug. Dihydroergotamine should not be used within 24 hours of taking a triptan, and it is contraindicated for patients who have hypertension or ischemic heart disease or who are pregnant or breastfeeding. There is also the potential for adverse drug interactions.¹⁵

A meta-analysis found that triptans at standard doses provided pain relief within 2 hours in 42% to 76% of patients, and sustained freedom from pain for 2 hours in 18% to 50% of patients.

Antiemetics may be helpful for migraine associated with severe nausea or vomiting. The dopamine antagonists metoclopramide, prochlorperazine, and chlorpromazine have demonstrated benefit in randomized ­placebo-controlled trials.¹¹ Ondansetron has not been studied extensively, but sometimes is used in clinical practice. Nonoral routes of administration may be useful in patients having trouble swallowing medications or in those experiencing significant nausea or vomiting early during migraine attacks.

Due to the high potential for abuse, opioids should not be used routinely for the treatment of migraine.¹² There is no high-quality evidence supporting the efficacy of barbiturates (ie, butalbital-containing compounds) for acute migraine treatment.¹¹ Moreover, use of these agents may increase the likelihood of progression from episodic to chronic migraine.¹⁶

Gepants for acute migraine treatment

Neuropeptide CGRP is released from trigeminal nerves and is a potent dilator of cerebral and dural vessels, playing a key role in regulating blood flow to the brain. Other roles of CGRP include the release of inflammatory agents from mast cells and the transmission of painful stimuli from intracranial vessels.¹⁷ The CGRP receptor or ligand can be targeted by small-molecule receptor antagonists for acute and preventive migraine treatment (and by monoclonal antibodies solely for prevention, discussed later). It has been theorized that gepants bind to CGRP receptors, resulting in decreased blood flow to the brain, inhibition of neurogenic inflammation, and reduced pain signaling.¹⁷ Unlike triptans and ergotamine derivatives, these novel treatments do not constrict blood vessels and may have a unique role in patients with contraindications to triptans.

The 3 gepants approved for acute treatment—ubrogepant (Ubrelvy),¹⁸ rimegepant (Nurtec),¹⁹ and zavegepant (Zavzpret)²⁰—were compared with placebo in clinical trials and were shown to increase the number of patients who were completely pain free at 2 hours, were free of the most bothersome associated symptom (photophobia, phonophobia, or nausea) at 2 hours, and remained pain free at 24 hours (TABLE 4^18-24).

Continue to: Ubrogrepant

Ubrogepant, in 2 Phase 3 trials (ACHIEVE I and ACHIEVE II) demonstrated effectiveness compared with placebo.^21,22 The most common adverse effects reported were nausea and somnolence at very low rates. Pain-relief rates at 2 hours post dose (> 60% of participants) were higher than pain-free rates, and a significantly higher percentage (> 40%) of ubrogepant-treated participants reported ability to function normally on the Functional Disability Scale.²⁵

Rimegepant was also superior to placebo (59% vs 43%) in pain relief at 2 hours post dose and other secondary endpoints.²³ Rimegepant also has potential drug interactions and dose adjustments (TABLE 4^18-24).

Zavegepant, approved in March 2023, is administered once daily as a 10-mg nasal spray. In its Phase 3 trial, zavegepant was significantly superior to placebo at 2 hours post dose in freedom from pain (24% v 15%), and in freedom from the most bothersome symptom (40% v 31%).²⁴ Dosage modifications are not needed with mild-to-moderate renal or hepatic disease.²⁰

Worth noting. The safety of using ubrogepant to treat more than 8 migraine episodes in a 30-day period has not been established. The safety of using more than 18 doses of zavegepant in a 30-day period also has not been established. With ubrogepant and rimegepant, there are dosing modifications for concomitant use with specific drugs (CYP3A4 inhibitors and inducers) due to potential interactions and in patients with hepatic or renal impairment.^18,19

There are no trials comparing efficacy of CGRP antagonists to triptans. Recognizing that these newer medications would be costly, the AHS position statement released in 2019 recommends that gepants be considered for those with contraindications to triptans or for whom at least 2 oral triptans have failed (as determined by a validated patient outcome questionnaire).¹⁰ Step therapy with documentation of previous trials and therapy failures is often required by insurance companies prior to gepant coverage.

Continue to: Preventive therapies

Preventive therapies

Preventive migraine therapies are used to reduce duration, frequency, and severity of attacks, the need for acute treatment, and overall headache disability.²⁶ Medications typically are chosen based on efficacy, adverse effect profile, and patient comorbidities. Barriers to successful use include poor patient adherence and tolerability, the need for slow dose titration, and long-term use (minimum of 2 months) at maximum tolerated or minimum effective doses. Medications with established efficacy (Level A^a) based on the 2012 guidelines from the American Academy of Neurology (AAN) and the AHS are given in TABLE 5.^27-29

Drugs having received the strongest level of evidence for migraine prevention are metoprolol, propranolol, timolol, topiramate, valproate sodium, divalproex sodium, and onabotulinumtoxinA (Botox), and frovatriptan for menstrual migraine prevention. Because these guidelines were last updated in 2012, they did not cover gepants (which will be discussed shortly). The AHS released a position statement in 2019 supporting the use of anti-CGRP monoclonal antibodies (mAbs) in those who cannot tolerate or have had an inadequate response to a 6-week trial of at least 2 AAN/AHA Level A or B^b treatments.¹⁰ No head-to-head trials exist between non-CGRP preventive therapies and the CGRP antagonists.

CGRP-targeted prevention

Four anti-CGRP mAbs and 2 gepants have been approved for migraine prevention in the United States. Differences between products include targets (ligand vs receptor), antibody IgG subtype, bioavailability, route of administration, and frequency of administration.²⁸ As noted in the Phase 3 studies (TABLE 6^19,30-47), these therapies are highly efficacious, safe, and tolerable.

Gepants. Rimegepant, discussed earlier for migraine treatment, is one of the CGRP receptor antagonists approved for prevention. The other is atogepant (Qulipta), approved only for prevention. Ubrogepant is not approved for prevention.

Anti-CGRP mAb is the only medication class specifically created for migraine prevention.^10,26 As already noted, several efficacious non-CGRP treatment options are available for migraine prevention. However, higher doses of those agents, if needed, can lead to intolerable adverse effects for some patients, thereby limiting overall efficacy. ­Anti-CGRP mAbs, a targeted, highly efficacious treatment option, offer efficacy comparable to non-CGRP agents with a more favorable adverse effect profile for those who cannot tolerate or achieve only minimal efficacy with traditional preventive therapies.¹⁰

Continue to: The targeted anti-CGRP approach...

The targeted anti-CGRP approach, which can be used by patients with liver or kidney disease, results in decreased toxicity and minimal drug interactions. Long half-lives allow for monthly or quarterly injections, possibly resulting in increased compliance.²⁸ Dose titration is not needed, allowing for more rapid symptom management. The large molecular size of a mAb limits its transfer across the blood-brain barrier, making central nervous system adverse effects unlikely.²⁸ Despite the compelling mAb pharmacologic properties, their use may be limited by a lack of long-term safety data and the need for parenteral administration. Although ­immunogenicity—the development of neutralizing antibodies—can limit long-term tolerability or efficacy of mAbs generally,^26,28 anti-CGRP mAbs were engineered to minimally activate the immune system and have not been associated with immune suppression, opportunistic infections, malignancies, or decreased efficacy.²⁸

Unlike triptans and ergotamine derivatives, gepants do not constrict blood vessels and may have a unique role in patients with contraindications to triptans.

A pooled meta-analysis including 4 trials (3166 patients) found that CGRP mAbs compared with placebo significantly improved patient response rates, defined as at least a 50% and 75% reduction in monthly ­headache/migraine days from baseline to Weeks 9 to 12.⁴⁸ Another meta-analysis including 8 trials (2292 patients) found a significant reduction from baseline in monthly migraine days and monthly acute migraine medication consumption among patients taking CGRP mAbs compared with those taking placebo.⁴⁹ Open-label extension studies have shown progressive and cumulative benefits in individuals who respond to anti-CGRP mAbs. Therefore, several treatment cycles may be necessary to determine overall efficacy of therapy.^10,28

Cost initially can be a barrier. Insurance companies often require step therapy before agreeing to cover mAb therapy, which aligns with the 2019 AHS position statement.¹⁰ Due to differences in insurance coverage, out-of-pocket expenses can vary greatly. However, options are available through online manufacturer assistance to reduce cost, making it comparable to other migraine treatments. Safety and efficacy studies of anti-CGRP mAbs use in pregnant individuals are limited. At this time, they should not be prescribed for those who are pregnant, planning to become pregnant, or breastfeeding. Counsel nonpregnant patients on appropriate contraception while using a mAb due to possible teratogenicity and negative pregnancy outcomes.^28,50

When combination treatment may be appropriate

Monotherapy is the usual approach to preventing migraine due to advantages of efficacy, simplified regimens, lower cost, and reduced adverse effects.⁵¹ However, if a patient does not benefit from monotherapy even after trying dose titrations as tolerated or switching therapies, trying complementary combination therapy is appropriate. Despite a shortage of clinical trials supporting the use of 2 or more preventive medications with different mechanisms of action, this strategy is used clinically.¹⁰ Consider combination therapy in those with refractory disease, partial responses, or intolerance to recommended doses.⁵² Articles reporting on case study reviews have rationalized the combined use of onabotulinumtoxinA and anti-CGRP mAbs, noting better migraine control.^51,53 The 2019 AHS position statement recommends adding a mAb to an existing preventive treatment regimen with no other changes until mAb effectiveness is determined, as the risk for drug interactions on dual therapy is low.¹⁰ Safety and efficacy also have been demonstrated with the combination of preventive anti-CGRP mAbs and acute treatment with gepants as needed.⁵⁴

Monoclonal antibodies are highly efficacious options for those who cannot tolerate or achieve only minimal efficacy with traditional preventive therapies.

Overall, gepants and mAbs are as effective as traditional acute and preventive treatments for migraine, and they cause fewer adverse effects and often allow a more simplified regimen. Gepants and mAbs are viable options in the primary care setting. Due to limited long-term data and high cost, however, they routinely are used for refractory migraine rather than as first-line agents. These therapies are especially favorable options for patients when traditional migraine therapies yield inadequate efficacy, cause intolerable adverse effects, are contraindicated, or introduce the risk for medication interactions.

CORRESPONDENCE
Emily Peterson, PharmD, BCACP, 3640 Middlebury Road, Iowa City, IA 52242; Emily-a-peterson@uiowa.edu

Migraine is a headache disorder that often causes unilateral pain, photophobia, phonophobia, nausea, and vomiting. More than 70% of office visits for migraine are made to primary care physicians.¹ Recent data suggest migraine may be caused primarily by neuronal dysfunction and only secondarily by vasodilation.² Although there are numerous classes of drugs used for migraine prevention and treatment, their success has been limited by inadequate efficacy, tolerability, and patient adherence.³ The discovery of pro-inflammatory markers such as calcitonin gene-related peptide (CGRP) has led to the development of new medications to prevent and treat migraine.⁴

IMAGE: © SCOTT BODELL

Pathophysiology, Dx and triggers, indications for pharmacotherapy

Pathophysiology. A migraine is thought to be caused by cortical spreading depression (CSD), a depolarization of glial and neuronal cell membranes.⁵ This results in increased cortical excitability, central trigeminal-thalamic sensitization, and defective descending pain modulatory activity.⁶ The activation of the trigeminal sensory pathways, primarily the ophthalmic branch, sends nociceptive signals to second-order neurons mediated by the release of neurotransmitters, such as CGRPs.⁵ This activation explains in part the primary location for a migraine, which is around the eye and the neighboring cranial regions. The pain perceived by the patient is caused by these second-order neurons.

It has been theorized that gepants bind to calcitonin gene-related peptide receptors, resulting in decreased blood flow to the brain, inhibition of neurogenic inflammation, and reduced pain signaling.

Dx and triggers. In 2018, the International Headache Society revised its guidelines for the diagnosis of migraine.⁷ According to the 3rd edition of The International Classification of Headache Disorders (ICHD-3), the diagnosis of migraine is made when a patient has at least 5 headache attacks that last 4 to 72 hours and have at least 2 of the following characteristics: (1) unilateral location, (2) pulsating quality, (3) moderate-to-severe pain intensity, and (4) aggravated by or causing avoidance of routine physical activity.⁷ The headache attacks also should have (1) associated nausea or vomiting or (2) photophobia and phonophobia.⁷ The presence of atypical signs or symptoms as indicated by the SNNOOP10 mnemonic raises concerns for secondary headaches and the need for further investigation into the cause of the headache (TABLE 1).⁸ It is not possible to detect every secondary headache with standard neuroimaging, but the SNNOOP10 red flags can help determine when imaging may be indicated.⁸ Potential triggers for migraine can be found in TABLE 2.⁹

Indications for pharmacotherapy. All patients receiving a diagnosis of migraine should be offered acute pharmacologic treatment. Consider preventive therapy anytime there are ≥ 4 headache days per month, debilitating attacks despite acute therapy, overuse of acute medication (> 2 d/wk), difficulty tolerating acute medication, patient preference, or presence of certain migraine subtypes.^7,10

Acute treatments

Abortive therapies for migraine include analgesics such as nonsteroidal anti-­inflammatory drugs (NSAIDs) and acetaminophen, and ergot alkaloids, triptans, or small-molecule CGRP receptor antagonists (gepants). Prompt administration increases the chance of success with acute therapy. Medications with the highest levels of efficacy based on the 2015 guidelines from the American Headache Society (AHS) are given in TABLE 3.¹¹ Lasmiditan (Reyvow) is not included in the 2015 guidelines, as it was approved after publication of the guidelines.

Non-CGRP first-line therapies

NSAIDs and acetaminophen. NSAIDs such as aspirin, diclofenac, ibuprofen, and naproxen have a high level of evidence to support their use as first-line treatments for mild-to-moderate migraine attacks. Trials consistently demonstrate their superiority to placebo in headache relief and complete pain relief at 2 hours. There is no recommendation for selecting one NSAID over another; however, consider their frequency of dosing and ­adverse effect profiles. The number needed to treat for complete pain relief at 2 hours ranges from 7 to 10 for most NSAIDs.^11,12 In some placebo-controlled studies, acetaminophen was less effective than NSAIDs, but was safer because it did not cause gastric irritation or antiplatelet effects.¹²

Triptans inhibit 5-HT_1B/1D receptors. Consider formulation, route of administration, cost, and pharmacokinetics when selecting a triptan. Patients who do not respond well to one triptan may respond favorably to another. A meta-analysis of the effectiveness of the 7 available agents found that triptans at standard doses provided pain relief within 2 hours in 42% to 76% of patients, and sustained freedom from pain for 2 hours in 18% to 50% of patients.¹³ Lasmiditan is a selective serotonin receptor (5-HT_1F) agonist that lacks vasoconstrictor activity. This is an option for patients with relative contraindications to triptans due to cardiovascular risk factors.¹⁰

Continue to: Second-line therapies

 

 

Second-line therapies

Intranasal dihydroergotamine has a favorable adverse event profile and greater evidence for efficacy compared with ergotamine. Compared with triptans, intranasal dihydroergotamine has a high level of efficacy but causes more adverse effects.¹⁴ Severe nausea is common, and dihydroergotamine often is used in combination with an antiemetic drug. Dihydroergotamine should not be used within 24 hours of taking a triptan, and it is contraindicated for patients who have hypertension or ischemic heart disease or who are pregnant or breastfeeding. There is also the potential for adverse drug interactions.¹⁵

A meta-analysis found that triptans at standard doses provided pain relief within 2 hours in 42% to 76% of patients, and sustained freedom from pain for 2 hours in 18% to 50% of patients.

Antiemetics may be helpful for migraine associated with severe nausea or vomiting. The dopamine antagonists metoclopramide, prochlorperazine, and chlorpromazine have demonstrated benefit in randomized ­placebo-controlled trials.¹¹ Ondansetron has not been studied extensively, but sometimes is used in clinical practice. Nonoral routes of administration may be useful in patients having trouble swallowing medications or in those experiencing significant nausea or vomiting early during migraine attacks.

Due to the high potential for abuse, opioids should not be used routinely for the treatment of migraine.¹² There is no high-quality evidence supporting the efficacy of barbiturates (ie, butalbital-containing compounds) for acute migraine treatment.¹¹ Moreover, use of these agents may increase the likelihood of progression from episodic to chronic migraine.¹⁶

Gepants for acute migraine treatment

Neuropeptide CGRP is released from trigeminal nerves and is a potent dilator of cerebral and dural vessels, playing a key role in regulating blood flow to the brain. Other roles of CGRP include the release of inflammatory agents from mast cells and the transmission of painful stimuli from intracranial vessels.¹⁷ The CGRP receptor or ligand can be targeted by small-molecule receptor antagonists for acute and preventive migraine treatment (and by monoclonal antibodies solely for prevention, discussed later). It has been theorized that gepants bind to CGRP receptors, resulting in decreased blood flow to the brain, inhibition of neurogenic inflammation, and reduced pain signaling.¹⁷ Unlike triptans and ergotamine derivatives, these novel treatments do not constrict blood vessels and may have a unique role in patients with contraindications to triptans.

The 3 gepants approved for acute treatment—ubrogepant (Ubrelvy),¹⁸ rimegepant (Nurtec),¹⁹ and zavegepant (Zavzpret)²⁰—were compared with placebo in clinical trials and were shown to increase the number of patients who were completely pain free at 2 hours, were free of the most bothersome associated symptom (photophobia, phonophobia, or nausea) at 2 hours, and remained pain free at 24 hours (TABLE 4^18-24).

Continue to: Ubrogrepant

Ubrogepant, in 2 Phase 3 trials (ACHIEVE I and ACHIEVE II) demonstrated effectiveness compared with placebo.^21,22 The most common adverse effects reported were nausea and somnolence at very low rates. Pain-relief rates at 2 hours post dose (> 60% of participants) were higher than pain-free rates, and a significantly higher percentage (> 40%) of ubrogepant-treated participants reported ability to function normally on the Functional Disability Scale.²⁵

Rimegepant was also superior to placebo (59% vs 43%) in pain relief at 2 hours post dose and other secondary endpoints.²³ Rimegepant also has potential drug interactions and dose adjustments (TABLE 4^18-24).

Zavegepant, approved in March 2023, is administered once daily as a 10-mg nasal spray. In its Phase 3 trial, zavegepant was significantly superior to placebo at 2 hours post dose in freedom from pain (24% v 15%), and in freedom from the most bothersome symptom (40% v 31%).²⁴ Dosage modifications are not needed with mild-to-moderate renal or hepatic disease.²⁰

Worth noting. The safety of using ubrogepant to treat more than 8 migraine episodes in a 30-day period has not been established. The safety of using more than 18 doses of zavegepant in a 30-day period also has not been established. With ubrogepant and rimegepant, there are dosing modifications for concomitant use with specific drugs (CYP3A4 inhibitors and inducers) due to potential interactions and in patients with hepatic or renal impairment.^18,19

There are no trials comparing efficacy of CGRP antagonists to triptans. Recognizing that these newer medications would be costly, the AHS position statement released in 2019 recommends that gepants be considered for those with contraindications to triptans or for whom at least 2 oral triptans have failed (as determined by a validated patient outcome questionnaire).¹⁰ Step therapy with documentation of previous trials and therapy failures is often required by insurance companies prior to gepant coverage.

Continue to: Preventive therapies

Preventive therapies

Preventive migraine therapies are used to reduce duration, frequency, and severity of attacks, the need for acute treatment, and overall headache disability.²⁶ Medications typically are chosen based on efficacy, adverse effect profile, and patient comorbidities. Barriers to successful use include poor patient adherence and tolerability, the need for slow dose titration, and long-term use (minimum of 2 months) at maximum tolerated or minimum effective doses. Medications with established efficacy (Level A^a) based on the 2012 guidelines from the American Academy of Neurology (AAN) and the AHS are given in TABLE 5.^27-29

Drugs having received the strongest level of evidence for migraine prevention are metoprolol, propranolol, timolol, topiramate, valproate sodium, divalproex sodium, and onabotulinumtoxinA (Botox), and frovatriptan for menstrual migraine prevention. Because these guidelines were last updated in 2012, they did not cover gepants (which will be discussed shortly). The AHS released a position statement in 2019 supporting the use of anti-CGRP monoclonal antibodies (mAbs) in those who cannot tolerate or have had an inadequate response to a 6-week trial of at least 2 AAN/AHA Level A or B^b treatments.¹⁰ No head-to-head trials exist between non-CGRP preventive therapies and the CGRP antagonists.

CGRP-targeted prevention

Four anti-CGRP mAbs and 2 gepants have been approved for migraine prevention in the United States. Differences between products include targets (ligand vs receptor), antibody IgG subtype, bioavailability, route of administration, and frequency of administration.²⁸ As noted in the Phase 3 studies (TABLE 6^19,30-47), these therapies are highly efficacious, safe, and tolerable.

Gepants. Rimegepant, discussed earlier for migraine treatment, is one of the CGRP receptor antagonists approved for prevention. The other is atogepant (Qulipta), approved only for prevention. Ubrogepant is not approved for prevention.

Anti-CGRP mAb is the only medication class specifically created for migraine prevention.^10,26 As already noted, several efficacious non-CGRP treatment options are available for migraine prevention. However, higher doses of those agents, if needed, can lead to intolerable adverse effects for some patients, thereby limiting overall efficacy. ­Anti-CGRP mAbs, a targeted, highly efficacious treatment option, offer efficacy comparable to non-CGRP agents with a more favorable adverse effect profile for those who cannot tolerate or achieve only minimal efficacy with traditional preventive therapies.¹⁰

Continue to: The targeted anti-CGRP approach...

The targeted anti-CGRP approach, which can be used by patients with liver or kidney disease, results in decreased toxicity and minimal drug interactions. Long half-lives allow for monthly or quarterly injections, possibly resulting in increased compliance.²⁸ Dose titration is not needed, allowing for more rapid symptom management. The large molecular size of a mAb limits its transfer across the blood-brain barrier, making central nervous system adverse effects unlikely.²⁸ Despite the compelling mAb pharmacologic properties, their use may be limited by a lack of long-term safety data and the need for parenteral administration. Although ­immunogenicity—the development of neutralizing antibodies—can limit long-term tolerability or efficacy of mAbs generally,^26,28 anti-CGRP mAbs were engineered to minimally activate the immune system and have not been associated with immune suppression, opportunistic infections, malignancies, or decreased efficacy.²⁸

Unlike triptans and ergotamine derivatives, gepants do not constrict blood vessels and may have a unique role in patients with contraindications to triptans.

A pooled meta-analysis including 4 trials (3166 patients) found that CGRP mAbs compared with placebo significantly improved patient response rates, defined as at least a 50% and 75% reduction in monthly ­headache/migraine days from baseline to Weeks 9 to 12.⁴⁸ Another meta-analysis including 8 trials (2292 patients) found a significant reduction from baseline in monthly migraine days and monthly acute migraine medication consumption among patients taking CGRP mAbs compared with those taking placebo.⁴⁹ Open-label extension studies have shown progressive and cumulative benefits in individuals who respond to anti-CGRP mAbs. Therefore, several treatment cycles may be necessary to determine overall efficacy of therapy.^10,28

Cost initially can be a barrier. Insurance companies often require step therapy before agreeing to cover mAb therapy, which aligns with the 2019 AHS position statement.¹⁰ Due to differences in insurance coverage, out-of-pocket expenses can vary greatly. However, options are available through online manufacturer assistance to reduce cost, making it comparable to other migraine treatments. Safety and efficacy studies of anti-CGRP mAbs use in pregnant individuals are limited. At this time, they should not be prescribed for those who are pregnant, planning to become pregnant, or breastfeeding. Counsel nonpregnant patients on appropriate contraception while using a mAb due to possible teratogenicity and negative pregnancy outcomes.^28,50

When combination treatment may be appropriate

Monotherapy is the usual approach to preventing migraine due to advantages of efficacy, simplified regimens, lower cost, and reduced adverse effects.⁵¹ However, if a patient does not benefit from monotherapy even after trying dose titrations as tolerated or switching therapies, trying complementary combination therapy is appropriate. Despite a shortage of clinical trials supporting the use of 2 or more preventive medications with different mechanisms of action, this strategy is used clinically.¹⁰ Consider combination therapy in those with refractory disease, partial responses, or intolerance to recommended doses.⁵² Articles reporting on case study reviews have rationalized the combined use of onabotulinumtoxinA and anti-CGRP mAbs, noting better migraine control.^51,53 The 2019 AHS position statement recommends adding a mAb to an existing preventive treatment regimen with no other changes until mAb effectiveness is determined, as the risk for drug interactions on dual therapy is low.¹⁰ Safety and efficacy also have been demonstrated with the combination of preventive anti-CGRP mAbs and acute treatment with gepants as needed.⁵⁴

Monoclonal antibodies are highly efficacious options for those who cannot tolerate or achieve only minimal efficacy with traditional preventive therapies.

Overall, gepants and mAbs are as effective as traditional acute and preventive treatments for migraine, and they cause fewer adverse effects and often allow a more simplified regimen. Gepants and mAbs are viable options in the primary care setting. Due to limited long-term data and high cost, however, they routinely are used for refractory migraine rather than as first-line agents. These therapies are especially favorable options for patients when traditional migraine therapies yield inadequate efficacy, cause intolerable adverse effects, are contraindicated, or introduce the risk for medication interactions.

CORRESPONDENCE
Emily Peterson, PharmD, BCACP, 3640 Middlebury Road, Iowa City, IA 52242; Emily-a-peterson@uiowa.edu

Despite a growing list of Janus kinase (JAK) inhibitors, ruxolitinib remains the go-to for patients with symptomatic, higher risk myelofibrosis, according to Anthony M. Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta.

“We are thankfully starting to be blessed with more options than we’ve ever had,” he said, but “in the front-line proliferative setting, ruxolitinib has remained the standard of care.” It’s “well established in higher-risk patients and very much an option for very symptomatic lower-risk patients.”

Dr. Hunter helped his colleagues navigate the evolving field of JAK inhibition for myelofibrosis in a presentation titled “Choosing and Properly Using a JAK Inhibitor in Myelofibrosis,”at the Society of Hematologic Oncology annual meeting.

Ruxolitinib was the first JAK inhibitor for myelofibrosis on the U.S. market, approved in 2011. Two more have followed, fedratinib in 2019 and pacritinib in 2022.

A fourth JAK inhibitor for myelofibrosis, momelotinib, is under Food and Drug Administration review with a decision expected shortly.

JAK inhibitors disrupt a key pathogenic pathway in myelofibrosis and are a mainstay of treatment, but Dr. Hunter noted that they should not replace allogeneic transplants in patients who are candidates because transplants remain “the best way to achieve long term survival, especially in higher risk patients.”

He noted that not every patient needs a JAK inhibitor, especially “lower-risk, more asymptomatic patients who are predominantly manifesting with cytopenias. [They] are less likely to benefit.”

Dr. Hunter said that although ruxolitinib remains a treatment of choice, fedratinib “is certainly an option” with comparable rates of symptom control and splenomegaly reduction. Also, while ruxolitinib is dosed according to platelet levels, fedratinib allows for full dosing down to a platelet count of 50 x 10⁹/L.

“But there’s more GI toxicity than with ruxolitinib, especially in the first couple of months,” he said, as well as a black box warning of Wernicke’s encephalopathy. “I generally put all my [fedratinib] patients on thiamine repletion as a precaution.”

One of the most challenging aspects of using JAK inhibitors for myelofibrosis is their tendency to cause cytopenia, particularly anemia and thrombocytopenia, which, ironically, are also hallmarks of myelofibrosis itself.

Although there’s an alternative low-dose ruxolitinib regimen that can be effective in anemic settings, the approval of pacritinib and most likely momelotinib is particularly helpful for cytopenic patients, “a population which historically has been very hard to treat with our prior agents,” Dr. Hunter said.

Pacritinib is approved specifically for patients with platelet counts below 50 x 10⁹/L; momelotinib also included lower platelet counts in several studies. Both agents indirectly boost erythropoiesis with subsequent amelioration of anemia.

“Momelotinib is an important emerging agent for these more anemic patients,” with a spleen response comparable to ruxolitinib and significantly higher rates of transfusion independence, but with lower rates of symptom control, Dr. Hunter said.

Pacritinib “really helps extend the benefit of JAK inhibitors to a group of thrombocytopenic patients who have been hard to treat with ruxolitinib,” with the added potential of improving anemia, although, like fedratinib, it has more GI toxicity, he said.

There are multiple add-on options for JAK inhibitor patients with anemia, including luspatercept, an erythropoiesis-stimulating agent approved for anemia in patients with myelodysplastic syndromes; promising results were reported recently for myelofibrosis.

Fedratinib, pacritinib, and momelotinib all have activity in the second line after ruxolitinib failure, Dr. Hunter noted, but he cautioned that ruxolitinib must be tapered over a few weeks, not stopped abruptly, to avoid withdrawal symptoms. Some clinicians overlap JAK inhibitors a day or two to avoid issues.

“Clinical trials should still be considered in many of these settings,” he said, adding that emerging agents are under development, including multiple combination therapies, often with JAK inhibitors as the background.

No disclosure information was reported.

Despite a growing list of Janus kinase (JAK) inhibitors, ruxolitinib remains the go-to for patients with symptomatic, higher risk myelofibrosis, according to Anthony M. Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta.

“We are thankfully starting to be blessed with more options than we’ve ever had,” he said, but “in the front-line proliferative setting, ruxolitinib has remained the standard of care.” It’s “well established in higher-risk patients and very much an option for very symptomatic lower-risk patients.”

Dr. Hunter helped his colleagues navigate the evolving field of JAK inhibition for myelofibrosis in a presentation titled “Choosing and Properly Using a JAK Inhibitor in Myelofibrosis,”at the Society of Hematologic Oncology annual meeting.

Ruxolitinib was the first JAK inhibitor for myelofibrosis on the U.S. market, approved in 2011. Two more have followed, fedratinib in 2019 and pacritinib in 2022.

A fourth JAK inhibitor for myelofibrosis, momelotinib, is under Food and Drug Administration review with a decision expected shortly.

JAK inhibitors disrupt a key pathogenic pathway in myelofibrosis and are a mainstay of treatment, but Dr. Hunter noted that they should not replace allogeneic transplants in patients who are candidates because transplants remain “the best way to achieve long term survival, especially in higher risk patients.”

He noted that not every patient needs a JAK inhibitor, especially “lower-risk, more asymptomatic patients who are predominantly manifesting with cytopenias. [They] are less likely to benefit.”

Dr. Hunter said that although ruxolitinib remains a treatment of choice, fedratinib “is certainly an option” with comparable rates of symptom control and splenomegaly reduction. Also, while ruxolitinib is dosed according to platelet levels, fedratinib allows for full dosing down to a platelet count of 50 x 10⁹/L.

“But there’s more GI toxicity than with ruxolitinib, especially in the first couple of months,” he said, as well as a black box warning of Wernicke’s encephalopathy. “I generally put all my [fedratinib] patients on thiamine repletion as a precaution.”

One of the most challenging aspects of using JAK inhibitors for myelofibrosis is their tendency to cause cytopenia, particularly anemia and thrombocytopenia, which, ironically, are also hallmarks of myelofibrosis itself.

Although there’s an alternative low-dose ruxolitinib regimen that can be effective in anemic settings, the approval of pacritinib and most likely momelotinib is particularly helpful for cytopenic patients, “a population which historically has been very hard to treat with our prior agents,” Dr. Hunter said.

Pacritinib is approved specifically for patients with platelet counts below 50 x 10⁹/L; momelotinib also included lower platelet counts in several studies. Both agents indirectly boost erythropoiesis with subsequent amelioration of anemia.

“Momelotinib is an important emerging agent for these more anemic patients,” with a spleen response comparable to ruxolitinib and significantly higher rates of transfusion independence, but with lower rates of symptom control, Dr. Hunter said.

Pacritinib “really helps extend the benefit of JAK inhibitors to a group of thrombocytopenic patients who have been hard to treat with ruxolitinib,” with the added potential of improving anemia, although, like fedratinib, it has more GI toxicity, he said.

There are multiple add-on options for JAK inhibitor patients with anemia, including luspatercept, an erythropoiesis-stimulating agent approved for anemia in patients with myelodysplastic syndromes; promising results were reported recently for myelofibrosis.

Fedratinib, pacritinib, and momelotinib all have activity in the second line after ruxolitinib failure, Dr. Hunter noted, but he cautioned that ruxolitinib must be tapered over a few weeks, not stopped abruptly, to avoid withdrawal symptoms. Some clinicians overlap JAK inhibitors a day or two to avoid issues.

“Clinical trials should still be considered in many of these settings,” he said, adding that emerging agents are under development, including multiple combination therapies, often with JAK inhibitors as the background.

No disclosure information was reported.

Despite a growing list of Janus kinase (JAK) inhibitors, ruxolitinib remains the go-to for patients with symptomatic, higher risk myelofibrosis, according to Anthony M. Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta.

“We are thankfully starting to be blessed with more options than we’ve ever had,” he said, but “in the front-line proliferative setting, ruxolitinib has remained the standard of care.” It’s “well established in higher-risk patients and very much an option for very symptomatic lower-risk patients.”

Dr. Hunter helped his colleagues navigate the evolving field of JAK inhibition for myelofibrosis in a presentation titled “Choosing and Properly Using a JAK Inhibitor in Myelofibrosis,”at the Society of Hematologic Oncology annual meeting.

Ruxolitinib was the first JAK inhibitor for myelofibrosis on the U.S. market, approved in 2011. Two more have followed, fedratinib in 2019 and pacritinib in 2022.

A fourth JAK inhibitor for myelofibrosis, momelotinib, is under Food and Drug Administration review with a decision expected shortly.

JAK inhibitors disrupt a key pathogenic pathway in myelofibrosis and are a mainstay of treatment, but Dr. Hunter noted that they should not replace allogeneic transplants in patients who are candidates because transplants remain “the best way to achieve long term survival, especially in higher risk patients.”

He noted that not every patient needs a JAK inhibitor, especially “lower-risk, more asymptomatic patients who are predominantly manifesting with cytopenias. [They] are less likely to benefit.”

Dr. Hunter said that although ruxolitinib remains a treatment of choice, fedratinib “is certainly an option” with comparable rates of symptom control and splenomegaly reduction. Also, while ruxolitinib is dosed according to platelet levels, fedratinib allows for full dosing down to a platelet count of 50 x 10⁹/L.

“But there’s more GI toxicity than with ruxolitinib, especially in the first couple of months,” he said, as well as a black box warning of Wernicke’s encephalopathy. “I generally put all my [fedratinib] patients on thiamine repletion as a precaution.”

One of the most challenging aspects of using JAK inhibitors for myelofibrosis is their tendency to cause cytopenia, particularly anemia and thrombocytopenia, which, ironically, are also hallmarks of myelofibrosis itself.

Although there’s an alternative low-dose ruxolitinib regimen that can be effective in anemic settings, the approval of pacritinib and most likely momelotinib is particularly helpful for cytopenic patients, “a population which historically has been very hard to treat with our prior agents,” Dr. Hunter said.

Pacritinib is approved specifically for patients with platelet counts below 50 x 10⁹/L; momelotinib also included lower platelet counts in several studies. Both agents indirectly boost erythropoiesis with subsequent amelioration of anemia.

“Momelotinib is an important emerging agent for these more anemic patients,” with a spleen response comparable to ruxolitinib and significantly higher rates of transfusion independence, but with lower rates of symptom control, Dr. Hunter said.

Pacritinib “really helps extend the benefit of JAK inhibitors to a group of thrombocytopenic patients who have been hard to treat with ruxolitinib,” with the added potential of improving anemia, although, like fedratinib, it has more GI toxicity, he said.

There are multiple add-on options for JAK inhibitor patients with anemia, including luspatercept, an erythropoiesis-stimulating agent approved for anemia in patients with myelodysplastic syndromes; promising results were reported recently for myelofibrosis.

Fedratinib, pacritinib, and momelotinib all have activity in the second line after ruxolitinib failure, Dr. Hunter noted, but he cautioned that ruxolitinib must be tapered over a few weeks, not stopped abruptly, to avoid withdrawal symptoms. Some clinicians overlap JAK inhibitors a day or two to avoid issues.

“Clinical trials should still be considered in many of these settings,” he said, adding that emerging agents are under development, including multiple combination therapies, often with JAK inhibitors as the background.

No disclosure information was reported.

BACKGROUND

The Pharmacogenomic Testing for Veterans (PHASER) program provides preemptive pharmacogenomic testing for Veterans nationally. Program implementation at the Madison VA began in the hematology and oncology (hem/onc) clinics. In these clinics, PHASER test results are reviewed by the hem/onc clinical pharmacist practitioner (CPP) who provides recommendations regarding therapy via an electronic health record note. The purpose of this retrospective chart review was to assess the impact of the CPP on medication management informed by pharmacogenomics.

METHODS

A retrospective chart review was completed for all Veterans enrolled in hem/onc services and offered PHASER testing between April 1, 2022 and November 1, 2022. The number and type of interventions recommended by the hem/onc CPP, acceptance of recommended interventions, and hem/onc CPP time spent were collected for all patients who accepted and completed PHASER testing. Interventions were categorized and descriptive statistics were used to summarize data.

RESULTS

Of the 98 patients reviewed by the CPP, 75 (77%) were prescribed a medication with potential pharmacogenomic implications. At least one actionable recommendation for medication therapy adjustment was identified for 40 (53%) of those patients based on their pharmacogenomic test results. The CPP spent an average of 12 minutes per patient review (range 5 to 30 minutes) and 100% of CPP recommendations were accepted.

CONCLUSIONS

The CPP efficiently reviewed pharmacogenomic test results and made meaningful recommendations for medication therapy adjustments. CPP recommendations were highly accepted in the hem/onc setting.

BACKGROUND

The Pharmacogenomic Testing for Veterans (PHASER) program provides preemptive pharmacogenomic testing for Veterans nationally. Program implementation at the Madison VA began in the hematology and oncology (hem/onc) clinics. In these clinics, PHASER test results are reviewed by the hem/onc clinical pharmacist practitioner (CPP) who provides recommendations regarding therapy via an electronic health record note. The purpose of this retrospective chart review was to assess the impact of the CPP on medication management informed by pharmacogenomics.

METHODS

A retrospective chart review was completed for all Veterans enrolled in hem/onc services and offered PHASER testing between April 1, 2022 and November 1, 2022. The number and type of interventions recommended by the hem/onc CPP, acceptance of recommended interventions, and hem/onc CPP time spent were collected for all patients who accepted and completed PHASER testing. Interventions were categorized and descriptive statistics were used to summarize data.

RESULTS

Of the 98 patients reviewed by the CPP, 75 (77%) were prescribed a medication with potential pharmacogenomic implications. At least one actionable recommendation for medication therapy adjustment was identified for 40 (53%) of those patients based on their pharmacogenomic test results. The CPP spent an average of 12 minutes per patient review (range 5 to 30 minutes) and 100% of CPP recommendations were accepted.

CONCLUSIONS

The CPP efficiently reviewed pharmacogenomic test results and made meaningful recommendations for medication therapy adjustments. CPP recommendations were highly accepted in the hem/onc setting.

BACKGROUND

The Pharmacogenomic Testing for Veterans (PHASER) program provides preemptive pharmacogenomic testing for Veterans nationally. Program implementation at the Madison VA began in the hematology and oncology (hem/onc) clinics. In these clinics, PHASER test results are reviewed by the hem/onc clinical pharmacist practitioner (CPP) who provides recommendations regarding therapy via an electronic health record note. The purpose of this retrospective chart review was to assess the impact of the CPP on medication management informed by pharmacogenomics.

METHODS

A retrospective chart review was completed for all Veterans enrolled in hem/onc services and offered PHASER testing between April 1, 2022 and November 1, 2022. The number and type of interventions recommended by the hem/onc CPP, acceptance of recommended interventions, and hem/onc CPP time spent were collected for all patients who accepted and completed PHASER testing. Interventions were categorized and descriptive statistics were used to summarize data.

RESULTS

Of the 98 patients reviewed by the CPP, 75 (77%) were prescribed a medication with potential pharmacogenomic implications. At least one actionable recommendation for medication therapy adjustment was identified for 40 (53%) of those patients based on their pharmacogenomic test results. The CPP spent an average of 12 minutes per patient review (range 5 to 30 minutes) and 100% of CPP recommendations were accepted.

CONCLUSIONS

The CPP efficiently reviewed pharmacogenomic test results and made meaningful recommendations for medication therapy adjustments. CPP recommendations were highly accepted in the hem/onc setting.