ANSWER
The correct answer is pyogenic granuloma (choice “d”), further discussion of which follows. Bacillary angiomatosis (choice “a”) is a lesion caused by infection with a species of Bartonella—a distinctly unusual problem. While a retained foreign body (choice “b”), such as a splinter, could trigger a similar lesion, there was no relevant history to suggest this was the case here. The most concerning differential item, melanoma (choice “c”), can present as a glistening red nodule, especially in children, but this too would be quite unusual.

DISCUSSION
Pyogenic granuloma (PG) was the name originally given to these common lesions, which are neither pyogenic (pus producing) nor truly granulomatous (demonstrating a classic histologic pattern). Rather, they are the body’s frustrated attempt to lay down new blood supply in a healing but oft-traumatized lesion (eg, acne lesion, tag, nevus, or wart).

Other names for them include sclerosing hemangioma and lobular capillary hemangioma. Their appearance can vary from the classic look seen in this case to older lesions that tend to be drier and more warty.

PGs are far more common in children than in adults and greatly favor females over males. Pregnancy appears to trigger them, especially in the mouth, but they can appear on fingers, nipples, or even the scalp. Certain drugs, such as isotretinoin and certain chemotherapy agents, predispose to their formation.

PGs removed from children (by shave technique, followed by electrodesiccation and curettage) must be sent for pathologic examination to rule out nodular melanoma. That’s what was done in this case, with the pathology report confirming the expected vascular nature of the lesion.

ANSWER
The correct answer is pyogenic granuloma (choice “d”), further discussion of which follows. Bacillary angiomatosis (choice “a”) is a lesion caused by infection with a species of Bartonella—a distinctly unusual problem. While a retained foreign body (choice “b”), such as a splinter, could trigger a similar lesion, there was no relevant history to suggest this was the case here. The most concerning differential item, melanoma (choice “c”), can present as a glistening red nodule, especially in children, but this too would be quite unusual.

DISCUSSION
Pyogenic granuloma (PG) was the name originally given to these common lesions, which are neither pyogenic (pus producing) nor truly granulomatous (demonstrating a classic histologic pattern). Rather, they are the body’s frustrated attempt to lay down new blood supply in a healing but oft-traumatized lesion (eg, acne lesion, tag, nevus, or wart).

Other names for them include sclerosing hemangioma and lobular capillary hemangioma. Their appearance can vary from the classic look seen in this case to older lesions that tend to be drier and more warty.

PGs are far more common in children than in adults and greatly favor females over males. Pregnancy appears to trigger them, especially in the mouth, but they can appear on fingers, nipples, or even the scalp. Certain drugs, such as isotretinoin and certain chemotherapy agents, predispose to their formation.

PGs removed from children (by shave technique, followed by electrodesiccation and curettage) must be sent for pathologic examination to rule out nodular melanoma. That’s what was done in this case, with the pathology report confirming the expected vascular nature of the lesion.

ANSWER
The correct answer is pyogenic granuloma (choice “d”), further discussion of which follows. Bacillary angiomatosis (choice “a”) is a lesion caused by infection with a species of Bartonella—a distinctly unusual problem. While a retained foreign body (choice “b”), such as a splinter, could trigger a similar lesion, there was no relevant history to suggest this was the case here. The most concerning differential item, melanoma (choice “c”), can present as a glistening red nodule, especially in children, but this too would be quite unusual.

DISCUSSION
Pyogenic granuloma (PG) was the name originally given to these common lesions, which are neither pyogenic (pus producing) nor truly granulomatous (demonstrating a classic histologic pattern). Rather, they are the body’s frustrated attempt to lay down new blood supply in a healing but oft-traumatized lesion (eg, acne lesion, tag, nevus, or wart).

Other names for them include sclerosing hemangioma and lobular capillary hemangioma. Their appearance can vary from the classic look seen in this case to older lesions that tend to be drier and more warty.

PGs are far more common in children than in adults and greatly favor females over males. Pregnancy appears to trigger them, especially in the mouth, but they can appear on fingers, nipples, or even the scalp. Certain drugs, such as isotretinoin and certain chemotherapy agents, predispose to their formation.

PGs removed from children (by shave technique, followed by electrodesiccation and curettage) must be sent for pathologic examination to rule out nodular melanoma. That’s what was done in this case, with the pathology report confirming the expected vascular nature of the lesion.

A 30-year-old pregnant woman presented to a rural Panamanian hospital with new onset genital pain, vaginal itching, and dysuria that she’d had for 48 hours. The patient was in the first trimester of her pregnancy and indicated that she’d had recent unprotected sex with a new partner who wasn’t the father of the developing fetus. The patient had never experienced symptoms like these before and denied ever having a sexually transmitted infection (STI). On physical exam, the physician noted numerous pustules covering tender, swollen labia (FIGURE). A small amount of white discharge was noted at the introitus.

Diagnosis: Herpes simplex virus

The physician on-call diagnosed candida vaginitis along with a bacterial skin infection, and admitted the patient to the hospital for intravenous (IV) antibiotics. Fortunately, we were there on a medical mission and were consulted on the case.

We diagnosed a primary herpes simplex virus type 2 (HSV-2) infection in this patient, based on the classic presentation of grouped pustules and vesicles on erythematous and swollen labia, and the patient’s complaint of dysuria.

Herpes cultures weren’t available in the hospital, but the clinical picture was unmistakable for HSV infection. Since multiple STIs may occur simultaneously, we ordered a serum rapid plasma reagin (RPR) test for syphilis, and tested her urine for gonorrhea and chlamydia. The tests were negative.

Differential Dx includes other STIs and a fixed drug eruption

Herpes is a common STI and most people don’t have symptoms. In 2012, an estimated 417 million people worldwide were living with genital herpes caused by HSV-2.¹

The differential diagnosis for HSV infection includes primary syphilis, chancroid, folliculitis, and fixed drug eruptions.

Primary syphilis (Treponema pallidum) commonly presents with a painless, ulcerated, clean-based ulcer. While the chancre of primary syphilis can sometimes be painful, this patient did not have ulcers at the time of her presentation. Her pustules would likely ulcerate over time, but would not resemble the chancre of syphilis.

Chancroid (Haemophilus ducreyi) is a less common STI than syphilis and HSV infection. It presents with deep, sharply defined, purulent ulcers that are often associated with painful adenopathy. The ulcers can appear grey or yellowish in color.

Folliculitis presents with pustules surrounding hair follicles. Some of the pustules were surrounding hair follicles in this patient’s case, but others were independent of the hair. The patient’s marked swelling and tenderness along with dysuria also did not fit the characteristics of folliculitis.

Fixed drug eruptions can occur in the genital region, but the patient had neither bullous nor ulcerated eruptions (as one would expect with this condition). Fixed drug eruptions are usually hyperpigmented and require a history of taking medication, such as an antibiotic or a nonsteroidal anti-inflammatory drug.

Questions that help narrow the differential. Zeroing in on the cause of a patient’s genital lesions requires that you ask whether the lesions are painful, if the patient has dysuria, if there are any constitutional symptoms, and if this has happened before. Other distinguishing factors include enlarged lymph nodes and the presence of multiple (vs single) lesions.

Viral cell cultures are the preferred lab test

Antiviral therapy is most effective if begun within 72 hours of symptom onset in primary herpes genitalis.

Common laboratory tests to make the diagnosis include viral culture, direct fluorescence antibody (DFA), polymerase chain reaction (PCR), and type-specific serologic tests.

Viral cell culture is the preferred test for suspected HSV of the skin and mucous membranes.² PCR is the preferred test for suspected herpes meningitis or encephalitis when cerebrospinal fluid has been obtained through lumbar puncture.³ DFA and herpes culture can be ordered simultaneously. DFA can provide a quick result, and herpes culture can provide a more sensitive result (this may take 5-7 days before results are available).

No evidence that antivirals pose risk during pregnancy

Treatment with antivirals (acyclovir, famciclovir, or valacyclovir) may help to reduce the length of the outbreak. Oral antivirals are usually sufficient for uncomplicated HSV; IV antivirals may be needed in complicated cases. The current recommendation for acyclovir (the most commonly prescribed drug for HSV infection) is 400 mg 3 times daily or 200 mg 5 times daily for 7 to 10 days in a primary outbreak.³

Antiviral therapy is most effective if begun within 72 hours of symptom onset in primary herpes genitalis.⁴ Analgesics can help with pain control and sitz baths are helpful for women with severe dysuria.

Maternal–fetal transmission of HSV is associated with significant morbidity and mortality in children.⁵ The Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists recommend that cesarean delivery be offered as soon as possible to women who have active HSV lesions or, in those with a history of genital herpes, symptoms of vulvar pain or burning at the time of delivery.³

There is no evidence that the use of antiviral agents in women who are pregnant and have a history of genital herpes prevents perinatal transmission of HSV to neonates.⁶ However, antenatal antiviral prophylaxis has been shown to reduce viral shedding, recurrences at delivery, and the need for cesarean delivery.⁷

Our patient was treated with oral acyclovir 400 mg 3 times a day for 10 days. One day after seeking care, she had less pain, swelling, and tenderness and was discharged. (Based on the severity of the outbreak and lack of sanitary living conditions, hospitalization was the safest and most reliable option.) The patient was counseled on the ramifications of HSV infection in pregnancy, including the fact that she might need a cesarean section. She was told that she must get prenatal care and that she needed to tell her primary care physician about her HSV infection. She was also warned about the risk of disease transmission to sexual partners and the importance of using barrier contraception to minimize the risk of future transmission.

CORRESPONDENCE
Luke Wallis, BS, 6410 Rambling Trail Drive, San Antonio, TX 78240; [email protected].

A 30-year-old pregnant woman presented to a rural Panamanian hospital with new onset genital pain, vaginal itching, and dysuria that she’d had for 48 hours. The patient was in the first trimester of her pregnancy and indicated that she’d had recent unprotected sex with a new partner who wasn’t the father of the developing fetus. The patient had never experienced symptoms like these before and denied ever having a sexually transmitted infection (STI). On physical exam, the physician noted numerous pustules covering tender, swollen labia (FIGURE). A small amount of white discharge was noted at the introitus.

Diagnosis: Herpes simplex virus

The physician on-call diagnosed candida vaginitis along with a bacterial skin infection, and admitted the patient to the hospital for intravenous (IV) antibiotics. Fortunately, we were there on a medical mission and were consulted on the case.

We diagnosed a primary herpes simplex virus type 2 (HSV-2) infection in this patient, based on the classic presentation of grouped pustules and vesicles on erythematous and swollen labia, and the patient’s complaint of dysuria.

Herpes cultures weren’t available in the hospital, but the clinical picture was unmistakable for HSV infection. Since multiple STIs may occur simultaneously, we ordered a serum rapid plasma reagin (RPR) test for syphilis, and tested her urine for gonorrhea and chlamydia. The tests were negative.

Differential Dx includes other STIs and a fixed drug eruption

Herpes is a common STI and most people don’t have symptoms. In 2012, an estimated 417 million people worldwide were living with genital herpes caused by HSV-2.¹

The differential diagnosis for HSV infection includes primary syphilis, chancroid, folliculitis, and fixed drug eruptions.

Primary syphilis (Treponema pallidum) commonly presents with a painless, ulcerated, clean-based ulcer. While the chancre of primary syphilis can sometimes be painful, this patient did not have ulcers at the time of her presentation. Her pustules would likely ulcerate over time, but would not resemble the chancre of syphilis.

Chancroid (Haemophilus ducreyi) is a less common STI than syphilis and HSV infection. It presents with deep, sharply defined, purulent ulcers that are often associated with painful adenopathy. The ulcers can appear grey or yellowish in color.

Folliculitis presents with pustules surrounding hair follicles. Some of the pustules were surrounding hair follicles in this patient’s case, but others were independent of the hair. The patient’s marked swelling and tenderness along with dysuria also did not fit the characteristics of folliculitis.

Fixed drug eruptions can occur in the genital region, but the patient had neither bullous nor ulcerated eruptions (as one would expect with this condition). Fixed drug eruptions are usually hyperpigmented and require a history of taking medication, such as an antibiotic or a nonsteroidal anti-inflammatory drug.

Questions that help narrow the differential. Zeroing in on the cause of a patient’s genital lesions requires that you ask whether the lesions are painful, if the patient has dysuria, if there are any constitutional symptoms, and if this has happened before. Other distinguishing factors include enlarged lymph nodes and the presence of multiple (vs single) lesions.

Viral cell cultures are the preferred lab test

Antiviral therapy is most effective if begun within 72 hours of symptom onset in primary herpes genitalis.

Common laboratory tests to make the diagnosis include viral culture, direct fluorescence antibody (DFA), polymerase chain reaction (PCR), and type-specific serologic tests.

Viral cell culture is the preferred test for suspected HSV of the skin and mucous membranes.² PCR is the preferred test for suspected herpes meningitis or encephalitis when cerebrospinal fluid has been obtained through lumbar puncture.³ DFA and herpes culture can be ordered simultaneously. DFA can provide a quick result, and herpes culture can provide a more sensitive result (this may take 5-7 days before results are available).

No evidence that antivirals pose risk during pregnancy

Treatment with antivirals (acyclovir, famciclovir, or valacyclovir) may help to reduce the length of the outbreak. Oral antivirals are usually sufficient for uncomplicated HSV; IV antivirals may be needed in complicated cases. The current recommendation for acyclovir (the most commonly prescribed drug for HSV infection) is 400 mg 3 times daily or 200 mg 5 times daily for 7 to 10 days in a primary outbreak.³

Antiviral therapy is most effective if begun within 72 hours of symptom onset in primary herpes genitalis.⁴ Analgesics can help with pain control and sitz baths are helpful for women with severe dysuria.

Maternal–fetal transmission of HSV is associated with significant morbidity and mortality in children.⁵ The Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists recommend that cesarean delivery be offered as soon as possible to women who have active HSV lesions or, in those with a history of genital herpes, symptoms of vulvar pain or burning at the time of delivery.³

There is no evidence that the use of antiviral agents in women who are pregnant and have a history of genital herpes prevents perinatal transmission of HSV to neonates.⁶ However, antenatal antiviral prophylaxis has been shown to reduce viral shedding, recurrences at delivery, and the need for cesarean delivery.⁷

Our patient was treated with oral acyclovir 400 mg 3 times a day for 10 days. One day after seeking care, she had less pain, swelling, and tenderness and was discharged. (Based on the severity of the outbreak and lack of sanitary living conditions, hospitalization was the safest and most reliable option.) The patient was counseled on the ramifications of HSV infection in pregnancy, including the fact that she might need a cesarean section. She was told that she must get prenatal care and that she needed to tell her primary care physician about her HSV infection. She was also warned about the risk of disease transmission to sexual partners and the importance of using barrier contraception to minimize the risk of future transmission.

CORRESPONDENCE
Luke Wallis, BS, 6410 Rambling Trail Drive, San Antonio, TX 78240; [email protected].

A 30-year-old pregnant woman presented to a rural Panamanian hospital with new onset genital pain, vaginal itching, and dysuria that she’d had for 48 hours. The patient was in the first trimester of her pregnancy and indicated that she’d had recent unprotected sex with a new partner who wasn’t the father of the developing fetus. The patient had never experienced symptoms like these before and denied ever having a sexually transmitted infection (STI). On physical exam, the physician noted numerous pustules covering tender, swollen labia (FIGURE). A small amount of white discharge was noted at the introitus.

Diagnosis: Herpes simplex virus

The physician on-call diagnosed candida vaginitis along with a bacterial skin infection, and admitted the patient to the hospital for intravenous (IV) antibiotics. Fortunately, we were there on a medical mission and were consulted on the case.

We diagnosed a primary herpes simplex virus type 2 (HSV-2) infection in this patient, based on the classic presentation of grouped pustules and vesicles on erythematous and swollen labia, and the patient’s complaint of dysuria.

Herpes cultures weren’t available in the hospital, but the clinical picture was unmistakable for HSV infection. Since multiple STIs may occur simultaneously, we ordered a serum rapid plasma reagin (RPR) test for syphilis, and tested her urine for gonorrhea and chlamydia. The tests were negative.

Differential Dx includes other STIs and a fixed drug eruption

Herpes is a common STI and most people don’t have symptoms. In 2012, an estimated 417 million people worldwide were living with genital herpes caused by HSV-2.¹

The differential diagnosis for HSV infection includes primary syphilis, chancroid, folliculitis, and fixed drug eruptions.

Primary syphilis (Treponema pallidum) commonly presents with a painless, ulcerated, clean-based ulcer. While the chancre of primary syphilis can sometimes be painful, this patient did not have ulcers at the time of her presentation. Her pustules would likely ulcerate over time, but would not resemble the chancre of syphilis.

Chancroid (Haemophilus ducreyi) is a less common STI than syphilis and HSV infection. It presents with deep, sharply defined, purulent ulcers that are often associated with painful adenopathy. The ulcers can appear grey or yellowish in color.

Folliculitis presents with pustules surrounding hair follicles. Some of the pustules were surrounding hair follicles in this patient’s case, but others were independent of the hair. The patient’s marked swelling and tenderness along with dysuria also did not fit the characteristics of folliculitis.

Fixed drug eruptions can occur in the genital region, but the patient had neither bullous nor ulcerated eruptions (as one would expect with this condition). Fixed drug eruptions are usually hyperpigmented and require a history of taking medication, such as an antibiotic or a nonsteroidal anti-inflammatory drug.

Questions that help narrow the differential. Zeroing in on the cause of a patient’s genital lesions requires that you ask whether the lesions are painful, if the patient has dysuria, if there are any constitutional symptoms, and if this has happened before. Other distinguishing factors include enlarged lymph nodes and the presence of multiple (vs single) lesions.

Viral cell cultures are the preferred lab test

Antiviral therapy is most effective if begun within 72 hours of symptom onset in primary herpes genitalis.

Common laboratory tests to make the diagnosis include viral culture, direct fluorescence antibody (DFA), polymerase chain reaction (PCR), and type-specific serologic tests.

Viral cell culture is the preferred test for suspected HSV of the skin and mucous membranes.² PCR is the preferred test for suspected herpes meningitis or encephalitis when cerebrospinal fluid has been obtained through lumbar puncture.³ DFA and herpes culture can be ordered simultaneously. DFA can provide a quick result, and herpes culture can provide a more sensitive result (this may take 5-7 days before results are available).

No evidence that antivirals pose risk during pregnancy

Treatment with antivirals (acyclovir, famciclovir, or valacyclovir) may help to reduce the length of the outbreak. Oral antivirals are usually sufficient for uncomplicated HSV; IV antivirals may be needed in complicated cases. The current recommendation for acyclovir (the most commonly prescribed drug for HSV infection) is 400 mg 3 times daily or 200 mg 5 times daily for 7 to 10 days in a primary outbreak.³

Antiviral therapy is most effective if begun within 72 hours of symptom onset in primary herpes genitalis.⁴ Analgesics can help with pain control and sitz baths are helpful for women with severe dysuria.

Maternal–fetal transmission of HSV is associated with significant morbidity and mortality in children.⁵ The Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists recommend that cesarean delivery be offered as soon as possible to women who have active HSV lesions or, in those with a history of genital herpes, symptoms of vulvar pain or burning at the time of delivery.³

There is no evidence that the use of antiviral agents in women who are pregnant and have a history of genital herpes prevents perinatal transmission of HSV to neonates.⁶ However, antenatal antiviral prophylaxis has been shown to reduce viral shedding, recurrences at delivery, and the need for cesarean delivery.⁷

Our patient was treated with oral acyclovir 400 mg 3 times a day for 10 days. One day after seeking care, she had less pain, swelling, and tenderness and was discharged. (Based on the severity of the outbreak and lack of sanitary living conditions, hospitalization was the safest and most reliable option.) The patient was counseled on the ramifications of HSV infection in pregnancy, including the fact that she might need a cesarean section. She was told that she must get prenatal care and that she needed to tell her primary care physician about her HSV infection. She was also warned about the risk of disease transmission to sexual partners and the importance of using barrier contraception to minimize the risk of future transmission.

CORRESPONDENCE
Luke Wallis, BS, 6410 Rambling Trail Drive, San Antonio, TX 78240; [email protected].

The clerical work involved in managing the electronic medical record (EMR) is clearly not at the top of the skill set for physicians, yet many office-based clinicians find themselves bogged down in this work with no easy way out.

However, practices that are adopting team-based care—where each team member works at the top of his or her skill set—are finding a solution in the form of scribing, or team documentation. This approach can ease that burden and perhaps even help to curb physician burnout in the process. But many questions still surround this approach, notably: What do we know about the quality of this documentation?

Research conducted by Misra-Hebert et al reported on in this issue provides some insight—and reason for optimism. (See “Medical scribes: How do their notes stack up?”) Their study found that scribes’ outpatient notes stack up quite well when compared to those of physicians. And having worked with this approach to documentation, I can attest to its benefits, as well.

Misra-Hebert et al’s study in this issue attests to the quality of scribes’ notes. My personal experience is that charts are usually closed at the end of each half-day.

Two approaches, one goal. There are 2 different ways that physicians can get help with documentation. One involves the use of trained scribes, who come from a variety of backgrounds and are charged with writing down, or scribing, what the physician says. The other involves training staff, usually certified medical assistants (CMAs) or licensed practical nurses (LPNs), to take on a wide variety of additional duties including refill management, care gap closure, and most of the duties concerning the EMR—including documentation.

Misra-Hebert et al studied the second approach and found important evidence that using staff in this way does not adversely affect—and may even enhance—documentation previously done entirely by physicians.

This change in the way we approach EMRs involves commitment, as I’ve seen first hand. There needs to be significant training to make this work and there needs to be more staff, since physicians require 2 of these valuable team members to function effectively. (At least that’s been our experience.)

We are in the process of implementing team-based care throughout our 32-location health care system and have found that using CMAs and LPNs to assist with documentation is a “win” for everyone.

1. A win for the patient. Patients immediately notice that their physicians are now able to focus on them during the office visit, since they no longer have to tend to the demands of the computer. In addition, since the CMAs/LPNs are with patients during the entire visit, the patients bond with them and feel the extra support from this relationship.  

2. A win for the care team. Physician satisfaction has never been higher. Charts are usually closed at the end of each half-day. There is no need to take work home at night. CMAs/LPNs feel empowered and meaningfully involved in patient care. Their increase in satisfaction mirrors that of the physicians.

3. A win for the system. Not only are quality measures improving, but access improves since this team support increases efficiency. The biggest surprise of all for us was a financial one. We are able to see more patients per day and are billing at a higher level of service, since there is more time to attend to more of the patient’s needs (thanks to the additional team support).

There is much talk about putting joy back into the practice of medicine. But the benchmark of any change needs to be whether it helps our patients. I believe that team documentation does. Happier, less burned-out physicians are able to better focus on patients during their visit. As one patient recently said to me at the end of a visit, “I feel like I’ve got my doctor back.”

That’s something that patients, and doctors alike, can feel good about.

The clerical work involved in managing the electronic medical record (EMR) is clearly not at the top of the skill set for physicians, yet many office-based clinicians find themselves bogged down in this work with no easy way out.

However, practices that are adopting team-based care—where each team member works at the top of his or her skill set—are finding a solution in the form of scribing, or team documentation. This approach can ease that burden and perhaps even help to curb physician burnout in the process. But many questions still surround this approach, notably: What do we know about the quality of this documentation?

Research conducted by Misra-Hebert et al reported on in this issue provides some insight—and reason for optimism. (See “Medical scribes: How do their notes stack up?”) Their study found that scribes’ outpatient notes stack up quite well when compared to those of physicians. And having worked with this approach to documentation, I can attest to its benefits, as well.

Misra-Hebert et al’s study in this issue attests to the quality of scribes’ notes. My personal experience is that charts are usually closed at the end of each half-day.

Two approaches, one goal. There are 2 different ways that physicians can get help with documentation. One involves the use of trained scribes, who come from a variety of backgrounds and are charged with writing down, or scribing, what the physician says. The other involves training staff, usually certified medical assistants (CMAs) or licensed practical nurses (LPNs), to take on a wide variety of additional duties including refill management, care gap closure, and most of the duties concerning the EMR—including documentation.

Misra-Hebert et al studied the second approach and found important evidence that using staff in this way does not adversely affect—and may even enhance—documentation previously done entirely by physicians.

This change in the way we approach EMRs involves commitment, as I’ve seen first hand. There needs to be significant training to make this work and there needs to be more staff, since physicians require 2 of these valuable team members to function effectively. (At least that’s been our experience.)

We are in the process of implementing team-based care throughout our 32-location health care system and have found that using CMAs and LPNs to assist with documentation is a “win” for everyone.

1. A win for the patient. Patients immediately notice that their physicians are now able to focus on them during the office visit, since they no longer have to tend to the demands of the computer. In addition, since the CMAs/LPNs are with patients during the entire visit, the patients bond with them and feel the extra support from this relationship.  

2. A win for the care team. Physician satisfaction has never been higher. Charts are usually closed at the end of each half-day. There is no need to take work home at night. CMAs/LPNs feel empowered and meaningfully involved in patient care. Their increase in satisfaction mirrors that of the physicians.

3. A win for the system. Not only are quality measures improving, but access improves since this team support increases efficiency. The biggest surprise of all for us was a financial one. We are able to see more patients per day and are billing at a higher level of service, since there is more time to attend to more of the patient’s needs (thanks to the additional team support).

There is much talk about putting joy back into the practice of medicine. But the benchmark of any change needs to be whether it helps our patients. I believe that team documentation does. Happier, less burned-out physicians are able to better focus on patients during their visit. As one patient recently said to me at the end of a visit, “I feel like I’ve got my doctor back.”

That’s something that patients, and doctors alike, can feel good about.

The clerical work involved in managing the electronic medical record (EMR) is clearly not at the top of the skill set for physicians, yet many office-based clinicians find themselves bogged down in this work with no easy way out.

However, practices that are adopting team-based care—where each team member works at the top of his or her skill set—are finding a solution in the form of scribing, or team documentation. This approach can ease that burden and perhaps even help to curb physician burnout in the process. But many questions still surround this approach, notably: What do we know about the quality of this documentation?

Research conducted by Misra-Hebert et al reported on in this issue provides some insight—and reason for optimism. (See “Medical scribes: How do their notes stack up?”) Their study found that scribes’ outpatient notes stack up quite well when compared to those of physicians. And having worked with this approach to documentation, I can attest to its benefits, as well.

Misra-Hebert et al’s study in this issue attests to the quality of scribes’ notes. My personal experience is that charts are usually closed at the end of each half-day.

Two approaches, one goal. There are 2 different ways that physicians can get help with documentation. One involves the use of trained scribes, who come from a variety of backgrounds and are charged with writing down, or scribing, what the physician says. The other involves training staff, usually certified medical assistants (CMAs) or licensed practical nurses (LPNs), to take on a wide variety of additional duties including refill management, care gap closure, and most of the duties concerning the EMR—including documentation.

Misra-Hebert et al studied the second approach and found important evidence that using staff in this way does not adversely affect—and may even enhance—documentation previously done entirely by physicians.

This change in the way we approach EMRs involves commitment, as I’ve seen first hand. There needs to be significant training to make this work and there needs to be more staff, since physicians require 2 of these valuable team members to function effectively. (At least that’s been our experience.)

We are in the process of implementing team-based care throughout our 32-location health care system and have found that using CMAs and LPNs to assist with documentation is a “win” for everyone.

1. A win for the patient. Patients immediately notice that their physicians are now able to focus on them during the office visit, since they no longer have to tend to the demands of the computer. In addition, since the CMAs/LPNs are with patients during the entire visit, the patients bond with them and feel the extra support from this relationship.  

2. A win for the care team. Physician satisfaction has never been higher. Charts are usually closed at the end of each half-day. There is no need to take work home at night. CMAs/LPNs feel empowered and meaningfully involved in patient care. Their increase in satisfaction mirrors that of the physicians.

3. A win for the system. Not only are quality measures improving, but access improves since this team support increases efficiency. The biggest surprise of all for us was a financial one. We are able to see more patients per day and are billing at a higher level of service, since there is more time to attend to more of the patient’s needs (thanks to the additional team support).

There is much talk about putting joy back into the practice of medicine. But the benchmark of any change needs to be whether it helps our patients. I believe that team documentation does. Happier, less burned-out physicians are able to better focus on patients during their visit. As one patient recently said to me at the end of a visit, “I feel like I’ve got my doctor back.”

That’s something that patients, and doctors alike, can feel good about.

THE CASE

A 52-year-old woman presented to our family clinic for a well woman exam. The only complaints she had were fatigue, which she attributed to a work day that began at 4 am, and hot flashes. She denied fever, weight loss, abdominal pain, medication use, or recent foreign travel. She had a history of hyperlipidemia and surgical removal of a cutaneous melanoma at age 12.

Her vital signs and physical exam were normal with the exception of 3 enlarged left inguinal lymph nodes and approximately 5 enlarged right inguinal lymph nodes. The nodes were freely moveable and non-tender. No additional lymphadenopathy or splenomegaly was found.

THE DIAGNOSIS

The patient’s work-up included a Pap smear, complete blood count (CBC), comprehensive metabolic panel (CMP), and pelvic and inguinal ultrasound. All tests were normal, except the ultrasound, which revealed 3 solid left inguinal lymph nodes measuring 1.2 to 1.6 cm and 6 solid right inguinal lymph nodes measuring 1.1 to 1.8 cm. An abdominal and pelvic computed tomography (CT) scan with contrast identified nonspecific mesenteric, inguinal, retrocrural, and retroperitoneal adenopathy. An open biopsy of the largest inguinal lymph node revealed follicular lymphoma, a form of non-Hodgkin’s lymphoma. (Hodgkin’s and non-Hodgkin’s lymphoma (NHL) are uncommon causes of inguinal lymphadenopathy.¹)

We consulted Oncology and they recommended a positron emission tomography (PET)/CT scan, which showed widespread lymphadenopathy. A bone marrow biopsy confirmed follicular lymphoma grade II, Ann Arbor stage III.

DISCUSSION

Generalized lymphadenopathy involves lymph node enlargement in more than one region of the body. Lymph nodes >1 cm in adults are considered abnormal and the differential diagnosis is broad (TABLE^2-5). A patient’s age is a significant factor in the evaluation of peripheral lymphadenopathy.^2-5 Results from one study of 628 patients who underwent nodal biopsy for peripheral lymphadenopathy revealed approximately 80% of nodes in patients under age 30 were noncancerous and likely had an infectious cause.³ However, among patients over age 50, only 40% were noncancerous.³

Node enlargement can be palpated in the head, neck, axilla, inguinal, and popliteal areas. Inguinal lymph nodes up to 2 cm in size may be palpable in healthy patients who spend time barefoot outdoors, have chronic leg trauma or infections, or have sexually transmitted infections.⁶ However, any lymph node >1 cm in adults should be considered abnormal.^2-5

Method of diagnosis depends on malignancy risk

A definitive diagnosis in patients with lymph nodes >1 cm can be made by open lymph node biopsy (the gold standard) or fine needle aspiration (FNA); however, these procedures are rarely needed if malignancy risk is low.

Data on the prevalence of malignant peripheral lymphadenopathy is limited.⁴ Fijten et al reported that among 2556 patients who presented to a family medicine clinic with unexplained lymphadenopathy, the prevalence of malignancy was as low as 1.1%.⁷ However, the prevalence of malignant lymph nodes among patients referred to a surgical center for biopsy by primary care physicians was approximately 40% to 60%.³ This highlights the importance of a thorough history, physical exam, and referral when appropriate to increase the yield of diagnostic biopsies.

Low risk for malignancy is suggested when lymphadenopathy is present for less than 2 weeks or persists for more than one year with no increase in size.² Benign causes such as sexually transmitted infections, Epstein-Barr virus, or medications should be treated appropriately. With no cause identified, 4 weeks of observation is recommended before biopsy.^2,4,5,8 CT, PET, and biopsy should be considered early for large, concerning masses. No evidence supports empiric antibiotic use for unknown causes.^2,5

High risk for malignancy is suggested in patients who are ≥50 years, present with constitutional symptoms, have lymphadenopathy >1 cm in >2 regions of the body, history of cancer, or have nodes that are rapidly enlarging, firm, fixed, or painless.^2,3,5,7,9 Supraclavicular lymphadenopathy has the highest risk for malignancy, especially in patients ≥40 years.⁷ Enlarged iliac, popliteal, epitrochlear, and umbilical lymph nodes are never normal.^2,4,5,7,10 Biopsy should be considered early in these patients.^2-4,7 FNA or core needle biopsy is acceptable for an initial diagnosis, but negative results may require open biopsy.^1,5,8 Prior to biopsy, imaging with ultrasound is recommended.^1,2,8,11

Our patient was offered rituximab alone or rituximab in addition to cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone (R-CHOP). The patient chose rituximab alone, which resulted in a 30% reduction in the size of her intra-abdominal disease. At this point, the patient and her oncologist chose to stop treatment and monitor her clinically.

Three months later, the patient returned to our family clinic complaining of postnasal drip, throat pain, and neck fullness that she’d had for one month that weren’t responsive to over-the-counter remedies and antibiotics. A supervised osteopathic medical student’s exam revealed right tonsillar enlargement (grade 3+) with minimal erythema and no exudates. A neck CT confirmed right tonsillar enlargement. The patient was referred to Otolaryngology, and the surgeon performed a tonsillectomy that demonstrated disease progression to follicular lymphoma grade IIIa. Given the new findings, Oncology recommended R-CHOP and the patient agreed.

The patient completed R-CHOP and her cancer was in remission one year later.

THE TAKEAWAY

Peripheral lymphadenopathy presents a diagnostic challenge that requires a thorough history and physical exam. General wellness exams should incorporate a comprehensive physical that includes the palpation of lymph nodes. Exam challenges include distinguishing benign lymphadenopathy (reactive lymphadenitis) from malignant lymphadenopathy.

In patients with low risk for malignancy, a period of 4 weeks of observation is reasonable. Biopsy should be considered early for risk factors including patient’s age ≥50, constitutional symptoms, lymphadenopathy >1 cm in >2 regions of the body, history of cancer, or rapidly enlarging nodes.

THE CASE

A 52-year-old woman presented to our family clinic for a well woman exam. The only complaints she had were fatigue, which she attributed to a work day that began at 4 am, and hot flashes. She denied fever, weight loss, abdominal pain, medication use, or recent foreign travel. She had a history of hyperlipidemia and surgical removal of a cutaneous melanoma at age 12.

Her vital signs and physical exam were normal with the exception of 3 enlarged left inguinal lymph nodes and approximately 5 enlarged right inguinal lymph nodes. The nodes were freely moveable and non-tender. No additional lymphadenopathy or splenomegaly was found.

THE DIAGNOSIS

The patient’s work-up included a Pap smear, complete blood count (CBC), comprehensive metabolic panel (CMP), and pelvic and inguinal ultrasound. All tests were normal, except the ultrasound, which revealed 3 solid left inguinal lymph nodes measuring 1.2 to 1.6 cm and 6 solid right inguinal lymph nodes measuring 1.1 to 1.8 cm. An abdominal and pelvic computed tomography (CT) scan with contrast identified nonspecific mesenteric, inguinal, retrocrural, and retroperitoneal adenopathy. An open biopsy of the largest inguinal lymph node revealed follicular lymphoma, a form of non-Hodgkin’s lymphoma. (Hodgkin’s and non-Hodgkin’s lymphoma (NHL) are uncommon causes of inguinal lymphadenopathy.¹)

We consulted Oncology and they recommended a positron emission tomography (PET)/CT scan, which showed widespread lymphadenopathy. A bone marrow biopsy confirmed follicular lymphoma grade II, Ann Arbor stage III.

DISCUSSION

Generalized lymphadenopathy involves lymph node enlargement in more than one region of the body. Lymph nodes >1 cm in adults are considered abnormal and the differential diagnosis is broad (TABLE^2-5). A patient’s age is a significant factor in the evaluation of peripheral lymphadenopathy.^2-5 Results from one study of 628 patients who underwent nodal biopsy for peripheral lymphadenopathy revealed approximately 80% of nodes in patients under age 30 were noncancerous and likely had an infectious cause.³ However, among patients over age 50, only 40% were noncancerous.³

Node enlargement can be palpated in the head, neck, axilla, inguinal, and popliteal areas. Inguinal lymph nodes up to 2 cm in size may be palpable in healthy patients who spend time barefoot outdoors, have chronic leg trauma or infections, or have sexually transmitted infections.⁶ However, any lymph node >1 cm in adults should be considered abnormal.^2-5

Method of diagnosis depends on malignancy risk

A definitive diagnosis in patients with lymph nodes >1 cm can be made by open lymph node biopsy (the gold standard) or fine needle aspiration (FNA); however, these procedures are rarely needed if malignancy risk is low.

Data on the prevalence of malignant peripheral lymphadenopathy is limited.⁴ Fijten et al reported that among 2556 patients who presented to a family medicine clinic with unexplained lymphadenopathy, the prevalence of malignancy was as low as 1.1%.⁷ However, the prevalence of malignant lymph nodes among patients referred to a surgical center for biopsy by primary care physicians was approximately 40% to 60%.³ This highlights the importance of a thorough history, physical exam, and referral when appropriate to increase the yield of diagnostic biopsies.

Low risk for malignancy is suggested when lymphadenopathy is present for less than 2 weeks or persists for more than one year with no increase in size.² Benign causes such as sexually transmitted infections, Epstein-Barr virus, or medications should be treated appropriately. With no cause identified, 4 weeks of observation is recommended before biopsy.^2,4,5,8 CT, PET, and biopsy should be considered early for large, concerning masses. No evidence supports empiric antibiotic use for unknown causes.^2,5

High risk for malignancy is suggested in patients who are ≥50 years, present with constitutional symptoms, have lymphadenopathy >1 cm in >2 regions of the body, history of cancer, or have nodes that are rapidly enlarging, firm, fixed, or painless.^2,3,5,7,9 Supraclavicular lymphadenopathy has the highest risk for malignancy, especially in patients ≥40 years.⁷ Enlarged iliac, popliteal, epitrochlear, and umbilical lymph nodes are never normal.^2,4,5,7,10 Biopsy should be considered early in these patients.^2-4,7 FNA or core needle biopsy is acceptable for an initial diagnosis, but negative results may require open biopsy.^1,5,8 Prior to biopsy, imaging with ultrasound is recommended.^1,2,8,11

Our patient was offered rituximab alone or rituximab in addition to cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone (R-CHOP). The patient chose rituximab alone, which resulted in a 30% reduction in the size of her intra-abdominal disease. At this point, the patient and her oncologist chose to stop treatment and monitor her clinically.

Three months later, the patient returned to our family clinic complaining of postnasal drip, throat pain, and neck fullness that she’d had for one month that weren’t responsive to over-the-counter remedies and antibiotics. A supervised osteopathic medical student’s exam revealed right tonsillar enlargement (grade 3+) with minimal erythema and no exudates. A neck CT confirmed right tonsillar enlargement. The patient was referred to Otolaryngology, and the surgeon performed a tonsillectomy that demonstrated disease progression to follicular lymphoma grade IIIa. Given the new findings, Oncology recommended R-CHOP and the patient agreed.

The patient completed R-CHOP and her cancer was in remission one year later.

THE TAKEAWAY

Peripheral lymphadenopathy presents a diagnostic challenge that requires a thorough history and physical exam. General wellness exams should incorporate a comprehensive physical that includes the palpation of lymph nodes. Exam challenges include distinguishing benign lymphadenopathy (reactive lymphadenitis) from malignant lymphadenopathy.

In patients with low risk for malignancy, a period of 4 weeks of observation is reasonable. Biopsy should be considered early for risk factors including patient’s age ≥50, constitutional symptoms, lymphadenopathy >1 cm in >2 regions of the body, history of cancer, or rapidly enlarging nodes.

THE CASE

A 52-year-old woman presented to our family clinic for a well woman exam. The only complaints she had were fatigue, which she attributed to a work day that began at 4 am, and hot flashes. She denied fever, weight loss, abdominal pain, medication use, or recent foreign travel. She had a history of hyperlipidemia and surgical removal of a cutaneous melanoma at age 12.

Her vital signs and physical exam were normal with the exception of 3 enlarged left inguinal lymph nodes and approximately 5 enlarged right inguinal lymph nodes. The nodes were freely moveable and non-tender. No additional lymphadenopathy or splenomegaly was found.

THE DIAGNOSIS

The patient’s work-up included a Pap smear, complete blood count (CBC), comprehensive metabolic panel (CMP), and pelvic and inguinal ultrasound. All tests were normal, except the ultrasound, which revealed 3 solid left inguinal lymph nodes measuring 1.2 to 1.6 cm and 6 solid right inguinal lymph nodes measuring 1.1 to 1.8 cm. An abdominal and pelvic computed tomography (CT) scan with contrast identified nonspecific mesenteric, inguinal, retrocrural, and retroperitoneal adenopathy. An open biopsy of the largest inguinal lymph node revealed follicular lymphoma, a form of non-Hodgkin’s lymphoma. (Hodgkin’s and non-Hodgkin’s lymphoma (NHL) are uncommon causes of inguinal lymphadenopathy.¹)

We consulted Oncology and they recommended a positron emission tomography (PET)/CT scan, which showed widespread lymphadenopathy. A bone marrow biopsy confirmed follicular lymphoma grade II, Ann Arbor stage III.

DISCUSSION

Generalized lymphadenopathy involves lymph node enlargement in more than one region of the body. Lymph nodes >1 cm in adults are considered abnormal and the differential diagnosis is broad (TABLE^2-5). A patient’s age is a significant factor in the evaluation of peripheral lymphadenopathy.^2-5 Results from one study of 628 patients who underwent nodal biopsy for peripheral lymphadenopathy revealed approximately 80% of nodes in patients under age 30 were noncancerous and likely had an infectious cause.³ However, among patients over age 50, only 40% were noncancerous.³

Node enlargement can be palpated in the head, neck, axilla, inguinal, and popliteal areas. Inguinal lymph nodes up to 2 cm in size may be palpable in healthy patients who spend time barefoot outdoors, have chronic leg trauma or infections, or have sexually transmitted infections.⁶ However, any lymph node >1 cm in adults should be considered abnormal.^2-5

Method of diagnosis depends on malignancy risk

A definitive diagnosis in patients with lymph nodes >1 cm can be made by open lymph node biopsy (the gold standard) or fine needle aspiration (FNA); however, these procedures are rarely needed if malignancy risk is low.

Data on the prevalence of malignant peripheral lymphadenopathy is limited.⁴ Fijten et al reported that among 2556 patients who presented to a family medicine clinic with unexplained lymphadenopathy, the prevalence of malignancy was as low as 1.1%.⁷ However, the prevalence of malignant lymph nodes among patients referred to a surgical center for biopsy by primary care physicians was approximately 40% to 60%.³ This highlights the importance of a thorough history, physical exam, and referral when appropriate to increase the yield of diagnostic biopsies.

Low risk for malignancy is suggested when lymphadenopathy is present for less than 2 weeks or persists for more than one year with no increase in size.² Benign causes such as sexually transmitted infections, Epstein-Barr virus, or medications should be treated appropriately. With no cause identified, 4 weeks of observation is recommended before biopsy.^2,4,5,8 CT, PET, and biopsy should be considered early for large, concerning masses. No evidence supports empiric antibiotic use for unknown causes.^2,5

High risk for malignancy is suggested in patients who are ≥50 years, present with constitutional symptoms, have lymphadenopathy >1 cm in >2 regions of the body, history of cancer, or have nodes that are rapidly enlarging, firm, fixed, or painless.^2,3,5,7,9 Supraclavicular lymphadenopathy has the highest risk for malignancy, especially in patients ≥40 years.⁷ Enlarged iliac, popliteal, epitrochlear, and umbilical lymph nodes are never normal.^2,4,5,7,10 Biopsy should be considered early in these patients.^2-4,7 FNA or core needle biopsy is acceptable for an initial diagnosis, but negative results may require open biopsy.^1,5,8 Prior to biopsy, imaging with ultrasound is recommended.^1,2,8,11

Our patient was offered rituximab alone or rituximab in addition to cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone (R-CHOP). The patient chose rituximab alone, which resulted in a 30% reduction in the size of her intra-abdominal disease. At this point, the patient and her oncologist chose to stop treatment and monitor her clinically.

Three months later, the patient returned to our family clinic complaining of postnasal drip, throat pain, and neck fullness that she’d had for one month that weren’t responsive to over-the-counter remedies and antibiotics. A supervised osteopathic medical student’s exam revealed right tonsillar enlargement (grade 3+) with minimal erythema and no exudates. A neck CT confirmed right tonsillar enlargement. The patient was referred to Otolaryngology, and the surgeon performed a tonsillectomy that demonstrated disease progression to follicular lymphoma grade IIIa. Given the new findings, Oncology recommended R-CHOP and the patient agreed.

The patient completed R-CHOP and her cancer was in remission one year later.

THE TAKEAWAY

Peripheral lymphadenopathy presents a diagnostic challenge that requires a thorough history and physical exam. General wellness exams should incorporate a comprehensive physical that includes the palpation of lymph nodes. Exam challenges include distinguishing benign lymphadenopathy (reactive lymphadenitis) from malignant lymphadenopathy.

In patients with low risk for malignancy, a period of 4 weeks of observation is reasonable. Biopsy should be considered early for risk factors including patient’s age ≥50, constitutional symptoms, lymphadenopathy >1 cm in >2 regions of the body, history of cancer, or rapidly enlarging nodes.

Americans who suffer from migraine headaches are far more likely than those who don’t to turn to complementary and alternative medicine (CAM). A 2007 National Health Interview Survey and a subsequent analysis of the results found that just under 50% of adults with migraine headaches used alternative therapies; among those without migraine, 34% did.^1,2 What’s more, only about half of the migraine patients who reported the use of CAM modalities mentioned it to their health care providers.²

With migraine affecting some 36 million Americans,³ chances are you are caring for many of them. It is likely, too, that you are unaware of which of your headache patients are using alternative treatments, or what modalities they have tried. The only way to find out is to ask.

Women, who are 3 times more likely than men to suffer from migraine headache,⁴ are also the greatest users of CAM, particularly biologically based therapies and mind-body practices.⁵ Use is highly individualized and typically does not involve professional supervision.⁵

A number of alternative modalities look promising for migraine prevention. As a family physician, you are in an ideal position to guide patients in the use of safe and effective CAM therapies. To do so, however, you need to be familiar with the evidence for or against various options—many of which can be used in conjunction with pharmacotherapy.

An integrative approach to the treatment of migraine headaches makes use of the best available evidence for both conventional and alternative therapies and takes into account the whole person, including all aspects of his or her belief system and lifestyle. It also emphasizes a strong physician-patient relationship, which can have a powerful therapeutic effect.

We wrote this evidence-based update with such an approach in mind. In the text and table that follow, we present the latest findings. But first, a brief review of what constitutes migraine headache and an overview of conventional treatment.

A conventional approach to migraine

Migraine headache is a common and disabling neurologic disorder that frequently goes unrecognized and undertreated.⁶ It is generally characterized as recurrent headaches that are unilateral, pulsating, moderately severe, aggravated by physical activity, and associated with nausea, vomiting, photophobia, phonophobia, and sometimes a preceding aura. Conventional treatment typically includes abortive treatment for acute migraine, with medications such as the triptans and dihydroergotamine. Acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and the combination of acetaminophen/aspirin/caffeine are also effective. Opiates are efficacious, but not recommended.⁷

Prophylactic medications are generally offered to patients experiencing more than 4 migraines per month. The American Academy of Neurology cites strong evidence for the use of divalproex, valproate, topiramate, and beta-blockers, including metoprolol, propranolol, and timolol. Frovatriptan has strong evidence for prevention of menstrual-associated migraine. Common adverse effects include weight loss and parasthesias with topiramate and weight gain and somnolence with valproate, divalproex, and beta-blockers. There is also moderate evidence for the use of amitriptyline, venlafaxine, atenolol, and nadolol. Potential adverse effects must be considered to determine the optimal therapy for individual patients, and trial and error are often required.⁸

Triggers such as visual disturbances and odors are good candidates for desensitization, while others, such as sleep deprivation and skipping meals, are better served by avoidance.

Addressing triggers

Conventional treatment also focuses on identifying and avoiding triggers to the extent possible. Physicians typically advise patients to keep a headache diary, recording details about diet and lifestyle, triggers, frequency and intensity of attacks, and possible patterns of headaches due to medication overuse.

Sleep disturbances and stress are common triggers, and instruction in sleep hygiene and stress reduction, as well as screening for anxiety or depression, can be beneficial. Other frequently reported factors believed to trigger or aggravate migraine attacks are skipping meals, particular foods, alcohol, weather changes, and exposure to light, sounds, and odors.

Despite the focus on migraine triggers, however, clinical studies of the role they play have shown conflicting results. A recent study involving 27 patients⁷ found that when attempting to provoke migraine with aura using participants’ self-reported triggers, only 3 individuals reported that the provocation actually led to a migraine.⁹ Additional studies suggest that exposure to headache triggers has the same effect as exposure to anxiety, with short-term exposure associated with an increased pain response and prolonged exposure leading to a decreased response.^10,11 Thus, it may be beneficial to advise patients to learn to cope with controlled exposure to triggers rather than to aim for trigger avoidance.¹²

If noise is identified as a trigger, for instance, repeated exposure in a relaxed environment can help desensitize the patient. Triggers such as visual disturbances and odors are also good candidates for desensitization, while others, such as sleep deprivation and skipping meals, are better served by avoidance.¹²

CAM approaches: A look at the evidence

Acupuncture, butterbur, feverfew, magnesium, riboflavin, and biofeedback look promising for migraine prevention. Many of our patients are already using these and other alternative therapies. Here’s what the latest studies show (TABLE).^{2,9-11, 13-51}

Can acupuncture help?

A 2009 Cochrane review of 22 high-quality studies with a total of 4419 participants supports the use of acupuncture for migraine prophylaxis.¹³ Acupuncture was found to be superior to no prophylactic treatment and acute treatment alone, and as effective as conventional preventive medications. Interestingly, though, among studies included in the Cochrane review that compared true acupuncture with sham interventions, no significant difference in results was found.

A more recent meta-analysis of 29 studies representing nearly 18,000 patients did show true acupuncture to be statistically superior to sham acupuncture, although the difference was of small clinical significance. Sham acupuncture was also shown to have a larger clinical effect than oral placebos, raising questions about the importance of exact point location.¹⁴

In a 2015 study comparing real and sham acupuncture over a 20-week period, however, the differences were more marked. Those who received real acupuncture reported significantly fewer migraine days and less severe headaches, and there were more responders in the treatment group compared with recipients of the sham procedures.¹⁵ Overall, the evidence indicates that acupuncture is at least as effective as conventional drug treatment for migraine prophylaxis, but with fewer adverse effects.^13-17

Butterbur raises concerns about toxicity

Butterbur (Petasites hybridus) is one of the best-studied natural remedies for migraine. The research has primarily focused on an extract of 15% petasin and isopetasin sold under the trade name Petadolex. A study of patients using this herbal preparation for 16 weeks showed a response rate of 48% for reduction in headache frequency among those taking 75 mg twice daily and a 36% reduction in those taking 50 mg twice a day. The primary adverse effect was burping.¹⁸

Proper processing is crucial. The key concern about butterbur is that it naturally contains hepatotoxic compounds called pyrrolizidine alkaloids (PA), which may remain if the product is not properly processed.^18-20 The labeling on many butterbur products states that they are “PA-free,” but because the manufacturers, rather than the US Food and Drug Administration (FDA), bear the responsibility for the safety and labeling of supplements, there is little oversight.

In fact, supplement quality is of considerable concern and subject to ongoing research. DNA bar-coding studies have confirmed that many common herbal preparations either contain ingredients not listed on the label or, conversely, fail to contain all the ingredients that are listed.⁵² Patients should be advised to look for evidence of quality assurance when purchasing herbal supplements, such as that offered by the US Pharmacopeia (USP) on a limited range of products. (We have not found any butterbur supplements with USP verification.)

Acupuncture is at least as effective as conventional pharmacotherapy for migraine prophylaxis, but with fewer adverse effects.

Feverfew yields mixed results

Studies of feverfew extract for migraine have had conflicting results, probably because different extracts have been tested. A recent Cochrane review, however, cited one clinical trial (N=218) that added positive evidence to previously inconclusive findings.²¹

The study in question assessed a proprietary extract of feverfew (MIG-99) and found a small decrease in frequency of migraines (0.6 per month) compared with placebo. Adverse effects were gastrointestinal disturbances and mouth ulcers.²²

Warn women of childbearing age that feverfew may cause uterine contractions and is contraindicated for those who are pregnant or trying to conceive.²³ In addition, patients who are allergic to ragweed, chrysanthemums, or other members of the daisy family may be allergic to feverfew, as well.²⁴

Magnesium is helpful for some

While magnesium is used for both acute relief of migraine and as prophylaxis, evidence of its efficacy is mixed. Studies have been promising in women with low magnesium levels and those who suffer from menstrual migraines, and for use in children with migraine headaches as both acute and preventive treatment.^25,26

One RCT involving 160 children ages 5 to 16 years found magnesium to have a synergistic effect with acetaminophen or ibuprofen, leading to greater acute pain relief and reducing migraine frequency.²⁷ A recent meta-analysis, however, concluded that intravenous magnesium is not likely to be effective for acute treatment.⁵³ The main adverse effects seen with magnesium are diarrhea and soft stools.

Patients with renal disease should avoid magnesium supplementation. Food sources of magnesium include whole grains, spinach, nuts, legumes, and white potatoes.⁵⁴

Riboflavin shows promise

Riboflavin (B2) plays an important role in cellular energy production and is an important antioxidant in mitochondria. Several small studies have shown promising results with high-dose (400 mg) riboflavin in migraine prevention, with evidence suggesting that it may be as effective as beta-blockers such as bisoprolol and metoprolol.^28-30 Discoloration of urine, which turns bright yellow, is the primary adverse effect.

CoQ10 helps those with low levels

Like riboflavin, coenzyme Q10 (CoQ10) is involved in mitochondrial transport and plays an important role in cellular energy metabolism. Several small studies have shown efficacy in migraine prevention in doses of 150 to 300 mg/d, with response rates between 30% and 50%.^31,32 Based on data in adults, the American Academy of Neurology guidelines give CoQ10 a Level C rating, indicating that it is possibly effective in preventing migraine.²⁹

An open label study of children with migraine found that close to a third were below the reference range for CoQ10 levels. Their serum levels increased when they began taking CoQ10 supplements, resulting in a significant reduction in headache frequency and an improvement in migraine-related disability.³³

Combination supplements have little efficacy

In a study published in 2015,³⁴ a proprietary supplement containing magnesium 600 mg, riboflavin 400 mg, CoQ10 150 mg, and low-dose multivitamins, taken daily, did not show statistically significant efficacy in the reduction of migraine days. After 3 months of supplementation, however, the severity of migraine pain improved. Adverse effects included abdominal discomfort and diarrhea.

Another study compared a combination of riboflavin 400 mg, magnesium 300 mg, and feverfew 100 mg with low-dose riboflavin (25 mg) as placebo, and found that the combination did not reduce the frequency or severity of migraine any more than the placebo.³⁵

Botox may relieve chronic migraine

Onabotulinumtoxin A (Botox) has FDA approval for the prevention of chronic migraines—ie, migraines that occur >15 days per month and at least 4 hours or more per day.⁵⁵ Botox is administered by injection every 12 weeks, across 31 sites on the head and neck. The recommended dose is 155 units, with 5 units delivered into each injection site.

This protocol has been found to reduce the number of headache days by 50% in half of those being treated after one cycle, and in more than 70% of patients after 3 cycles.³⁶ Potential adverse effects include blepharoptosis, neck muscle weakness, and the risk of botulism at sites distant from the injections.^37-39

Mind-body therapies are most widely used

Of all the CAM therapies used by patients with migraine headaches, mind-body modalities are the most prevalent. Overall, 30% of headache patients use them, compared with 17% of the general population.²

Many of these modalities have been found to be effective and safe to use with the conventional migraine treatments with which patients commonly combine them.

Meditation. Both spiritual and secular forms of meditation have been studied for acute and preventive treatment of migraine and found to be effective. A recent small study suggests that spiritual meditation may be more effective,⁴⁰ but secular mindfulness-based stress reduction training has also shown promise in migraine treatment.

One positive effect is that those who meditate typically use less migraine medication,⁴¹ decreasing the burden of disease. Meditation is increasingly available via a range of options, including both in-person groups and online sessions, and can easily augment conventional medical treatments.

Yoga, which typically combines physical postures, breathing techniques, and mental concentration/meditation, is increasingly widespread. While there is compelling evidence of its effect in treating chronic pain and stress-related conditions,⁴² studies specific to migraine are lacking. Several small studies comparing yoga to NSAIDs, educational handouts, and conventional care for headache suggest that yoga has efficacy for the treatment of migraine, but the findings are limited by methodology and sample size.^42,43

Advise patients who use herbal supplements to look for products with US Pharmacopeia quality assurance.

Relaxation training. Various types of relaxation are described in the literature, often combining progressive muscle relaxation, diaphragmatic breathing, and relaxation-inducing imagery. Although the consensus is that these techniques are effective, differences in standards, frequency, and duration of training make it hard to draw conclusions.⁴⁴

Biofeedback is similar to relaxation training, with the key difference being that it uses monitoring to train patients to alter their physiological state, thereby leading to desired changes—eg, fewer headaches and lower intensity of pain. Monitors evaluate skin temperature, electromyography, heart rate variability (blood-volume-pulse), and skin conductance, among other measures.

A robust collection of studies has shown the efficacy of skin temperature feedback, blood-volume-pulse feedback, and electromyography feedback as treatment for migraine.⁴⁵ Blood-volume-pulse feedback in combination with additional home training is perhaps more effective than other modalities. Despite convincing evidence of its efficacy for migraine headaches, however, only about 1% of patients with migraine use biofeedback. That’s likely due to a lack of availability outside of urban medical centers, limited insurance coverage, and time constraints.^2,45

Behavioral therapy can be of help

Cognitive behavioral therapy (CBT) focuses on adjusting maladaptive thoughts and behaviors. For migraine patients, this may include identifying and changing the patient’s response to migraine triggers such as stress, sleep deprivation, and fear of headache pain. Relaxation techniques may be incorporated into the therapy.

The effect size of CBT for prevention is comparable to prophylactic medication use, with 34% to 40% of patients achieving a clinically significant decrease in the number of attacks. Additive effects are especially promising, with more than two-thirds of patients achieving decreased frequency when CBT is combined with preventative medications.^2,44,46

A transcranial magnetic stimulator should not be used by patients who are at risk for seizures or have an implanted device.

Acceptance and commitment therapy (ACT) is a newer variant of CBT that has recently been studied.⁴⁴ Unlike CBT, in which patients are taught to control and revise their maladaptive thoughts and feelings, ACT focuses on noticing and accepting such unwanted thoughts and feelings and changing the way individuals respond to them rather than changing the thoughts themselves. Further study is needed to determine whether ACT is an effective treatment for migraine.

FDA-approved devices take aim at migraine

A transcranial magnetic stimulator (TMS) (Cerena, eNeura Inc, Sunnyvale, Calif) received FDA approval in 2013.⁵⁶ The single-pulse TMS is the first device authorized for the treatment of migraine headache pain. It is geared specifically to patients suffering from migraine with aura and requires a prescription.

In a study of 201 patients, the group using the TMS device at the onset of aura had a 38% response rate, compared with a 17% response among those in the sham control group. Dizziness was reported as an adverse effect. Caution patients who express an interest in it that the device should not be used by those who are at risk for seizures or have an implanted device, such as a pacemaker or deep brain stimulator.⁴⁷

Transcutaneous electrical nerve stimulation (TENS) has long been used for chronic pain, but in 2014 the FDA approved the first TENS device aimed at the prevention of migraine headaches in patients age 18 and older.⁵⁷ It is also the first such device approved for use prior to the onset of pain.

While physical activity can be a trigger for acute migraine, regular exercise has been shown to decrease the frequency of migraine attacks.

The Cefaly (Cefaly US, Inc., Wilton, Conn), which requires a prescription, is worn like a headband. It is positioned on the forehead just above the eyes, using an adhesive electrode, and is worn once a day for 20 minutes. The device applies an electrical current to the skin and underlying tissues to stimulate branches of the trigeminal nerve, which can cause a tingling or massaging sensation. Several small studies have shown a decrease in migraine frequency comparable with other preventive treatments. The main adverse effect reported was sedation, but more than half of those who used it were satisfied and willing to purchase the device.^48,49

Regular exercise has little downside

While physical activity can be a trigger for acute migraine, regular exercise has been shown to decrease the frequency of migraine attacks. And, although aerobic exercise is no more effective as migraine prophylaxis than conventional drug treatments, it has few adverse effects. For patients who want to stay fit and avoid taking preventive medications, exercise is a valuable adjunct to conventional treatments.^50,51

CORRESPONDENCE
Laura Armstrong, MD, Memorial Hermann Family Medicine Residency Program, 14023 Southwest Freeway, Sugar Land, TX 77478; [email protected].

Americans who suffer from migraine headaches are far more likely than those who don’t to turn to complementary and alternative medicine (CAM). A 2007 National Health Interview Survey and a subsequent analysis of the results found that just under 50% of adults with migraine headaches used alternative therapies; among those without migraine, 34% did.^1,2 What’s more, only about half of the migraine patients who reported the use of CAM modalities mentioned it to their health care providers.²

With migraine affecting some 36 million Americans,³ chances are you are caring for many of them. It is likely, too, that you are unaware of which of your headache patients are using alternative treatments, or what modalities they have tried. The only way to find out is to ask.

Women, who are 3 times more likely than men to suffer from migraine headache,⁴ are also the greatest users of CAM, particularly biologically based therapies and mind-body practices.⁵ Use is highly individualized and typically does not involve professional supervision.⁵

A number of alternative modalities look promising for migraine prevention. As a family physician, you are in an ideal position to guide patients in the use of safe and effective CAM therapies. To do so, however, you need to be familiar with the evidence for or against various options—many of which can be used in conjunction with pharmacotherapy.

An integrative approach to the treatment of migraine headaches makes use of the best available evidence for both conventional and alternative therapies and takes into account the whole person, including all aspects of his or her belief system and lifestyle. It also emphasizes a strong physician-patient relationship, which can have a powerful therapeutic effect.

We wrote this evidence-based update with such an approach in mind. In the text and table that follow, we present the latest findings. But first, a brief review of what constitutes migraine headache and an overview of conventional treatment.

A conventional approach to migraine

Migraine headache is a common and disabling neurologic disorder that frequently goes unrecognized and undertreated.⁶ It is generally characterized as recurrent headaches that are unilateral, pulsating, moderately severe, aggravated by physical activity, and associated with nausea, vomiting, photophobia, phonophobia, and sometimes a preceding aura. Conventional treatment typically includes abortive treatment for acute migraine, with medications such as the triptans and dihydroergotamine. Acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and the combination of acetaminophen/aspirin/caffeine are also effective. Opiates are efficacious, but not recommended.⁷

Prophylactic medications are generally offered to patients experiencing more than 4 migraines per month. The American Academy of Neurology cites strong evidence for the use of divalproex, valproate, topiramate, and beta-blockers, including metoprolol, propranolol, and timolol. Frovatriptan has strong evidence for prevention of menstrual-associated migraine. Common adverse effects include weight loss and parasthesias with topiramate and weight gain and somnolence with valproate, divalproex, and beta-blockers. There is also moderate evidence for the use of amitriptyline, venlafaxine, atenolol, and nadolol. Potential adverse effects must be considered to determine the optimal therapy for individual patients, and trial and error are often required.⁸

Triggers such as visual disturbances and odors are good candidates for desensitization, while others, such as sleep deprivation and skipping meals, are better served by avoidance.

Addressing triggers

Conventional treatment also focuses on identifying and avoiding triggers to the extent possible. Physicians typically advise patients to keep a headache diary, recording details about diet and lifestyle, triggers, frequency and intensity of attacks, and possible patterns of headaches due to medication overuse.

Sleep disturbances and stress are common triggers, and instruction in sleep hygiene and stress reduction, as well as screening for anxiety or depression, can be beneficial. Other frequently reported factors believed to trigger or aggravate migraine attacks are skipping meals, particular foods, alcohol, weather changes, and exposure to light, sounds, and odors.

Despite the focus on migraine triggers, however, clinical studies of the role they play have shown conflicting results. A recent study involving 27 patients⁷ found that when attempting to provoke migraine with aura using participants’ self-reported triggers, only 3 individuals reported that the provocation actually led to a migraine.⁹ Additional studies suggest that exposure to headache triggers has the same effect as exposure to anxiety, with short-term exposure associated with an increased pain response and prolonged exposure leading to a decreased response.^10,11 Thus, it may be beneficial to advise patients to learn to cope with controlled exposure to triggers rather than to aim for trigger avoidance.¹²

If noise is identified as a trigger, for instance, repeated exposure in a relaxed environment can help desensitize the patient. Triggers such as visual disturbances and odors are also good candidates for desensitization, while others, such as sleep deprivation and skipping meals, are better served by avoidance.¹²

CAM approaches: A look at the evidence

Acupuncture, butterbur, feverfew, magnesium, riboflavin, and biofeedback look promising for migraine prevention. Many of our patients are already using these and other alternative therapies. Here’s what the latest studies show (TABLE).^{2,9-11, 13-51}

Can acupuncture help?

A 2009 Cochrane review of 22 high-quality studies with a total of 4419 participants supports the use of acupuncture for migraine prophylaxis.¹³ Acupuncture was found to be superior to no prophylactic treatment and acute treatment alone, and as effective as conventional preventive medications. Interestingly, though, among studies included in the Cochrane review that compared true acupuncture with sham interventions, no significant difference in results was found.

A more recent meta-analysis of 29 studies representing nearly 18,000 patients did show true acupuncture to be statistically superior to sham acupuncture, although the difference was of small clinical significance. Sham acupuncture was also shown to have a larger clinical effect than oral placebos, raising questions about the importance of exact point location.¹⁴

In a 2015 study comparing real and sham acupuncture over a 20-week period, however, the differences were more marked. Those who received real acupuncture reported significantly fewer migraine days and less severe headaches, and there were more responders in the treatment group compared with recipients of the sham procedures.¹⁵ Overall, the evidence indicates that acupuncture is at least as effective as conventional drug treatment for migraine prophylaxis, but with fewer adverse effects.^13-17

Butterbur raises concerns about toxicity

Butterbur (Petasites hybridus) is one of the best-studied natural remedies for migraine. The research has primarily focused on an extract of 15% petasin and isopetasin sold under the trade name Petadolex. A study of patients using this herbal preparation for 16 weeks showed a response rate of 48% for reduction in headache frequency among those taking 75 mg twice daily and a 36% reduction in those taking 50 mg twice a day. The primary adverse effect was burping.¹⁸

Proper processing is crucial. The key concern about butterbur is that it naturally contains hepatotoxic compounds called pyrrolizidine alkaloids (PA), which may remain if the product is not properly processed.^18-20 The labeling on many butterbur products states that they are “PA-free,” but because the manufacturers, rather than the US Food and Drug Administration (FDA), bear the responsibility for the safety and labeling of supplements, there is little oversight.

In fact, supplement quality is of considerable concern and subject to ongoing research. DNA bar-coding studies have confirmed that many common herbal preparations either contain ingredients not listed on the label or, conversely, fail to contain all the ingredients that are listed.⁵² Patients should be advised to look for evidence of quality assurance when purchasing herbal supplements, such as that offered by the US Pharmacopeia (USP) on a limited range of products. (We have not found any butterbur supplements with USP verification.)

Acupuncture is at least as effective as conventional pharmacotherapy for migraine prophylaxis, but with fewer adverse effects.

Feverfew yields mixed results

Studies of feverfew extract for migraine have had conflicting results, probably because different extracts have been tested. A recent Cochrane review, however, cited one clinical trial (N=218) that added positive evidence to previously inconclusive findings.²¹

The study in question assessed a proprietary extract of feverfew (MIG-99) and found a small decrease in frequency of migraines (0.6 per month) compared with placebo. Adverse effects were gastrointestinal disturbances and mouth ulcers.²²

Warn women of childbearing age that feverfew may cause uterine contractions and is contraindicated for those who are pregnant or trying to conceive.²³ In addition, patients who are allergic to ragweed, chrysanthemums, or other members of the daisy family may be allergic to feverfew, as well.²⁴

Magnesium is helpful for some

While magnesium is used for both acute relief of migraine and as prophylaxis, evidence of its efficacy is mixed. Studies have been promising in women with low magnesium levels and those who suffer from menstrual migraines, and for use in children with migraine headaches as both acute and preventive treatment.^25,26

One RCT involving 160 children ages 5 to 16 years found magnesium to have a synergistic effect with acetaminophen or ibuprofen, leading to greater acute pain relief and reducing migraine frequency.²⁷ A recent meta-analysis, however, concluded that intravenous magnesium is not likely to be effective for acute treatment.⁵³ The main adverse effects seen with magnesium are diarrhea and soft stools.

Patients with renal disease should avoid magnesium supplementation. Food sources of magnesium include whole grains, spinach, nuts, legumes, and white potatoes.⁵⁴

Riboflavin shows promise

Riboflavin (B2) plays an important role in cellular energy production and is an important antioxidant in mitochondria. Several small studies have shown promising results with high-dose (400 mg) riboflavin in migraine prevention, with evidence suggesting that it may be as effective as beta-blockers such as bisoprolol and metoprolol.^28-30 Discoloration of urine, which turns bright yellow, is the primary adverse effect.

CoQ10 helps those with low levels

Like riboflavin, coenzyme Q10 (CoQ10) is involved in mitochondrial transport and plays an important role in cellular energy metabolism. Several small studies have shown efficacy in migraine prevention in doses of 150 to 300 mg/d, with response rates between 30% and 50%.^31,32 Based on data in adults, the American Academy of Neurology guidelines give CoQ10 a Level C rating, indicating that it is possibly effective in preventing migraine.²⁹

An open label study of children with migraine found that close to a third were below the reference range for CoQ10 levels. Their serum levels increased when they began taking CoQ10 supplements, resulting in a significant reduction in headache frequency and an improvement in migraine-related disability.³³

Combination supplements have little efficacy

In a study published in 2015,³⁴ a proprietary supplement containing magnesium 600 mg, riboflavin 400 mg, CoQ10 150 mg, and low-dose multivitamins, taken daily, did not show statistically significant efficacy in the reduction of migraine days. After 3 months of supplementation, however, the severity of migraine pain improved. Adverse effects included abdominal discomfort and diarrhea.

Another study compared a combination of riboflavin 400 mg, magnesium 300 mg, and feverfew 100 mg with low-dose riboflavin (25 mg) as placebo, and found that the combination did not reduce the frequency or severity of migraine any more than the placebo.³⁵

Botox may relieve chronic migraine

Onabotulinumtoxin A (Botox) has FDA approval for the prevention of chronic migraines—ie, migraines that occur >15 days per month and at least 4 hours or more per day.⁵⁵ Botox is administered by injection every 12 weeks, across 31 sites on the head and neck. The recommended dose is 155 units, with 5 units delivered into each injection site.

This protocol has been found to reduce the number of headache days by 50% in half of those being treated after one cycle, and in more than 70% of patients after 3 cycles.³⁶ Potential adverse effects include blepharoptosis, neck muscle weakness, and the risk of botulism at sites distant from the injections.^37-39

Mind-body therapies are most widely used

Of all the CAM therapies used by patients with migraine headaches, mind-body modalities are the most prevalent. Overall, 30% of headache patients use them, compared with 17% of the general population.²

Many of these modalities have been found to be effective and safe to use with the conventional migraine treatments with which patients commonly combine them.

Meditation. Both spiritual and secular forms of meditation have been studied for acute and preventive treatment of migraine and found to be effective. A recent small study suggests that spiritual meditation may be more effective,⁴⁰ but secular mindfulness-based stress reduction training has also shown promise in migraine treatment.

One positive effect is that those who meditate typically use less migraine medication,⁴¹ decreasing the burden of disease. Meditation is increasingly available via a range of options, including both in-person groups and online sessions, and can easily augment conventional medical treatments.

Yoga, which typically combines physical postures, breathing techniques, and mental concentration/meditation, is increasingly widespread. While there is compelling evidence of its effect in treating chronic pain and stress-related conditions,⁴² studies specific to migraine are lacking. Several small studies comparing yoga to NSAIDs, educational handouts, and conventional care for headache suggest that yoga has efficacy for the treatment of migraine, but the findings are limited by methodology and sample size.^42,43

Advise patients who use herbal supplements to look for products with US Pharmacopeia quality assurance.

Relaxation training. Various types of relaxation are described in the literature, often combining progressive muscle relaxation, diaphragmatic breathing, and relaxation-inducing imagery. Although the consensus is that these techniques are effective, differences in standards, frequency, and duration of training make it hard to draw conclusions.⁴⁴

Biofeedback is similar to relaxation training, with the key difference being that it uses monitoring to train patients to alter their physiological state, thereby leading to desired changes—eg, fewer headaches and lower intensity of pain. Monitors evaluate skin temperature, electromyography, heart rate variability (blood-volume-pulse), and skin conductance, among other measures.

A robust collection of studies has shown the efficacy of skin temperature feedback, blood-volume-pulse feedback, and electromyography feedback as treatment for migraine.⁴⁵ Blood-volume-pulse feedback in combination with additional home training is perhaps more effective than other modalities. Despite convincing evidence of its efficacy for migraine headaches, however, only about 1% of patients with migraine use biofeedback. That’s likely due to a lack of availability outside of urban medical centers, limited insurance coverage, and time constraints.^2,45

Behavioral therapy can be of help

Cognitive behavioral therapy (CBT) focuses on adjusting maladaptive thoughts and behaviors. For migraine patients, this may include identifying and changing the patient’s response to migraine triggers such as stress, sleep deprivation, and fear of headache pain. Relaxation techniques may be incorporated into the therapy.

The effect size of CBT for prevention is comparable to prophylactic medication use, with 34% to 40% of patients achieving a clinically significant decrease in the number of attacks. Additive effects are especially promising, with more than two-thirds of patients achieving decreased frequency when CBT is combined with preventative medications.^2,44,46

A transcranial magnetic stimulator should not be used by patients who are at risk for seizures or have an implanted device.

Acceptance and commitment therapy (ACT) is a newer variant of CBT that has recently been studied.⁴⁴ Unlike CBT, in which patients are taught to control and revise their maladaptive thoughts and feelings, ACT focuses on noticing and accepting such unwanted thoughts and feelings and changing the way individuals respond to them rather than changing the thoughts themselves. Further study is needed to determine whether ACT is an effective treatment for migraine.

FDA-approved devices take aim at migraine

A transcranial magnetic stimulator (TMS) (Cerena, eNeura Inc, Sunnyvale, Calif) received FDA approval in 2013.⁵⁶ The single-pulse TMS is the first device authorized for the treatment of migraine headache pain. It is geared specifically to patients suffering from migraine with aura and requires a prescription.

In a study of 201 patients, the group using the TMS device at the onset of aura had a 38% response rate, compared with a 17% response among those in the sham control group. Dizziness was reported as an adverse effect. Caution patients who express an interest in it that the device should not be used by those who are at risk for seizures or have an implanted device, such as a pacemaker or deep brain stimulator.⁴⁷

Transcutaneous electrical nerve stimulation (TENS) has long been used for chronic pain, but in 2014 the FDA approved the first TENS device aimed at the prevention of migraine headaches in patients age 18 and older.⁵⁷ It is also the first such device approved for use prior to the onset of pain.

While physical activity can be a trigger for acute migraine, regular exercise has been shown to decrease the frequency of migraine attacks.

The Cefaly (Cefaly US, Inc., Wilton, Conn), which requires a prescription, is worn like a headband. It is positioned on the forehead just above the eyes, using an adhesive electrode, and is worn once a day for 20 minutes. The device applies an electrical current to the skin and underlying tissues to stimulate branches of the trigeminal nerve, which can cause a tingling or massaging sensation. Several small studies have shown a decrease in migraine frequency comparable with other preventive treatments. The main adverse effect reported was sedation, but more than half of those who used it were satisfied and willing to purchase the device.^48,49

Regular exercise has little downside

While physical activity can be a trigger for acute migraine, regular exercise has been shown to decrease the frequency of migraine attacks. And, although aerobic exercise is no more effective as migraine prophylaxis than conventional drug treatments, it has few adverse effects. For patients who want to stay fit and avoid taking preventive medications, exercise is a valuable adjunct to conventional treatments.^50,51

CORRESPONDENCE
Laura Armstrong, MD, Memorial Hermann Family Medicine Residency Program, 14023 Southwest Freeway, Sugar Land, TX 77478; [email protected].

Americans who suffer from migraine headaches are far more likely than those who don’t to turn to complementary and alternative medicine (CAM). A 2007 National Health Interview Survey and a subsequent analysis of the results found that just under 50% of adults with migraine headaches used alternative therapies; among those without migraine, 34% did.^1,2 What’s more, only about half of the migraine patients who reported the use of CAM modalities mentioned it to their health care providers.²

With migraine affecting some 36 million Americans,³ chances are you are caring for many of them. It is likely, too, that you are unaware of which of your headache patients are using alternative treatments, or what modalities they have tried. The only way to find out is to ask.

Women, who are 3 times more likely than men to suffer from migraine headache,⁴ are also the greatest users of CAM, particularly biologically based therapies and mind-body practices.⁵ Use is highly individualized and typically does not involve professional supervision.⁵

A number of alternative modalities look promising for migraine prevention. As a family physician, you are in an ideal position to guide patients in the use of safe and effective CAM therapies. To do so, however, you need to be familiar with the evidence for or against various options—many of which can be used in conjunction with pharmacotherapy.

An integrative approach to the treatment of migraine headaches makes use of the best available evidence for both conventional and alternative therapies and takes into account the whole person, including all aspects of his or her belief system and lifestyle. It also emphasizes a strong physician-patient relationship, which can have a powerful therapeutic effect.

We wrote this evidence-based update with such an approach in mind. In the text and table that follow, we present the latest findings. But first, a brief review of what constitutes migraine headache and an overview of conventional treatment.

A conventional approach to migraine

Migraine headache is a common and disabling neurologic disorder that frequently goes unrecognized and undertreated.⁶ It is generally characterized as recurrent headaches that are unilateral, pulsating, moderately severe, aggravated by physical activity, and associated with nausea, vomiting, photophobia, phonophobia, and sometimes a preceding aura. Conventional treatment typically includes abortive treatment for acute migraine, with medications such as the triptans and dihydroergotamine. Acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and the combination of acetaminophen/aspirin/caffeine are also effective. Opiates are efficacious, but not recommended.⁷

Prophylactic medications are generally offered to patients experiencing more than 4 migraines per month. The American Academy of Neurology cites strong evidence for the use of divalproex, valproate, topiramate, and beta-blockers, including metoprolol, propranolol, and timolol. Frovatriptan has strong evidence for prevention of menstrual-associated migraine. Common adverse effects include weight loss and parasthesias with topiramate and weight gain and somnolence with valproate, divalproex, and beta-blockers. There is also moderate evidence for the use of amitriptyline, venlafaxine, atenolol, and nadolol. Potential adverse effects must be considered to determine the optimal therapy for individual patients, and trial and error are often required.⁸

Triggers such as visual disturbances and odors are good candidates for desensitization, while others, such as sleep deprivation and skipping meals, are better served by avoidance.

Addressing triggers

Conventional treatment also focuses on identifying and avoiding triggers to the extent possible. Physicians typically advise patients to keep a headache diary, recording details about diet and lifestyle, triggers, frequency and intensity of attacks, and possible patterns of headaches due to medication overuse.

Sleep disturbances and stress are common triggers, and instruction in sleep hygiene and stress reduction, as well as screening for anxiety or depression, can be beneficial. Other frequently reported factors believed to trigger or aggravate migraine attacks are skipping meals, particular foods, alcohol, weather changes, and exposure to light, sounds, and odors.

Despite the focus on migraine triggers, however, clinical studies of the role they play have shown conflicting results. A recent study involving 27 patients⁷ found that when attempting to provoke migraine with aura using participants’ self-reported triggers, only 3 individuals reported that the provocation actually led to a migraine.⁹ Additional studies suggest that exposure to headache triggers has the same effect as exposure to anxiety, with short-term exposure associated with an increased pain response and prolonged exposure leading to a decreased response.^10,11 Thus, it may be beneficial to advise patients to learn to cope with controlled exposure to triggers rather than to aim for trigger avoidance.¹²

If noise is identified as a trigger, for instance, repeated exposure in a relaxed environment can help desensitize the patient. Triggers such as visual disturbances and odors are also good candidates for desensitization, while others, such as sleep deprivation and skipping meals, are better served by avoidance.¹²

CAM approaches: A look at the evidence

Acupuncture, butterbur, feverfew, magnesium, riboflavin, and biofeedback look promising for migraine prevention. Many of our patients are already using these and other alternative therapies. Here’s what the latest studies show (TABLE).^{2,9-11, 13-51}

Can acupuncture help?

A 2009 Cochrane review of 22 high-quality studies with a total of 4419 participants supports the use of acupuncture for migraine prophylaxis.¹³ Acupuncture was found to be superior to no prophylactic treatment and acute treatment alone, and as effective as conventional preventive medications. Interestingly, though, among studies included in the Cochrane review that compared true acupuncture with sham interventions, no significant difference in results was found.

A more recent meta-analysis of 29 studies representing nearly 18,000 patients did show true acupuncture to be statistically superior to sham acupuncture, although the difference was of small clinical significance. Sham acupuncture was also shown to have a larger clinical effect than oral placebos, raising questions about the importance of exact point location.¹⁴

In a 2015 study comparing real and sham acupuncture over a 20-week period, however, the differences were more marked. Those who received real acupuncture reported significantly fewer migraine days and less severe headaches, and there were more responders in the treatment group compared with recipients of the sham procedures.¹⁵ Overall, the evidence indicates that acupuncture is at least as effective as conventional drug treatment for migraine prophylaxis, but with fewer adverse effects.^13-17

Butterbur raises concerns about toxicity

Butterbur (Petasites hybridus) is one of the best-studied natural remedies for migraine. The research has primarily focused on an extract of 15% petasin and isopetasin sold under the trade name Petadolex. A study of patients using this herbal preparation for 16 weeks showed a response rate of 48% for reduction in headache frequency among those taking 75 mg twice daily and a 36% reduction in those taking 50 mg twice a day. The primary adverse effect was burping.¹⁸

Proper processing is crucial. The key concern about butterbur is that it naturally contains hepatotoxic compounds called pyrrolizidine alkaloids (PA), which may remain if the product is not properly processed.^18-20 The labeling on many butterbur products states that they are “PA-free,” but because the manufacturers, rather than the US Food and Drug Administration (FDA), bear the responsibility for the safety and labeling of supplements, there is little oversight.

In fact, supplement quality is of considerable concern and subject to ongoing research. DNA bar-coding studies have confirmed that many common herbal preparations either contain ingredients not listed on the label or, conversely, fail to contain all the ingredients that are listed.⁵² Patients should be advised to look for evidence of quality assurance when purchasing herbal supplements, such as that offered by the US Pharmacopeia (USP) on a limited range of products. (We have not found any butterbur supplements with USP verification.)

Acupuncture is at least as effective as conventional pharmacotherapy for migraine prophylaxis, but with fewer adverse effects.

Feverfew yields mixed results

Studies of feverfew extract for migraine have had conflicting results, probably because different extracts have been tested. A recent Cochrane review, however, cited one clinical trial (N=218) that added positive evidence to previously inconclusive findings.²¹

The study in question assessed a proprietary extract of feverfew (MIG-99) and found a small decrease in frequency of migraines (0.6 per month) compared with placebo. Adverse effects were gastrointestinal disturbances and mouth ulcers.²²

Warn women of childbearing age that feverfew may cause uterine contractions and is contraindicated for those who are pregnant or trying to conceive.²³ In addition, patients who are allergic to ragweed, chrysanthemums, or other members of the daisy family may be allergic to feverfew, as well.²⁴

Magnesium is helpful for some

While magnesium is used for both acute relief of migraine and as prophylaxis, evidence of its efficacy is mixed. Studies have been promising in women with low magnesium levels and those who suffer from menstrual migraines, and for use in children with migraine headaches as both acute and preventive treatment.^25,26

One RCT involving 160 children ages 5 to 16 years found magnesium to have a synergistic effect with acetaminophen or ibuprofen, leading to greater acute pain relief and reducing migraine frequency.²⁷ A recent meta-analysis, however, concluded that intravenous magnesium is not likely to be effective for acute treatment.⁵³ The main adverse effects seen with magnesium are diarrhea and soft stools.

Patients with renal disease should avoid magnesium supplementation. Food sources of magnesium include whole grains, spinach, nuts, legumes, and white potatoes.⁵⁴

Riboflavin shows promise

Riboflavin (B2) plays an important role in cellular energy production and is an important antioxidant in mitochondria. Several small studies have shown promising results with high-dose (400 mg) riboflavin in migraine prevention, with evidence suggesting that it may be as effective as beta-blockers such as bisoprolol and metoprolol.^28-30 Discoloration of urine, which turns bright yellow, is the primary adverse effect.

CoQ10 helps those with low levels

Like riboflavin, coenzyme Q10 (CoQ10) is involved in mitochondrial transport and plays an important role in cellular energy metabolism. Several small studies have shown efficacy in migraine prevention in doses of 150 to 300 mg/d, with response rates between 30% and 50%.^31,32 Based on data in adults, the American Academy of Neurology guidelines give CoQ10 a Level C rating, indicating that it is possibly effective in preventing migraine.²⁹

An open label study of children with migraine found that close to a third were below the reference range for CoQ10 levels. Their serum levels increased when they began taking CoQ10 supplements, resulting in a significant reduction in headache frequency and an improvement in migraine-related disability.³³

Combination supplements have little efficacy

In a study published in 2015,³⁴ a proprietary supplement containing magnesium 600 mg, riboflavin 400 mg, CoQ10 150 mg, and low-dose multivitamins, taken daily, did not show statistically significant efficacy in the reduction of migraine days. After 3 months of supplementation, however, the severity of migraine pain improved. Adverse effects included abdominal discomfort and diarrhea.

Another study compared a combination of riboflavin 400 mg, magnesium 300 mg, and feverfew 100 mg with low-dose riboflavin (25 mg) as placebo, and found that the combination did not reduce the frequency or severity of migraine any more than the placebo.³⁵

Botox may relieve chronic migraine

Onabotulinumtoxin A (Botox) has FDA approval for the prevention of chronic migraines—ie, migraines that occur >15 days per month and at least 4 hours or more per day.⁵⁵ Botox is administered by injection every 12 weeks, across 31 sites on the head and neck. The recommended dose is 155 units, with 5 units delivered into each injection site.

This protocol has been found to reduce the number of headache days by 50% in half of those being treated after one cycle, and in more than 70% of patients after 3 cycles.³⁶ Potential adverse effects include blepharoptosis, neck muscle weakness, and the risk of botulism at sites distant from the injections.^37-39

Mind-body therapies are most widely used

Of all the CAM therapies used by patients with migraine headaches, mind-body modalities are the most prevalent. Overall, 30% of headache patients use them, compared with 17% of the general population.²

Many of these modalities have been found to be effective and safe to use with the conventional migraine treatments with which patients commonly combine them.

Meditation. Both spiritual and secular forms of meditation have been studied for acute and preventive treatment of migraine and found to be effective. A recent small study suggests that spiritual meditation may be more effective,⁴⁰ but secular mindfulness-based stress reduction training has also shown promise in migraine treatment.

One positive effect is that those who meditate typically use less migraine medication,⁴¹ decreasing the burden of disease. Meditation is increasingly available via a range of options, including both in-person groups and online sessions, and can easily augment conventional medical treatments.

Yoga, which typically combines physical postures, breathing techniques, and mental concentration/meditation, is increasingly widespread. While there is compelling evidence of its effect in treating chronic pain and stress-related conditions,⁴² studies specific to migraine are lacking. Several small studies comparing yoga to NSAIDs, educational handouts, and conventional care for headache suggest that yoga has efficacy for the treatment of migraine, but the findings are limited by methodology and sample size.^42,43

Advise patients who use herbal supplements to look for products with US Pharmacopeia quality assurance.

Relaxation training. Various types of relaxation are described in the literature, often combining progressive muscle relaxation, diaphragmatic breathing, and relaxation-inducing imagery. Although the consensus is that these techniques are effective, differences in standards, frequency, and duration of training make it hard to draw conclusions.⁴⁴

Biofeedback is similar to relaxation training, with the key difference being that it uses monitoring to train patients to alter their physiological state, thereby leading to desired changes—eg, fewer headaches and lower intensity of pain. Monitors evaluate skin temperature, electromyography, heart rate variability (blood-volume-pulse), and skin conductance, among other measures.

A robust collection of studies has shown the efficacy of skin temperature feedback, blood-volume-pulse feedback, and electromyography feedback as treatment for migraine.⁴⁵ Blood-volume-pulse feedback in combination with additional home training is perhaps more effective than other modalities. Despite convincing evidence of its efficacy for migraine headaches, however, only about 1% of patients with migraine use biofeedback. That’s likely due to a lack of availability outside of urban medical centers, limited insurance coverage, and time constraints.^2,45

Behavioral therapy can be of help

Cognitive behavioral therapy (CBT) focuses on adjusting maladaptive thoughts and behaviors. For migraine patients, this may include identifying and changing the patient’s response to migraine triggers such as stress, sleep deprivation, and fear of headache pain. Relaxation techniques may be incorporated into the therapy.

The effect size of CBT for prevention is comparable to prophylactic medication use, with 34% to 40% of patients achieving a clinically significant decrease in the number of attacks. Additive effects are especially promising, with more than two-thirds of patients achieving decreased frequency when CBT is combined with preventative medications.^2,44,46

A transcranial magnetic stimulator should not be used by patients who are at risk for seizures or have an implanted device.

Acceptance and commitment therapy (ACT) is a newer variant of CBT that has recently been studied.⁴⁴ Unlike CBT, in which patients are taught to control and revise their maladaptive thoughts and feelings, ACT focuses on noticing and accepting such unwanted thoughts and feelings and changing the way individuals respond to them rather than changing the thoughts themselves. Further study is needed to determine whether ACT is an effective treatment for migraine.

FDA-approved devices take aim at migraine

A transcranial magnetic stimulator (TMS) (Cerena, eNeura Inc, Sunnyvale, Calif) received FDA approval in 2013.⁵⁶ The single-pulse TMS is the first device authorized for the treatment of migraine headache pain. It is geared specifically to patients suffering from migraine with aura and requires a prescription.

In a study of 201 patients, the group using the TMS device at the onset of aura had a 38% response rate, compared with a 17% response among those in the sham control group. Dizziness was reported as an adverse effect. Caution patients who express an interest in it that the device should not be used by those who are at risk for seizures or have an implanted device, such as a pacemaker or deep brain stimulator.⁴⁷

Transcutaneous electrical nerve stimulation (TENS) has long been used for chronic pain, but in 2014 the FDA approved the first TENS device aimed at the prevention of migraine headaches in patients age 18 and older.⁵⁷ It is also the first such device approved for use prior to the onset of pain.

While physical activity can be a trigger for acute migraine, regular exercise has been shown to decrease the frequency of migraine attacks.

The Cefaly (Cefaly US, Inc., Wilton, Conn), which requires a prescription, is worn like a headband. It is positioned on the forehead just above the eyes, using an adhesive electrode, and is worn once a day for 20 minutes. The device applies an electrical current to the skin and underlying tissues to stimulate branches of the trigeminal nerve, which can cause a tingling or massaging sensation. Several small studies have shown a decrease in migraine frequency comparable with other preventive treatments. The main adverse effect reported was sedation, but more than half of those who used it were satisfied and willing to purchase the device.^48,49

Regular exercise has little downside

While physical activity can be a trigger for acute migraine, regular exercise has been shown to decrease the frequency of migraine attacks. And, although aerobic exercise is no more effective as migraine prophylaxis than conventional drug treatments, it has few adverse effects. For patients who want to stay fit and avoid taking preventive medications, exercise is a valuable adjunct to conventional treatments.^50,51

CORRESPONDENCE
Laura Armstrong, MD, Memorial Hermann Family Medicine Residency Program, 14023 Southwest Freeway, Sugar Land, TX 77478; [email protected].

Managing anticoagulation in patients with infectious endocarditis requires an individualized approach, using a careful risk-benefit assessment on a case-by-case basis. There is a dearth of high-quality evidence; consequently, the recommendations also vary according to the clinical situation.

Newly diagnosed native valve infectious endocarditis in itself is not an indication for anticoagulation.^1–3 The question of whether to anticoagulate arises in patients who have a preexisting or coexisting indication for anticoagulation such as atrial fibrillation, deep vein thrombosis, pulmonary embolism, or a mechanical prosthetic heart valve. The question becomes yet more complex in patients with cerebrovascular complications and a coexistent strong indication for anticoagulation, creating what is often a very thorny dilemma.

Based on a review of available evidence, recommendations for anticoagulation in patients with infectious endocarditis are summarized below.

AVAILABLE EVIDENCE IS SCARCE AND MIXED

Earlier observational studies suggested a significant risk of cerebral hemorrhage with anticoagulation in patients with native valve endocarditis, although none of these studies were recent (some of them took place in the 1940s), and none are methodologically compelling.^4–8 Consequently, some experts have expressed skepticism regarding their findings, particularly in recent years.

In part, this skepticism arises from studies that showed a lower incidence of cerebrovascular complications and smaller vegetation size in patients with prosthetic valve infectious endocarditis, studies in which many of the patients received anticoagulation therapy.^9,10 The mechanism responsible for this effect is theorized to be that the vegetation is an amalgam of destroyed cells, platelets, and fibrin, with anticoagulation preventing this aggregation from further growth and propagation.

How great is the benefit or the potential harm?

Some experts argue that the incidence of ischemic stroke with hemorrhagic transformation in patients with infectious endocarditis receiving anticoagulation is overestimated. According to this view, the beneficial effects of anticoagulation at least counterbalance the potential harmful effects.

In addition to the studies cited above, recent studies have shown that patients on anticoagulation tend to have smaller vegetations and fewer cerebrovascular complications.^11–13 Snygg-Martin et al¹¹ and Rasmussen et al¹² found not only that cerebrovascular complications were less common in patients already on anticoagulation at the time infectious endocarditis was diagnosed, but also that no increase in the rate of hemorrhagic lesions was reported.

These were all nonrandomized studies, and most of the patients in them had native valve infectious endocarditis diagnosed at an early stage. Importantly, these studies found that the beneficial effects of anticoagulation were only present if the patient was receiving warfarin before infectious endocarditis was diagnosed and antibiotic therapy was initiated. No benefits from anticoagulation were demonstrated once antimicrobial therapy was begun.

Similarly, Anavekar et al¹⁴ showed that embolic events occurred significantly less often in those who were currently on continuous daily antiplatelet therapy, suggesting that receiving antiplatelet agents at baseline protects against cardioembolic events in patients who develop infective endocarditis. However, the only randomized trial examining the initiation of antiplatelet therapy in patients diagnosed with infectious endocarditis receiving antibiotic treatment showed that adding aspirin did not reduce the risk of embolic events and was associated with a trend toward increased risk of bleeding.¹⁵

A recent large cohort study suggested that infectious endocarditis patients who receive anticoagulation therapy may have a higher incidence of cerebrovascular complications (hazard ratio 1.31, 95% confidence interval 1.00–1.72, P = .048), with a particular association of anticoagulation therapy with intracranial bleeding (hazard ratio 2.71, 95% confidence interval 1.54–4.76, P = .001).¹⁶

Another provocative link supported by the same study was a higher incidence of hemorrhagic complications with anticoagulation in patients with infectious endocarditis caused by Staphylococcus aureus, an association also suggested by older data from Tornos et al,⁸ but not seen in a study by Rasmussen et al.¹²

Continuing anticoagulation is an individualized decision

The benefit or harm of anticoagulation in patients with infectious endocarditis may be determined at least in part by a complex mix of factors including the valve involved (embolic events are more common with mitral valve vegetations than with aortic valve vegetations), vegetation size (higher risk if > 1 cm), mobility of vegetations, and perhaps the virulence of the causative organism.^16,17 The fact that antimicrobial therapy obviates any beneficial effect of anticoagulation speaks strongly against starting anticoagulation therapy in infectious endocarditis patients with the sole purpose of reducing stroke risk.

Without large randomized trials to better delineate the risks and benefits of continuing preexisting anticoagulation in all patients with infectious endocarditis, patients already receiving anticoagulants need a careful, individualized risk-benefit assessment. Current guidelines agree that newly diagnosed infectious endocarditis per se is not an indication for anticoagulation or aspirin therapy (Table 1).^1–3

TAKE-HOME POINTS

• Starting antiplatelet and anticoagulation therapy for the sole purpose of stroke prevention is not recommended in patients with newly diagnosed infectious endocarditis.
• In most cases, anticoagulation and antiplatelet therapy should be temporarily discontinued in patients with infectious endocarditis and stroke or suspected stroke.
• Patients need careful assessment on a case-by-case basis, and the presence of risk factors predisposing patients to cerebrovascular complications (eg, large or very mobile vegetations, causative pathogens such as S aureus or Candida spp) may prompt temporary suspension of anticoagulation and antiplatelet therapy.
• If there is a clear preexisting or coexisting indication for these agents and surgery is not anticipated, consider continuing antiplatelet and anticoagulant therapy in patients with infectious endocarditis, provided they lack the risk factors described above and stroke has been excluded.
• If there is a clear preexisting or coexisting indication for these agents and surgery is being considered, consider using a short-acting anticoagulant such as intravenous or low-molecular weight heparin as a bridge to surgery.

Managing anticoagulation in patients with infectious endocarditis requires an individualized approach, using a careful risk-benefit assessment on a case-by-case basis. There is a dearth of high-quality evidence; consequently, the recommendations also vary according to the clinical situation.

Newly diagnosed native valve infectious endocarditis in itself is not an indication for anticoagulation.^1–3 The question of whether to anticoagulate arises in patients who have a preexisting or coexisting indication for anticoagulation such as atrial fibrillation, deep vein thrombosis, pulmonary embolism, or a mechanical prosthetic heart valve. The question becomes yet more complex in patients with cerebrovascular complications and a coexistent strong indication for anticoagulation, creating what is often a very thorny dilemma.

Based on a review of available evidence, recommendations for anticoagulation in patients with infectious endocarditis are summarized below.

AVAILABLE EVIDENCE IS SCARCE AND MIXED

Earlier observational studies suggested a significant risk of cerebral hemorrhage with anticoagulation in patients with native valve endocarditis, although none of these studies were recent (some of them took place in the 1940s), and none are methodologically compelling.^4–8 Consequently, some experts have expressed skepticism regarding their findings, particularly in recent years.

In part, this skepticism arises from studies that showed a lower incidence of cerebrovascular complications and smaller vegetation size in patients with prosthetic valve infectious endocarditis, studies in which many of the patients received anticoagulation therapy.^9,10 The mechanism responsible for this effect is theorized to be that the vegetation is an amalgam of destroyed cells, platelets, and fibrin, with anticoagulation preventing this aggregation from further growth and propagation.

How great is the benefit or the potential harm?

Some experts argue that the incidence of ischemic stroke with hemorrhagic transformation in patients with infectious endocarditis receiving anticoagulation is overestimated. According to this view, the beneficial effects of anticoagulation at least counterbalance the potential harmful effects.

In addition to the studies cited above, recent studies have shown that patients on anticoagulation tend to have smaller vegetations and fewer cerebrovascular complications.^11–13 Snygg-Martin et al¹¹ and Rasmussen et al¹² found not only that cerebrovascular complications were less common in patients already on anticoagulation at the time infectious endocarditis was diagnosed, but also that no increase in the rate of hemorrhagic lesions was reported.

These were all nonrandomized studies, and most of the patients in them had native valve infectious endocarditis diagnosed at an early stage. Importantly, these studies found that the beneficial effects of anticoagulation were only present if the patient was receiving warfarin before infectious endocarditis was diagnosed and antibiotic therapy was initiated. No benefits from anticoagulation were demonstrated once antimicrobial therapy was begun.

Similarly, Anavekar et al¹⁴ showed that embolic events occurred significantly less often in those who were currently on continuous daily antiplatelet therapy, suggesting that receiving antiplatelet agents at baseline protects against cardioembolic events in patients who develop infective endocarditis. However, the only randomized trial examining the initiation of antiplatelet therapy in patients diagnosed with infectious endocarditis receiving antibiotic treatment showed that adding aspirin did not reduce the risk of embolic events and was associated with a trend toward increased risk of bleeding.¹⁵

A recent large cohort study suggested that infectious endocarditis patients who receive anticoagulation therapy may have a higher incidence of cerebrovascular complications (hazard ratio 1.31, 95% confidence interval 1.00–1.72, P = .048), with a particular association of anticoagulation therapy with intracranial bleeding (hazard ratio 2.71, 95% confidence interval 1.54–4.76, P = .001).¹⁶

Another provocative link supported by the same study was a higher incidence of hemorrhagic complications with anticoagulation in patients with infectious endocarditis caused by Staphylococcus aureus, an association also suggested by older data from Tornos et al,⁸ but not seen in a study by Rasmussen et al.¹²

Continuing anticoagulation is an individualized decision

The benefit or harm of anticoagulation in patients with infectious endocarditis may be determined at least in part by a complex mix of factors including the valve involved (embolic events are more common with mitral valve vegetations than with aortic valve vegetations), vegetation size (higher risk if > 1 cm), mobility of vegetations, and perhaps the virulence of the causative organism.^16,17 The fact that antimicrobial therapy obviates any beneficial effect of anticoagulation speaks strongly against starting anticoagulation therapy in infectious endocarditis patients with the sole purpose of reducing stroke risk.

Without large randomized trials to better delineate the risks and benefits of continuing preexisting anticoagulation in all patients with infectious endocarditis, patients already receiving anticoagulants need a careful, individualized risk-benefit assessment. Current guidelines agree that newly diagnosed infectious endocarditis per se is not an indication for anticoagulation or aspirin therapy (Table 1).^1–3

TAKE-HOME POINTS

• Starting antiplatelet and anticoagulation therapy for the sole purpose of stroke prevention is not recommended in patients with newly diagnosed infectious endocarditis.
• In most cases, anticoagulation and antiplatelet therapy should be temporarily discontinued in patients with infectious endocarditis and stroke or suspected stroke.
• Patients need careful assessment on a case-by-case basis, and the presence of risk factors predisposing patients to cerebrovascular complications (eg, large or very mobile vegetations, causative pathogens such as S aureus or Candida spp) may prompt temporary suspension of anticoagulation and antiplatelet therapy.
• If there is a clear preexisting or coexisting indication for these agents and surgery is not anticipated, consider continuing antiplatelet and anticoagulant therapy in patients with infectious endocarditis, provided they lack the risk factors described above and stroke has been excluded.
• If there is a clear preexisting or coexisting indication for these agents and surgery is being considered, consider using a short-acting anticoagulant such as intravenous or low-molecular weight heparin as a bridge to surgery.

Managing anticoagulation in patients with infectious endocarditis requires an individualized approach, using a careful risk-benefit assessment on a case-by-case basis. There is a dearth of high-quality evidence; consequently, the recommendations also vary according to the clinical situation.

Newly diagnosed native valve infectious endocarditis in itself is not an indication for anticoagulation.^1–3 The question of whether to anticoagulate arises in patients who have a preexisting or coexisting indication for anticoagulation such as atrial fibrillation, deep vein thrombosis, pulmonary embolism, or a mechanical prosthetic heart valve. The question becomes yet more complex in patients with cerebrovascular complications and a coexistent strong indication for anticoagulation, creating what is often a very thorny dilemma.

Based on a review of available evidence, recommendations for anticoagulation in patients with infectious endocarditis are summarized below.

AVAILABLE EVIDENCE IS SCARCE AND MIXED

Earlier observational studies suggested a significant risk of cerebral hemorrhage with anticoagulation in patients with native valve endocarditis, although none of these studies were recent (some of them took place in the 1940s), and none are methodologically compelling.^4–8 Consequently, some experts have expressed skepticism regarding their findings, particularly in recent years.

In part, this skepticism arises from studies that showed a lower incidence of cerebrovascular complications and smaller vegetation size in patients with prosthetic valve infectious endocarditis, studies in which many of the patients received anticoagulation therapy.^9,10 The mechanism responsible for this effect is theorized to be that the vegetation is an amalgam of destroyed cells, platelets, and fibrin, with anticoagulation preventing this aggregation from further growth and propagation.

How great is the benefit or the potential harm?

Some experts argue that the incidence of ischemic stroke with hemorrhagic transformation in patients with infectious endocarditis receiving anticoagulation is overestimated. According to this view, the beneficial effects of anticoagulation at least counterbalance the potential harmful effects.

In addition to the studies cited above, recent studies have shown that patients on anticoagulation tend to have smaller vegetations and fewer cerebrovascular complications.^11–13 Snygg-Martin et al¹¹ and Rasmussen et al¹² found not only that cerebrovascular complications were less common in patients already on anticoagulation at the time infectious endocarditis was diagnosed, but also that no increase in the rate of hemorrhagic lesions was reported.

These were all nonrandomized studies, and most of the patients in them had native valve infectious endocarditis diagnosed at an early stage. Importantly, these studies found that the beneficial effects of anticoagulation were only present if the patient was receiving warfarin before infectious endocarditis was diagnosed and antibiotic therapy was initiated. No benefits from anticoagulation were demonstrated once antimicrobial therapy was begun.

Similarly, Anavekar et al¹⁴ showed that embolic events occurred significantly less often in those who were currently on continuous daily antiplatelet therapy, suggesting that receiving antiplatelet agents at baseline protects against cardioembolic events in patients who develop infective endocarditis. However, the only randomized trial examining the initiation of antiplatelet therapy in patients diagnosed with infectious endocarditis receiving antibiotic treatment showed that adding aspirin did not reduce the risk of embolic events and was associated with a trend toward increased risk of bleeding.¹⁵

A recent large cohort study suggested that infectious endocarditis patients who receive anticoagulation therapy may have a higher incidence of cerebrovascular complications (hazard ratio 1.31, 95% confidence interval 1.00–1.72, P = .048), with a particular association of anticoagulation therapy with intracranial bleeding (hazard ratio 2.71, 95% confidence interval 1.54–4.76, P = .001).¹⁶

Another provocative link supported by the same study was a higher incidence of hemorrhagic complications with anticoagulation in patients with infectious endocarditis caused by Staphylococcus aureus, an association also suggested by older data from Tornos et al,⁸ but not seen in a study by Rasmussen et al.¹²

Continuing anticoagulation is an individualized decision

The benefit or harm of anticoagulation in patients with infectious endocarditis may be determined at least in part by a complex mix of factors including the valve involved (embolic events are more common with mitral valve vegetations than with aortic valve vegetations), vegetation size (higher risk if > 1 cm), mobility of vegetations, and perhaps the virulence of the causative organism.^16,17 The fact that antimicrobial therapy obviates any beneficial effect of anticoagulation speaks strongly against starting anticoagulation therapy in infectious endocarditis patients with the sole purpose of reducing stroke risk.

Without large randomized trials to better delineate the risks and benefits of continuing preexisting anticoagulation in all patients with infectious endocarditis, patients already receiving anticoagulants need a careful, individualized risk-benefit assessment. Current guidelines agree that newly diagnosed infectious endocarditis per se is not an indication for anticoagulation or aspirin therapy (Table 1).^1–3

TAKE-HOME POINTS

• Starting antiplatelet and anticoagulation therapy for the sole purpose of stroke prevention is not recommended in patients with newly diagnosed infectious endocarditis.
• In most cases, anticoagulation and antiplatelet therapy should be temporarily discontinued in patients with infectious endocarditis and stroke or suspected stroke.
• Patients need careful assessment on a case-by-case basis, and the presence of risk factors predisposing patients to cerebrovascular complications (eg, large or very mobile vegetations, causative pathogens such as S aureus or Candida spp) may prompt temporary suspension of anticoagulation and antiplatelet therapy.
• If there is a clear preexisting or coexisting indication for these agents and surgery is not anticipated, consider continuing antiplatelet and anticoagulant therapy in patients with infectious endocarditis, provided they lack the risk factors described above and stroke has been excluded.
• If there is a clear preexisting or coexisting indication for these agents and surgery is being considered, consider using a short-acting anticoagulant such as intravenous or low-molecular weight heparin as a bridge to surgery.

The annual update of immunization schedules by the Centers for Disease Control and Prevention (CDC)—one for adults and one for infants, children, and adolescents—was published recently in Morbidity and Mortality Weekly Report.^1,2 The Advisory Committee on Immunization Practices (ACIP) made a few new recommendations in 2015 (although no major changes from the previous year), which are summarized in this Practice Alert.

HPV vaccine: 9-valent formulation available

While the recommended recipients of the human papillomavirus (HPV) vaccine have not changed (TABLE 1),³ the 9-valent human papillomavirus vaccine (HPV9) has been added to the immunization schedule. Licensed in December 2014, HPV9 added 5 high-risk HPV antigens to the quadrivalent HPV vaccine (HPV4). The antigen types in HPV4 cause 66% of cervical cancers, while those in HPV9 cause 81%.³

Three HPV vaccines are available for use in the United States (TABLE 2).³ All require 3 doses, given on a schedule of 0, 1 to 2, and 6 months, beginning at 11 through 12 years of age. HPV4 will likely become unavailable as its supply is used up in the transition to HPV9.

Although HPV9 offers wider protection than HPV4, the recommendation is to start or continue a series of HPV vaccine, as indicated, without waiting for HPV9 if it is not immediately available. Those who are in the middle of a 3-dose HPV4 schedule can finish the remaining doses with HPV9. ACIP has not recommended that HPV9 be administered to those who have completed a series of HPV4 or HPV2.

Pneumococcal vaccines: Give one year apart, regardless of sequence

There are 2 pneumococcal vaccines in the United States: a 23-valent polysaccharide vaccine (PPSV23) and a 13-valent conjugate vaccine (PCV13). Adults ages 65 years or older should receive both vaccines. The preferred order of administration is PCV13 first, then PPSV23. The recommended interval between injections in this order had been 6 to 12 months. If the vaccines were given in the reverse order, PCV13 was to be administered at least one year later. Thus, the timing interval differed depending on the order of administration.⁴ However, to complicate matters, Medicare will pay for 2 pneumococcal vaccinations only if they are separated by a year.

ACIP reexamined the data and found little evidence to support any specific interval, regardless of the order of administration. Therefore, to simplify the schedule and reconcile with Medicare, the new recommendation states it is best to administer PCV13 first, but, regardless of the order, to separate the 2 vaccines by one year. If, for logistical reasons or error, the interval is less than one year, neither vaccine needs to be repeated.

Meningococcal B vaccine

ACIP’s immunization schedule now recommends giving meningococcal B vaccine to individuals in high-risk groups and those exposed to community outbreaks. It gives a “B” recommendation (can be provided if an individual wants it) for vaccine use in all adolescents. These recommendations were described in greater detail in a recent Practice Alert.⁵

Smallpox vaccine recommendations are reaffirmed

In June 2015, ACIP, having reviewed recent clinical data, reaffirmed the CDC’s standing recommendations that the live vaccinia virus smallpox vaccine ACAM2000 (which replaced Dryvax in 2008) be administered routinely to those with occupational exposure to orthopox viruses (eg, laboratory personnel who work with monkeypox, variola, or smallpox viruses).⁶ Health care workers who administer the vaccine or care for someone who might be infected with an orthopox virus may be offered the vaccine.⁶ And some members of the Armed Forces are required to receive it.⁷

Information about smallpox vaccination, including potential adverse reactions to the vaccine and what to do about them, can be found on the CDC Web site at http://www.emergency.cdc.gov/agent/smallpox/clinicians.asp.

Yellow fever vaccine: Boosters needed only for some

Yellow fever vaccine is required for travelers who are visiting areas where the disease is endemic. After reviewing data on the duration of protection provided by the current vaccine, ACIP changed its recommendation in June 2015 to bring it in line with that of the World Health Organization, which states that one dose of vaccine provides long-lasting protection and that a booster is no longer recommended for most travelers.

Three exceptions to the booster exemption are noted: women who are pregnant when they receive their first dose of vaccine; those who undergo stem-cell transplantation following vaccination; and HIV-positive individuals, who should be vaccinated every 10 years.⁸

A “B” recommendation for the vaccine applies to those who were vaccinated 10 or more years previously and who will be traveling to highly endemic areas for prolonged periods. Laboratory personnel who work with yellow fever virus should have their antibody titers checked every 10 years and receive a booster dose if the titers are low.⁸

New vaccines coming soon

No cholera vaccine is licensed for use in the United States, but a new single-dose, live attenuated oral cholera vaccine will likely be licensed this year.

A new adjuvanted herpes zoster vaccine has completed a phase-3 study and the results were presented to ACIP in June 2015. It is expected to be approved sometime this year.

Finally, a new combination vaccine for infants is being developed cooperatively between Sanofi Pasteur and Merck & Co. It will offer protection against diphtheria, pertussis, tetanus, polio, Haemophilus influenzae type B, and hepatitis B. When available, it will offer an option that means fewer injections than current combination products (TABLE 3).⁹

The annual update of immunization schedules by the Centers for Disease Control and Prevention (CDC)—one for adults and one for infants, children, and adolescents—was published recently in Morbidity and Mortality Weekly Report.^1,2 The Advisory Committee on Immunization Practices (ACIP) made a few new recommendations in 2015 (although no major changes from the previous year), which are summarized in this Practice Alert.

HPV vaccine: 9-valent formulation available

While the recommended recipients of the human papillomavirus (HPV) vaccine have not changed (TABLE 1),³ the 9-valent human papillomavirus vaccine (HPV9) has been added to the immunization schedule. Licensed in December 2014, HPV9 added 5 high-risk HPV antigens to the quadrivalent HPV vaccine (HPV4). The antigen types in HPV4 cause 66% of cervical cancers, while those in HPV9 cause 81%.³

Three HPV vaccines are available for use in the United States (TABLE 2).³ All require 3 doses, given on a schedule of 0, 1 to 2, and 6 months, beginning at 11 through 12 years of age. HPV4 will likely become unavailable as its supply is used up in the transition to HPV9.

Although HPV9 offers wider protection than HPV4, the recommendation is to start or continue a series of HPV vaccine, as indicated, without waiting for HPV9 if it is not immediately available. Those who are in the middle of a 3-dose HPV4 schedule can finish the remaining doses with HPV9. ACIP has not recommended that HPV9 be administered to those who have completed a series of HPV4 or HPV2.

Pneumococcal vaccines: Give one year apart, regardless of sequence

There are 2 pneumococcal vaccines in the United States: a 23-valent polysaccharide vaccine (PPSV23) and a 13-valent conjugate vaccine (PCV13). Adults ages 65 years or older should receive both vaccines. The preferred order of administration is PCV13 first, then PPSV23. The recommended interval between injections in this order had been 6 to 12 months. If the vaccines were given in the reverse order, PCV13 was to be administered at least one year later. Thus, the timing interval differed depending on the order of administration.⁴ However, to complicate matters, Medicare will pay for 2 pneumococcal vaccinations only if they are separated by a year.

ACIP reexamined the data and found little evidence to support any specific interval, regardless of the order of administration. Therefore, to simplify the schedule and reconcile with Medicare, the new recommendation states it is best to administer PCV13 first, but, regardless of the order, to separate the 2 vaccines by one year. If, for logistical reasons or error, the interval is less than one year, neither vaccine needs to be repeated.

Meningococcal B vaccine

ACIP’s immunization schedule now recommends giving meningococcal B vaccine to individuals in high-risk groups and those exposed to community outbreaks. It gives a “B” recommendation (can be provided if an individual wants it) for vaccine use in all adolescents. These recommendations were described in greater detail in a recent Practice Alert.⁵

Smallpox vaccine recommendations are reaffirmed

In June 2015, ACIP, having reviewed recent clinical data, reaffirmed the CDC’s standing recommendations that the live vaccinia virus smallpox vaccine ACAM2000 (which replaced Dryvax in 2008) be administered routinely to those with occupational exposure to orthopox viruses (eg, laboratory personnel who work with monkeypox, variola, or smallpox viruses).⁶ Health care workers who administer the vaccine or care for someone who might be infected with an orthopox virus may be offered the vaccine.⁶ And some members of the Armed Forces are required to receive it.⁷

Information about smallpox vaccination, including potential adverse reactions to the vaccine and what to do about them, can be found on the CDC Web site at http://www.emergency.cdc.gov/agent/smallpox/clinicians.asp.

Yellow fever vaccine: Boosters needed only for some

Yellow fever vaccine is required for travelers who are visiting areas where the disease is endemic. After reviewing data on the duration of protection provided by the current vaccine, ACIP changed its recommendation in June 2015 to bring it in line with that of the World Health Organization, which states that one dose of vaccine provides long-lasting protection and that a booster is no longer recommended for most travelers.

Three exceptions to the booster exemption are noted: women who are pregnant when they receive their first dose of vaccine; those who undergo stem-cell transplantation following vaccination; and HIV-positive individuals, who should be vaccinated every 10 years.⁸

A “B” recommendation for the vaccine applies to those who were vaccinated 10 or more years previously and who will be traveling to highly endemic areas for prolonged periods. Laboratory personnel who work with yellow fever virus should have their antibody titers checked every 10 years and receive a booster dose if the titers are low.⁸

New vaccines coming soon

No cholera vaccine is licensed for use in the United States, but a new single-dose, live attenuated oral cholera vaccine will likely be licensed this year.

A new adjuvanted herpes zoster vaccine has completed a phase-3 study and the results were presented to ACIP in June 2015. It is expected to be approved sometime this year.

Finally, a new combination vaccine for infants is being developed cooperatively between Sanofi Pasteur and Merck & Co. It will offer protection against diphtheria, pertussis, tetanus, polio, Haemophilus influenzae type B, and hepatitis B. When available, it will offer an option that means fewer injections than current combination products (TABLE 3).⁹

The annual update of immunization schedules by the Centers for Disease Control and Prevention (CDC)—one for adults and one for infants, children, and adolescents—was published recently in Morbidity and Mortality Weekly Report.^1,2 The Advisory Committee on Immunization Practices (ACIP) made a few new recommendations in 2015 (although no major changes from the previous year), which are summarized in this Practice Alert.

HPV vaccine: 9-valent formulation available

While the recommended recipients of the human papillomavirus (HPV) vaccine have not changed (TABLE 1),³ the 9-valent human papillomavirus vaccine (HPV9) has been added to the immunization schedule. Licensed in December 2014, HPV9 added 5 high-risk HPV antigens to the quadrivalent HPV vaccine (HPV4). The antigen types in HPV4 cause 66% of cervical cancers, while those in HPV9 cause 81%.³

Three HPV vaccines are available for use in the United States (TABLE 2).³ All require 3 doses, given on a schedule of 0, 1 to 2, and 6 months, beginning at 11 through 12 years of age. HPV4 will likely become unavailable as its supply is used up in the transition to HPV9.

Although HPV9 offers wider protection than HPV4, the recommendation is to start or continue a series of HPV vaccine, as indicated, without waiting for HPV9 if it is not immediately available. Those who are in the middle of a 3-dose HPV4 schedule can finish the remaining doses with HPV9. ACIP has not recommended that HPV9 be administered to those who have completed a series of HPV4 or HPV2.

Pneumococcal vaccines: Give one year apart, regardless of sequence

There are 2 pneumococcal vaccines in the United States: a 23-valent polysaccharide vaccine (PPSV23) and a 13-valent conjugate vaccine (PCV13). Adults ages 65 years or older should receive both vaccines. The preferred order of administration is PCV13 first, then PPSV23. The recommended interval between injections in this order had been 6 to 12 months. If the vaccines were given in the reverse order, PCV13 was to be administered at least one year later. Thus, the timing interval differed depending on the order of administration.⁴ However, to complicate matters, Medicare will pay for 2 pneumococcal vaccinations only if they are separated by a year.

ACIP reexamined the data and found little evidence to support any specific interval, regardless of the order of administration. Therefore, to simplify the schedule and reconcile with Medicare, the new recommendation states it is best to administer PCV13 first, but, regardless of the order, to separate the 2 vaccines by one year. If, for logistical reasons or error, the interval is less than one year, neither vaccine needs to be repeated.

Meningococcal B vaccine

ACIP’s immunization schedule now recommends giving meningococcal B vaccine to individuals in high-risk groups and those exposed to community outbreaks. It gives a “B” recommendation (can be provided if an individual wants it) for vaccine use in all adolescents. These recommendations were described in greater detail in a recent Practice Alert.⁵

Smallpox vaccine recommendations are reaffirmed

In June 2015, ACIP, having reviewed recent clinical data, reaffirmed the CDC’s standing recommendations that the live vaccinia virus smallpox vaccine ACAM2000 (which replaced Dryvax in 2008) be administered routinely to those with occupational exposure to orthopox viruses (eg, laboratory personnel who work with monkeypox, variola, or smallpox viruses).⁶ Health care workers who administer the vaccine or care for someone who might be infected with an orthopox virus may be offered the vaccine.⁶ And some members of the Armed Forces are required to receive it.⁷

Information about smallpox vaccination, including potential adverse reactions to the vaccine and what to do about them, can be found on the CDC Web site at http://www.emergency.cdc.gov/agent/smallpox/clinicians.asp.

Yellow fever vaccine: Boosters needed only for some

Yellow fever vaccine is required for travelers who are visiting areas where the disease is endemic. After reviewing data on the duration of protection provided by the current vaccine, ACIP changed its recommendation in June 2015 to bring it in line with that of the World Health Organization, which states that one dose of vaccine provides long-lasting protection and that a booster is no longer recommended for most travelers.

Three exceptions to the booster exemption are noted: women who are pregnant when they receive their first dose of vaccine; those who undergo stem-cell transplantation following vaccination; and HIV-positive individuals, who should be vaccinated every 10 years.⁸

A “B” recommendation for the vaccine applies to those who were vaccinated 10 or more years previously and who will be traveling to highly endemic areas for prolonged periods. Laboratory personnel who work with yellow fever virus should have their antibody titers checked every 10 years and receive a booster dose if the titers are low.⁸

New vaccines coming soon

No cholera vaccine is licensed for use in the United States, but a new single-dose, live attenuated oral cholera vaccine will likely be licensed this year.

A new adjuvanted herpes zoster vaccine has completed a phase-3 study and the results were presented to ACIP in June 2015. It is expected to be approved sometime this year.

Finally, a new combination vaccine for infants is being developed cooperatively between Sanofi Pasteur and Merck & Co. It will offer protection against diphtheria, pertussis, tetanus, polio, Haemophilus influenzae type B, and hepatitis B. When available, it will offer an option that means fewer injections than current combination products (TABLE 3).⁹

CASE › Gladys B, a 68-year-old patient with a history of peripheral neuropathy related to chemotherapy she underwent years ago, has been treated alternately with acetaminophen with codeine, tramadol, gabapentin, and morphine. Each provided only minimal relief. Your state recently legalized medical marijuana, and she wants to know whether it might alleviate her pain.

If Ms. B were your patient, how would you respond?

Medical marijuana is now legal in 23 states and Washington, DC. Other states are considering legalization or have authorized particular components for use as medical treatment.¹ As such laws proliferate and garner more media attention, it is increasingly likely that patients will turn to their primary care physicians with questions about the use of marijuana for medicinal purposes. What can you tell them?

Conversations about medical marijuana should be based on the understanding that while many claims have been made about the therapeutic effects of marijuana, only a few of these claims have evidence to back them up. Major medical organizations, including the American Academy of Family Physicians,² the American College of Physicians,³ and the Institute of Medicine,⁴ recognize its potential as a treatment for various conditions, but emphasize the need for additional research rather than wholesale adoption.

Most commonly, medical marijuana is used to treat pain symptoms, but it is also used for a host of other conditions. A 2015 systematic review and meta-analysis⁵ found moderate-quality evidence to support its use for the treatment of chronic and neuropathic pain and spasticity associated with multiple sclerosis (MS), and low-quality evidence for the treatment of nausea and vomiting associated with chemotherapy, for weight gain in patients with human immunodeficiency virus (HIV), and to treat Tourette syndrome. (TABLE 1 lists the conditions for which medical marijuana has been found to be indicated.^5-13) For most other conditions that qualify for the use of medical marijuana under state laws, however—insomnia, hepatitis C, Crohn’s disease, and anxiety and depression, among others—the evidence is either of very low quality or nonexistent.⁵

Evaluating marijuana is difficult

Recommend marijuana only after standard medications, including FDA-approved cannabinoids, and nonpharmaceutical approaches have proven inadequate.

It is important to note that marijuana comprises more than 60 pharmacologically active cannabinoids, which makes it difficult to study. Both exogenous ligands, such as the cannabinoids from marijuana, and endogenous ligands (endocannabinoids), such as anandamide and 2-arachidonoylglycerol, act on cannabinoid receptors. These receptors are found throughout the body, but are primarily in the brain and spinal cord.¹⁴

The main cannabinoids contained in marijuana are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC produces the euphoria for which recreational marijuana is known, but can also induce psychosis. CBD is not psychoactive and is thought to have antianxiety and possibly antipsychotic properties. Thus, marijuana’s therapeutic effects depend on the concentration of THC in a given formulation. Because CBD has the ability to mitigate psychoactive effects, the ratio of THC to CBD is important, as well.¹⁵

What’s more, medical marijuana is available in various forms. It can be smoked—the most widely used route—or inhaled with an inhalation device, ingested in food or as a tea, taken orally, administered via an oromucosal spray, or even applied topically. Medical marijuana may be extracted naturally from the cannabis plant, produced by the isomerization of CBD, manufactured synthetically, or provided as an herbal formulation.

There are also cannabinoids that have been approved by the US Food and Drug Administration (FDA)—dronabinol (a synthetic version of THC) and nabilone (a synthetic cannabinoid). Nabiximols, a cannabis extract in the form of an oromucosal spray, is licensed in the UK for the treatment of symptoms associated with multiple sclerosis, but has not yet received FDA approval.^16,17

As with any treatment or medication, the benefits must be weighed against the risks. Scientific studies have documented many adverse health effects associated with marijuana, including the risk of addiction and the potential for marijuana to be used as a gateway drug; its effect on brain development, school performance, and lifetime achievement; a potential relationship to mental illness; and the risk of cancer and motor vehicle accidents.^1,16,18 Patients in clinical trials have reported dizziness, dysphoria, hallucinations, and paranoia, as well.¹²

What’s more, marijuana remains classified as a Schedule I agent.¹⁹ Because of its high potential for abuse, physicians in states where medical marijuana has been legalized should adhere to off-label prescribing principles: Recommend it only after standard medications, including FDA-approved cannabinoids, and nonpharmaceutical approaches have proven to be inadequate.^6,20,21

Marijuana’s therapeutic effects depend on the concentration of THC in a formulation and on the ratio of THC to cannabidiol.

Medical marijuana for your patient? A look at the evidence

The meta-analysis cited earlier included 79 randomized clinical trials (RCTs) of medical marijuana used for a variety of conditions in a number of delivery modes. However, only 4 were judged to be of low risk of bias.⁵ Nonetheless, here’s a look at this and other evidence.

Chronic and neuropathic pain

Twenty-eight of the 79 studies addressed chronic pain, with half assessing the oromucosal spray (nabiximols). Most others studied marijuana that was smoked or inhaled. Neuropathic pain was most frequently studied, but cancer pain, fibromyalgia, and musculoskeletal pain, among others, were also evaluated.⁵

The average number of patients who reported a reduction in pain of ≥30% was greater with marijuana compared with placebo (odds ratio=1.41; 95% confidence interval, .99-2.0). Delivery mode did not affect outcomes; different forms of administration were not associated with any significant difference in pain relief. Nor were there significant differences in results among the various pain conditions studied. Notably, however, quality of life measurements did not reflect any overall improvement.⁵

The authors of a literature review of marijuana for chronic and neuropathic pain and MS-induced spasticity did find high-quality evidence of its efficacy in several of the trials they assessed.⁶ And a review of well-conducted observational trials of smoked marijuana as a treatment for severe neuropathic pain revealed that it may be indicated for those who fail to respond to FDA-approved cannabinoids and standard analgesics.¹⁰ Neither functional status nor quality of life was evaluated, however, and none of the observational studies compared smoked cannabis to standard analgesics.

Notably, the authors did not recommend smoked marijuana for pain conditions such as low back pain and fibromyalgia, which are commonly seen in practice. That’s because the safety and efficacy of smoked cannabis has not been studied for these conditions and because evidence-based treatments for these disorders exist.¹⁰

CASE › Before considering medical marijuana for Ms. B, you suggest a trial of dronabinol. The patient agrees, and you prescribe 2.5 mg twice a day. You schedule a visit in 4 weeks to review the drug’s efficacy and tell her to call if she develops psychiatric symptoms, such as hallucinations or paranoia, or impaired cognition. You also advise her that dronabinol may increase the risk of auto accidents and caution her to avoid driving for 6 hours after taking the drug—or longer if she experiences an initial “high.”

MS symptoms

A comprehensive review of medical marijuana studies spanning nearly 7 decades revealed 12 trials focusing on MS—and found its use in treating MS-related spasticity supported by high-quality evidence.⁶

Those taking cannabinoids were more likely than patients taking other antiemetics to withdraw from studies due to adverse effects, such as dizziness and hallucinations.

Two of the largest studies were done in the UK.^7,8 One multicenter trial included 630 participants randomized to treatment with an oral cannabinoid extract, THC, or placebo for 6 weeks.⁷

There was no change in the primary outcome measure, the Ashworth spasticity scale. However, there was a treatment effect on patient-reported spasticity and pain, with improvement in spasticity reported by 61% of those treated with the cannabinoid extract, 60% of those treated with THC, and 46% of those treated with placebo.⁷

The other UK trial involved 22 centers and 279 patients, randomized to either oral cannabis extract or placebo. The primary outcome measure involved a category rating scale that reported on change in muscle stiffness since baseline and on body pain, spasms, and sleep quality. This study used a 2-week titration phase and a 10-week maintenance phase. The rate of relief from muscle stiffness after 12 weeks was almost twice as high in the cannabis extract group (29%) compared with placebo (16%).⁸

A systematic review of the efficacy and safety of medical marijuana by the American Academy of Neurology (AAN) concluded that oral cannabis extract, THC, and nabiximols are “probably effective” in reducing patient-centered measures of spasticity and pain associated with MS.⁹

Little help for other neurologic disorders. Studies of the efficacy and safety of medical marijuana for other neurologic disorders have been less encouraging. The AAN concluded that cannabinoids are probably ineffective for the treatment of tremors, and that oral cannabis extract is probably ineffective for treating levodopa-induced dyskinesias in patients with Parkinson’s disease.

A 2014 systematic review found that oral cannabinoids were of unknown efficacy in treating nonchorea-related symptoms of Huntington’s disease, Tourette syndrome, cervical dystonia, and epilepsy.⁹ The 2015 systematic review and meta-analysis cited earlier, however, suggests that there is low-quality evidence that cannabinoids improve symptoms associated with sleep disorders and Tourette symptoms.⁵

Vaporization of marijuana may eliminate some of the irritating—and possibly carcinogenic—substances contained in marijuana smoke.

Cancer-related symptoms

In 1985, the FDA approved dronabinol for the treatment of chemotherapy-induced nausea and vomiting (CINV) not controlled by other medications. Nabilone followed, receiving FDA approval in 1992.¹¹

Serotonin receptor antagonists (5-HT3 receptor antagonists) were also introduced in the early 1990s. In 2001, a systematic review of 30 RCTs with a total of 1366 patients looked at how cannabinoids—including oral dronabinol, oral nabilone, and intramuscular levonantradol, a synthetic drug that does not have FDA approval—compared with placebo or other antiemetics.¹²

The researchers found the FDA-approved cannabinoids to be more effective than prochlorperazine, metoclopramide, chlorpromazine, and other antiemetics for most patients. (The included studies did not compare cannabinoids with 5-HT3 agents.) That was not the case, however, for patients receiving either very low or very highly emetogenic chemotherapy.

In crossover studies, participants reported that they preferred cannabinoids for future CINV control. Although they cited the “high,” sedation, and euphoria as potential beneficial effects, those taking cannabinoids were also more likely than patients receiving other antiemetics to withdraw from studies due to adverse effects, including dizziness, dysphoria, depression, hallucinations, and paranoia. The authors concluded that cannabinoids might be useful as mood-enhancing adjuvants for controlling CINV, but that short-term adverse effects were likely to limit their widespread use.¹²

Recommended antiemetic regimens for patients with highly emetogenic regimens or those whose chemotherapy comes with a high risk of delayed CINV include the serotonin antagonist dexamethasone, with or without aprepitant or fosaprepitant. Because of the availability of safer and more effective agents, the National Comprehensive Cancer Network (NCCN) does not consider cannabinoids first-line treatment for the prevention of CINV. Instead, they are reserved for breakthrough symptoms or refractory nausea and vomiting.¹¹

In fact, NCCN practice guidelines do not recommend medical marijuana for the management of CINV because of both medical and legal concerns. Even in states in which medical marijuana is legal, the organization states, its use is controversial.¹¹

Combatting anorexia and cachexia. An estimated 50% of cancer patients develop anorexia and cachexia. The systemic inflammation and loss of protein, energy, and lean body mass is associated not only with a poor response to chemotherapy and decreased survival rates, but also with a lower quality of life. While therapies to alleviate these symptoms typically focus on palliation and reduction of distress rather than on prolonging life, some agents, such as megestrol and medroxyprogesterone, are reported to improve survival rates as well as quality of life.²²

Cannabinoids have also been used to increase appetite and food intake and facilitate weight gain in cancer patients. The exact mechanism by which this effect occurs is not known; in fact, questions about the extent of the effect itself remain.

Diversion of medical marijuana is a major concern; patients should be advised to store it safely.

Two RCTs failed to show benefits in this regard compared with megestrol or placebo. One study of 469 patients with advanced cancer compared dronabinol, administered alone or in combination with megestrol, with megestrol alone. Using a Functional Assessment of Anorexia/Cachexia Therapy Questionnaire to assess quality of life, the researchers found that megestrol provided better palliation of anorexia than dronabinol alone and that the combination of dronabinol and megestrol showed no advantage over megestrol alone.¹³

The second study was a multicenter Phase III double-blind RCT comparing cannabis extract (CE), THC, and placebo in 289 cancer patients. The researchers found no differences in appetite, quality of life, or toxicity among those in the 3 arms of the study. A data review board subsequently recommended that study recruitment be stopped because of the absence of significant differences.²³

HIV and AIDS-related morbidity and mortality

Evidence of the efficacy and safety of cannabinoid use among adult patients with HIV or acquired immune deficiency syndrome (AIDS) is lacking, according to a 2013 Cochrane review.²⁴ The review looked at RCTs that compared any marijuana intervention in this patient population to either placebo or a known treatment, such as megestrol or medroxyprogesterone.Worth noting, however, is that the review included studies that were of short duration, involved small numbers of patients, and focused on short-term measures of efficacy.

Long-term studies indicating that cannabinoids have a sustained effect on AIDS-related morbidity and mortality in patients being treated with antiretroviral therapy have yet to be conducted.²⁴ The systematic review and meta-analysis published in 2015, however, did find evidence suggesting that cannabinoids were associated with weight gain in patients with HIV.⁵ Dronabinol has had FDA approval for treatment of weight loss associated with AIDS-related anorexia since 1992.

Before you recommend medical marijuana…

Although medical marijuana is not actually “prescribed,” there are steps to take before recommending or facilitating its use for a particular patient (TABLE 2).^25-29

After ensuring that he or she has a condition for which there is evidence to support it, you need to do a risk evaluation, drawing on the opioid-prescribing paradigm to look for contraindications to the use of a controlled substance or factors that indicate the need for additional precaution (TABLE 3).^10,25,26

Take a thorough medical history and use screening tools

A thorough patient and family medical history, along with principles of Screening, Brief Intervention, and Referral for Treatment (SBIRT), can be used to identify addiction-prone substance use.²⁸ You can also use a validated tool such as the Cannabis Use Disorder Test (CUDIT-R), available at http://sfmi.wufoo.com/forms/qulgngl12rydww/.Body fluid (usually urine) testing is also recommended.³⁰ You may be able to access your state’s Prescription Drug Monitoring Program to check for worrisome prescribing, as well.

Stratify risk

The next step is to determine whether the patient is at low, intermediate, or high risk for use of a controlled substance based on your findings. Patients who are younger than 25 years, for example, have an increased risk.And high-risk patients—those with a history of substance abuse, psychiatric illness, or sexual trauma—are unlikely to be good candidates for medical marijuana^10,25,26 and should be informed in a nonjudgmental manner that their problem is better addressed without it.

If the risk/benefit balance is favorable and the patient is willing to give medical marijuana a try, complete a signed certification of a medical condition for which medical marijuana is authorized in your state. Details of state laws are available at medicalmarijuana.procon.org/view.resource.php?resourceID=000881.

Because the individuals who dispense medical marijuana have varying skills, physicians should collaborate with clinicians judged to be knowledgeable about the best strains of marijuana, the best administration route, and the lowest effective dose—typically a pain management specialist or a physician experienced in recommending medical marijuana appropriately. Vaporization of marijuana, for use with an inhalation device, may prevent some of the potentially negative consequences of smoking it.³¹ Vaporizing is thought to eliminate some of the irritating—and possibly carcinogenic—materials contained in marijuana smoke.

Follow risk mitigation principles

Because marijuana is a controlled substance, you will need to talk to the patient about how to store and, if necessary, dispose of it to avoid the risk of diversion—a major concern about the legalization of marijuana.

You can cite a small study of adolescents in substance abuse treatment, in which 3 out of 4 reported having used someone else’s medical marijuana a median of 50 times.³² Adolescents who used medical marijuana had an earlier age of regular marijuana use, more marijuana abuse, and more dependence and conduct disorder symptoms compared with teens who had not used medical marijuana.³²

It is important, too, to obtain informed consent and draw up a controlled substance agreement, signed by the patient and you. The agreement should outline expected patient behavior, including regular monitoring and body fluid testing, and the consequences of a lack of adherence. (Using a certified laboratory for drug testing is important, as it avoids the possibility of actions based on inaccurate in-office screening.³³) Regular follow-up also provides an opportunity to assess symptom and functional improvement.

If the patient fails to keep appointments and does not respond to efforts to address the problem, the marijuana recommendation may have to be rescinded. Adverse effects, continued aberrant behavior, or evidence of cannabis use disorder may necessitate immediate cessation of the drug. Depending on the scope of the problem, collaboration with addiction therapy may be necessary. Discharge from the practice, of course, should be the last resort.

CASE › At a subsequent visit—after a trial with the maximal dose of dronabinol—Ms. B states that although she had some relief, she continues to have a high degree of breakthrough pain. You suspect that medical marijuana may do more to alleviate her pain, and establish a regimen to quickly taper her off dronabinol.

You consult with a pain management specialist, who suggests that the patient begin with raw marijuana with a 10% THC content, smoking 0.6 gm tid. You obtain informed consent and ask her to sign a controlled substance agreement, explaining that you will need to monitor her closely for dizziness, dysphoria, and hallucinations, among other adverse effects. You instruct her not to drive for 6 hours after smoking marijuana, and you schedule a follow-up appointment in 2 weeks.

Before she leaves, Ms. B receives a copy of your clinic note and written recommendation that she can take to the state dispensary. The note indicates that she will use marijuana for neuropathic pain.

CORRESPONDENCE
Julius Metts, MD, California Substance Abuse Treatment Facility and State Prison, CDCR, 900 Quebec Avenue, Corcoran, CA 93212; [email protected].

CASE › Gladys B, a 68-year-old patient with a history of peripheral neuropathy related to chemotherapy she underwent years ago, has been treated alternately with acetaminophen with codeine, tramadol, gabapentin, and morphine. Each provided only minimal relief. Your state recently legalized medical marijuana, and she wants to know whether it might alleviate her pain.

If Ms. B were your patient, how would you respond?

Medical marijuana is now legal in 23 states and Washington, DC. Other states are considering legalization or have authorized particular components for use as medical treatment.¹ As such laws proliferate and garner more media attention, it is increasingly likely that patients will turn to their primary care physicians with questions about the use of marijuana for medicinal purposes. What can you tell them?

Conversations about medical marijuana should be based on the understanding that while many claims have been made about the therapeutic effects of marijuana, only a few of these claims have evidence to back them up. Major medical organizations, including the American Academy of Family Physicians,² the American College of Physicians,³ and the Institute of Medicine,⁴ recognize its potential as a treatment for various conditions, but emphasize the need for additional research rather than wholesale adoption.

Most commonly, medical marijuana is used to treat pain symptoms, but it is also used for a host of other conditions. A 2015 systematic review and meta-analysis⁵ found moderate-quality evidence to support its use for the treatment of chronic and neuropathic pain and spasticity associated with multiple sclerosis (MS), and low-quality evidence for the treatment of nausea and vomiting associated with chemotherapy, for weight gain in patients with human immunodeficiency virus (HIV), and to treat Tourette syndrome. (TABLE 1 lists the conditions for which medical marijuana has been found to be indicated.^5-13) For most other conditions that qualify for the use of medical marijuana under state laws, however—insomnia, hepatitis C, Crohn’s disease, and anxiety and depression, among others—the evidence is either of very low quality or nonexistent.⁵

Evaluating marijuana is difficult

Recommend marijuana only after standard medications, including FDA-approved cannabinoids, and nonpharmaceutical approaches have proven inadequate.

It is important to note that marijuana comprises more than 60 pharmacologically active cannabinoids, which makes it difficult to study. Both exogenous ligands, such as the cannabinoids from marijuana, and endogenous ligands (endocannabinoids), such as anandamide and 2-arachidonoylglycerol, act on cannabinoid receptors. These receptors are found throughout the body, but are primarily in the brain and spinal cord.¹⁴

The main cannabinoids contained in marijuana are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC produces the euphoria for which recreational marijuana is known, but can also induce psychosis. CBD is not psychoactive and is thought to have antianxiety and possibly antipsychotic properties. Thus, marijuana’s therapeutic effects depend on the concentration of THC in a given formulation. Because CBD has the ability to mitigate psychoactive effects, the ratio of THC to CBD is important, as well.¹⁵

What’s more, medical marijuana is available in various forms. It can be smoked—the most widely used route—or inhaled with an inhalation device, ingested in food or as a tea, taken orally, administered via an oromucosal spray, or even applied topically. Medical marijuana may be extracted naturally from the cannabis plant, produced by the isomerization of CBD, manufactured synthetically, or provided as an herbal formulation.

There are also cannabinoids that have been approved by the US Food and Drug Administration (FDA)—dronabinol (a synthetic version of THC) and nabilone (a synthetic cannabinoid). Nabiximols, a cannabis extract in the form of an oromucosal spray, is licensed in the UK for the treatment of symptoms associated with multiple sclerosis, but has not yet received FDA approval.^16,17

As with any treatment or medication, the benefits must be weighed against the risks. Scientific studies have documented many adverse health effects associated with marijuana, including the risk of addiction and the potential for marijuana to be used as a gateway drug; its effect on brain development, school performance, and lifetime achievement; a potential relationship to mental illness; and the risk of cancer and motor vehicle accidents.^1,16,18 Patients in clinical trials have reported dizziness, dysphoria, hallucinations, and paranoia, as well.¹²

What’s more, marijuana remains classified as a Schedule I agent.¹⁹ Because of its high potential for abuse, physicians in states where medical marijuana has been legalized should adhere to off-label prescribing principles: Recommend it only after standard medications, including FDA-approved cannabinoids, and nonpharmaceutical approaches have proven to be inadequate.^6,20,21

Marijuana’s therapeutic effects depend on the concentration of THC in a formulation and on the ratio of THC to cannabidiol.

Medical marijuana for your patient? A look at the evidence

The meta-analysis cited earlier included 79 randomized clinical trials (RCTs) of medical marijuana used for a variety of conditions in a number of delivery modes. However, only 4 were judged to be of low risk of bias.⁵ Nonetheless, here’s a look at this and other evidence.

Chronic and neuropathic pain

Twenty-eight of the 79 studies addressed chronic pain, with half assessing the oromucosal spray (nabiximols). Most others studied marijuana that was smoked or inhaled. Neuropathic pain was most frequently studied, but cancer pain, fibromyalgia, and musculoskeletal pain, among others, were also evaluated.⁵

The average number of patients who reported a reduction in pain of ≥30% was greater with marijuana compared with placebo (odds ratio=1.41; 95% confidence interval, .99-2.0). Delivery mode did not affect outcomes; different forms of administration were not associated with any significant difference in pain relief. Nor were there significant differences in results among the various pain conditions studied. Notably, however, quality of life measurements did not reflect any overall improvement.⁵

The authors of a literature review of marijuana for chronic and neuropathic pain and MS-induced spasticity did find high-quality evidence of its efficacy in several of the trials they assessed.⁶ And a review of well-conducted observational trials of smoked marijuana as a treatment for severe neuropathic pain revealed that it may be indicated for those who fail to respond to FDA-approved cannabinoids and standard analgesics.¹⁰ Neither functional status nor quality of life was evaluated, however, and none of the observational studies compared smoked cannabis to standard analgesics.

Notably, the authors did not recommend smoked marijuana for pain conditions such as low back pain and fibromyalgia, which are commonly seen in practice. That’s because the safety and efficacy of smoked cannabis has not been studied for these conditions and because evidence-based treatments for these disorders exist.¹⁰

CASE › Before considering medical marijuana for Ms. B, you suggest a trial of dronabinol. The patient agrees, and you prescribe 2.5 mg twice a day. You schedule a visit in 4 weeks to review the drug’s efficacy and tell her to call if she develops psychiatric symptoms, such as hallucinations or paranoia, or impaired cognition. You also advise her that dronabinol may increase the risk of auto accidents and caution her to avoid driving for 6 hours after taking the drug—or longer if she experiences an initial “high.”

MS symptoms

A comprehensive review of medical marijuana studies spanning nearly 7 decades revealed 12 trials focusing on MS—and found its use in treating MS-related spasticity supported by high-quality evidence.⁶

Those taking cannabinoids were more likely than patients taking other antiemetics to withdraw from studies due to adverse effects, such as dizziness and hallucinations.

Two of the largest studies were done in the UK.^7,8 One multicenter trial included 630 participants randomized to treatment with an oral cannabinoid extract, THC, or placebo for 6 weeks.⁷

There was no change in the primary outcome measure, the Ashworth spasticity scale. However, there was a treatment effect on patient-reported spasticity and pain, with improvement in spasticity reported by 61% of those treated with the cannabinoid extract, 60% of those treated with THC, and 46% of those treated with placebo.⁷

The other UK trial involved 22 centers and 279 patients, randomized to either oral cannabis extract or placebo. The primary outcome measure involved a category rating scale that reported on change in muscle stiffness since baseline and on body pain, spasms, and sleep quality. This study used a 2-week titration phase and a 10-week maintenance phase. The rate of relief from muscle stiffness after 12 weeks was almost twice as high in the cannabis extract group (29%) compared with placebo (16%).⁸

A systematic review of the efficacy and safety of medical marijuana by the American Academy of Neurology (AAN) concluded that oral cannabis extract, THC, and nabiximols are “probably effective” in reducing patient-centered measures of spasticity and pain associated with MS.⁹

Little help for other neurologic disorders. Studies of the efficacy and safety of medical marijuana for other neurologic disorders have been less encouraging. The AAN concluded that cannabinoids are probably ineffective for the treatment of tremors, and that oral cannabis extract is probably ineffective for treating levodopa-induced dyskinesias in patients with Parkinson’s disease.

A 2014 systematic review found that oral cannabinoids were of unknown efficacy in treating nonchorea-related symptoms of Huntington’s disease, Tourette syndrome, cervical dystonia, and epilepsy.⁹ The 2015 systematic review and meta-analysis cited earlier, however, suggests that there is low-quality evidence that cannabinoids improve symptoms associated with sleep disorders and Tourette symptoms.⁵

Vaporization of marijuana may eliminate some of the irritating—and possibly carcinogenic—substances contained in marijuana smoke.

Cancer-related symptoms

In 1985, the FDA approved dronabinol for the treatment of chemotherapy-induced nausea and vomiting (CINV) not controlled by other medications. Nabilone followed, receiving FDA approval in 1992.¹¹

Serotonin receptor antagonists (5-HT3 receptor antagonists) were also introduced in the early 1990s. In 2001, a systematic review of 30 RCTs with a total of 1366 patients looked at how cannabinoids—including oral dronabinol, oral nabilone, and intramuscular levonantradol, a synthetic drug that does not have FDA approval—compared with placebo or other antiemetics.¹²

The researchers found the FDA-approved cannabinoids to be more effective than prochlorperazine, metoclopramide, chlorpromazine, and other antiemetics for most patients. (The included studies did not compare cannabinoids with 5-HT3 agents.) That was not the case, however, for patients receiving either very low or very highly emetogenic chemotherapy.

In crossover studies, participants reported that they preferred cannabinoids for future CINV control. Although they cited the “high,” sedation, and euphoria as potential beneficial effects, those taking cannabinoids were also more likely than patients receiving other antiemetics to withdraw from studies due to adverse effects, including dizziness, dysphoria, depression, hallucinations, and paranoia. The authors concluded that cannabinoids might be useful as mood-enhancing adjuvants for controlling CINV, but that short-term adverse effects were likely to limit their widespread use.¹²

Recommended antiemetic regimens for patients with highly emetogenic regimens or those whose chemotherapy comes with a high risk of delayed CINV include the serotonin antagonist dexamethasone, with or without aprepitant or fosaprepitant. Because of the availability of safer and more effective agents, the National Comprehensive Cancer Network (NCCN) does not consider cannabinoids first-line treatment for the prevention of CINV. Instead, they are reserved for breakthrough symptoms or refractory nausea and vomiting.¹¹

In fact, NCCN practice guidelines do not recommend medical marijuana for the management of CINV because of both medical and legal concerns. Even in states in which medical marijuana is legal, the organization states, its use is controversial.¹¹

Combatting anorexia and cachexia. An estimated 50% of cancer patients develop anorexia and cachexia. The systemic inflammation and loss of protein, energy, and lean body mass is associated not only with a poor response to chemotherapy and decreased survival rates, but also with a lower quality of life. While therapies to alleviate these symptoms typically focus on palliation and reduction of distress rather than on prolonging life, some agents, such as megestrol and medroxyprogesterone, are reported to improve survival rates as well as quality of life.²²

Cannabinoids have also been used to increase appetite and food intake and facilitate weight gain in cancer patients. The exact mechanism by which this effect occurs is not known; in fact, questions about the extent of the effect itself remain.

Diversion of medical marijuana is a major concern; patients should be advised to store it safely.

Two RCTs failed to show benefits in this regard compared with megestrol or placebo. One study of 469 patients with advanced cancer compared dronabinol, administered alone or in combination with megestrol, with megestrol alone. Using a Functional Assessment of Anorexia/Cachexia Therapy Questionnaire to assess quality of life, the researchers found that megestrol provided better palliation of anorexia than dronabinol alone and that the combination of dronabinol and megestrol showed no advantage over megestrol alone.¹³

The second study was a multicenter Phase III double-blind RCT comparing cannabis extract (CE), THC, and placebo in 289 cancer patients. The researchers found no differences in appetite, quality of life, or toxicity among those in the 3 arms of the study. A data review board subsequently recommended that study recruitment be stopped because of the absence of significant differences.²³

HIV and AIDS-related morbidity and mortality

Evidence of the efficacy and safety of cannabinoid use among adult patients with HIV or acquired immune deficiency syndrome (AIDS) is lacking, according to a 2013 Cochrane review.²⁴ The review looked at RCTs that compared any marijuana intervention in this patient population to either placebo or a known treatment, such as megestrol or medroxyprogesterone.Worth noting, however, is that the review included studies that were of short duration, involved small numbers of patients, and focused on short-term measures of efficacy.

Long-term studies indicating that cannabinoids have a sustained effect on AIDS-related morbidity and mortality in patients being treated with antiretroviral therapy have yet to be conducted.²⁴ The systematic review and meta-analysis published in 2015, however, did find evidence suggesting that cannabinoids were associated with weight gain in patients with HIV.⁵ Dronabinol has had FDA approval for treatment of weight loss associated with AIDS-related anorexia since 1992.

Before you recommend medical marijuana…

Although medical marijuana is not actually “prescribed,” there are steps to take before recommending or facilitating its use for a particular patient (TABLE 2).^25-29

After ensuring that he or she has a condition for which there is evidence to support it, you need to do a risk evaluation, drawing on the opioid-prescribing paradigm to look for contraindications to the use of a controlled substance or factors that indicate the need for additional precaution (TABLE 3).^10,25,26

Take a thorough medical history and use screening tools

A thorough patient and family medical history, along with principles of Screening, Brief Intervention, and Referral for Treatment (SBIRT), can be used to identify addiction-prone substance use.²⁸ You can also use a validated tool such as the Cannabis Use Disorder Test (CUDIT-R), available at http://sfmi.wufoo.com/forms/qulgngl12rydww/.Body fluid (usually urine) testing is also recommended.³⁰ You may be able to access your state’s Prescription Drug Monitoring Program to check for worrisome prescribing, as well.

Stratify risk

The next step is to determine whether the patient is at low, intermediate, or high risk for use of a controlled substance based on your findings. Patients who are younger than 25 years, for example, have an increased risk.And high-risk patients—those with a history of substance abuse, psychiatric illness, or sexual trauma—are unlikely to be good candidates for medical marijuana^10,25,26 and should be informed in a nonjudgmental manner that their problem is better addressed without it.

If the risk/benefit balance is favorable and the patient is willing to give medical marijuana a try, complete a signed certification of a medical condition for which medical marijuana is authorized in your state. Details of state laws are available at medicalmarijuana.procon.org/view.resource.php?resourceID=000881.

Because the individuals who dispense medical marijuana have varying skills, physicians should collaborate with clinicians judged to be knowledgeable about the best strains of marijuana, the best administration route, and the lowest effective dose—typically a pain management specialist or a physician experienced in recommending medical marijuana appropriately. Vaporization of marijuana, for use with an inhalation device, may prevent some of the potentially negative consequences of smoking it.³¹ Vaporizing is thought to eliminate some of the irritating—and possibly carcinogenic—materials contained in marijuana smoke.

Follow risk mitigation principles

Because marijuana is a controlled substance, you will need to talk to the patient about how to store and, if necessary, dispose of it to avoid the risk of diversion—a major concern about the legalization of marijuana.

You can cite a small study of adolescents in substance abuse treatment, in which 3 out of 4 reported having used someone else’s medical marijuana a median of 50 times.³² Adolescents who used medical marijuana had an earlier age of regular marijuana use, more marijuana abuse, and more dependence and conduct disorder symptoms compared with teens who had not used medical marijuana.³²

It is important, too, to obtain informed consent and draw up a controlled substance agreement, signed by the patient and you. The agreement should outline expected patient behavior, including regular monitoring and body fluid testing, and the consequences of a lack of adherence. (Using a certified laboratory for drug testing is important, as it avoids the possibility of actions based on inaccurate in-office screening.³³) Regular follow-up also provides an opportunity to assess symptom and functional improvement.

If the patient fails to keep appointments and does not respond to efforts to address the problem, the marijuana recommendation may have to be rescinded. Adverse effects, continued aberrant behavior, or evidence of cannabis use disorder may necessitate immediate cessation of the drug. Depending on the scope of the problem, collaboration with addiction therapy may be necessary. Discharge from the practice, of course, should be the last resort.

CASE › At a subsequent visit—after a trial with the maximal dose of dronabinol—Ms. B states that although she had some relief, she continues to have a high degree of breakthrough pain. You suspect that medical marijuana may do more to alleviate her pain, and establish a regimen to quickly taper her off dronabinol.

You consult with a pain management specialist, who suggests that the patient begin with raw marijuana with a 10% THC content, smoking 0.6 gm tid. You obtain informed consent and ask her to sign a controlled substance agreement, explaining that you will need to monitor her closely for dizziness, dysphoria, and hallucinations, among other adverse effects. You instruct her not to drive for 6 hours after smoking marijuana, and you schedule a follow-up appointment in 2 weeks.

Before she leaves, Ms. B receives a copy of your clinic note and written recommendation that she can take to the state dispensary. The note indicates that she will use marijuana for neuropathic pain.

CORRESPONDENCE
Julius Metts, MD, California Substance Abuse Treatment Facility and State Prison, CDCR, 900 Quebec Avenue, Corcoran, CA 93212; [email protected].

CASE › Gladys B, a 68-year-old patient with a history of peripheral neuropathy related to chemotherapy she underwent years ago, has been treated alternately with acetaminophen with codeine, tramadol, gabapentin, and morphine. Each provided only minimal relief. Your state recently legalized medical marijuana, and she wants to know whether it might alleviate her pain.

If Ms. B were your patient, how would you respond?

Medical marijuana is now legal in 23 states and Washington, DC. Other states are considering legalization or have authorized particular components for use as medical treatment.¹ As such laws proliferate and garner more media attention, it is increasingly likely that patients will turn to their primary care physicians with questions about the use of marijuana for medicinal purposes. What can you tell them?

Conversations about medical marijuana should be based on the understanding that while many claims have been made about the therapeutic effects of marijuana, only a few of these claims have evidence to back them up. Major medical organizations, including the American Academy of Family Physicians,² the American College of Physicians,³ and the Institute of Medicine,⁴ recognize its potential as a treatment for various conditions, but emphasize the need for additional research rather than wholesale adoption.

Most commonly, medical marijuana is used to treat pain symptoms, but it is also used for a host of other conditions. A 2015 systematic review and meta-analysis⁵ found moderate-quality evidence to support its use for the treatment of chronic and neuropathic pain and spasticity associated with multiple sclerosis (MS), and low-quality evidence for the treatment of nausea and vomiting associated with chemotherapy, for weight gain in patients with human immunodeficiency virus (HIV), and to treat Tourette syndrome. (TABLE 1 lists the conditions for which medical marijuana has been found to be indicated.^5-13) For most other conditions that qualify for the use of medical marijuana under state laws, however—insomnia, hepatitis C, Crohn’s disease, and anxiety and depression, among others—the evidence is either of very low quality or nonexistent.⁵

Evaluating marijuana is difficult

Recommend marijuana only after standard medications, including FDA-approved cannabinoids, and nonpharmaceutical approaches have proven inadequate.

It is important to note that marijuana comprises more than 60 pharmacologically active cannabinoids, which makes it difficult to study. Both exogenous ligands, such as the cannabinoids from marijuana, and endogenous ligands (endocannabinoids), such as anandamide and 2-arachidonoylglycerol, act on cannabinoid receptors. These receptors are found throughout the body, but are primarily in the brain and spinal cord.¹⁴

The main cannabinoids contained in marijuana are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC produces the euphoria for which recreational marijuana is known, but can also induce psychosis. CBD is not psychoactive and is thought to have antianxiety and possibly antipsychotic properties. Thus, marijuana’s therapeutic effects depend on the concentration of THC in a given formulation. Because CBD has the ability to mitigate psychoactive effects, the ratio of THC to CBD is important, as well.¹⁵

What’s more, medical marijuana is available in various forms. It can be smoked—the most widely used route—or inhaled with an inhalation device, ingested in food or as a tea, taken orally, administered via an oromucosal spray, or even applied topically. Medical marijuana may be extracted naturally from the cannabis plant, produced by the isomerization of CBD, manufactured synthetically, or provided as an herbal formulation.

There are also cannabinoids that have been approved by the US Food and Drug Administration (FDA)—dronabinol (a synthetic version of THC) and nabilone (a synthetic cannabinoid). Nabiximols, a cannabis extract in the form of an oromucosal spray, is licensed in the UK for the treatment of symptoms associated with multiple sclerosis, but has not yet received FDA approval.^16,17

As with any treatment or medication, the benefits must be weighed against the risks. Scientific studies have documented many adverse health effects associated with marijuana, including the risk of addiction and the potential for marijuana to be used as a gateway drug; its effect on brain development, school performance, and lifetime achievement; a potential relationship to mental illness; and the risk of cancer and motor vehicle accidents.^1,16,18 Patients in clinical trials have reported dizziness, dysphoria, hallucinations, and paranoia, as well.¹²

What’s more, marijuana remains classified as a Schedule I agent.¹⁹ Because of its high potential for abuse, physicians in states where medical marijuana has been legalized should adhere to off-label prescribing principles: Recommend it only after standard medications, including FDA-approved cannabinoids, and nonpharmaceutical approaches have proven to be inadequate.^6,20,21

Marijuana’s therapeutic effects depend on the concentration of THC in a formulation and on the ratio of THC to cannabidiol.

Medical marijuana for your patient? A look at the evidence

The meta-analysis cited earlier included 79 randomized clinical trials (RCTs) of medical marijuana used for a variety of conditions in a number of delivery modes. However, only 4 were judged to be of low risk of bias.⁵ Nonetheless, here’s a look at this and other evidence.

Chronic and neuropathic pain

Twenty-eight of the 79 studies addressed chronic pain, with half assessing the oromucosal spray (nabiximols). Most others studied marijuana that was smoked or inhaled. Neuropathic pain was most frequently studied, but cancer pain, fibromyalgia, and musculoskeletal pain, among others, were also evaluated.⁵

The average number of patients who reported a reduction in pain of ≥30% was greater with marijuana compared with placebo (odds ratio=1.41; 95% confidence interval, .99-2.0). Delivery mode did not affect outcomes; different forms of administration were not associated with any significant difference in pain relief. Nor were there significant differences in results among the various pain conditions studied. Notably, however, quality of life measurements did not reflect any overall improvement.⁵

The authors of a literature review of marijuana for chronic and neuropathic pain and MS-induced spasticity did find high-quality evidence of its efficacy in several of the trials they assessed.⁶ And a review of well-conducted observational trials of smoked marijuana as a treatment for severe neuropathic pain revealed that it may be indicated for those who fail to respond to FDA-approved cannabinoids and standard analgesics.¹⁰ Neither functional status nor quality of life was evaluated, however, and none of the observational studies compared smoked cannabis to standard analgesics.

Notably, the authors did not recommend smoked marijuana for pain conditions such as low back pain and fibromyalgia, which are commonly seen in practice. That’s because the safety and efficacy of smoked cannabis has not been studied for these conditions and because evidence-based treatments for these disorders exist.¹⁰

CASE › Before considering medical marijuana for Ms. B, you suggest a trial of dronabinol. The patient agrees, and you prescribe 2.5 mg twice a day. You schedule a visit in 4 weeks to review the drug’s efficacy and tell her to call if she develops psychiatric symptoms, such as hallucinations or paranoia, or impaired cognition. You also advise her that dronabinol may increase the risk of auto accidents and caution her to avoid driving for 6 hours after taking the drug—or longer if she experiences an initial “high.”

MS symptoms

A comprehensive review of medical marijuana studies spanning nearly 7 decades revealed 12 trials focusing on MS—and found its use in treating MS-related spasticity supported by high-quality evidence.⁶

Those taking cannabinoids were more likely than patients taking other antiemetics to withdraw from studies due to adverse effects, such as dizziness and hallucinations.

Two of the largest studies were done in the UK.^7,8 One multicenter trial included 630 participants randomized to treatment with an oral cannabinoid extract, THC, or placebo for 6 weeks.⁷

There was no change in the primary outcome measure, the Ashworth spasticity scale. However, there was a treatment effect on patient-reported spasticity and pain, with improvement in spasticity reported by 61% of those treated with the cannabinoid extract, 60% of those treated with THC, and 46% of those treated with placebo.⁷

The other UK trial involved 22 centers and 279 patients, randomized to either oral cannabis extract or placebo. The primary outcome measure involved a category rating scale that reported on change in muscle stiffness since baseline and on body pain, spasms, and sleep quality. This study used a 2-week titration phase and a 10-week maintenance phase. The rate of relief from muscle stiffness after 12 weeks was almost twice as high in the cannabis extract group (29%) compared with placebo (16%).⁸

A systematic review of the efficacy and safety of medical marijuana by the American Academy of Neurology (AAN) concluded that oral cannabis extract, THC, and nabiximols are “probably effective” in reducing patient-centered measures of spasticity and pain associated with MS.⁹

Little help for other neurologic disorders. Studies of the efficacy and safety of medical marijuana for other neurologic disorders have been less encouraging. The AAN concluded that cannabinoids are probably ineffective for the treatment of tremors, and that oral cannabis extract is probably ineffective for treating levodopa-induced dyskinesias in patients with Parkinson’s disease.

A 2014 systematic review found that oral cannabinoids were of unknown efficacy in treating nonchorea-related symptoms of Huntington’s disease, Tourette syndrome, cervical dystonia, and epilepsy.⁹ The 2015 systematic review and meta-analysis cited earlier, however, suggests that there is low-quality evidence that cannabinoids improve symptoms associated with sleep disorders and Tourette symptoms.⁵

Vaporization of marijuana may eliminate some of the irritating—and possibly carcinogenic—substances contained in marijuana smoke.

Cancer-related symptoms

In 1985, the FDA approved dronabinol for the treatment of chemotherapy-induced nausea and vomiting (CINV) not controlled by other medications. Nabilone followed, receiving FDA approval in 1992.¹¹

Serotonin receptor antagonists (5-HT3 receptor antagonists) were also introduced in the early 1990s. In 2001, a systematic review of 30 RCTs with a total of 1366 patients looked at how cannabinoids—including oral dronabinol, oral nabilone, and intramuscular levonantradol, a synthetic drug that does not have FDA approval—compared with placebo or other antiemetics.¹²

The researchers found the FDA-approved cannabinoids to be more effective than prochlorperazine, metoclopramide, chlorpromazine, and other antiemetics for most patients. (The included studies did not compare cannabinoids with 5-HT3 agents.) That was not the case, however, for patients receiving either very low or very highly emetogenic chemotherapy.

In crossover studies, participants reported that they preferred cannabinoids for future CINV control. Although they cited the “high,” sedation, and euphoria as potential beneficial effects, those taking cannabinoids were also more likely than patients receiving other antiemetics to withdraw from studies due to adverse effects, including dizziness, dysphoria, depression, hallucinations, and paranoia. The authors concluded that cannabinoids might be useful as mood-enhancing adjuvants for controlling CINV, but that short-term adverse effects were likely to limit their widespread use.¹²

Recommended antiemetic regimens for patients with highly emetogenic regimens or those whose chemotherapy comes with a high risk of delayed CINV include the serotonin antagonist dexamethasone, with or without aprepitant or fosaprepitant. Because of the availability of safer and more effective agents, the National Comprehensive Cancer Network (NCCN) does not consider cannabinoids first-line treatment for the prevention of CINV. Instead, they are reserved for breakthrough symptoms or refractory nausea and vomiting.¹¹

In fact, NCCN practice guidelines do not recommend medical marijuana for the management of CINV because of both medical and legal concerns. Even in states in which medical marijuana is legal, the organization states, its use is controversial.¹¹

Combatting anorexia and cachexia. An estimated 50% of cancer patients develop anorexia and cachexia. The systemic inflammation and loss of protein, energy, and lean body mass is associated not only with a poor response to chemotherapy and decreased survival rates, but also with a lower quality of life. While therapies to alleviate these symptoms typically focus on palliation and reduction of distress rather than on prolonging life, some agents, such as megestrol and medroxyprogesterone, are reported to improve survival rates as well as quality of life.²²

Cannabinoids have also been used to increase appetite and food intake and facilitate weight gain in cancer patients. The exact mechanism by which this effect occurs is not known; in fact, questions about the extent of the effect itself remain.

Diversion of medical marijuana is a major concern; patients should be advised to store it safely.

Two RCTs failed to show benefits in this regard compared with megestrol or placebo. One study of 469 patients with advanced cancer compared dronabinol, administered alone or in combination with megestrol, with megestrol alone. Using a Functional Assessment of Anorexia/Cachexia Therapy Questionnaire to assess quality of life, the researchers found that megestrol provided better palliation of anorexia than dronabinol alone and that the combination of dronabinol and megestrol showed no advantage over megestrol alone.¹³

The second study was a multicenter Phase III double-blind RCT comparing cannabis extract (CE), THC, and placebo in 289 cancer patients. The researchers found no differences in appetite, quality of life, or toxicity among those in the 3 arms of the study. A data review board subsequently recommended that study recruitment be stopped because of the absence of significant differences.²³

HIV and AIDS-related morbidity and mortality

Evidence of the efficacy and safety of cannabinoid use among adult patients with HIV or acquired immune deficiency syndrome (AIDS) is lacking, according to a 2013 Cochrane review.²⁴ The review looked at RCTs that compared any marijuana intervention in this patient population to either placebo or a known treatment, such as megestrol or medroxyprogesterone.Worth noting, however, is that the review included studies that were of short duration, involved small numbers of patients, and focused on short-term measures of efficacy.

Long-term studies indicating that cannabinoids have a sustained effect on AIDS-related morbidity and mortality in patients being treated with antiretroviral therapy have yet to be conducted.²⁴ The systematic review and meta-analysis published in 2015, however, did find evidence suggesting that cannabinoids were associated with weight gain in patients with HIV.⁵ Dronabinol has had FDA approval for treatment of weight loss associated with AIDS-related anorexia since 1992.

Before you recommend medical marijuana…

Although medical marijuana is not actually “prescribed,” there are steps to take before recommending or facilitating its use for a particular patient (TABLE 2).^25-29

After ensuring that he or she has a condition for which there is evidence to support it, you need to do a risk evaluation, drawing on the opioid-prescribing paradigm to look for contraindications to the use of a controlled substance or factors that indicate the need for additional precaution (TABLE 3).^10,25,26

Take a thorough medical history and use screening tools

A thorough patient and family medical history, along with principles of Screening, Brief Intervention, and Referral for Treatment (SBIRT), can be used to identify addiction-prone substance use.²⁸ You can also use a validated tool such as the Cannabis Use Disorder Test (CUDIT-R), available at http://sfmi.wufoo.com/forms/qulgngl12rydww/.Body fluid (usually urine) testing is also recommended.³⁰ You may be able to access your state’s Prescription Drug Monitoring Program to check for worrisome prescribing, as well.

Stratify risk

The next step is to determine whether the patient is at low, intermediate, or high risk for use of a controlled substance based on your findings. Patients who are younger than 25 years, for example, have an increased risk.And high-risk patients—those with a history of substance abuse, psychiatric illness, or sexual trauma—are unlikely to be good candidates for medical marijuana^10,25,26 and should be informed in a nonjudgmental manner that their problem is better addressed without it.

If the risk/benefit balance is favorable and the patient is willing to give medical marijuana a try, complete a signed certification of a medical condition for which medical marijuana is authorized in your state. Details of state laws are available at medicalmarijuana.procon.org/view.resource.php?resourceID=000881.

Because the individuals who dispense medical marijuana have varying skills, physicians should collaborate with clinicians judged to be knowledgeable about the best strains of marijuana, the best administration route, and the lowest effective dose—typically a pain management specialist or a physician experienced in recommending medical marijuana appropriately. Vaporization of marijuana, for use with an inhalation device, may prevent some of the potentially negative consequences of smoking it.³¹ Vaporizing is thought to eliminate some of the irritating—and possibly carcinogenic—materials contained in marijuana smoke.

Follow risk mitigation principles

Because marijuana is a controlled substance, you will need to talk to the patient about how to store and, if necessary, dispose of it to avoid the risk of diversion—a major concern about the legalization of marijuana.

You can cite a small study of adolescents in substance abuse treatment, in which 3 out of 4 reported having used someone else’s medical marijuana a median of 50 times.³² Adolescents who used medical marijuana had an earlier age of regular marijuana use, more marijuana abuse, and more dependence and conduct disorder symptoms compared with teens who had not used medical marijuana.³²

It is important, too, to obtain informed consent and draw up a controlled substance agreement, signed by the patient and you. The agreement should outline expected patient behavior, including regular monitoring and body fluid testing, and the consequences of a lack of adherence. (Using a certified laboratory for drug testing is important, as it avoids the possibility of actions based on inaccurate in-office screening.³³) Regular follow-up also provides an opportunity to assess symptom and functional improvement.

If the patient fails to keep appointments and does not respond to efforts to address the problem, the marijuana recommendation may have to be rescinded. Adverse effects, continued aberrant behavior, or evidence of cannabis use disorder may necessitate immediate cessation of the drug. Depending on the scope of the problem, collaboration with addiction therapy may be necessary. Discharge from the practice, of course, should be the last resort.

CASE › At a subsequent visit—after a trial with the maximal dose of dronabinol—Ms. B states that although she had some relief, she continues to have a high degree of breakthrough pain. You suspect that medical marijuana may do more to alleviate her pain, and establish a regimen to quickly taper her off dronabinol.

You consult with a pain management specialist, who suggests that the patient begin with raw marijuana with a 10% THC content, smoking 0.6 gm tid. You obtain informed consent and ask her to sign a controlled substance agreement, explaining that you will need to monitor her closely for dizziness, dysphoria, and hallucinations, among other adverse effects. You instruct her not to drive for 6 hours after smoking marijuana, and you schedule a follow-up appointment in 2 weeks.

Before she leaves, Ms. B receives a copy of your clinic note and written recommendation that she can take to the state dispensary. The note indicates that she will use marijuana for neuropathic pain.

CORRESPONDENCE
Julius Metts, MD, California Substance Abuse Treatment Facility and State Prison, CDCR, 900 Quebec Avenue, Corcoran, CA 93212; [email protected].

The focus of treatment. CF is not limited to the classic picture of lung and pancreas destruction with subsequent loss of function. The underlying pathology can occur in body epithelial tissues from the intestinal lining to sweat glands. These tissues contain cystic fibrosis transmembrane conductance regulator (CFTR), a protein that allows for the transport of chloride across epithelial cell membranes.² In individuals homozygous for mutated CFTR genes, chloride transport can be impaired. In addition to regulating chloride transport, CFTR is part of a larger, complex interaction of ion transport proteins such as the epithelial sodium channel (ENaC) and others that regulate bicarbonate secretion.² Decreased chloride ion transport in mutant CFTR negatively affects the ion transport complex; the result is a higher-than-normal viscosity of secreted body fluids.

Reason for hope. It is this impairment of chloride ion transport that leads to the classic phenotypic features of CF (eg, pulmonary function decline, pancreatic insufficiency, malnutrition, chronic respiratory infection), and is the target of both established and emerging therapies³—both of which I will review here.

For 90% of adults with cystic fibrosis, sweat chloride will be in the abnormal range of >60 mmol/L.

When to consider a CF diagnosis

Cystic fibrosis remains a clinical diagnosis when evidence of at least one phenotypic feature of the disease (TABLE 1) exists in the presence of laboratory evidence of a CFTR abnormality.⁴ Confirmation of CFTR dysfunction is demonstrated by an abnormality on sweat testing or identification of a CF-causing mutation in each copy of CFTR (ie, one on each chromosome).⁵ All 50 states now have neonatal laboratory screening programs;⁴ despite this, 30% of cases in 2012 were still diagnosed in those older than 1 year of age, with 3% to 5% diagnosed after age 18.¹

A sweat chloride reading in the abnormal range (>60 mmol/L) is present in 90% of patients diagnosed with CF in adulthood; this test remains the gold standard in the diagnosis of CF and the initial test of choice in suspected cases.⁴ Newborn screening programs identify those at risk by detecting persistent hypertrypsinogenemia and referring those with positive results for definitive testing with sweat chloride evaluation. Keep CF in mind when evaluating adolescents and adults who have chronic sinusitis, chronic/recurrent pulmonary infections, chronic/recurrent pancreatitis, or infertility from absence of the vas deferens.⁴ When features of the CF phenotype are present, especially if there is a known positive family history of CF or CF carrier status, order sweat chloride testing.

Traditional therapies

Both maintenance and acute therapies are directed throughout the body at decreasing fluid viscosity, clearing fluid with a high viscosity, or treating the tissue destruction that results from highly-viscous fluid.³ The traditional classic picture of CF is one of lung and pancreas destruction with subsequent loss of function. However, CF is, in reality, a full-body disease.

Respiratory system: Lungs

CFTR dysfunction in the lungs results in thick pulmonary secretions as the aqueous surface layer (ASL) lining the alveolar epithelium becomes dehydrated and creates a prime environment for the development of chronic infection. What ensues is a recurrent cycle of chronic infection, inflammation, and tissue destruction with loss of lung volume and function. Current therapies interrupt this cycle at multiple points.⁶

Airway clearance is one of the hallmarks of CF therapy, using both chemical and mechanical treatments. Daily, most patients will use either a therapy vest that administers sheering forces to the chest cavity or an airflow device that creates positive expiratory pressure and laminar flow to aid in expectorating pulmonary secretions.⁷ Because exercise has yielded comparable results to mechanical or airflow clearance devices, it is recommended that all CF patients who are not otherwise prohibited engage in regular, vigorous exercise in accordance with standard recommendations for the general public.⁷

Mechanical therapies are often preceded by airway dilation with short- and long-acting bronchodilators and inhaled steroids that open airways for optimal airway clearance.⁴ Thick secretions can be treated directly and enzymatically with nebulized dornase alpha,^4,8 which is also best administered before mechanical clearance therapy. Finally, viscosity of airway secretions can be decreased by improving the hydration of the ASL with nebulized 7% hypertonic saline.^4,8

Infection suppression. Thickened pulmonary secretions create a fertile environment for the development of chronic infection. By the time most CF patients reach adulthood, many are colonized with mucoid producing strains of Pseudomonas aeruginosa.^4,8-10 Many may also have chronic infection with Staphylococcus aureus, some strains of which may be methicillin-resistant. Quarterly culture and sensitivity results can be essential in directing acute antibiotic therapy, both in the hospital and ambulatory settings. In addition, in the case of Pseudomonas, inhaled antibiotics suppress chronic infection, improve lung function, decrease pulmonary secretions, and reduce inflammation.

Formulations are available for tobramycin and aztreonam, both of which are administered every other month to reduce toxicities and to deter antibiotic resistance. Some patients may use a single agent or may alternate agents every month. When acute antibiotic therapy is necessary for a pulmonary exacerbation, the inhaled agent is generally withheld. If outpatient treatment is warranted, the only available oral antibiotics with anti-pseudomonal activity are ciprofloxacin and levofloxacin.^4,8-10S aureus can be treated with trimethoprim/sulfamethoxazole or doxycycline.^4,8-10

Inflammation reduction is addressed with high-dose ibuprofen twice daily, azithromycin daily or 3 times weekly, or both. Children up to age 18 benefit from ibuprofen, which also improves forced expiratory volume in one second (FEV₁) to a greater extent than azithromycin.⁸ Adults, however, face the risk of gastrointestinal bleeding and renal dysfunction with ibuprofen, which must be weighed against its potential anti-inflammatory benefit. Both populations, however, benefit from chronic azithromycin, whose mechanism of action in this setting is believed to be more anti-inflammatory than bacterial suppression, since it has no direct bactericidal effect on the primary colonizing microbe, P aeruginosa.^4,11

Gastrointestinal system: Pancreas

Cystic fibrosis was first comprehensively described in 1938 and was named for the diseased appearance of the pancreas.¹² As happens in the lungs, thick pancreatic duct secretions create a cycle of tissue destruction, inflammation, and dysfunction.² CF patients lack adequate secretion of pancreatic enzymes and bicarbonate into the small bowel, which progressively leads to pancreatic dysfunction in most patients.

As malabsorption of nutrients advances, patients suffer varying degrees of malnutrition and vitamin deficiency, especially of the fat-soluble vitamins A, D, E, and K. Over 85% of CF patients have deficient pancreatic function, requiring pancreatic enzyme supplementation with all food intake and daily vitamin supplementation.²

Because exercise has yielded comparable results to mechanical or airflow clearance devices, CF patients should engage in regular, vigorous exercise.

Ensuring adequate nutrition. Most CF patients experience a chronic mismatch of dietary intake against caloric expenditure and benefit from aggressive nutritional management featuring a high-calorie diet with supplementation in the form of nutrition shakes or bars.² There is a well-documented linear relationship between BMI and FEV₁. Lung function declines in CF when a man’s body mass index (BMI) falls below 23 kg/m² and a woman’s BMI drops below 22 kg/m².² For this reason, the goal for caloric intake can be as high as 200% of the customary recommended daily allowance.²

Watch for CF-related diabetes. Since the pancreas is also the major source of endogenous insulin, nearly half of adults with CF will develop cystic fibrosis-related diabetes (CFRD) as pancreatic deficiency progresses.¹³ Similar to the relationship between BMI and FEV₁, there is a relationship between glucose intolerance and FEV₁. For this reason, annual diabetes screening is recommended for all CF patients ages 10 years and older.¹³ Because glycated hemoglobin (HbA1c) may not accurately reflect low levels of glucose intolerance, screen for CFRD with a 2-hour 75-g oral glucose tolerance test.¹³ Early insulin therapy can help maintain BMI and lower average blood sugar in support of FEV₁. Once CFRD is diagnosed, the goals and recommendations for control are largely the same as those recommended by the American Diabetes Association for other forms of diabetes.¹³

Gastrointestinal system: Alimentary canal

CF is often mistakenly believed to be primarily a pulmonary disease since 85% of the mortality is due to lung dysfunction,⁷ but intermittent abdominal pain is a common experience for most patients, and disorders can range from gastroesophageal reflux disease (GERD) to small bowel bacterial overgrowth (SBBO) to constipation. Up to 85% of adult patients experience symptoms of reflux, with as many as 40% of cases occurring silently.² Proton pump inhibitors are a first-line treatment, but they can also contribute to intestinal bacterial overgrowth and pulmonary infections.

In SBBO, gram-negative colonic bacteria colonize the small bowel and can contribute to abdominal pain and malabsorption, weight loss, and malnutrition. Treatment requires antibiotics with activity against gram-negative organisms, or non-absorbable agents such as rifamyxin, sometimes on a chronic, recurrent, or rotating basis.²

Chronic constipation is also quite common among CF patients and many require daily administration of poly-ethylene-glycol. Before newborn screening programs were introduced, infants would on occasion present with complete distal intestinal obstruction. Adults are not immune to obstructive complications and may require hospitalization for bowel cleansing.

Because HbA1c may not accurately reflect low levels of glucose intolerance, screen for CF-related diabetes with a 2-hour 75-g oral glucose tolerance test.

Gastrointestinal system: Liver

Liver disease is relatively common in CF, with up to 24% of adults experiencing hepatomegaly or persistently elevated liver function tests (LFT).⁴ Progressive biliary fibrosis and cirrhosis are encountered more often as the median survival age has increased. There is evidence that ursodeoxycholic acid (UDCA) can be a useful adjunct in the treatment of cholestasis, but it is not clear if it alters mortality or progression to cirrhosis. Only CF patients with elevated LFTs should be started on UDCA.⁴

Other areas of concern: Sinuses, serum sodium levels

Chronic, symptomatic sinus disease in CF patients—chiefly polyposis—is common and may require repeat surgery, although most patients with extensive nasal polyps find symptom relief with daily sinus rinses. Intranasal steroids and intranasal antibiotics are also often employed, and many CF patients need to be in regular contact with an otolaryngologist.¹⁴ For symptoms of allergic rhinitis, recommend OTC antihistamines in standard dosages.

Exercise is recommended for all CF patients, as noted earlier, and as life expectancy increases, many are engaging in more strenuous and longer duration activities.¹⁵ Due to high sweat sodium loss, CF patients are at risk for hyponatremia, especially when exercising on days with high temperatures and humidity. CF patients need to replace sodium losses in these conditions and when exercising for extended periods.

There are no evidence-based guidelines for sodium replacement. The Cystic Fibrosis Foundation (CFF) recommends that patients increase salt in the diet when under conditions likely to result in increased sodium loss, such as exercise. It has been thought that CF patients can easily dehydrate due to an impaired thirst mechanism and, when exercising, should consume fluids beyond the need to quench thirst.^16,17 More recent evidence suggests, however, that the thirst mechanism in those with CF remains normally intact and that overconsumption of fluids beyond the level of thirst may predispose the individual to exercise-associated hyponatremia as serum sodium is diluted.¹⁵

For Pseudomonas aeruginosa infection, inhaled antibiotics suppress chronic infection, improve lung function, decrease pulmonary secretions, and reduce inflammation.

New therapies

Small-molecule CFTR-modulating compounds are a promising development in the treatment of CF. The first such available medication was ivacaftor in 2012. Because these molecules are mutation specific, ivacaftor was available at first only for patients with at least one copy of the G551D mutation,¹⁸ which means about 5% of patients with CF.³

Ivacaftor increases the likelihood that the CFTR chloride channel will open and patients will exhibit a reduction in sweat chloride levels. In the first reported clinical trial of ivacaftor involving patients with the G551D mutation, FEV₁ improvements of 10% occurred by the second week of therapy and persisted for 48 weeks.¹⁸ The drug has now been approved by the US Food and Drug Administration (FDA) for patients 12 years of age and older with at least one of the following mutations: R117H, G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D.¹⁹

A medication combining ivacaftor with lumacaftor is also now available for patients with a copy of F508del on both chromosomes. F508del is the most common CFTR mutation, with one copy present in almost 87% of people with CF in the United States.¹ Since 47% of CF patients have 2 copies of F508del,¹ about half of those with CF in the United States are now eligible for small-molecule therapy. Lumacaftor acts by facilitating transport of a misfolded CFTR to the cell membrane where ivacaftor then increases the probability of an open chloride channel. This combination medication has improved lung function by about 5%.

The ivacaftor/lumacaftor combination was approved by the FDA in July 2015. Both ivacaftor and the ivacaftor/lumacaftor combination were deemed by the FDA to demonstrate statistically significant and sustained FEV₁ improvements over placebo.

The CFF was instrumental in providing financial support for the development of both ivacaftor and the ivacaftor/lumacaftor combination and continues to provide significant research advancement. According to the CFF (www.cff.org), medications currently in the development pipeline include compounds that provide CFTR modulation, surface airway liquid restoration, anti-inflammation, inhaled anti-infection, and pancreatic enzyme function. For more on CFF, see "The traditional CF care model.”^4,20

CORRESPONDENCE
Douglas Lewis, MD, 1121 S. Clifton, Wichita, KS 67218; [email protected].

The focus of treatment. CF is not limited to the classic picture of lung and pancreas destruction with subsequent loss of function. The underlying pathology can occur in body epithelial tissues from the intestinal lining to sweat glands. These tissues contain cystic fibrosis transmembrane conductance regulator (CFTR), a protein that allows for the transport of chloride across epithelial cell membranes.² In individuals homozygous for mutated CFTR genes, chloride transport can be impaired. In addition to regulating chloride transport, CFTR is part of a larger, complex interaction of ion transport proteins such as the epithelial sodium channel (ENaC) and others that regulate bicarbonate secretion.² Decreased chloride ion transport in mutant CFTR negatively affects the ion transport complex; the result is a higher-than-normal viscosity of secreted body fluids.

Reason for hope. It is this impairment of chloride ion transport that leads to the classic phenotypic features of CF (eg, pulmonary function decline, pancreatic insufficiency, malnutrition, chronic respiratory infection), and is the target of both established and emerging therapies³—both of which I will review here.

For 90% of adults with cystic fibrosis, sweat chloride will be in the abnormal range of >60 mmol/L.

When to consider a CF diagnosis

Cystic fibrosis remains a clinical diagnosis when evidence of at least one phenotypic feature of the disease (TABLE 1) exists in the presence of laboratory evidence of a CFTR abnormality.⁴ Confirmation of CFTR dysfunction is demonstrated by an abnormality on sweat testing or identification of a CF-causing mutation in each copy of CFTR (ie, one on each chromosome).⁵ All 50 states now have neonatal laboratory screening programs;⁴ despite this, 30% of cases in 2012 were still diagnosed in those older than 1 year of age, with 3% to 5% diagnosed after age 18.¹

A sweat chloride reading in the abnormal range (>60 mmol/L) is present in 90% of patients diagnosed with CF in adulthood; this test remains the gold standard in the diagnosis of CF and the initial test of choice in suspected cases.⁴ Newborn screening programs identify those at risk by detecting persistent hypertrypsinogenemia and referring those with positive results for definitive testing with sweat chloride evaluation. Keep CF in mind when evaluating adolescents and adults who have chronic sinusitis, chronic/recurrent pulmonary infections, chronic/recurrent pancreatitis, or infertility from absence of the vas deferens.⁴ When features of the CF phenotype are present, especially if there is a known positive family history of CF or CF carrier status, order sweat chloride testing.

Traditional therapies

Both maintenance and acute therapies are directed throughout the body at decreasing fluid viscosity, clearing fluid with a high viscosity, or treating the tissue destruction that results from highly-viscous fluid.³ The traditional classic picture of CF is one of lung and pancreas destruction with subsequent loss of function. However, CF is, in reality, a full-body disease.

Respiratory system: Lungs

CFTR dysfunction in the lungs results in thick pulmonary secretions as the aqueous surface layer (ASL) lining the alveolar epithelium becomes dehydrated and creates a prime environment for the development of chronic infection. What ensues is a recurrent cycle of chronic infection, inflammation, and tissue destruction with loss of lung volume and function. Current therapies interrupt this cycle at multiple points.⁶

Airway clearance is one of the hallmarks of CF therapy, using both chemical and mechanical treatments. Daily, most patients will use either a therapy vest that administers sheering forces to the chest cavity or an airflow device that creates positive expiratory pressure and laminar flow to aid in expectorating pulmonary secretions.⁷ Because exercise has yielded comparable results to mechanical or airflow clearance devices, it is recommended that all CF patients who are not otherwise prohibited engage in regular, vigorous exercise in accordance with standard recommendations for the general public.⁷

Mechanical therapies are often preceded by airway dilation with short- and long-acting bronchodilators and inhaled steroids that open airways for optimal airway clearance.⁴ Thick secretions can be treated directly and enzymatically with nebulized dornase alpha,^4,8 which is also best administered before mechanical clearance therapy. Finally, viscosity of airway secretions can be decreased by improving the hydration of the ASL with nebulized 7% hypertonic saline.^4,8

Infection suppression. Thickened pulmonary secretions create a fertile environment for the development of chronic infection. By the time most CF patients reach adulthood, many are colonized with mucoid producing strains of Pseudomonas aeruginosa.^4,8-10 Many may also have chronic infection with Staphylococcus aureus, some strains of which may be methicillin-resistant. Quarterly culture and sensitivity results can be essential in directing acute antibiotic therapy, both in the hospital and ambulatory settings. In addition, in the case of Pseudomonas, inhaled antibiotics suppress chronic infection, improve lung function, decrease pulmonary secretions, and reduce inflammation.

Formulations are available for tobramycin and aztreonam, both of which are administered every other month to reduce toxicities and to deter antibiotic resistance. Some patients may use a single agent or may alternate agents every month. When acute antibiotic therapy is necessary for a pulmonary exacerbation, the inhaled agent is generally withheld. If outpatient treatment is warranted, the only available oral antibiotics with anti-pseudomonal activity are ciprofloxacin and levofloxacin.^4,8-10S aureus can be treated with trimethoprim/sulfamethoxazole or doxycycline.^4,8-10

Inflammation reduction is addressed with high-dose ibuprofen twice daily, azithromycin daily or 3 times weekly, or both. Children up to age 18 benefit from ibuprofen, which also improves forced expiratory volume in one second (FEV₁) to a greater extent than azithromycin.⁸ Adults, however, face the risk of gastrointestinal bleeding and renal dysfunction with ibuprofen, which must be weighed against its potential anti-inflammatory benefit. Both populations, however, benefit from chronic azithromycin, whose mechanism of action in this setting is believed to be more anti-inflammatory than bacterial suppression, since it has no direct bactericidal effect on the primary colonizing microbe, P aeruginosa.^4,11

Gastrointestinal system: Pancreas

Cystic fibrosis was first comprehensively described in 1938 and was named for the diseased appearance of the pancreas.¹² As happens in the lungs, thick pancreatic duct secretions create a cycle of tissue destruction, inflammation, and dysfunction.² CF patients lack adequate secretion of pancreatic enzymes and bicarbonate into the small bowel, which progressively leads to pancreatic dysfunction in most patients.

As malabsorption of nutrients advances, patients suffer varying degrees of malnutrition and vitamin deficiency, especially of the fat-soluble vitamins A, D, E, and K. Over 85% of CF patients have deficient pancreatic function, requiring pancreatic enzyme supplementation with all food intake and daily vitamin supplementation.²

Because exercise has yielded comparable results to mechanical or airflow clearance devices, CF patients should engage in regular, vigorous exercise.

Ensuring adequate nutrition. Most CF patients experience a chronic mismatch of dietary intake against caloric expenditure and benefit from aggressive nutritional management featuring a high-calorie diet with supplementation in the form of nutrition shakes or bars.² There is a well-documented linear relationship between BMI and FEV₁. Lung function declines in CF when a man’s body mass index (BMI) falls below 23 kg/m² and a woman’s BMI drops below 22 kg/m².² For this reason, the goal for caloric intake can be as high as 200% of the customary recommended daily allowance.²

Watch for CF-related diabetes. Since the pancreas is also the major source of endogenous insulin, nearly half of adults with CF will develop cystic fibrosis-related diabetes (CFRD) as pancreatic deficiency progresses.¹³ Similar to the relationship between BMI and FEV₁, there is a relationship between glucose intolerance and FEV₁. For this reason, annual diabetes screening is recommended for all CF patients ages 10 years and older.¹³ Because glycated hemoglobin (HbA1c) may not accurately reflect low levels of glucose intolerance, screen for CFRD with a 2-hour 75-g oral glucose tolerance test.¹³ Early insulin therapy can help maintain BMI and lower average blood sugar in support of FEV₁. Once CFRD is diagnosed, the goals and recommendations for control are largely the same as those recommended by the American Diabetes Association for other forms of diabetes.¹³

Gastrointestinal system: Alimentary canal

CF is often mistakenly believed to be primarily a pulmonary disease since 85% of the mortality is due to lung dysfunction,⁷ but intermittent abdominal pain is a common experience for most patients, and disorders can range from gastroesophageal reflux disease (GERD) to small bowel bacterial overgrowth (SBBO) to constipation. Up to 85% of adult patients experience symptoms of reflux, with as many as 40% of cases occurring silently.² Proton pump inhibitors are a first-line treatment, but they can also contribute to intestinal bacterial overgrowth and pulmonary infections.

In SBBO, gram-negative colonic bacteria colonize the small bowel and can contribute to abdominal pain and malabsorption, weight loss, and malnutrition. Treatment requires antibiotics with activity against gram-negative organisms, or non-absorbable agents such as rifamyxin, sometimes on a chronic, recurrent, or rotating basis.²

Chronic constipation is also quite common among CF patients and many require daily administration of poly-ethylene-glycol. Before newborn screening programs were introduced, infants would on occasion present with complete distal intestinal obstruction. Adults are not immune to obstructive complications and may require hospitalization for bowel cleansing.

Because HbA1c may not accurately reflect low levels of glucose intolerance, screen for CF-related diabetes with a 2-hour 75-g oral glucose tolerance test.

Gastrointestinal system: Liver

Liver disease is relatively common in CF, with up to 24% of adults experiencing hepatomegaly or persistently elevated liver function tests (LFT).⁴ Progressive biliary fibrosis and cirrhosis are encountered more often as the median survival age has increased. There is evidence that ursodeoxycholic acid (UDCA) can be a useful adjunct in the treatment of cholestasis, but it is not clear if it alters mortality or progression to cirrhosis. Only CF patients with elevated LFTs should be started on UDCA.⁴

Other areas of concern: Sinuses, serum sodium levels

Chronic, symptomatic sinus disease in CF patients—chiefly polyposis—is common and may require repeat surgery, although most patients with extensive nasal polyps find symptom relief with daily sinus rinses. Intranasal steroids and intranasal antibiotics are also often employed, and many CF patients need to be in regular contact with an otolaryngologist.¹⁴ For symptoms of allergic rhinitis, recommend OTC antihistamines in standard dosages.

Exercise is recommended for all CF patients, as noted earlier, and as life expectancy increases, many are engaging in more strenuous and longer duration activities.¹⁵ Due to high sweat sodium loss, CF patients are at risk for hyponatremia, especially when exercising on days with high temperatures and humidity. CF patients need to replace sodium losses in these conditions and when exercising for extended periods.

There are no evidence-based guidelines for sodium replacement. The Cystic Fibrosis Foundation (CFF) recommends that patients increase salt in the diet when under conditions likely to result in increased sodium loss, such as exercise. It has been thought that CF patients can easily dehydrate due to an impaired thirst mechanism and, when exercising, should consume fluids beyond the need to quench thirst.^16,17 More recent evidence suggests, however, that the thirst mechanism in those with CF remains normally intact and that overconsumption of fluids beyond the level of thirst may predispose the individual to exercise-associated hyponatremia as serum sodium is diluted.¹⁵

For Pseudomonas aeruginosa infection, inhaled antibiotics suppress chronic infection, improve lung function, decrease pulmonary secretions, and reduce inflammation.

New therapies

Small-molecule CFTR-modulating compounds are a promising development in the treatment of CF. The first such available medication was ivacaftor in 2012. Because these molecules are mutation specific, ivacaftor was available at first only for patients with at least one copy of the G551D mutation,¹⁸ which means about 5% of patients with CF.³

Ivacaftor increases the likelihood that the CFTR chloride channel will open and patients will exhibit a reduction in sweat chloride levels. In the first reported clinical trial of ivacaftor involving patients with the G551D mutation, FEV₁ improvements of 10% occurred by the second week of therapy and persisted for 48 weeks.¹⁸ The drug has now been approved by the US Food and Drug Administration (FDA) for patients 12 years of age and older with at least one of the following mutations: R117H, G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D.¹⁹

A medication combining ivacaftor with lumacaftor is also now available for patients with a copy of F508del on both chromosomes. F508del is the most common CFTR mutation, with one copy present in almost 87% of people with CF in the United States.¹ Since 47% of CF patients have 2 copies of F508del,¹ about half of those with CF in the United States are now eligible for small-molecule therapy. Lumacaftor acts by facilitating transport of a misfolded CFTR to the cell membrane where ivacaftor then increases the probability of an open chloride channel. This combination medication has improved lung function by about 5%.

The ivacaftor/lumacaftor combination was approved by the FDA in July 2015. Both ivacaftor and the ivacaftor/lumacaftor combination were deemed by the FDA to demonstrate statistically significant and sustained FEV₁ improvements over placebo.

The CFF was instrumental in providing financial support for the development of both ivacaftor and the ivacaftor/lumacaftor combination and continues to provide significant research advancement. According to the CFF (www.cff.org), medications currently in the development pipeline include compounds that provide CFTR modulation, surface airway liquid restoration, anti-inflammation, inhaled anti-infection, and pancreatic enzyme function. For more on CFF, see "The traditional CF care model.”^4,20

CORRESPONDENCE
Douglas Lewis, MD, 1121 S. Clifton, Wichita, KS 67218; [email protected].

The focus of treatment. CF is not limited to the classic picture of lung and pancreas destruction with subsequent loss of function. The underlying pathology can occur in body epithelial tissues from the intestinal lining to sweat glands. These tissues contain cystic fibrosis transmembrane conductance regulator (CFTR), a protein that allows for the transport of chloride across epithelial cell membranes.² In individuals homozygous for mutated CFTR genes, chloride transport can be impaired. In addition to regulating chloride transport, CFTR is part of a larger, complex interaction of ion transport proteins such as the epithelial sodium channel (ENaC) and others that regulate bicarbonate secretion.² Decreased chloride ion transport in mutant CFTR negatively affects the ion transport complex; the result is a higher-than-normal viscosity of secreted body fluids.

Reason for hope. It is this impairment of chloride ion transport that leads to the classic phenotypic features of CF (eg, pulmonary function decline, pancreatic insufficiency, malnutrition, chronic respiratory infection), and is the target of both established and emerging therapies³—both of which I will review here.

For 90% of adults with cystic fibrosis, sweat chloride will be in the abnormal range of >60 mmol/L.

When to consider a CF diagnosis

Cystic fibrosis remains a clinical diagnosis when evidence of at least one phenotypic feature of the disease (TABLE 1) exists in the presence of laboratory evidence of a CFTR abnormality.⁴ Confirmation of CFTR dysfunction is demonstrated by an abnormality on sweat testing or identification of a CF-causing mutation in each copy of CFTR (ie, one on each chromosome).⁵ All 50 states now have neonatal laboratory screening programs;⁴ despite this, 30% of cases in 2012 were still diagnosed in those older than 1 year of age, with 3% to 5% diagnosed after age 18.¹

A sweat chloride reading in the abnormal range (>60 mmol/L) is present in 90% of patients diagnosed with CF in adulthood; this test remains the gold standard in the diagnosis of CF and the initial test of choice in suspected cases.⁴ Newborn screening programs identify those at risk by detecting persistent hypertrypsinogenemia and referring those with positive results for definitive testing with sweat chloride evaluation. Keep CF in mind when evaluating adolescents and adults who have chronic sinusitis, chronic/recurrent pulmonary infections, chronic/recurrent pancreatitis, or infertility from absence of the vas deferens.⁴ When features of the CF phenotype are present, especially if there is a known positive family history of CF or CF carrier status, order sweat chloride testing.

Traditional therapies

Both maintenance and acute therapies are directed throughout the body at decreasing fluid viscosity, clearing fluid with a high viscosity, or treating the tissue destruction that results from highly-viscous fluid.³ The traditional classic picture of CF is one of lung and pancreas destruction with subsequent loss of function. However, CF is, in reality, a full-body disease.

Respiratory system: Lungs

CFTR dysfunction in the lungs results in thick pulmonary secretions as the aqueous surface layer (ASL) lining the alveolar epithelium becomes dehydrated and creates a prime environment for the development of chronic infection. What ensues is a recurrent cycle of chronic infection, inflammation, and tissue destruction with loss of lung volume and function. Current therapies interrupt this cycle at multiple points.⁶

Airway clearance is one of the hallmarks of CF therapy, using both chemical and mechanical treatments. Daily, most patients will use either a therapy vest that administers sheering forces to the chest cavity or an airflow device that creates positive expiratory pressure and laminar flow to aid in expectorating pulmonary secretions.⁷ Because exercise has yielded comparable results to mechanical or airflow clearance devices, it is recommended that all CF patients who are not otherwise prohibited engage in regular, vigorous exercise in accordance with standard recommendations for the general public.⁷

Mechanical therapies are often preceded by airway dilation with short- and long-acting bronchodilators and inhaled steroids that open airways for optimal airway clearance.⁴ Thick secretions can be treated directly and enzymatically with nebulized dornase alpha,^4,8 which is also best administered before mechanical clearance therapy. Finally, viscosity of airway secretions can be decreased by improving the hydration of the ASL with nebulized 7% hypertonic saline.^4,8

Infection suppression. Thickened pulmonary secretions create a fertile environment for the development of chronic infection. By the time most CF patients reach adulthood, many are colonized with mucoid producing strains of Pseudomonas aeruginosa.^4,8-10 Many may also have chronic infection with Staphylococcus aureus, some strains of which may be methicillin-resistant. Quarterly culture and sensitivity results can be essential in directing acute antibiotic therapy, both in the hospital and ambulatory settings. In addition, in the case of Pseudomonas, inhaled antibiotics suppress chronic infection, improve lung function, decrease pulmonary secretions, and reduce inflammation.

Formulations are available for tobramycin and aztreonam, both of which are administered every other month to reduce toxicities and to deter antibiotic resistance. Some patients may use a single agent or may alternate agents every month. When acute antibiotic therapy is necessary for a pulmonary exacerbation, the inhaled agent is generally withheld. If outpatient treatment is warranted, the only available oral antibiotics with anti-pseudomonal activity are ciprofloxacin and levofloxacin.^4,8-10S aureus can be treated with trimethoprim/sulfamethoxazole or doxycycline.^4,8-10

Inflammation reduction is addressed with high-dose ibuprofen twice daily, azithromycin daily or 3 times weekly, or both. Children up to age 18 benefit from ibuprofen, which also improves forced expiratory volume in one second (FEV₁) to a greater extent than azithromycin.⁸ Adults, however, face the risk of gastrointestinal bleeding and renal dysfunction with ibuprofen, which must be weighed against its potential anti-inflammatory benefit. Both populations, however, benefit from chronic azithromycin, whose mechanism of action in this setting is believed to be more anti-inflammatory than bacterial suppression, since it has no direct bactericidal effect on the primary colonizing microbe, P aeruginosa.^4,11

Gastrointestinal system: Pancreas

Cystic fibrosis was first comprehensively described in 1938 and was named for the diseased appearance of the pancreas.¹² As happens in the lungs, thick pancreatic duct secretions create a cycle of tissue destruction, inflammation, and dysfunction.² CF patients lack adequate secretion of pancreatic enzymes and bicarbonate into the small bowel, which progressively leads to pancreatic dysfunction in most patients.

As malabsorption of nutrients advances, patients suffer varying degrees of malnutrition and vitamin deficiency, especially of the fat-soluble vitamins A, D, E, and K. Over 85% of CF patients have deficient pancreatic function, requiring pancreatic enzyme supplementation with all food intake and daily vitamin supplementation.²

Because exercise has yielded comparable results to mechanical or airflow clearance devices, CF patients should engage in regular, vigorous exercise.

Ensuring adequate nutrition. Most CF patients experience a chronic mismatch of dietary intake against caloric expenditure and benefit from aggressive nutritional management featuring a high-calorie diet with supplementation in the form of nutrition shakes or bars.² There is a well-documented linear relationship between BMI and FEV₁. Lung function declines in CF when a man’s body mass index (BMI) falls below 23 kg/m² and a woman’s BMI drops below 22 kg/m².² For this reason, the goal for caloric intake can be as high as 200% of the customary recommended daily allowance.²

Watch for CF-related diabetes. Since the pancreas is also the major source of endogenous insulin, nearly half of adults with CF will develop cystic fibrosis-related diabetes (CFRD) as pancreatic deficiency progresses.¹³ Similar to the relationship between BMI and FEV₁, there is a relationship between glucose intolerance and FEV₁. For this reason, annual diabetes screening is recommended for all CF patients ages 10 years and older.¹³ Because glycated hemoglobin (HbA1c) may not accurately reflect low levels of glucose intolerance, screen for CFRD with a 2-hour 75-g oral glucose tolerance test.¹³ Early insulin therapy can help maintain BMI and lower average blood sugar in support of FEV₁. Once CFRD is diagnosed, the goals and recommendations for control are largely the same as those recommended by the American Diabetes Association for other forms of diabetes.¹³

Gastrointestinal system: Alimentary canal

CF is often mistakenly believed to be primarily a pulmonary disease since 85% of the mortality is due to lung dysfunction,⁷ but intermittent abdominal pain is a common experience for most patients, and disorders can range from gastroesophageal reflux disease (GERD) to small bowel bacterial overgrowth (SBBO) to constipation. Up to 85% of adult patients experience symptoms of reflux, with as many as 40% of cases occurring silently.² Proton pump inhibitors are a first-line treatment, but they can also contribute to intestinal bacterial overgrowth and pulmonary infections.

In SBBO, gram-negative colonic bacteria colonize the small bowel and can contribute to abdominal pain and malabsorption, weight loss, and malnutrition. Treatment requires antibiotics with activity against gram-negative organisms, or non-absorbable agents such as rifamyxin, sometimes on a chronic, recurrent, or rotating basis.²

Chronic constipation is also quite common among CF patients and many require daily administration of poly-ethylene-glycol. Before newborn screening programs were introduced, infants would on occasion present with complete distal intestinal obstruction. Adults are not immune to obstructive complications and may require hospitalization for bowel cleansing.

Because HbA1c may not accurately reflect low levels of glucose intolerance, screen for CF-related diabetes with a 2-hour 75-g oral glucose tolerance test.

Gastrointestinal system: Liver

Liver disease is relatively common in CF, with up to 24% of adults experiencing hepatomegaly or persistently elevated liver function tests (LFT).⁴ Progressive biliary fibrosis and cirrhosis are encountered more often as the median survival age has increased. There is evidence that ursodeoxycholic acid (UDCA) can be a useful adjunct in the treatment of cholestasis, but it is not clear if it alters mortality or progression to cirrhosis. Only CF patients with elevated LFTs should be started on UDCA.⁴

Other areas of concern: Sinuses, serum sodium levels

Chronic, symptomatic sinus disease in CF patients—chiefly polyposis—is common and may require repeat surgery, although most patients with extensive nasal polyps find symptom relief with daily sinus rinses. Intranasal steroids and intranasal antibiotics are also often employed, and many CF patients need to be in regular contact with an otolaryngologist.¹⁴ For symptoms of allergic rhinitis, recommend OTC antihistamines in standard dosages.

Exercise is recommended for all CF patients, as noted earlier, and as life expectancy increases, many are engaging in more strenuous and longer duration activities.¹⁵ Due to high sweat sodium loss, CF patients are at risk for hyponatremia, especially when exercising on days with high temperatures and humidity. CF patients need to replace sodium losses in these conditions and when exercising for extended periods.

There are no evidence-based guidelines for sodium replacement. The Cystic Fibrosis Foundation (CFF) recommends that patients increase salt in the diet when under conditions likely to result in increased sodium loss, such as exercise. It has been thought that CF patients can easily dehydrate due to an impaired thirst mechanism and, when exercising, should consume fluids beyond the need to quench thirst.^16,17 More recent evidence suggests, however, that the thirst mechanism in those with CF remains normally intact and that overconsumption of fluids beyond the level of thirst may predispose the individual to exercise-associated hyponatremia as serum sodium is diluted.¹⁵

For Pseudomonas aeruginosa infection, inhaled antibiotics suppress chronic infection, improve lung function, decrease pulmonary secretions, and reduce inflammation.

New therapies

Small-molecule CFTR-modulating compounds are a promising development in the treatment of CF. The first such available medication was ivacaftor in 2012. Because these molecules are mutation specific, ivacaftor was available at first only for patients with at least one copy of the G551D mutation,¹⁸ which means about 5% of patients with CF.³

Ivacaftor increases the likelihood that the CFTR chloride channel will open and patients will exhibit a reduction in sweat chloride levels. In the first reported clinical trial of ivacaftor involving patients with the G551D mutation, FEV₁ improvements of 10% occurred by the second week of therapy and persisted for 48 weeks.¹⁸ The drug has now been approved by the US Food and Drug Administration (FDA) for patients 12 years of age and older with at least one of the following mutations: R117H, G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D.¹⁹

A medication combining ivacaftor with lumacaftor is also now available for patients with a copy of F508del on both chromosomes. F508del is the most common CFTR mutation, with one copy present in almost 87% of people with CF in the United States.¹ Since 47% of CF patients have 2 copies of F508del,¹ about half of those with CF in the United States are now eligible for small-molecule therapy. Lumacaftor acts by facilitating transport of a misfolded CFTR to the cell membrane where ivacaftor then increases the probability of an open chloride channel. This combination medication has improved lung function by about 5%.

The ivacaftor/lumacaftor combination was approved by the FDA in July 2015. Both ivacaftor and the ivacaftor/lumacaftor combination were deemed by the FDA to demonstrate statistically significant and sustained FEV₁ improvements over placebo.

The CFF was instrumental in providing financial support for the development of both ivacaftor and the ivacaftor/lumacaftor combination and continues to provide significant research advancement. According to the CFF (www.cff.org), medications currently in the development pipeline include compounds that provide CFTR modulation, surface airway liquid restoration, anti-inflammation, inhaled anti-infection, and pancreatic enzyme function. For more on CFF, see "The traditional CF care model.”^4,20

CORRESPONDENCE
Douglas Lewis, MD, 1121 S. Clifton, Wichita, KS 67218; [email protected].

To the Editor: Two considerations concerning the interpretation of the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial are not addressed in the article by Sabe et al regarding a new class of drugs for systolic heart failure.¹ First of all, the PARADIGM-HF trial compared the maximal dose of sacubitril with a less-than-maximal dose of enalapril. Secondly, sacubitril lowered blood pressure more than enalapril.

The angiotensin receptor blocker dose in sacubitril 200 mg is equivalent to valsartan 160 mg.² Accordingly, the angiotensin receptor blocker in sacubitril 200 mg twice daily is equivalent to the maximal dosage of valsartan approved by the US Food and Drug Administration. The dosage of enalapril in the PARADIGM-HF trial was 10 mg twice daily. While the target enalapril dosage for heart failure is 10 to 20 mg twice daily,³ the dosage of enalapril in PARADIGM-HF was half the maximal approved dosage.

In the PARADIGM-HF trial, sacubitril 200 mg twice daily reduced the incidence of cardiovascular death by 19% compared with enalapril 10 mg twice daily (the rates were 16.5% vs 13.3%, respectively).² That sacubitril lowered mean systolic blood pressure 3.2 ± 0.4 mm Hg more than enalapril^2,4 may account for much of this benefit.

A 2002 study by Lewington et al⁵ found that a 2-mm Hg decrease in systolic blood pressure reduces the risk of cardiovascular death by 7% in middle-aged adults. Granted, this study did not involve heart failure patients, but if its results are remotely applicable, a 3.2-mm Hg reduction in systolic blood pressure might be expected to reduce the rate of cardiovascular deaths by 10% to 11%.

Would sacubitril be superior to enalapril if the maximal dose of enalapril were compared to the maximal dose of sacubitril? Would sacubitril be superior to enalapril if blood pressure were lowered comparably between the two groups? These are relevant questions that the PARADIGM-HF trial fails to answer.

To the Editor: Two considerations concerning the interpretation of the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial are not addressed in the article by Sabe et al regarding a new class of drugs for systolic heart failure.¹ First of all, the PARADIGM-HF trial compared the maximal dose of sacubitril with a less-than-maximal dose of enalapril. Secondly, sacubitril lowered blood pressure more than enalapril.

The angiotensin receptor blocker dose in sacubitril 200 mg is equivalent to valsartan 160 mg.² Accordingly, the angiotensin receptor blocker in sacubitril 200 mg twice daily is equivalent to the maximal dosage of valsartan approved by the US Food and Drug Administration. The dosage of enalapril in the PARADIGM-HF trial was 10 mg twice daily. While the target enalapril dosage for heart failure is 10 to 20 mg twice daily,³ the dosage of enalapril in PARADIGM-HF was half the maximal approved dosage.

In the PARADIGM-HF trial, sacubitril 200 mg twice daily reduced the incidence of cardiovascular death by 19% compared with enalapril 10 mg twice daily (the rates were 16.5% vs 13.3%, respectively).² That sacubitril lowered mean systolic blood pressure 3.2 ± 0.4 mm Hg more than enalapril^2,4 may account for much of this benefit.

A 2002 study by Lewington et al⁵ found that a 2-mm Hg decrease in systolic blood pressure reduces the risk of cardiovascular death by 7% in middle-aged adults. Granted, this study did not involve heart failure patients, but if its results are remotely applicable, a 3.2-mm Hg reduction in systolic blood pressure might be expected to reduce the rate of cardiovascular deaths by 10% to 11%.

Would sacubitril be superior to enalapril if the maximal dose of enalapril were compared to the maximal dose of sacubitril? Would sacubitril be superior to enalapril if blood pressure were lowered comparably between the two groups? These are relevant questions that the PARADIGM-HF trial fails to answer.

To the Editor: Two considerations concerning the interpretation of the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial are not addressed in the article by Sabe et al regarding a new class of drugs for systolic heart failure.¹ First of all, the PARADIGM-HF trial compared the maximal dose of sacubitril with a less-than-maximal dose of enalapril. Secondly, sacubitril lowered blood pressure more than enalapril.

The angiotensin receptor blocker dose in sacubitril 200 mg is equivalent to valsartan 160 mg.² Accordingly, the angiotensin receptor blocker in sacubitril 200 mg twice daily is equivalent to the maximal dosage of valsartan approved by the US Food and Drug Administration. The dosage of enalapril in the PARADIGM-HF trial was 10 mg twice daily. While the target enalapril dosage for heart failure is 10 to 20 mg twice daily,³ the dosage of enalapril in PARADIGM-HF was half the maximal approved dosage.

In the PARADIGM-HF trial, sacubitril 200 mg twice daily reduced the incidence of cardiovascular death by 19% compared with enalapril 10 mg twice daily (the rates were 16.5% vs 13.3%, respectively).² That sacubitril lowered mean systolic blood pressure 3.2 ± 0.4 mm Hg more than enalapril^2,4 may account for much of this benefit.

A 2002 study by Lewington et al⁵ found that a 2-mm Hg decrease in systolic blood pressure reduces the risk of cardiovascular death by 7% in middle-aged adults. Granted, this study did not involve heart failure patients, but if its results are remotely applicable, a 3.2-mm Hg reduction in systolic blood pressure might be expected to reduce the rate of cardiovascular deaths by 10% to 11%.

Would sacubitril be superior to enalapril if the maximal dose of enalapril were compared to the maximal dose of sacubitril? Would sacubitril be superior to enalapril if blood pressure were lowered comparably between the two groups? These are relevant questions that the PARADIGM-HF trial fails to answer.