Women's Health

Moderate reductions in kidney function in older women are associated with an increased short-term risk of fractures, according to a study published in Osteoporosis International.

However, the longitudinal, population-based cohort study did not find an association with fracture risk either in women older than 80 years or in those with worse kidney function.

“Since the kidneys regulate homeostasis of PTH [parathyroid hormone], phosphate, calcium, and vitamin D, any disruption in function can be expected to disturb bone remodeling and have implications for skeletal health,” wrote Linnea Malmgren, MD, and colleagues from Skåne University Hospital in Malmö, Sweden.

Previous studies have found that a large proportion of older women have reduced kidney function equivalent to a diagnosis of chronic kidney disease and that it is associated with bone loss. However, there have been few studies exploring that association in a population without a diagnosis of chronic kidney disease.

In their study, Dr. Malmgren and colleagues followed 981 women aged 75 years and 685 women aged 80 years, who underwent assessment of kidney function and bone mineral density and were followed up for fracture.

They found that women who experienced an osteoporotic fracture between the ages of 75 and 80 years had significantly lower baseline kidney function, compared with those who did not experience a fracture.

Compared with women with normal kidney function at age 75, women with intermediate kidney function (estimated glomerular filtration rate 45-59 mL/min per 1.73m²⁾ had a significant 2.21-fold higher risk of osteoporotic fracture within 2 years, a 1.51-fold higher risk up to 5 years, and an elevated risk of hip fracture.

A similar trend was seen in women with poor kidney function (eGFR less than 45 mL/min per 1.73m²), but it was not statistically significant.

The analysis also found that kidney function at age 80 years was not significantly associated with long-term fracture risk, nor was there a significant association for 10-year fracture risk in those aged 75 years.

Reduced kidney function was also associated with a higher fracture risk even in women without osteoporosis.

“As expected, fracture risk was high among those with osteoporosis, but risk seemed to further increase in women with both osteoporosis and reduced kidney function, compared with those with osteoporosis and normal function,” the authors reported.

“These findings indicate that implications for bone health and fracture risk might occur in the very common modest reduction of kidney function in the elderly, and also possibly before a diagnosis of CKD-MBD [chronic kidney disease–mineral and bone disorder].”

The study was supported by Lund University; the Swedish Research Council; Forte, Greta and Johan Kock Foundation; A. Påhlsson Foundation; A. Osterlund Foundation; H Järnhardt Foundation; King Gustav V 80-year Fund; Thelma Zoegas Foundation; Swedish Rheumatism Foundation; Skåne University Hospital Research Fund; and the Research and Development Council of Region Skåne, Sweden. No conflicts of interest were declared.

SOURCE: Malmgren L et al. Osteoporos Int. 2019 Nov 21. doi: 10.1007/s00198-019-05152-x.

Moderate reductions in kidney function in older women are associated with an increased short-term risk of fractures, according to a study published in Osteoporosis International.

However, the longitudinal, population-based cohort study did not find an association with fracture risk either in women older than 80 years or in those with worse kidney function.

“Since the kidneys regulate homeostasis of PTH [parathyroid hormone], phosphate, calcium, and vitamin D, any disruption in function can be expected to disturb bone remodeling and have implications for skeletal health,” wrote Linnea Malmgren, MD, and colleagues from Skåne University Hospital in Malmö, Sweden.

Previous studies have found that a large proportion of older women have reduced kidney function equivalent to a diagnosis of chronic kidney disease and that it is associated with bone loss. However, there have been few studies exploring that association in a population without a diagnosis of chronic kidney disease.

In their study, Dr. Malmgren and colleagues followed 981 women aged 75 years and 685 women aged 80 years, who underwent assessment of kidney function and bone mineral density and were followed up for fracture.

They found that women who experienced an osteoporotic fracture between the ages of 75 and 80 years had significantly lower baseline kidney function, compared with those who did not experience a fracture.

Compared with women with normal kidney function at age 75, women with intermediate kidney function (estimated glomerular filtration rate 45-59 mL/min per 1.73m²⁾ had a significant 2.21-fold higher risk of osteoporotic fracture within 2 years, a 1.51-fold higher risk up to 5 years, and an elevated risk of hip fracture.

A similar trend was seen in women with poor kidney function (eGFR less than 45 mL/min per 1.73m²), but it was not statistically significant.

The analysis also found that kidney function at age 80 years was not significantly associated with long-term fracture risk, nor was there a significant association for 10-year fracture risk in those aged 75 years.

Reduced kidney function was also associated with a higher fracture risk even in women without osteoporosis.

“As expected, fracture risk was high among those with osteoporosis, but risk seemed to further increase in women with both osteoporosis and reduced kidney function, compared with those with osteoporosis and normal function,” the authors reported.

“These findings indicate that implications for bone health and fracture risk might occur in the very common modest reduction of kidney function in the elderly, and also possibly before a diagnosis of CKD-MBD [chronic kidney disease–mineral and bone disorder].”

The study was supported by Lund University; the Swedish Research Council; Forte, Greta and Johan Kock Foundation; A. Påhlsson Foundation; A. Osterlund Foundation; H Järnhardt Foundation; King Gustav V 80-year Fund; Thelma Zoegas Foundation; Swedish Rheumatism Foundation; Skåne University Hospital Research Fund; and the Research and Development Council of Region Skåne, Sweden. No conflicts of interest were declared.

SOURCE: Malmgren L et al. Osteoporos Int. 2019 Nov 21. doi: 10.1007/s00198-019-05152-x.

Moderate reductions in kidney function in older women are associated with an increased short-term risk of fractures, according to a study published in Osteoporosis International.

However, the longitudinal, population-based cohort study did not find an association with fracture risk either in women older than 80 years or in those with worse kidney function.

“Since the kidneys regulate homeostasis of PTH [parathyroid hormone], phosphate, calcium, and vitamin D, any disruption in function can be expected to disturb bone remodeling and have implications for skeletal health,” wrote Linnea Malmgren, MD, and colleagues from Skåne University Hospital in Malmö, Sweden.

Previous studies have found that a large proportion of older women have reduced kidney function equivalent to a diagnosis of chronic kidney disease and that it is associated with bone loss. However, there have been few studies exploring that association in a population without a diagnosis of chronic kidney disease.

In their study, Dr. Malmgren and colleagues followed 981 women aged 75 years and 685 women aged 80 years, who underwent assessment of kidney function and bone mineral density and were followed up for fracture.

They found that women who experienced an osteoporotic fracture between the ages of 75 and 80 years had significantly lower baseline kidney function, compared with those who did not experience a fracture.

Compared with women with normal kidney function at age 75, women with intermediate kidney function (estimated glomerular filtration rate 45-59 mL/min per 1.73m²⁾ had a significant 2.21-fold higher risk of osteoporotic fracture within 2 years, a 1.51-fold higher risk up to 5 years, and an elevated risk of hip fracture.

A similar trend was seen in women with poor kidney function (eGFR less than 45 mL/min per 1.73m²), but it was not statistically significant.

The analysis also found that kidney function at age 80 years was not significantly associated with long-term fracture risk, nor was there a significant association for 10-year fracture risk in those aged 75 years.

Reduced kidney function was also associated with a higher fracture risk even in women without osteoporosis.

“As expected, fracture risk was high among those with osteoporosis, but risk seemed to further increase in women with both osteoporosis and reduced kidney function, compared with those with osteoporosis and normal function,” the authors reported.

“These findings indicate that implications for bone health and fracture risk might occur in the very common modest reduction of kidney function in the elderly, and also possibly before a diagnosis of CKD-MBD [chronic kidney disease–mineral and bone disorder].”

The study was supported by Lund University; the Swedish Research Council; Forte, Greta and Johan Kock Foundation; A. Påhlsson Foundation; A. Osterlund Foundation; H Järnhardt Foundation; King Gustav V 80-year Fund; Thelma Zoegas Foundation; Swedish Rheumatism Foundation; Skåne University Hospital Research Fund; and the Research and Development Council of Region Skåne, Sweden. No conflicts of interest were declared.

SOURCE: Malmgren L et al. Osteoporos Int. 2019 Nov 21. doi: 10.1007/s00198-019-05152-x.

This year in the United States, there were an estimated 22,530 new cases of ovarian cancer and an estimated 13,980 ovarian cancer deaths.¹ Ovarian cancer accounts for more deaths than any other female reproductive system cancer.² The high mortality rate is attributed to the advanced stage of cancer at initial presentation: Women diagnosed with localized disease have an estimated 5-year survival rate of 92%, while those diagnosed with advanced disease have a 5-year survival rate of 29%.³ For this reason, early detection of ovarian cancer is paramount.

A Personal Story

I think about ovarian cancer every day, because I am a survivor of this deadly disease. In 2018, at age 53, I received the diagnosis of stage 1A high-grade serous carcinoma of the left ovary. My cancer was discovered incidentally: I presented to my health care provider with a 6-month history of metrorrhagia and a prior history of regular menstruation with dysmenorrhea controlled with ibuprofen. My family and personal history of cancer was negative, I had a normal BMI, I didn’t smoke and consumed alcohol only moderately, my lifestyle was active, and I had no chronic diseases and used no medications regularly. My clinician performed a pelvic exam and ordered sexually transmitted infection testing and blood work (complete blood count, metabolic panel, and TSH). The differential diagnosis at this point included

• Thyroid dysfunction
• Perimenopause
• Sexually transmitted infection
• Coagulation defect
• Foreign body
• Infection.

All testing yielded normal findings. At my follow-up appointment, we discussed perimenopause symptoms and agreed that I would continue monitoring the bleeding. If at a later date I wanted to pursue an ultrasound, I was instructed to call the office. It was not suggested that I schedule a follow-up office visit.

Several months later, persistent metrorrhagia prompted me to request a transvaginal ultrasound (TVU)—resulting in the discovery of a left adnexal solid mass and probable endometrial polyp. A referral to a gynecologic oncologist resulted in further imaging, which confirmed the TVU results. Surgical intervention was recommended.

One week later, I underwent robotic-assisted total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, left pelvic and periaortic lymph node dissection, and omentectomy. The pathology report confirmed stage 1A high-grade serous carcinoma of the left ovary, as well as stage 1A grade 1 endometrioid adenocarcinoma of the uterus. I required 6 cycles of chemotherapy before follow-up imaging yielded negative results, with no evidence of metastatic disease.

A Call to Action

The recently updated US Preventive Services Task Force guidelines continue not to recommend annual screening with TVU and/or cancer antigen 125 (CA-125) blood testing for ovarian cancer in asymptomatic, average-risk women. A review of the evidence found no mortality benefit and high false-positive rates, which led to unnecessary surgeries and physiologic stress due to excess cancer worry.⁴ This (lack of) recommendation leaves the clinician in the position of not performing or ordering screening tests, except in cases in which the patient presents with symptoms or requests screening for ovarian cancer.

Yet it cannot be overstated: The clinician’s role in identifying risk factors for and recognizing symptoms of ovarian cancer is extremely important in the absence of routine screening recommendations. Risk factors include a positive family history of gynecologic, breast, or colon cancers; genetic predisposition; personal history of breast cancer; use of menopausal hormone therapy; excess body weight; smoking; and sedentary lifestyle.³ In my case, my risk for ovarian cancer was average.

Continue to: With regard to symptoms...

With regard to symptoms, most women do not report any until ovarian cancer has reached advanced stages—and even then, the symptoms are vague and nonspecific.⁵ They may include urinary urgency or frequency; change in bowel habit; difficulty eating or feeling full quickly; persistent back, pelvic, or abdominal pain; extreme tiredness; vaginal bleeding after menopause; increased abdominal size; or bloating on most days.⁵

So what can we as clinicians do? First, if I may offer a word of caution: When confronted with those vague and nonspecific symptoms, be careful not to dismiss them out of hand as a result of aging, stress, or menopause. As my case demonstrates, for example, metrorrhagia is not necessarily a benign condition for the premenopausal woman.

Furthermore, we can empower patients by educating them about ovarian cancer symptoms and risk factors, information that may promote help-seeking behaviors that aid in early detection. In my case, the continued symptom of abnormal uterine bleeding prompted me to seek further assessment, which led to the discovery of ovarian cancer. Had I not been an educated and empowered patient, I would be telling a completely different story today—most likely one that would include advanced staging. Partner with your patient to discuss available diagnostic testing options and schedule follow-up appointments to monitor presenting complaints.

We also need to partner with our oncology colleagues and researchers. A positive diagnostic test result for possible malignancy necessitates referral to a gynecologic oncologist. Treatment by specialists in high-volume hospitals results in improved ovarian cancer outcomes.⁶ And we should advocate for continued research to support the discovery of an efficient population screening protocol for this deadly disease.

Finally, and perhaps most radically, I encourage you not to take a watch-and-wait approach in these situations. Ultrasounds are inexpensive, have low mortality risk, and achieve high sensitivity and specificity in detecting and managing adnexal abnormalities.⁷ In my opinion, the endorsement of TVU testing in this clinical situation is a proactive, prudent, and reasonable action compared with watching and waiting, and it may result in early detection as opposed to advanced disease.

Continue to: I hope that...

I hope that sharing my personal experience with ovarian cancer will compel health care providers to consider this disease as a differential diagnosis and perform appropriate testing when average-risk patients present with nonspecific symptoms. Ultimately, our collective goal should be to increase the survival rate and reduce the suffering associated with ovarian cancer.

This year in the United States, there were an estimated 22,530 new cases of ovarian cancer and an estimated 13,980 ovarian cancer deaths.¹ Ovarian cancer accounts for more deaths than any other female reproductive system cancer.² The high mortality rate is attributed to the advanced stage of cancer at initial presentation: Women diagnosed with localized disease have an estimated 5-year survival rate of 92%, while those diagnosed with advanced disease have a 5-year survival rate of 29%.³ For this reason, early detection of ovarian cancer is paramount.

A Personal Story

I think about ovarian cancer every day, because I am a survivor of this deadly disease. In 2018, at age 53, I received the diagnosis of stage 1A high-grade serous carcinoma of the left ovary. My cancer was discovered incidentally: I presented to my health care provider with a 6-month history of metrorrhagia and a prior history of regular menstruation with dysmenorrhea controlled with ibuprofen. My family and personal history of cancer was negative, I had a normal BMI, I didn’t smoke and consumed alcohol only moderately, my lifestyle was active, and I had no chronic diseases and used no medications regularly. My clinician performed a pelvic exam and ordered sexually transmitted infection testing and blood work (complete blood count, metabolic panel, and TSH). The differential diagnosis at this point included

• Thyroid dysfunction
• Perimenopause
• Sexually transmitted infection
• Coagulation defect
• Foreign body
• Infection.

All testing yielded normal findings. At my follow-up appointment, we discussed perimenopause symptoms and agreed that I would continue monitoring the bleeding. If at a later date I wanted to pursue an ultrasound, I was instructed to call the office. It was not suggested that I schedule a follow-up office visit.

Several months later, persistent metrorrhagia prompted me to request a transvaginal ultrasound (TVU)—resulting in the discovery of a left adnexal solid mass and probable endometrial polyp. A referral to a gynecologic oncologist resulted in further imaging, which confirmed the TVU results. Surgical intervention was recommended.

One week later, I underwent robotic-assisted total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, left pelvic and periaortic lymph node dissection, and omentectomy. The pathology report confirmed stage 1A high-grade serous carcinoma of the left ovary, as well as stage 1A grade 1 endometrioid adenocarcinoma of the uterus. I required 6 cycles of chemotherapy before follow-up imaging yielded negative results, with no evidence of metastatic disease.

A Call to Action

The recently updated US Preventive Services Task Force guidelines continue not to recommend annual screening with TVU and/or cancer antigen 125 (CA-125) blood testing for ovarian cancer in asymptomatic, average-risk women. A review of the evidence found no mortality benefit and high false-positive rates, which led to unnecessary surgeries and physiologic stress due to excess cancer worry.⁴ This (lack of) recommendation leaves the clinician in the position of not performing or ordering screening tests, except in cases in which the patient presents with symptoms or requests screening for ovarian cancer.

Yet it cannot be overstated: The clinician’s role in identifying risk factors for and recognizing symptoms of ovarian cancer is extremely important in the absence of routine screening recommendations. Risk factors include a positive family history of gynecologic, breast, or colon cancers; genetic predisposition; personal history of breast cancer; use of menopausal hormone therapy; excess body weight; smoking; and sedentary lifestyle.³ In my case, my risk for ovarian cancer was average.

Continue to: With regard to symptoms...

With regard to symptoms, most women do not report any until ovarian cancer has reached advanced stages—and even then, the symptoms are vague and nonspecific.⁵ They may include urinary urgency or frequency; change in bowel habit; difficulty eating or feeling full quickly; persistent back, pelvic, or abdominal pain; extreme tiredness; vaginal bleeding after menopause; increased abdominal size; or bloating on most days.⁵

So what can we as clinicians do? First, if I may offer a word of caution: When confronted with those vague and nonspecific symptoms, be careful not to dismiss them out of hand as a result of aging, stress, or menopause. As my case demonstrates, for example, metrorrhagia is not necessarily a benign condition for the premenopausal woman.

Furthermore, we can empower patients by educating them about ovarian cancer symptoms and risk factors, information that may promote help-seeking behaviors that aid in early detection. In my case, the continued symptom of abnormal uterine bleeding prompted me to seek further assessment, which led to the discovery of ovarian cancer. Had I not been an educated and empowered patient, I would be telling a completely different story today—most likely one that would include advanced staging. Partner with your patient to discuss available diagnostic testing options and schedule follow-up appointments to monitor presenting complaints.

We also need to partner with our oncology colleagues and researchers. A positive diagnostic test result for possible malignancy necessitates referral to a gynecologic oncologist. Treatment by specialists in high-volume hospitals results in improved ovarian cancer outcomes.⁶ And we should advocate for continued research to support the discovery of an efficient population screening protocol for this deadly disease.

Finally, and perhaps most radically, I encourage you not to take a watch-and-wait approach in these situations. Ultrasounds are inexpensive, have low mortality risk, and achieve high sensitivity and specificity in detecting and managing adnexal abnormalities.⁷ In my opinion, the endorsement of TVU testing in this clinical situation is a proactive, prudent, and reasonable action compared with watching and waiting, and it may result in early detection as opposed to advanced disease.

Continue to: I hope that...

I hope that sharing my personal experience with ovarian cancer will compel health care providers to consider this disease as a differential diagnosis and perform appropriate testing when average-risk patients present with nonspecific symptoms. Ultimately, our collective goal should be to increase the survival rate and reduce the suffering associated with ovarian cancer.

This year in the United States, there were an estimated 22,530 new cases of ovarian cancer and an estimated 13,980 ovarian cancer deaths.¹ Ovarian cancer accounts for more deaths than any other female reproductive system cancer.² The high mortality rate is attributed to the advanced stage of cancer at initial presentation: Women diagnosed with localized disease have an estimated 5-year survival rate of 92%, while those diagnosed with advanced disease have a 5-year survival rate of 29%.³ For this reason, early detection of ovarian cancer is paramount.

A Personal Story

I think about ovarian cancer every day, because I am a survivor of this deadly disease. In 2018, at age 53, I received the diagnosis of stage 1A high-grade serous carcinoma of the left ovary. My cancer was discovered incidentally: I presented to my health care provider with a 6-month history of metrorrhagia and a prior history of regular menstruation with dysmenorrhea controlled with ibuprofen. My family and personal history of cancer was negative, I had a normal BMI, I didn’t smoke and consumed alcohol only moderately, my lifestyle was active, and I had no chronic diseases and used no medications regularly. My clinician performed a pelvic exam and ordered sexually transmitted infection testing and blood work (complete blood count, metabolic panel, and TSH). The differential diagnosis at this point included

• Thyroid dysfunction
• Perimenopause
• Sexually transmitted infection
• Coagulation defect
• Foreign body
• Infection.

All testing yielded normal findings. At my follow-up appointment, we discussed perimenopause symptoms and agreed that I would continue monitoring the bleeding. If at a later date I wanted to pursue an ultrasound, I was instructed to call the office. It was not suggested that I schedule a follow-up office visit.

Several months later, persistent metrorrhagia prompted me to request a transvaginal ultrasound (TVU)—resulting in the discovery of a left adnexal solid mass and probable endometrial polyp. A referral to a gynecologic oncologist resulted in further imaging, which confirmed the TVU results. Surgical intervention was recommended.

One week later, I underwent robotic-assisted total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, left pelvic and periaortic lymph node dissection, and omentectomy. The pathology report confirmed stage 1A high-grade serous carcinoma of the left ovary, as well as stage 1A grade 1 endometrioid adenocarcinoma of the uterus. I required 6 cycles of chemotherapy before follow-up imaging yielded negative results, with no evidence of metastatic disease.

A Call to Action

The recently updated US Preventive Services Task Force guidelines continue not to recommend annual screening with TVU and/or cancer antigen 125 (CA-125) blood testing for ovarian cancer in asymptomatic, average-risk women. A review of the evidence found no mortality benefit and high false-positive rates, which led to unnecessary surgeries and physiologic stress due to excess cancer worry.⁴ This (lack of) recommendation leaves the clinician in the position of not performing or ordering screening tests, except in cases in which the patient presents with symptoms or requests screening for ovarian cancer.

Yet it cannot be overstated: The clinician’s role in identifying risk factors for and recognizing symptoms of ovarian cancer is extremely important in the absence of routine screening recommendations. Risk factors include a positive family history of gynecologic, breast, or colon cancers; genetic predisposition; personal history of breast cancer; use of menopausal hormone therapy; excess body weight; smoking; and sedentary lifestyle.³ In my case, my risk for ovarian cancer was average.

Continue to: With regard to symptoms...

With regard to symptoms, most women do not report any until ovarian cancer has reached advanced stages—and even then, the symptoms are vague and nonspecific.⁵ They may include urinary urgency or frequency; change in bowel habit; difficulty eating or feeling full quickly; persistent back, pelvic, or abdominal pain; extreme tiredness; vaginal bleeding after menopause; increased abdominal size; or bloating on most days.⁵

So what can we as clinicians do? First, if I may offer a word of caution: When confronted with those vague and nonspecific symptoms, be careful not to dismiss them out of hand as a result of aging, stress, or menopause. As my case demonstrates, for example, metrorrhagia is not necessarily a benign condition for the premenopausal woman.

Furthermore, we can empower patients by educating them about ovarian cancer symptoms and risk factors, information that may promote help-seeking behaviors that aid in early detection. In my case, the continued symptom of abnormal uterine bleeding prompted me to seek further assessment, which led to the discovery of ovarian cancer. Had I not been an educated and empowered patient, I would be telling a completely different story today—most likely one that would include advanced staging. Partner with your patient to discuss available diagnostic testing options and schedule follow-up appointments to monitor presenting complaints.

We also need to partner with our oncology colleagues and researchers. A positive diagnostic test result for possible malignancy necessitates referral to a gynecologic oncologist. Treatment by specialists in high-volume hospitals results in improved ovarian cancer outcomes.⁶ And we should advocate for continued research to support the discovery of an efficient population screening protocol for this deadly disease.

Finally, and perhaps most radically, I encourage you not to take a watch-and-wait approach in these situations. Ultrasounds are inexpensive, have low mortality risk, and achieve high sensitivity and specificity in detecting and managing adnexal abnormalities.⁷ In my opinion, the endorsement of TVU testing in this clinical situation is a proactive, prudent, and reasonable action compared with watching and waiting, and it may result in early detection as opposed to advanced disease.

Continue to: I hope that...

I hope that sharing my personal experience with ovarian cancer will compel health care providers to consider this disease as a differential diagnosis and perform appropriate testing when average-risk patients present with nonspecific symptoms. Ultimately, our collective goal should be to increase the survival rate and reduce the suffering associated with ovarian cancer.

THE CASE

A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.

The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.

The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.

The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.

THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx

The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.

The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.

DISCUSSION

Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.¹ Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.

Continue to: Safety of nonroal estrogen therapy

Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.¹ Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.²

Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.^3-6

Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.⁶ In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.⁷

THE TAKEAWAY

All members of a patient’s household— including pets— may be subject to unintentional secondary exposure to topical estrogen formulations and thus, experience adverse effects.

Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.

CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; [email protected].

THE CASE

A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.

The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.

The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.

The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.

THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx

The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.

The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.

DISCUSSION

Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.¹ Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.

Continue to: Safety of nonroal estrogen therapy

Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.¹ Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.²

Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.^3-6

Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.⁶ In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.⁷

THE TAKEAWAY

All members of a patient’s household— including pets— may be subject to unintentional secondary exposure to topical estrogen formulations and thus, experience adverse effects.

Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.

CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; [email protected].

THE CASE

A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.

The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.

The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.

The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.

THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx

The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.

The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.

DISCUSSION

Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.¹ Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.

Continue to: Safety of nonroal estrogen therapy

Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.¹ Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.²

Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.^3-6

Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.⁶ In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.⁷

THE TAKEAWAY

All members of a patient’s household— including pets— may be subject to unintentional secondary exposure to topical estrogen formulations and thus, experience adverse effects.

Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.

CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; [email protected].

ILLUSTRATIVE CASE

Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?

Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.^2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.⁴

Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.^5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.⁵ However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.⁶

STUDY SUMMARY

Mifepristone before misoprostol improves efficacy for early pregnancy loss

The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.¹

This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone Tx prior to vaginal misoprostol administration in the medical management of early pregnancy loss.

Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.

Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.

Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.

Continue to: Demographics

Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.

Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.

WHAT’S NEW

A high-quality RCT demonstrates improved efficacy

Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.^1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.

CAVEATS

Would a placebo group—or other forms of misoprostol—change the results?

The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.

Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.⁷ It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

FDA restrictions limit availability of mifepristone

The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) ­restrictions, stipulating that a health provider be specially certified for prescribing; ­dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.⁸

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?

Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.^2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.⁴

Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.^5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.⁵ However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.⁶

STUDY SUMMARY

Mifepristone before misoprostol improves efficacy for early pregnancy loss

The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.¹

This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone Tx prior to vaginal misoprostol administration in the medical management of early pregnancy loss.

Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.

Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.

Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.

Continue to: Demographics

Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.

Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.

WHAT’S NEW

A high-quality RCT demonstrates improved efficacy

Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.^1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.

CAVEATS

Would a placebo group—or other forms of misoprostol—change the results?

The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.

Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.⁷ It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

FDA restrictions limit availability of mifepristone

The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) ­restrictions, stipulating that a health provider be specially certified for prescribing; ­dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.⁸

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?

Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.^2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.⁴

Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.^5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.⁵ However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.⁶

STUDY SUMMARY

Mifepristone before misoprostol improves efficacy for early pregnancy loss

The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.¹

This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone Tx prior to vaginal misoprostol administration in the medical management of early pregnancy loss.

Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.

Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.

Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.

Continue to: Demographics

Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.

Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.

WHAT’S NEW

A high-quality RCT demonstrates improved efficacy

Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.^1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.

CAVEATS

Would a placebo group—or other forms of misoprostol—change the results?

The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.

Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.⁷ It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

FDA restrictions limit availability of mifepristone

The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) ­restrictions, stipulating that a health provider be specially certified for prescribing; ­dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.⁸

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Bilateral mastectomy significantly decreases the risk for a second contralateral breast cancer, but does not decrease the risk of death, compared with breast-conserving therapy, results of a large retrospective study indicate.

Among 245,418 patients followed for a median of 6.7 years, the risk of death from breast cancer was similar for those who had undergone either breast-conserving therapy or bilateral mastectomy (BLM) but was 20% higher among women who had undergone unilateral mastectomy (ULM) when compared with breast-conserving therapy, reported Allison W. Kurian, MD, MSc, from Stanford (Calif.) University, and colleagues.

“Second breast cancers are rare, and their reduction should be weighed against the harms associated with BLM,” they wrote in a study published online in Cancer.

The investigators extracted data from the Surveillance, Epidemiology, and End Results program on all women diagnosed with American Joint Committee on Cancer stage 0 to stage III unilateral breast cancer in California from 1998 to 2015 who were treated with either BLM versus breast-conserving therapy, including surgery and radiation or unilateral mastectomy.­­

They calculated the absolute excess risk of contralateral breast cancer as the observed minus expected number of breast cancers in the general population divided by 10,000 person-years at risk.

­Of 421,643 women with a first diagnosis of primary breast cancer during the study period, 245,418 met the study criteria. Of this cohort, 7,784 (3.2%) developed a contralateral second breast cancer more than 6 months after diagnosis of the first, after a median 6.7 years of follow-up.

Slightly more than half of the cohort (52.1%) had undergone breast-conserving therapy, 37.5% underwent unilateral mastectomy, and 7.6% had bilateral mastectomy. An additional 2.9% of patients were women aged 70 years and older with stage I hormone receptor–positive, HER2-negative disease who underwent breast-conserving surgery without radiation (percentages exceed 100% because of rounding).

A multivariate-adjusted model showed that, as might be expected, patients who underwent bilateral mastectomy had a 90% reduction in risk of contralateral cancer (hazard ratio, 0.10; P less than .001), compared with breast-conserving therapy. In contrast, patients who underwent unilateral mastectomy had a slight but significant increase in risk for a second contralateral breast cancer (HR, 1.07; P = .008).

The absolute excess risk for second contralateral breast cancer was 5 per 10,000 person-years with breast-conserving therapy, 13.6 per 10,000 person-years with unilateral mastectomy, and –28.6 per 10,000 person-years with bilateral mastectomy.

When they looked at risk for death, however they found that, compared with breast-conserving therapy, breast-conserving surgery alone (HR, 1.36; P = .0001) and unilateral mastectomy (HR, 1.21; P less than .001), but not bilateral mastectomy (HR, 1.03; P = .35) were significantly associated with increased risk for breast cancer death.

The authors noted that their estimates of absolute risk of second contralateral breast cancer jibe with those of earlier studies, and can help clinicians frame the discussion of the benefits versus risks for individual patients.

“What one patient might consider to be a negligible benefit of BLM, weighed against its potential harms of greater pain, recovery time, and impact on body image and employment, might appear worthwhile to another,” they wrote.

The study was funded by the National Cancer Institute, National Institutes of Health, Department of Health & Human Services, Suzanne Pride Bryan Fund for Breast Cancer Research, Jan Weimer Faculty Chair for Breast Oncology, and the BRCA Foundation. Dr. Kurian disclosed institutional research funding from Myriad Genetics.

SOURCE: Kurin AW et al. Cancer. 2019 Nov 21. doi: 10.1002/cncr.32618.

Bilateral mastectomy significantly decreases the risk for a second contralateral breast cancer, but does not decrease the risk of death, compared with breast-conserving therapy, results of a large retrospective study indicate.

Among 245,418 patients followed for a median of 6.7 years, the risk of death from breast cancer was similar for those who had undergone either breast-conserving therapy or bilateral mastectomy (BLM) but was 20% higher among women who had undergone unilateral mastectomy (ULM) when compared with breast-conserving therapy, reported Allison W. Kurian, MD, MSc, from Stanford (Calif.) University, and colleagues.

“Second breast cancers are rare, and their reduction should be weighed against the harms associated with BLM,” they wrote in a study published online in Cancer.

The investigators extracted data from the Surveillance, Epidemiology, and End Results program on all women diagnosed with American Joint Committee on Cancer stage 0 to stage III unilateral breast cancer in California from 1998 to 2015 who were treated with either BLM versus breast-conserving therapy, including surgery and radiation or unilateral mastectomy.­­

They calculated the absolute excess risk of contralateral breast cancer as the observed minus expected number of breast cancers in the general population divided by 10,000 person-years at risk.

­Of 421,643 women with a first diagnosis of primary breast cancer during the study period, 245,418 met the study criteria. Of this cohort, 7,784 (3.2%) developed a contralateral second breast cancer more than 6 months after diagnosis of the first, after a median 6.7 years of follow-up.

Slightly more than half of the cohort (52.1%) had undergone breast-conserving therapy, 37.5% underwent unilateral mastectomy, and 7.6% had bilateral mastectomy. An additional 2.9% of patients were women aged 70 years and older with stage I hormone receptor–positive, HER2-negative disease who underwent breast-conserving surgery without radiation (percentages exceed 100% because of rounding).

A multivariate-adjusted model showed that, as might be expected, patients who underwent bilateral mastectomy had a 90% reduction in risk of contralateral cancer (hazard ratio, 0.10; P less than .001), compared with breast-conserving therapy. In contrast, patients who underwent unilateral mastectomy had a slight but significant increase in risk for a second contralateral breast cancer (HR, 1.07; P = .008).

The absolute excess risk for second contralateral breast cancer was 5 per 10,000 person-years with breast-conserving therapy, 13.6 per 10,000 person-years with unilateral mastectomy, and –28.6 per 10,000 person-years with bilateral mastectomy.

When they looked at risk for death, however they found that, compared with breast-conserving therapy, breast-conserving surgery alone (HR, 1.36; P = .0001) and unilateral mastectomy (HR, 1.21; P less than .001), but not bilateral mastectomy (HR, 1.03; P = .35) were significantly associated with increased risk for breast cancer death.

The authors noted that their estimates of absolute risk of second contralateral breast cancer jibe with those of earlier studies, and can help clinicians frame the discussion of the benefits versus risks for individual patients.

“What one patient might consider to be a negligible benefit of BLM, weighed against its potential harms of greater pain, recovery time, and impact on body image and employment, might appear worthwhile to another,” they wrote.

The study was funded by the National Cancer Institute, National Institutes of Health, Department of Health & Human Services, Suzanne Pride Bryan Fund for Breast Cancer Research, Jan Weimer Faculty Chair for Breast Oncology, and the BRCA Foundation. Dr. Kurian disclosed institutional research funding from Myriad Genetics.

SOURCE: Kurin AW et al. Cancer. 2019 Nov 21. doi: 10.1002/cncr.32618.

Bilateral mastectomy significantly decreases the risk for a second contralateral breast cancer, but does not decrease the risk of death, compared with breast-conserving therapy, results of a large retrospective study indicate.

Among 245,418 patients followed for a median of 6.7 years, the risk of death from breast cancer was similar for those who had undergone either breast-conserving therapy or bilateral mastectomy (BLM) but was 20% higher among women who had undergone unilateral mastectomy (ULM) when compared with breast-conserving therapy, reported Allison W. Kurian, MD, MSc, from Stanford (Calif.) University, and colleagues.

“Second breast cancers are rare, and their reduction should be weighed against the harms associated with BLM,” they wrote in a study published online in Cancer.

The investigators extracted data from the Surveillance, Epidemiology, and End Results program on all women diagnosed with American Joint Committee on Cancer stage 0 to stage III unilateral breast cancer in California from 1998 to 2015 who were treated with either BLM versus breast-conserving therapy, including surgery and radiation or unilateral mastectomy.­­

They calculated the absolute excess risk of contralateral breast cancer as the observed minus expected number of breast cancers in the general population divided by 10,000 person-years at risk.

­Of 421,643 women with a first diagnosis of primary breast cancer during the study period, 245,418 met the study criteria. Of this cohort, 7,784 (3.2%) developed a contralateral second breast cancer more than 6 months after diagnosis of the first, after a median 6.7 years of follow-up.

Slightly more than half of the cohort (52.1%) had undergone breast-conserving therapy, 37.5% underwent unilateral mastectomy, and 7.6% had bilateral mastectomy. An additional 2.9% of patients were women aged 70 years and older with stage I hormone receptor–positive, HER2-negative disease who underwent breast-conserving surgery without radiation (percentages exceed 100% because of rounding).

A multivariate-adjusted model showed that, as might be expected, patients who underwent bilateral mastectomy had a 90% reduction in risk of contralateral cancer (hazard ratio, 0.10; P less than .001), compared with breast-conserving therapy. In contrast, patients who underwent unilateral mastectomy had a slight but significant increase in risk for a second contralateral breast cancer (HR, 1.07; P = .008).

The absolute excess risk for second contralateral breast cancer was 5 per 10,000 person-years with breast-conserving therapy, 13.6 per 10,000 person-years with unilateral mastectomy, and –28.6 per 10,000 person-years with bilateral mastectomy.

When they looked at risk for death, however they found that, compared with breast-conserving therapy, breast-conserving surgery alone (HR, 1.36; P = .0001) and unilateral mastectomy (HR, 1.21; P less than .001), but not bilateral mastectomy (HR, 1.03; P = .35) were significantly associated with increased risk for breast cancer death.

The authors noted that their estimates of absolute risk of second contralateral breast cancer jibe with those of earlier studies, and can help clinicians frame the discussion of the benefits versus risks for individual patients.

“What one patient might consider to be a negligible benefit of BLM, weighed against its potential harms of greater pain, recovery time, and impact on body image and employment, might appear worthwhile to another,” they wrote.

The study was funded by the National Cancer Institute, National Institutes of Health, Department of Health & Human Services, Suzanne Pride Bryan Fund for Breast Cancer Research, Jan Weimer Faculty Chair for Breast Oncology, and the BRCA Foundation. Dr. Kurian disclosed institutional research funding from Myriad Genetics.

SOURCE: Kurin AW et al. Cancer. 2019 Nov 21. doi: 10.1002/cncr.32618.

CHICAGO – Women taking oral contraceptives had, on average, a hypothalamus that was 6% smaller than those who didn’t, in a small study that used magnetic resonance imaging. Pituitary volume was also smaller.

Courtesy RSNA

Though the sample size was relatively small, 50 women in total, it’s the only study to date that looks at the relationship between hypothalamic volume and oral contraceptive (OC) use, and the largest examining pituitary volume, according to Ke Xun (Kevin) Chen, MD, who presented the findings at the annual meeting of the Radiological Society of North America.

Using MRI, Dr. Chen and his colleagues found that hypothalamic volume was significantly smaller in women taking oral contraceptives than those who were naturally cycling (b value = –64.1; P = .006). The pituitary gland also was significantly smaller in those taking OCs (b = –92.8; P = .007).

“I was quite surprised [at the finding], because the magnitude of the effect is not small,” especially in the context of changes in volume of other brain structures, senior author Michael L. Lipton, MD, PhD, said in an interview. In Alzheimer’s disease, for example, a volume loss of 4% annually can be expected.

However, “it’s not shocking to me in a negative way at all. I can’t tell you what it means in terms of how it’s going to affect people,” since this is a cross-sectional study that only detected a correlation and can’t say anything about a causative relationship, he added. “We don’t even know that [OCs] cause this effect. ... It’s plausible that this is just a plasticity-related change that’s simply showing us the effect of the drug.

“We’re going to be much more careful to consider oral contraceptive use as a covariate in future research studies; that’s for sure,” he said.

Although OCs have been available since their 1960 Food and Drug Administration approval, and their effects in some areas of physiology and health have been well studied, there’s still not much known about how oral contraceptives affect brain function, said Dr. Lipton, professor of neuroradiology and psychiatry and behavioral sciences at Albert Einstein College of Medicine, in the Montefiore medical system, New York.

The spark for this study came from one of Dr. Lipton’s main areas of research – sex differences in susceptibility to and recovery from traumatic brain injury. “Women are more likely to exhibit changes in their brain [after injury] – and changes in their brain function – than men,” he said.

In the present study, “we went at this trying to understand the effect to which the hormone effect might be doing something in regular, healthy people that we need to consider as part of the bigger picture,” he said.

Dr. Lipton, Dr. Chen (then a radiology resident at Albert Einstein College of Medicine), and their coauthors constructed the study to look for differences in brain structure between women who were experiencing natural menstrual cycles and those who were taking exogenous hormones, to begin to learn how oral contraceptive use might modify risk and susceptibility for neurologic disease and injury.

It had already been established that global brain volume didn’t differ between naturally cycling women and those using OCs. However, some studies had shown differences in volume of some specific brain regions, and one study had shown smaller pituitary volume in OC users, according to the presentation by Dr. Chen, who is now a radiology fellow at Brigham and Women’s Hospital, Boston. Accurately measuring hypothalamic volume represents a technical challenge, and the effect of OCs on the structure’s volume hadn’t previously been studied.

Sex hormones, said Dr. Lipton, have known trophic effects on brain tissue and ovarian sex hormones cross the blood brain barrier, so the idea that there would be some plasticity in the brains of those taking OCs wasn’t completely surprising, especially since there are hormone receptors that lie within the central nervous system. However, he said he was “very surprised” by the effect size seen in the study.

The study included 21 healthy women taking combined oral contraceptives, and 29 naturally cycling women. Participants’ mean age was 23 years for the OC users, and 21 for the naturally cycling women. Body mass index and smoking history didn’t differ between groups. Women on OCs were significantly more likely to use alcohol and to drink more frequently than those not taking OCs (P = .001). Participants were included only if they were taking a combined estrogen-progestin pill; those on noncyclical contraceptives such as implants and hormone-emitting intrauterine devices were excluded, as were naturally cycling women with very long or irregular menstrual cycles.

After multivariable statistical analysis, the only two significant predictors of hypothalamic volume were total intracranial volume and OC use. For pituitary volume, body mass index and OC use remained significant.

Courtesy RSNA

In addition to the MRI scans, participants also completed neurobehavioral testing to assess mood and cognition. An exploratory analysis showed no correlation between hypothalamic volume and the cognitive testing battery results, which included assessments for verbal learning and memory, executive function, and working memory.

However, a moderate positive association was seen between hypothalamic volume and anger scores (r = 0.34; P = .02). The investigators found a “strong positive correlation of hypothalamic volume with depression,” said Dr. Chen (r = 0.25; P = .09).

The investigators found no menstrual cycle-related changes in hypothalamic and pituitary volume among naturally cycling women.

Hypothalamic volume was obtained using manual segmentation of the MRIs; a combined automated-manual approach was used to obtain pituitary volume. Reliability was tested by having 5 raters each assess volumes for a randomly selected subset of the scans; inter-rater reliability fell between 0.78 and 0.86, values considered to indicate “good” reliability.

Courtesy RSNA

In addition to the small sample size, Dr. Chen acknowledged several limitations to the study. These included the lack of accounting for details of OC use including duration, exact type of OC, and whether women were taking the placebo phase of their pill packs at the time of scanning. Additionally, women who were naturally cycling were not asked about prior history of OC use.

Also, women’s menstrual phase was estimated from the self-reported date of the last menstrual period, rather than obtained by direct measurement via serum hormone levels.

Dr. Lipton’s perspective adds a strong note of caution to avoid overinterpretation from the study. Dr. Chen and Dr. Lipton agreed, however, that OC use should be accounted for when brain structure and function are studied in female participants.

Dr. Chen, Dr. Lipton, and their coauthors reported that they had no conflicts of interest. The authors reported no outside sources of funding.
 

[email protected]

SOURCE: Chen K et al. RSNA 2019. Presentation SSM-1904.

CHICAGO – Women taking oral contraceptives had, on average, a hypothalamus that was 6% smaller than those who didn’t, in a small study that used magnetic resonance imaging. Pituitary volume was also smaller.

Courtesy RSNA

Though the sample size was relatively small, 50 women in total, it’s the only study to date that looks at the relationship between hypothalamic volume and oral contraceptive (OC) use, and the largest examining pituitary volume, according to Ke Xun (Kevin) Chen, MD, who presented the findings at the annual meeting of the Radiological Society of North America.

Using MRI, Dr. Chen and his colleagues found that hypothalamic volume was significantly smaller in women taking oral contraceptives than those who were naturally cycling (b value = –64.1; P = .006). The pituitary gland also was significantly smaller in those taking OCs (b = –92.8; P = .007).

“I was quite surprised [at the finding], because the magnitude of the effect is not small,” especially in the context of changes in volume of other brain structures, senior author Michael L. Lipton, MD, PhD, said in an interview. In Alzheimer’s disease, for example, a volume loss of 4% annually can be expected.

However, “it’s not shocking to me in a negative way at all. I can’t tell you what it means in terms of how it’s going to affect people,” since this is a cross-sectional study that only detected a correlation and can’t say anything about a causative relationship, he added. “We don’t even know that [OCs] cause this effect. ... It’s plausible that this is just a plasticity-related change that’s simply showing us the effect of the drug.

“We’re going to be much more careful to consider oral contraceptive use as a covariate in future research studies; that’s for sure,” he said.

Although OCs have been available since their 1960 Food and Drug Administration approval, and their effects in some areas of physiology and health have been well studied, there’s still not much known about how oral contraceptives affect brain function, said Dr. Lipton, professor of neuroradiology and psychiatry and behavioral sciences at Albert Einstein College of Medicine, in the Montefiore medical system, New York.

The spark for this study came from one of Dr. Lipton’s main areas of research – sex differences in susceptibility to and recovery from traumatic brain injury. “Women are more likely to exhibit changes in their brain [after injury] – and changes in their brain function – than men,” he said.

In the present study, “we went at this trying to understand the effect to which the hormone effect might be doing something in regular, healthy people that we need to consider as part of the bigger picture,” he said.

Dr. Lipton, Dr. Chen (then a radiology resident at Albert Einstein College of Medicine), and their coauthors constructed the study to look for differences in brain structure between women who were experiencing natural menstrual cycles and those who were taking exogenous hormones, to begin to learn how oral contraceptive use might modify risk and susceptibility for neurologic disease and injury.

It had already been established that global brain volume didn’t differ between naturally cycling women and those using OCs. However, some studies had shown differences in volume of some specific brain regions, and one study had shown smaller pituitary volume in OC users, according to the presentation by Dr. Chen, who is now a radiology fellow at Brigham and Women’s Hospital, Boston. Accurately measuring hypothalamic volume represents a technical challenge, and the effect of OCs on the structure’s volume hadn’t previously been studied.

Sex hormones, said Dr. Lipton, have known trophic effects on brain tissue and ovarian sex hormones cross the blood brain barrier, so the idea that there would be some plasticity in the brains of those taking OCs wasn’t completely surprising, especially since there are hormone receptors that lie within the central nervous system. However, he said he was “very surprised” by the effect size seen in the study.

The study included 21 healthy women taking combined oral contraceptives, and 29 naturally cycling women. Participants’ mean age was 23 years for the OC users, and 21 for the naturally cycling women. Body mass index and smoking history didn’t differ between groups. Women on OCs were significantly more likely to use alcohol and to drink more frequently than those not taking OCs (P = .001). Participants were included only if they were taking a combined estrogen-progestin pill; those on noncyclical contraceptives such as implants and hormone-emitting intrauterine devices were excluded, as were naturally cycling women with very long or irregular menstrual cycles.

After multivariable statistical analysis, the only two significant predictors of hypothalamic volume were total intracranial volume and OC use. For pituitary volume, body mass index and OC use remained significant.

Courtesy RSNA

In addition to the MRI scans, participants also completed neurobehavioral testing to assess mood and cognition. An exploratory analysis showed no correlation between hypothalamic volume and the cognitive testing battery results, which included assessments for verbal learning and memory, executive function, and working memory.

However, a moderate positive association was seen between hypothalamic volume and anger scores (r = 0.34; P = .02). The investigators found a “strong positive correlation of hypothalamic volume with depression,” said Dr. Chen (r = 0.25; P = .09).

The investigators found no menstrual cycle-related changes in hypothalamic and pituitary volume among naturally cycling women.

Hypothalamic volume was obtained using manual segmentation of the MRIs; a combined automated-manual approach was used to obtain pituitary volume. Reliability was tested by having 5 raters each assess volumes for a randomly selected subset of the scans; inter-rater reliability fell between 0.78 and 0.86, values considered to indicate “good” reliability.

Courtesy RSNA

In addition to the small sample size, Dr. Chen acknowledged several limitations to the study. These included the lack of accounting for details of OC use including duration, exact type of OC, and whether women were taking the placebo phase of their pill packs at the time of scanning. Additionally, women who were naturally cycling were not asked about prior history of OC use.

Also, women’s menstrual phase was estimated from the self-reported date of the last menstrual period, rather than obtained by direct measurement via serum hormone levels.

Dr. Lipton’s perspective adds a strong note of caution to avoid overinterpretation from the study. Dr. Chen and Dr. Lipton agreed, however, that OC use should be accounted for when brain structure and function are studied in female participants.

Dr. Chen, Dr. Lipton, and their coauthors reported that they had no conflicts of interest. The authors reported no outside sources of funding.
 

[email protected]

SOURCE: Chen K et al. RSNA 2019. Presentation SSM-1904.

CHICAGO – Women taking oral contraceptives had, on average, a hypothalamus that was 6% smaller than those who didn’t, in a small study that used magnetic resonance imaging. Pituitary volume was also smaller.

Courtesy RSNA

Though the sample size was relatively small, 50 women in total, it’s the only study to date that looks at the relationship between hypothalamic volume and oral contraceptive (OC) use, and the largest examining pituitary volume, according to Ke Xun (Kevin) Chen, MD, who presented the findings at the annual meeting of the Radiological Society of North America.

Using MRI, Dr. Chen and his colleagues found that hypothalamic volume was significantly smaller in women taking oral contraceptives than those who were naturally cycling (b value = –64.1; P = .006). The pituitary gland also was significantly smaller in those taking OCs (b = –92.8; P = .007).

“I was quite surprised [at the finding], because the magnitude of the effect is not small,” especially in the context of changes in volume of other brain structures, senior author Michael L. Lipton, MD, PhD, said in an interview. In Alzheimer’s disease, for example, a volume loss of 4% annually can be expected.

However, “it’s not shocking to me in a negative way at all. I can’t tell you what it means in terms of how it’s going to affect people,” since this is a cross-sectional study that only detected a correlation and can’t say anything about a causative relationship, he added. “We don’t even know that [OCs] cause this effect. ... It’s plausible that this is just a plasticity-related change that’s simply showing us the effect of the drug.

“We’re going to be much more careful to consider oral contraceptive use as a covariate in future research studies; that’s for sure,” he said.

Although OCs have been available since their 1960 Food and Drug Administration approval, and their effects in some areas of physiology and health have been well studied, there’s still not much known about how oral contraceptives affect brain function, said Dr. Lipton, professor of neuroradiology and psychiatry and behavioral sciences at Albert Einstein College of Medicine, in the Montefiore medical system, New York.

The spark for this study came from one of Dr. Lipton’s main areas of research – sex differences in susceptibility to and recovery from traumatic brain injury. “Women are more likely to exhibit changes in their brain [after injury] – and changes in their brain function – than men,” he said.

In the present study, “we went at this trying to understand the effect to which the hormone effect might be doing something in regular, healthy people that we need to consider as part of the bigger picture,” he said.

Dr. Lipton, Dr. Chen (then a radiology resident at Albert Einstein College of Medicine), and their coauthors constructed the study to look for differences in brain structure between women who were experiencing natural menstrual cycles and those who were taking exogenous hormones, to begin to learn how oral contraceptive use might modify risk and susceptibility for neurologic disease and injury.

It had already been established that global brain volume didn’t differ between naturally cycling women and those using OCs. However, some studies had shown differences in volume of some specific brain regions, and one study had shown smaller pituitary volume in OC users, according to the presentation by Dr. Chen, who is now a radiology fellow at Brigham and Women’s Hospital, Boston. Accurately measuring hypothalamic volume represents a technical challenge, and the effect of OCs on the structure’s volume hadn’t previously been studied.

Sex hormones, said Dr. Lipton, have known trophic effects on brain tissue and ovarian sex hormones cross the blood brain barrier, so the idea that there would be some plasticity in the brains of those taking OCs wasn’t completely surprising, especially since there are hormone receptors that lie within the central nervous system. However, he said he was “very surprised” by the effect size seen in the study.

The study included 21 healthy women taking combined oral contraceptives, and 29 naturally cycling women. Participants’ mean age was 23 years for the OC users, and 21 for the naturally cycling women. Body mass index and smoking history didn’t differ between groups. Women on OCs were significantly more likely to use alcohol and to drink more frequently than those not taking OCs (P = .001). Participants were included only if they were taking a combined estrogen-progestin pill; those on noncyclical contraceptives such as implants and hormone-emitting intrauterine devices were excluded, as were naturally cycling women with very long or irregular menstrual cycles.

After multivariable statistical analysis, the only two significant predictors of hypothalamic volume were total intracranial volume and OC use. For pituitary volume, body mass index and OC use remained significant.

Courtesy RSNA

In addition to the MRI scans, participants also completed neurobehavioral testing to assess mood and cognition. An exploratory analysis showed no correlation between hypothalamic volume and the cognitive testing battery results, which included assessments for verbal learning and memory, executive function, and working memory.

However, a moderate positive association was seen between hypothalamic volume and anger scores (r = 0.34; P = .02). The investigators found a “strong positive correlation of hypothalamic volume with depression,” said Dr. Chen (r = 0.25; P = .09).

The investigators found no menstrual cycle-related changes in hypothalamic and pituitary volume among naturally cycling women.

Hypothalamic volume was obtained using manual segmentation of the MRIs; a combined automated-manual approach was used to obtain pituitary volume. Reliability was tested by having 5 raters each assess volumes for a randomly selected subset of the scans; inter-rater reliability fell between 0.78 and 0.86, values considered to indicate “good” reliability.

Courtesy RSNA

In addition to the small sample size, Dr. Chen acknowledged several limitations to the study. These included the lack of accounting for details of OC use including duration, exact type of OC, and whether women were taking the placebo phase of their pill packs at the time of scanning. Additionally, women who were naturally cycling were not asked about prior history of OC use.

Also, women’s menstrual phase was estimated from the self-reported date of the last menstrual period, rather than obtained by direct measurement via serum hormone levels.

Dr. Lipton’s perspective adds a strong note of caution to avoid overinterpretation from the study. Dr. Chen and Dr. Lipton agreed, however, that OC use should be accounted for when brain structure and function are studied in female participants.

Dr. Chen, Dr. Lipton, and their coauthors reported that they had no conflicts of interest. The authors reported no outside sources of funding.
 

[email protected]

SOURCE: Chen K et al. RSNA 2019. Presentation SSM-1904.

Electronic cigarettes and other “vaping” devices have been increasing in popularity among youth and adults since their introduction in the US market in 2007.¹ This increase is partially driven by a public perception that vaping is harmless, or at least less harmful than cigarette smoking.² Vaping fans also argue that current smokers can use vaping as nicotine replacement therapy to help them quit smoking.³

We disagree. Research on the health effects of vaping, though still limited, is accumulating rapidly and making it increasingly clear that this habit is far from harmless. For youth, it is a gateway to addiction to nicotine and other substances. Whether it can help people quit smoking remains to be seen. And recent months have seen reports of serious respiratory illnesses and even deaths linked to vaping.⁴

In December 2016, the US Surgeon General warned that e-cigarette use among youth and young adults in the United States represents a “major public health concern,”⁵ and that more adolescents and young adults are now vaping than smoking conventional tobacco products.

This article reviews the issue of vaping in the United States, as well as available evidence regarding its safety.

YOUTH AT RISK

Retail sales of e-cigarettes and vaping devices approach an annual $7 billion.⁶ A 2014–2015 survey found that 2.4% of the general US population were current users of e-cigarettes, and 8.5% had tried them at least once.³

In 2014, for the first time, e-cigarette use became more common among US youth than traditional cigarettes.⁵

The odds of taking up vaping are higher among minority youth in the United States, particularly Hispanics.⁹ This trend is particularly worrisome because several longitudinal studies have shown that adolescents who use e-cigarettes are 3 times as likely to eventually become smokers of traditional cigarettes compared with adolescents who do not use e-cigarettes.^10–12

If US youth continue smoking at the current rate, 5.6 million of the current population under age 18, or 1 of every 13, will die early of a smoking-related illness.¹³ 

RECENT OUTBREAK OF VAPING-ASSOCIATED LUNG INJURY

As of November 5, 2019, there had been 2,051 cases of vaping-associated lung injury in 49 states (all except Alaska), the District of Columbia, and 1 US territory reported to the US Centers for Disease Control and Prevention (CDC), with 39 confirmed deaths.⁴ The reported cases include respiratory injury including acute eosinophilic pneumonia, organizing pneumonia, acute respiratory distress syndrome, and hypersensitivity pneumonitis.¹⁴

Most of these patients had been vaping tetrahydrocannabinol (THC), though many used both nicotine- and THC-containing products, and others used products containing nicotine exclusively.⁴ Thus, it is difficult to identify the exact substance or substances that may be contributing to this sudden outbreak among vape users, and many different product sources are currently under investigation.

One substance that may be linked to the epidemic is vitamin E acetate, which the New York State Department of Health has detected in high levels in cannabis vaping cartridges used by patients who developed lung injury.¹⁵ The US Food and Drug Administration (FDA) is continuing to analyze vape cartridge samples submitted by affected patients to look for other chemicals that can contribute to the development of serious pulmonary illness.

 

 

WHAT IS AN E-CIGARETTE? WHAT IS A VAPE PEN?

Source: The US Food and Drug Administration

Vape pens consist of similar elements but are not necessarily similar in appearance to a conventional cigarette, and may look more like a pen or a USB flash drive. In fact, the Juul device is recharged by plugging it into a USB port.

Vaping devices have many street names, including e-cigs, e-hookahs, vape pens, mods, vapes, and tank systems.

The first US patent application for a device resembling a modern e-cigarette was filed in 1963, but the product never made it to the market.¹⁶ Instead, the first commercially successful e-cigarette was created in Beijing in 2003 and introduced to US markets in 2007.

Newer-generation devices have larger batteries and can heat the liquid to higher temperatures, releasing more nicotine and forming additional toxicants such as formaldehyde. Devices lack standardization in terms of design, capacity for safely holding e-liquid, packaging of the e-liquid, and features designed to minimize hazards of use.

Not just nicotine

Many devices are designed for use with other drugs, including THC.¹⁷ In a 2018 study, 10.9% of college students reported vaping marijuana in the past 30 days, up from 5.2% in 2017.¹⁸

Other substances are being vaped as well.¹⁹ In theory, any heat-stable psychoactive recreational drug could be aerosolized and vaped. There are increasing reports of e-liquids containing recreational drugs such as synthetic cannabinoid receptor agonists, crack cocaine, LSD, and methamphetamine.¹⁷

Freedom, rebellion, glamour

Sales have risen rapidly since 2007 with widespread advertising on television and in print publications for popular brands, often featuring celebrities.²⁰ Spending on advertising for e-cigarettes and vape devices rose from $6.4 million in 2011 to $115 million in 2014—and that was before the advent of Juul (see below).²¹

Marketing campaigns for vaping devices mimic the themes previously used successfully by the tobacco industry, eg, freedom, rebellion, and glamour. They also make unsubstantiated claims about health benefits and smoking cessation, though initial websites contained endorsements from physicians, similar to the strategies of tobacco companies in old cigarette ads. Cigarette ads have been prohibited since 1971—but not e-cigarette ads. Moreover, vaping products appear as product placements in television shows and movies, with advocacy groups on social media.²²

By law, buyers have to be 18 or 21

Vaping devices can be purchased at vape shops, convenience stores, gas stations, and over the Internet; up to 50% of sales are conducted online.²⁴

Fruit flavors are popular

Zhu et al²⁵ estimated that 7,700 unique vaping flavors exist, with fruit and candy flavors predominating. The most popular flavors are tobacco and mint, followed by fruit, dessert and candy flavors, alcoholic flavors (strawberry daiquiri, margarita), and food flavors.²⁵ These flavors have been associated with higher usage in youth, leading to increased risk of nicotine addiction.²⁶

WHAT IS JUUL?

The Juul device (Juul Labs, www.juul.com) was developed in 2015 by 2 Stanford University graduates. Their goal was to produce a more satisfying and cigarette-like vaping experience, specifically by increasing the amount of nicotine delivered while maintaining smooth and pleasant inhalation. They created an e-liquid that could be vaporized effectively at lower temperatures.²⁷

While more than 400 brands of vaping devices are currently available in the United States,³ Juul has held the largest market share since 2017,²⁸ an estimated 72.1% as of August 2018.²⁹ The surge in popularity of this particular brand is attributed to its trendy design that is similar in size and appearance to a USB flash drive,²⁹ and its offering of sweet flavors such as “crème brûlée” and “cool mint.”

On April 24, 2018, in view of growing concern about the popularity of Juul products among youth, the FDA requested that the company submit documents regarding its marketing tactics, as well as research on the effects of this marketing on product design and public health impact, and information about adverse experiences and complaints.³⁰ The company was forced to change its marketing to appeal less to youth. Now it offers only 3 flavors: “Virginia tobacco,” “classic tobacco,” and “menthol,” although off-brand pods containing a variety of flavors are still available. And some pods are refillable, so users can essentially vape any substance they want.

Although the Juul device delivers a strong dose of nicotine, it is small and therefore easy to hide from parents and teachers, and widespread use has been reported among youth in middle and high schools. Hoodies, hemp jewelry, and backpacks have been designed to hide the devices and allow for easy, hands-free use. YouTube searches for terms such as “Juul,” “hiding Juul at school,” and “Juul in class,” yield thousands of results.³¹ A 2017 survey reported that 8% of Americans age 15 to 24 had used Juul in the month prior to the survey.³² “To juul” has become a verb.

Each Juul starter kit contains the rechargeable inhalation device plus 4 flavored pods. In the United States, each Juul pod contains nearly as much nicotine as 1 pack of 20 cigarettes in a concentration of 3% or 5%. (Israel and Europe have forced the company to replace the 5% nicotine pods with 1.7% nicotine pods.³³) A starter kit costs $49.99, and additional packs of 4 flavored liquid cartridges or pods cost $15.99.³⁴ Other brands of vape pens cost between $15 and $35, and 10-mL bottles of e-liquid cost approximately $⁷.

What is ‘dripping’?

Hard-core vapers seeking a more intense experience are taking their vaping devices apart and modifying them for “dripping,” ie, directly dripping vape liquids onto the heated coils for inhalation. In a survey, 1 in 4 high school students using vape devices also used them for dripping, citing desires for a thicker cloud of vapor, more intense flavor, “a stronger throat hit,” curiosity, and other reasons.³⁵ Dripping involves higher temperatures, which leads to higher amounts of nicotine delivered, along with more formaldehyde, acetaldehyde, and acetone (see below).³⁶

 

 

BAD THINGS IN E-LIQUID AEROSOL

Studies of vape liquids consistently confirm the presence of toxic substances in the resulting vape aerosol.^37–40 Depending on the combination of flavorings and solvents in a given e-liquid, a variety of chemicals can be detected in the aerosol from various vaping devices. Chemicals that may be detected include known irritants of respiratory mucosa, as well as various carcinogens. The list includes:

• Organic volatile compounds such as propylene glycol, glycerin, and toluene
• Aldehydes such as formaldehyde (released when propylene glycol is heated to high temperatures), acetaldehyde, and benzaldehyde
• Acetone and acrolein
• Carcinogenic nitrosamines
• Polycyclic aromatic hydrocarbons
• Particulate matter
• Metals including chromium, cadmium, nickel, and lead; and particles of copper, nickel, and silver have been found in electronic nicotine delivery system aerosol in higher levels than in conventional cigarette smoke.⁴¹

The specific chemicals detected can vary greatly between brands, even when the flavoring and nicotine content are equivalent, which frequently results in inconsistent and conflicting study findings. The chemicals detected also vary with the voltage or power used to generate the aerosol. Different flavors may carry varying levels of risk; for example, mint- and menthol-flavored e-cigarettes were shown to expose users to dangerous levels of pulegone, a carcinogenic compound banned as a food additive in 2018.⁴² The concentrations of some of these chemicals are sufficiently high to be of toxicologic concern; for example, one study reported the presence of benzaldehyde in e-cigarette aerosol at twice the workplace exposure limit.⁴³

Biologic effects

In an in vitro study,⁴⁴ 57% of e-liquids studied were found to be cytotoxic to human pulmonary fibroblasts, lung epithelial cells, and human embryonic stem cells. Fruit-flavored e-liquids in particular caused a significant increase in DNA fragmentation. Cell cultures treated with e-cigarette liquids showed increased oxidative stress, reduced cell proliferation, and increased DNA damage,⁴⁴ which may have implications for carcinogenic risk.

In another study,⁴⁵ exposure to e-cigarette aerosol as well as conventional cigarette smoke resulted in suppression of genes related to immune and inflammatory response in respiratory epithelial cells. All genes with decreased expression after exposure to conventional cigarette smoke also showed decreased expression with exposure to e-cigarette smoke, which the study authors suggested could lead to immune suppression at the level of the nasal mucosa. Diacetyl and acetoin, chemicals found in certain flavorings, have been linked to bronchiolitis obliterans, or “popcorn lung.”⁴⁶

Nicotine is not benign

The nicotine itself in many vaping liquids should also not be underestimated. Nicotine has harmful neurocognitive effects and addictive properties, particularly in the developing brains of adolescents and young adults.⁴⁷ Nicotine exposure during adolescence negatively affects memory, attention, and emotional regulation,⁴⁸ as well as executive functioning, reward processing, and learning.⁴⁹

The brain undergoes major structural remodeling in adolescence, and nicotine acetylcholine receptors regulate neural maturation. Early exposure to nicotine disrupts this process, leading to poor executive functioning, difficulty learning, decreased memory, and issues with reward processing.

Fetal exposure, if nicotine products are used during pregnancy, has also been linked to adverse consequences such as deficits in attention and cognition, behavioral effects, and sudden infant death syndrome.⁵

Much to learn about toxicity

Partly because vaping devices have been available to US consumers only since 2007, limited evidence is available regarding the long-term effects of exposure to the aerosol from these devices in humans.¹ Many of the studies mentioned above were in vitro studies or conducted in mouse models. Differences in device design and the composition of the e-liquid among device brands pose a challenge for developing well-designed studies of the long-term health effects of e-cigarette and vape use. Additionally, devices may have different health impacts when used to vape cannabis or other drugs besides nicotine, which requires further investigation.

E-CIGARETTES AND SMOKING CESSATION

Conventional cigarette smoking is a major public health threat, as tobacco use is responsible for 480,000 deaths annually in the United States.⁵⁰

And smoking is extremely difficult to quit: as many as 80% of smokers who attempt to quit resume smoking within the first month.⁵¹ The chance of successfully quitting improves by over 50% if the individual undergoes nicotine replacement therapy, and it improves even more with counseling.⁵⁰

There are currently 5 types of FDA-approved nicotine replacement therapy products (gum, patch, lozenge, inhaler, nasal spray) to help with smoking cessation. In addition, 2 non-nicotine prescription drugs (varenicline and bupropion) have been approved for treating tobacco dependence.

Can vaping devices be added to the list of nicotine replacement therapy products? Although some manufacturers try to brand their devices as smoking cessation aids, in one study,⁵² one-third of e-cigarette users said they had either never used conventional cigarettes or had formerly smoked them.

Bullen et al⁵³ randomized smokers interested in quitting to receive either e-cigarettes, nicotine patches, or placebo (nicotine-free) e-cigarettes and followed them for 6 months. Rates of tobacco cessation were less than predicted for the entire study population, resulting in insufficient power to determine the superiority of any single method, but the study authors concluded that nicotine e-cigarettes were “modestly effective” at helping smokers quit, and that abstinence rates may be similar to those with nicotine patches.⁵³

Hajek et al⁵⁴ randomized 886 smokers to e-cigarette or nicotine replacement products of their choice. After 1 year, 18% of e-cigarette users had stopped smoking, compared with  9.9% of nicotine replacement product users. However, 80% of the e-cigarette users were still using e-cigarettes after 1 year, while only 9% of nicotine replacement product users were still using nicotine replacement therapy products after 1 year.

While quitting conventional cigarette smoking altogether has widely established health benefits, little is known about the health benefits of transitioning from conventional cigarette smoking to reduced conventional cigarette smoking with concomitant use of e-cigarettes.

Campagna et al⁵⁵ found no beneficial health effects in smokers who partially substituted conventional cigarettes for e-cigarettes.

Many studies found that smokers use e-cigarettes to maintain their habit instead of quitting entirely.⁵⁶ It has been suggested that any slight increase in effectiveness in smoking cessation by using e-cigarettes compared with other nicotine replacement products could be linked to satisfying of the habitual smoking actions, such as inhaling and bringing the hand to the mouth,²⁴ which are absent when using other nicotine replacement methods such as a nicotine patch.

As with safety information, long-term outcomes regarding the use of vape devices for smoking cessation have not been yet established, as this option is still relatively new.

 

 

VAPING AS A GATEWAY DRUG

Another worrisome trend involving electronic nicotine delivery systems is their marketing and branding, which appear to be aimed directly at adolescents and young adults. Juul and other similar products cannot be sold to anyone under the age of 18 (or 21 in 18 states, including California, Massachusetts, New York, and now Ohio). Despite this, Juul and similar products continue to increase in popularity among middle school and high school students.⁵⁷

While smoking cessation and health improvement are cited as reasons for vaping among middle-aged and older adults, adolescents and young adults more often cite flavor, enjoyment, peer use, and curiosity as reasons for use.

Adolescents are more likely to report interest in trying a vape product flavored with menthol or fruit than tobacco, and commonly hold the belief that fruit-flavored e-cigarettes are less harmful than tobacco-flavored e-cigarettes.⁵⁸ Harrell et al⁵⁹ polled youth and young adults who used flavored e-cigarettes, and 78% said they would no longer use the product if their preferred flavor were not available. In September 2019, Michigan became the first state to ban the sale of flavored e-cigarettes in stores and online. Similar bills have been introduced in California, Massachusetts, and New York.⁶⁰

Myths and misperceptions abound among youth regarding smoking vs vaping. Young people view regular cigarette smoking negatively, as causing cancer, bad breath, and asthma exacerbations. Meanwhile, they believe marijuana is safer and less addictive than traditional cigarette smoking.⁶¹ Youth exposed to e-cigarette advertisements viewed e-cigarettes as healthier, more enjoyable, “cool,” safe, and fun.⁶¹ The overall public health impact of increasing initiation of smoking, particularly among youth and young adults, should not be underestimated.

SECONDHAND VAPE AND OTHER EXPOSURE RISKS

Cigarette smoking has been banned in many public places, in view of a large body of scientific evidence about the harmful effects of secondhand smoke. Advocates for allowing vaping in public places say that vaping emissions do not harm bystanders, but evidence is insufficient to support this claim.⁶² One study showed that passive exposure to e-cigarette aerosol generated increases in serum levels of cotinine (a nicotine metabolite) similar to those with passive exposure to conventional cigarette smoke.⁵

Accidental nicotine poisoning in children as a result of ingesting e-cigarette liquid is also a major concern,⁶³ particularly with sweet flavors such as bubblegum or cheesecake that may be attractive to children.

Calls to US poison control centers with respect to e-cigarettes and vaping increased from 1 per month in September 2010 to 215 in February 2014, with 51% involving children under age 5.⁶⁴ This trend resulted in the Child Nicotine Poisoning Prevention Act, which passed in 2015 and went into effect in 2016, requiring packaging that is difficult to open for children under age 5.⁵

Device malfunctions or battery failures have led to explosions that have resulted in substantial injuries to users, as well as house and car fires.⁴⁹

HOW DO WE DISCOURAGE ADOLESCENT USE?

There are currently no established treatment approaches for adolescents who have become addicted to vaping. A review of the literature regarding treatment modalities used to address adolescent use of tobacco and marijuana provides insight that options such as nicotine replacement therapy and counseling modalities such as cognitive behavioral therapy may be helpful in treating teen vaping addiction. However, more research is needed to determine the effectiveness of these treatments in youth addicted to vaping.

Given that youth who vape even once are more likely to try other types of tobacco, we recommend that parents and healthcare providers start conversations by asking what the young person has seen or heard about vaping. Young people can also be asked what they think the school’s response should be: Do they think vaping should be banned in public places, as cigarettes have been banned? What about the carbon footprint? What are their thoughts on the plastic waste, batteries, and other toxins generated by the e-cigarette industry?

New US laws ban the sale of e-cigarettes and vaping devices to minors in stores and online. These policies are modeled in many cases on environmental control policies that have been previously employed to reduce tobacco use, particularly by youth. For example, changing laws to mandate sales only to individuals age 21 and older in all states can help to decrease access to these products among middle school and high school students.

As with tobacco cessation, education will not be enough. Support of legislation that bans vaping in public places, increases pricing to discourage adolescent use, and other measures used successfully to decrease conventional cigarette smoking can be deployed to decrease the public health impact of e-cigarettes. We recommend further regulation of specific harmful chemicals and clear, detailed ingredient labeling to increase consumer understanding of the risks associated with these products. Additionally, we recommend eliminating flavored e-cigarettes, which are the most appealing type for young users, and raising prices of e-cigarettes and similar products to discourage use by youth.

If current cigarette smokers want to use e-cigarettes to quit, we recommend that clinicians counsel them to eventually completely stop use of traditional cigarettes and switch to using e-cigarettes, instead of becoming a dual user of both types of products or using e-cigarettes indefinitely. After making that switch, they should then work to gradually taper usage and nicotine addiction by reducing the amount of nicotine in the e-liquid. Clinicians should ask patients about use of e-cigarettes and vaping devices specifically, and should counsel nonsmokers to avoid initiation of use.

EVIDENCE OF HARM CONTINUES TO EMERGE

Data about respiratory effects, secondhand exposure, and long-term smoking cessation efficacy are still limited, and it remains as yet unknown what combinations of solvents, flavorings, and nicotine in a given e-liquid will result in the most harmful or least harmful effects. In addition, while much of the information about the safety of these components has been obtained using in vitro or mouse models, increasing reports of serious respiratory illness and rising numbers of deaths linked to vaping make it clear that these findings likely translate to harmful effects in humans.

E-cigarettes may ultimately prove to be less harmful than traditional cigarettes, but it seems likely that with further time and research, serious health risks of e-cigarette use will continue to emerge.

Electronic cigarettes and other “vaping” devices have been increasing in popularity among youth and adults since their introduction in the US market in 2007.¹ This increase is partially driven by a public perception that vaping is harmless, or at least less harmful than cigarette smoking.² Vaping fans also argue that current smokers can use vaping as nicotine replacement therapy to help them quit smoking.³

We disagree. Research on the health effects of vaping, though still limited, is accumulating rapidly and making it increasingly clear that this habit is far from harmless. For youth, it is a gateway to addiction to nicotine and other substances. Whether it can help people quit smoking remains to be seen. And recent months have seen reports of serious respiratory illnesses and even deaths linked to vaping.⁴

In December 2016, the US Surgeon General warned that e-cigarette use among youth and young adults in the United States represents a “major public health concern,”⁵ and that more adolescents and young adults are now vaping than smoking conventional tobacco products.

This article reviews the issue of vaping in the United States, as well as available evidence regarding its safety.

YOUTH AT RISK

Retail sales of e-cigarettes and vaping devices approach an annual $7 billion.⁶ A 2014–2015 survey found that 2.4% of the general US population were current users of e-cigarettes, and 8.5% had tried them at least once.³

In 2014, for the first time, e-cigarette use became more common among US youth than traditional cigarettes.⁵

The odds of taking up vaping are higher among minority youth in the United States, particularly Hispanics.⁹ This trend is particularly worrisome because several longitudinal studies have shown that adolescents who use e-cigarettes are 3 times as likely to eventually become smokers of traditional cigarettes compared with adolescents who do not use e-cigarettes.^10–12

If US youth continue smoking at the current rate, 5.6 million of the current population under age 18, or 1 of every 13, will die early of a smoking-related illness.¹³ 

RECENT OUTBREAK OF VAPING-ASSOCIATED LUNG INJURY

As of November 5, 2019, there had been 2,051 cases of vaping-associated lung injury in 49 states (all except Alaska), the District of Columbia, and 1 US territory reported to the US Centers for Disease Control and Prevention (CDC), with 39 confirmed deaths.⁴ The reported cases include respiratory injury including acute eosinophilic pneumonia, organizing pneumonia, acute respiratory distress syndrome, and hypersensitivity pneumonitis.¹⁴

Most of these patients had been vaping tetrahydrocannabinol (THC), though many used both nicotine- and THC-containing products, and others used products containing nicotine exclusively.⁴ Thus, it is difficult to identify the exact substance or substances that may be contributing to this sudden outbreak among vape users, and many different product sources are currently under investigation.

One substance that may be linked to the epidemic is vitamin E acetate, which the New York State Department of Health has detected in high levels in cannabis vaping cartridges used by patients who developed lung injury.¹⁵ The US Food and Drug Administration (FDA) is continuing to analyze vape cartridge samples submitted by affected patients to look for other chemicals that can contribute to the development of serious pulmonary illness.

 

 

WHAT IS AN E-CIGARETTE? WHAT IS A VAPE PEN?

Source: The US Food and Drug Administration

Vape pens consist of similar elements but are not necessarily similar in appearance to a conventional cigarette, and may look more like a pen or a USB flash drive. In fact, the Juul device is recharged by plugging it into a USB port.

Vaping devices have many street names, including e-cigs, e-hookahs, vape pens, mods, vapes, and tank systems.

The first US patent application for a device resembling a modern e-cigarette was filed in 1963, but the product never made it to the market.¹⁶ Instead, the first commercially successful e-cigarette was created in Beijing in 2003 and introduced to US markets in 2007.

Newer-generation devices have larger batteries and can heat the liquid to higher temperatures, releasing more nicotine and forming additional toxicants such as formaldehyde. Devices lack standardization in terms of design, capacity for safely holding e-liquid, packaging of the e-liquid, and features designed to minimize hazards of use.

Not just nicotine

Many devices are designed for use with other drugs, including THC.¹⁷ In a 2018 study, 10.9% of college students reported vaping marijuana in the past 30 days, up from 5.2% in 2017.¹⁸

Other substances are being vaped as well.¹⁹ In theory, any heat-stable psychoactive recreational drug could be aerosolized and vaped. There are increasing reports of e-liquids containing recreational drugs such as synthetic cannabinoid receptor agonists, crack cocaine, LSD, and methamphetamine.¹⁷

Freedom, rebellion, glamour

Sales have risen rapidly since 2007 with widespread advertising on television and in print publications for popular brands, often featuring celebrities.²⁰ Spending on advertising for e-cigarettes and vape devices rose from $6.4 million in 2011 to $115 million in 2014—and that was before the advent of Juul (see below).²¹

Marketing campaigns for vaping devices mimic the themes previously used successfully by the tobacco industry, eg, freedom, rebellion, and glamour. They also make unsubstantiated claims about health benefits and smoking cessation, though initial websites contained endorsements from physicians, similar to the strategies of tobacco companies in old cigarette ads. Cigarette ads have been prohibited since 1971—but not e-cigarette ads. Moreover, vaping products appear as product placements in television shows and movies, with advocacy groups on social media.²²

By law, buyers have to be 18 or 21

Vaping devices can be purchased at vape shops, convenience stores, gas stations, and over the Internet; up to 50% of sales are conducted online.²⁴

Fruit flavors are popular

Zhu et al²⁵ estimated that 7,700 unique vaping flavors exist, with fruit and candy flavors predominating. The most popular flavors are tobacco and mint, followed by fruit, dessert and candy flavors, alcoholic flavors (strawberry daiquiri, margarita), and food flavors.²⁵ These flavors have been associated with higher usage in youth, leading to increased risk of nicotine addiction.²⁶

WHAT IS JUUL?

The Juul device (Juul Labs, www.juul.com) was developed in 2015 by 2 Stanford University graduates. Their goal was to produce a more satisfying and cigarette-like vaping experience, specifically by increasing the amount of nicotine delivered while maintaining smooth and pleasant inhalation. They created an e-liquid that could be vaporized effectively at lower temperatures.²⁷

While more than 400 brands of vaping devices are currently available in the United States,³ Juul has held the largest market share since 2017,²⁸ an estimated 72.1% as of August 2018.²⁹ The surge in popularity of this particular brand is attributed to its trendy design that is similar in size and appearance to a USB flash drive,²⁹ and its offering of sweet flavors such as “crème brûlée” and “cool mint.”

On April 24, 2018, in view of growing concern about the popularity of Juul products among youth, the FDA requested that the company submit documents regarding its marketing tactics, as well as research on the effects of this marketing on product design and public health impact, and information about adverse experiences and complaints.³⁰ The company was forced to change its marketing to appeal less to youth. Now it offers only 3 flavors: “Virginia tobacco,” “classic tobacco,” and “menthol,” although off-brand pods containing a variety of flavors are still available. And some pods are refillable, so users can essentially vape any substance they want.

Although the Juul device delivers a strong dose of nicotine, it is small and therefore easy to hide from parents and teachers, and widespread use has been reported among youth in middle and high schools. Hoodies, hemp jewelry, and backpacks have been designed to hide the devices and allow for easy, hands-free use. YouTube searches for terms such as “Juul,” “hiding Juul at school,” and “Juul in class,” yield thousands of results.³¹ A 2017 survey reported that 8% of Americans age 15 to 24 had used Juul in the month prior to the survey.³² “To juul” has become a verb.

Each Juul starter kit contains the rechargeable inhalation device plus 4 flavored pods. In the United States, each Juul pod contains nearly as much nicotine as 1 pack of 20 cigarettes in a concentration of 3% or 5%. (Israel and Europe have forced the company to replace the 5% nicotine pods with 1.7% nicotine pods.³³) A starter kit costs $49.99, and additional packs of 4 flavored liquid cartridges or pods cost $15.99.³⁴ Other brands of vape pens cost between $15 and $35, and 10-mL bottles of e-liquid cost approximately $⁷.

What is ‘dripping’?

Hard-core vapers seeking a more intense experience are taking their vaping devices apart and modifying them for “dripping,” ie, directly dripping vape liquids onto the heated coils for inhalation. In a survey, 1 in 4 high school students using vape devices also used them for dripping, citing desires for a thicker cloud of vapor, more intense flavor, “a stronger throat hit,” curiosity, and other reasons.³⁵ Dripping involves higher temperatures, which leads to higher amounts of nicotine delivered, along with more formaldehyde, acetaldehyde, and acetone (see below).³⁶

 

 

BAD THINGS IN E-LIQUID AEROSOL

Studies of vape liquids consistently confirm the presence of toxic substances in the resulting vape aerosol.^37–40 Depending on the combination of flavorings and solvents in a given e-liquid, a variety of chemicals can be detected in the aerosol from various vaping devices. Chemicals that may be detected include known irritants of respiratory mucosa, as well as various carcinogens. The list includes:

• Organic volatile compounds such as propylene glycol, glycerin, and toluene
• Aldehydes such as formaldehyde (released when propylene glycol is heated to high temperatures), acetaldehyde, and benzaldehyde
• Acetone and acrolein
• Carcinogenic nitrosamines
• Polycyclic aromatic hydrocarbons
• Particulate matter
• Metals including chromium, cadmium, nickel, and lead; and particles of copper, nickel, and silver have been found in electronic nicotine delivery system aerosol in higher levels than in conventional cigarette smoke.⁴¹

The specific chemicals detected can vary greatly between brands, even when the flavoring and nicotine content are equivalent, which frequently results in inconsistent and conflicting study findings. The chemicals detected also vary with the voltage or power used to generate the aerosol. Different flavors may carry varying levels of risk; for example, mint- and menthol-flavored e-cigarettes were shown to expose users to dangerous levels of pulegone, a carcinogenic compound banned as a food additive in 2018.⁴² The concentrations of some of these chemicals are sufficiently high to be of toxicologic concern; for example, one study reported the presence of benzaldehyde in e-cigarette aerosol at twice the workplace exposure limit.⁴³

Biologic effects

In an in vitro study,⁴⁴ 57% of e-liquids studied were found to be cytotoxic to human pulmonary fibroblasts, lung epithelial cells, and human embryonic stem cells. Fruit-flavored e-liquids in particular caused a significant increase in DNA fragmentation. Cell cultures treated with e-cigarette liquids showed increased oxidative stress, reduced cell proliferation, and increased DNA damage,⁴⁴ which may have implications for carcinogenic risk.

In another study,⁴⁵ exposure to e-cigarette aerosol as well as conventional cigarette smoke resulted in suppression of genes related to immune and inflammatory response in respiratory epithelial cells. All genes with decreased expression after exposure to conventional cigarette smoke also showed decreased expression with exposure to e-cigarette smoke, which the study authors suggested could lead to immune suppression at the level of the nasal mucosa. Diacetyl and acetoin, chemicals found in certain flavorings, have been linked to bronchiolitis obliterans, or “popcorn lung.”⁴⁶

Nicotine is not benign

The nicotine itself in many vaping liquids should also not be underestimated. Nicotine has harmful neurocognitive effects and addictive properties, particularly in the developing brains of adolescents and young adults.⁴⁷ Nicotine exposure during adolescence negatively affects memory, attention, and emotional regulation,⁴⁸ as well as executive functioning, reward processing, and learning.⁴⁹

The brain undergoes major structural remodeling in adolescence, and nicotine acetylcholine receptors regulate neural maturation. Early exposure to nicotine disrupts this process, leading to poor executive functioning, difficulty learning, decreased memory, and issues with reward processing.

Fetal exposure, if nicotine products are used during pregnancy, has also been linked to adverse consequences such as deficits in attention and cognition, behavioral effects, and sudden infant death syndrome.⁵

Much to learn about toxicity

Partly because vaping devices have been available to US consumers only since 2007, limited evidence is available regarding the long-term effects of exposure to the aerosol from these devices in humans.¹ Many of the studies mentioned above were in vitro studies or conducted in mouse models. Differences in device design and the composition of the e-liquid among device brands pose a challenge for developing well-designed studies of the long-term health effects of e-cigarette and vape use. Additionally, devices may have different health impacts when used to vape cannabis or other drugs besides nicotine, which requires further investigation.

E-CIGARETTES AND SMOKING CESSATION

Conventional cigarette smoking is a major public health threat, as tobacco use is responsible for 480,000 deaths annually in the United States.⁵⁰

And smoking is extremely difficult to quit: as many as 80% of smokers who attempt to quit resume smoking within the first month.⁵¹ The chance of successfully quitting improves by over 50% if the individual undergoes nicotine replacement therapy, and it improves even more with counseling.⁵⁰

There are currently 5 types of FDA-approved nicotine replacement therapy products (gum, patch, lozenge, inhaler, nasal spray) to help with smoking cessation. In addition, 2 non-nicotine prescription drugs (varenicline and bupropion) have been approved for treating tobacco dependence.

Can vaping devices be added to the list of nicotine replacement therapy products? Although some manufacturers try to brand their devices as smoking cessation aids, in one study,⁵² one-third of e-cigarette users said they had either never used conventional cigarettes or had formerly smoked them.

Bullen et al⁵³ randomized smokers interested in quitting to receive either e-cigarettes, nicotine patches, or placebo (nicotine-free) e-cigarettes and followed them for 6 months. Rates of tobacco cessation were less than predicted for the entire study population, resulting in insufficient power to determine the superiority of any single method, but the study authors concluded that nicotine e-cigarettes were “modestly effective” at helping smokers quit, and that abstinence rates may be similar to those with nicotine patches.⁵³

Hajek et al⁵⁴ randomized 886 smokers to e-cigarette or nicotine replacement products of their choice. After 1 year, 18% of e-cigarette users had stopped smoking, compared with  9.9% of nicotine replacement product users. However, 80% of the e-cigarette users were still using e-cigarettes after 1 year, while only 9% of nicotine replacement product users were still using nicotine replacement therapy products after 1 year.

While quitting conventional cigarette smoking altogether has widely established health benefits, little is known about the health benefits of transitioning from conventional cigarette smoking to reduced conventional cigarette smoking with concomitant use of e-cigarettes.

Campagna et al⁵⁵ found no beneficial health effects in smokers who partially substituted conventional cigarettes for e-cigarettes.

Many studies found that smokers use e-cigarettes to maintain their habit instead of quitting entirely.⁵⁶ It has been suggested that any slight increase in effectiveness in smoking cessation by using e-cigarettes compared with other nicotine replacement products could be linked to satisfying of the habitual smoking actions, such as inhaling and bringing the hand to the mouth,²⁴ which are absent when using other nicotine replacement methods such as a nicotine patch.

As with safety information, long-term outcomes regarding the use of vape devices for smoking cessation have not been yet established, as this option is still relatively new.

 

 

VAPING AS A GATEWAY DRUG

Another worrisome trend involving electronic nicotine delivery systems is their marketing and branding, which appear to be aimed directly at adolescents and young adults. Juul and other similar products cannot be sold to anyone under the age of 18 (or 21 in 18 states, including California, Massachusetts, New York, and now Ohio). Despite this, Juul and similar products continue to increase in popularity among middle school and high school students.⁵⁷

While smoking cessation and health improvement are cited as reasons for vaping among middle-aged and older adults, adolescents and young adults more often cite flavor, enjoyment, peer use, and curiosity as reasons for use.

Adolescents are more likely to report interest in trying a vape product flavored with menthol or fruit than tobacco, and commonly hold the belief that fruit-flavored e-cigarettes are less harmful than tobacco-flavored e-cigarettes.⁵⁸ Harrell et al⁵⁹ polled youth and young adults who used flavored e-cigarettes, and 78% said they would no longer use the product if their preferred flavor were not available. In September 2019, Michigan became the first state to ban the sale of flavored e-cigarettes in stores and online. Similar bills have been introduced in California, Massachusetts, and New York.⁶⁰

Myths and misperceptions abound among youth regarding smoking vs vaping. Young people view regular cigarette smoking negatively, as causing cancer, bad breath, and asthma exacerbations. Meanwhile, they believe marijuana is safer and less addictive than traditional cigarette smoking.⁶¹ Youth exposed to e-cigarette advertisements viewed e-cigarettes as healthier, more enjoyable, “cool,” safe, and fun.⁶¹ The overall public health impact of increasing initiation of smoking, particularly among youth and young adults, should not be underestimated.

SECONDHAND VAPE AND OTHER EXPOSURE RISKS

Cigarette smoking has been banned in many public places, in view of a large body of scientific evidence about the harmful effects of secondhand smoke. Advocates for allowing vaping in public places say that vaping emissions do not harm bystanders, but evidence is insufficient to support this claim.⁶² One study showed that passive exposure to e-cigarette aerosol generated increases in serum levels of cotinine (a nicotine metabolite) similar to those with passive exposure to conventional cigarette smoke.⁵

Accidental nicotine poisoning in children as a result of ingesting e-cigarette liquid is also a major concern,⁶³ particularly with sweet flavors such as bubblegum or cheesecake that may be attractive to children.

Calls to US poison control centers with respect to e-cigarettes and vaping increased from 1 per month in September 2010 to 215 in February 2014, with 51% involving children under age 5.⁶⁴ This trend resulted in the Child Nicotine Poisoning Prevention Act, which passed in 2015 and went into effect in 2016, requiring packaging that is difficult to open for children under age 5.⁵

Device malfunctions or battery failures have led to explosions that have resulted in substantial injuries to users, as well as house and car fires.⁴⁹

HOW DO WE DISCOURAGE ADOLESCENT USE?

There are currently no established treatment approaches for adolescents who have become addicted to vaping. A review of the literature regarding treatment modalities used to address adolescent use of tobacco and marijuana provides insight that options such as nicotine replacement therapy and counseling modalities such as cognitive behavioral therapy may be helpful in treating teen vaping addiction. However, more research is needed to determine the effectiveness of these treatments in youth addicted to vaping.

Given that youth who vape even once are more likely to try other types of tobacco, we recommend that parents and healthcare providers start conversations by asking what the young person has seen or heard about vaping. Young people can also be asked what they think the school’s response should be: Do they think vaping should be banned in public places, as cigarettes have been banned? What about the carbon footprint? What are their thoughts on the plastic waste, batteries, and other toxins generated by the e-cigarette industry?

New US laws ban the sale of e-cigarettes and vaping devices to minors in stores and online. These policies are modeled in many cases on environmental control policies that have been previously employed to reduce tobacco use, particularly by youth. For example, changing laws to mandate sales only to individuals age 21 and older in all states can help to decrease access to these products among middle school and high school students.

As with tobacco cessation, education will not be enough. Support of legislation that bans vaping in public places, increases pricing to discourage adolescent use, and other measures used successfully to decrease conventional cigarette smoking can be deployed to decrease the public health impact of e-cigarettes. We recommend further regulation of specific harmful chemicals and clear, detailed ingredient labeling to increase consumer understanding of the risks associated with these products. Additionally, we recommend eliminating flavored e-cigarettes, which are the most appealing type for young users, and raising prices of e-cigarettes and similar products to discourage use by youth.

If current cigarette smokers want to use e-cigarettes to quit, we recommend that clinicians counsel them to eventually completely stop use of traditional cigarettes and switch to using e-cigarettes, instead of becoming a dual user of both types of products or using e-cigarettes indefinitely. After making that switch, they should then work to gradually taper usage and nicotine addiction by reducing the amount of nicotine in the e-liquid. Clinicians should ask patients about use of e-cigarettes and vaping devices specifically, and should counsel nonsmokers to avoid initiation of use.

EVIDENCE OF HARM CONTINUES TO EMERGE

Data about respiratory effects, secondhand exposure, and long-term smoking cessation efficacy are still limited, and it remains as yet unknown what combinations of solvents, flavorings, and nicotine in a given e-liquid will result in the most harmful or least harmful effects. In addition, while much of the information about the safety of these components has been obtained using in vitro or mouse models, increasing reports of serious respiratory illness and rising numbers of deaths linked to vaping make it clear that these findings likely translate to harmful effects in humans.

E-cigarettes may ultimately prove to be less harmful than traditional cigarettes, but it seems likely that with further time and research, serious health risks of e-cigarette use will continue to emerge.

Electronic cigarettes and other “vaping” devices have been increasing in popularity among youth and adults since their introduction in the US market in 2007.¹ This increase is partially driven by a public perception that vaping is harmless, or at least less harmful than cigarette smoking.² Vaping fans also argue that current smokers can use vaping as nicotine replacement therapy to help them quit smoking.³

We disagree. Research on the health effects of vaping, though still limited, is accumulating rapidly and making it increasingly clear that this habit is far from harmless. For youth, it is a gateway to addiction to nicotine and other substances. Whether it can help people quit smoking remains to be seen. And recent months have seen reports of serious respiratory illnesses and even deaths linked to vaping.⁴

In December 2016, the US Surgeon General warned that e-cigarette use among youth and young adults in the United States represents a “major public health concern,”⁵ and that more adolescents and young adults are now vaping than smoking conventional tobacco products.

This article reviews the issue of vaping in the United States, as well as available evidence regarding its safety.

YOUTH AT RISK

Retail sales of e-cigarettes and vaping devices approach an annual $7 billion.⁶ A 2014–2015 survey found that 2.4% of the general US population were current users of e-cigarettes, and 8.5% had tried them at least once.³

In 2014, for the first time, e-cigarette use became more common among US youth than traditional cigarettes.⁵

The odds of taking up vaping are higher among minority youth in the United States, particularly Hispanics.⁹ This trend is particularly worrisome because several longitudinal studies have shown that adolescents who use e-cigarettes are 3 times as likely to eventually become smokers of traditional cigarettes compared with adolescents who do not use e-cigarettes.^10–12

If US youth continue smoking at the current rate, 5.6 million of the current population under age 18, or 1 of every 13, will die early of a smoking-related illness.¹³ 

RECENT OUTBREAK OF VAPING-ASSOCIATED LUNG INJURY

As of November 5, 2019, there had been 2,051 cases of vaping-associated lung injury in 49 states (all except Alaska), the District of Columbia, and 1 US territory reported to the US Centers for Disease Control and Prevention (CDC), with 39 confirmed deaths.⁴ The reported cases include respiratory injury including acute eosinophilic pneumonia, organizing pneumonia, acute respiratory distress syndrome, and hypersensitivity pneumonitis.¹⁴

Most of these patients had been vaping tetrahydrocannabinol (THC), though many used both nicotine- and THC-containing products, and others used products containing nicotine exclusively.⁴ Thus, it is difficult to identify the exact substance or substances that may be contributing to this sudden outbreak among vape users, and many different product sources are currently under investigation.

One substance that may be linked to the epidemic is vitamin E acetate, which the New York State Department of Health has detected in high levels in cannabis vaping cartridges used by patients who developed lung injury.¹⁵ The US Food and Drug Administration (FDA) is continuing to analyze vape cartridge samples submitted by affected patients to look for other chemicals that can contribute to the development of serious pulmonary illness.

 

 

WHAT IS AN E-CIGARETTE? WHAT IS A VAPE PEN?

Source: The US Food and Drug Administration

Vape pens consist of similar elements but are not necessarily similar in appearance to a conventional cigarette, and may look more like a pen or a USB flash drive. In fact, the Juul device is recharged by plugging it into a USB port.

Vaping devices have many street names, including e-cigs, e-hookahs, vape pens, mods, vapes, and tank systems.

The first US patent application for a device resembling a modern e-cigarette was filed in 1963, but the product never made it to the market.¹⁶ Instead, the first commercially successful e-cigarette was created in Beijing in 2003 and introduced to US markets in 2007.

Newer-generation devices have larger batteries and can heat the liquid to higher temperatures, releasing more nicotine and forming additional toxicants such as formaldehyde. Devices lack standardization in terms of design, capacity for safely holding e-liquid, packaging of the e-liquid, and features designed to minimize hazards of use.

Not just nicotine

Many devices are designed for use with other drugs, including THC.¹⁷ In a 2018 study, 10.9% of college students reported vaping marijuana in the past 30 days, up from 5.2% in 2017.¹⁸

Other substances are being vaped as well.¹⁹ In theory, any heat-stable psychoactive recreational drug could be aerosolized and vaped. There are increasing reports of e-liquids containing recreational drugs such as synthetic cannabinoid receptor agonists, crack cocaine, LSD, and methamphetamine.¹⁷

Freedom, rebellion, glamour

Sales have risen rapidly since 2007 with widespread advertising on television and in print publications for popular brands, often featuring celebrities.²⁰ Spending on advertising for e-cigarettes and vape devices rose from $6.4 million in 2011 to $115 million in 2014—and that was before the advent of Juul (see below).²¹

Marketing campaigns for vaping devices mimic the themes previously used successfully by the tobacco industry, eg, freedom, rebellion, and glamour. They also make unsubstantiated claims about health benefits and smoking cessation, though initial websites contained endorsements from physicians, similar to the strategies of tobacco companies in old cigarette ads. Cigarette ads have been prohibited since 1971—but not e-cigarette ads. Moreover, vaping products appear as product placements in television shows and movies, with advocacy groups on social media.²²

By law, buyers have to be 18 or 21

Vaping devices can be purchased at vape shops, convenience stores, gas stations, and over the Internet; up to 50% of sales are conducted online.²⁴

Fruit flavors are popular

Zhu et al²⁵ estimated that 7,700 unique vaping flavors exist, with fruit and candy flavors predominating. The most popular flavors are tobacco and mint, followed by fruit, dessert and candy flavors, alcoholic flavors (strawberry daiquiri, margarita), and food flavors.²⁵ These flavors have been associated with higher usage in youth, leading to increased risk of nicotine addiction.²⁶

WHAT IS JUUL?

The Juul device (Juul Labs, www.juul.com) was developed in 2015 by 2 Stanford University graduates. Their goal was to produce a more satisfying and cigarette-like vaping experience, specifically by increasing the amount of nicotine delivered while maintaining smooth and pleasant inhalation. They created an e-liquid that could be vaporized effectively at lower temperatures.²⁷

While more than 400 brands of vaping devices are currently available in the United States,³ Juul has held the largest market share since 2017,²⁸ an estimated 72.1% as of August 2018.²⁹ The surge in popularity of this particular brand is attributed to its trendy design that is similar in size and appearance to a USB flash drive,²⁹ and its offering of sweet flavors such as “crème brûlée” and “cool mint.”

On April 24, 2018, in view of growing concern about the popularity of Juul products among youth, the FDA requested that the company submit documents regarding its marketing tactics, as well as research on the effects of this marketing on product design and public health impact, and information about adverse experiences and complaints.³⁰ The company was forced to change its marketing to appeal less to youth. Now it offers only 3 flavors: “Virginia tobacco,” “classic tobacco,” and “menthol,” although off-brand pods containing a variety of flavors are still available. And some pods are refillable, so users can essentially vape any substance they want.

Although the Juul device delivers a strong dose of nicotine, it is small and therefore easy to hide from parents and teachers, and widespread use has been reported among youth in middle and high schools. Hoodies, hemp jewelry, and backpacks have been designed to hide the devices and allow for easy, hands-free use. YouTube searches for terms such as “Juul,” “hiding Juul at school,” and “Juul in class,” yield thousands of results.³¹ A 2017 survey reported that 8% of Americans age 15 to 24 had used Juul in the month prior to the survey.³² “To juul” has become a verb.

Each Juul starter kit contains the rechargeable inhalation device plus 4 flavored pods. In the United States, each Juul pod contains nearly as much nicotine as 1 pack of 20 cigarettes in a concentration of 3% or 5%. (Israel and Europe have forced the company to replace the 5% nicotine pods with 1.7% nicotine pods.³³) A starter kit costs $49.99, and additional packs of 4 flavored liquid cartridges or pods cost $15.99.³⁴ Other brands of vape pens cost between $15 and $35, and 10-mL bottles of e-liquid cost approximately $⁷.

What is ‘dripping’?

Hard-core vapers seeking a more intense experience are taking their vaping devices apart and modifying them for “dripping,” ie, directly dripping vape liquids onto the heated coils for inhalation. In a survey, 1 in 4 high school students using vape devices also used them for dripping, citing desires for a thicker cloud of vapor, more intense flavor, “a stronger throat hit,” curiosity, and other reasons.³⁵ Dripping involves higher temperatures, which leads to higher amounts of nicotine delivered, along with more formaldehyde, acetaldehyde, and acetone (see below).³⁶

 

 

BAD THINGS IN E-LIQUID AEROSOL

Studies of vape liquids consistently confirm the presence of toxic substances in the resulting vape aerosol.^37–40 Depending on the combination of flavorings and solvents in a given e-liquid, a variety of chemicals can be detected in the aerosol from various vaping devices. Chemicals that may be detected include known irritants of respiratory mucosa, as well as various carcinogens. The list includes:

• Organic volatile compounds such as propylene glycol, glycerin, and toluene
• Aldehydes such as formaldehyde (released when propylene glycol is heated to high temperatures), acetaldehyde, and benzaldehyde
• Acetone and acrolein
• Carcinogenic nitrosamines
• Polycyclic aromatic hydrocarbons
• Particulate matter
• Metals including chromium, cadmium, nickel, and lead; and particles of copper, nickel, and silver have been found in electronic nicotine delivery system aerosol in higher levels than in conventional cigarette smoke.⁴¹

The specific chemicals detected can vary greatly between brands, even when the flavoring and nicotine content are equivalent, which frequently results in inconsistent and conflicting study findings. The chemicals detected also vary with the voltage or power used to generate the aerosol. Different flavors may carry varying levels of risk; for example, mint- and menthol-flavored e-cigarettes were shown to expose users to dangerous levels of pulegone, a carcinogenic compound banned as a food additive in 2018.⁴² The concentrations of some of these chemicals are sufficiently high to be of toxicologic concern; for example, one study reported the presence of benzaldehyde in e-cigarette aerosol at twice the workplace exposure limit.⁴³

Biologic effects

In an in vitro study,⁴⁴ 57% of e-liquids studied were found to be cytotoxic to human pulmonary fibroblasts, lung epithelial cells, and human embryonic stem cells. Fruit-flavored e-liquids in particular caused a significant increase in DNA fragmentation. Cell cultures treated with e-cigarette liquids showed increased oxidative stress, reduced cell proliferation, and increased DNA damage,⁴⁴ which may have implications for carcinogenic risk.

In another study,⁴⁵ exposure to e-cigarette aerosol as well as conventional cigarette smoke resulted in suppression of genes related to immune and inflammatory response in respiratory epithelial cells. All genes with decreased expression after exposure to conventional cigarette smoke also showed decreased expression with exposure to e-cigarette smoke, which the study authors suggested could lead to immune suppression at the level of the nasal mucosa. Diacetyl and acetoin, chemicals found in certain flavorings, have been linked to bronchiolitis obliterans, or “popcorn lung.”⁴⁶

Nicotine is not benign

The nicotine itself in many vaping liquids should also not be underestimated. Nicotine has harmful neurocognitive effects and addictive properties, particularly in the developing brains of adolescents and young adults.⁴⁷ Nicotine exposure during adolescence negatively affects memory, attention, and emotional regulation,⁴⁸ as well as executive functioning, reward processing, and learning.⁴⁹

The brain undergoes major structural remodeling in adolescence, and nicotine acetylcholine receptors regulate neural maturation. Early exposure to nicotine disrupts this process, leading to poor executive functioning, difficulty learning, decreased memory, and issues with reward processing.

Fetal exposure, if nicotine products are used during pregnancy, has also been linked to adverse consequences such as deficits in attention and cognition, behavioral effects, and sudden infant death syndrome.⁵

Much to learn about toxicity

Partly because vaping devices have been available to US consumers only since 2007, limited evidence is available regarding the long-term effects of exposure to the aerosol from these devices in humans.¹ Many of the studies mentioned above were in vitro studies or conducted in mouse models. Differences in device design and the composition of the e-liquid among device brands pose a challenge for developing well-designed studies of the long-term health effects of e-cigarette and vape use. Additionally, devices may have different health impacts when used to vape cannabis or other drugs besides nicotine, which requires further investigation.

E-CIGARETTES AND SMOKING CESSATION

Conventional cigarette smoking is a major public health threat, as tobacco use is responsible for 480,000 deaths annually in the United States.⁵⁰

And smoking is extremely difficult to quit: as many as 80% of smokers who attempt to quit resume smoking within the first month.⁵¹ The chance of successfully quitting improves by over 50% if the individual undergoes nicotine replacement therapy, and it improves even more with counseling.⁵⁰

There are currently 5 types of FDA-approved nicotine replacement therapy products (gum, patch, lozenge, inhaler, nasal spray) to help with smoking cessation. In addition, 2 non-nicotine prescription drugs (varenicline and bupropion) have been approved for treating tobacco dependence.

Can vaping devices be added to the list of nicotine replacement therapy products? Although some manufacturers try to brand their devices as smoking cessation aids, in one study,⁵² one-third of e-cigarette users said they had either never used conventional cigarettes or had formerly smoked them.

Bullen et al⁵³ randomized smokers interested in quitting to receive either e-cigarettes, nicotine patches, or placebo (nicotine-free) e-cigarettes and followed them for 6 months. Rates of tobacco cessation were less than predicted for the entire study population, resulting in insufficient power to determine the superiority of any single method, but the study authors concluded that nicotine e-cigarettes were “modestly effective” at helping smokers quit, and that abstinence rates may be similar to those with nicotine patches.⁵³

Hajek et al⁵⁴ randomized 886 smokers to e-cigarette or nicotine replacement products of their choice. After 1 year, 18% of e-cigarette users had stopped smoking, compared with  9.9% of nicotine replacement product users. However, 80% of the e-cigarette users were still using e-cigarettes after 1 year, while only 9% of nicotine replacement product users were still using nicotine replacement therapy products after 1 year.

While quitting conventional cigarette smoking altogether has widely established health benefits, little is known about the health benefits of transitioning from conventional cigarette smoking to reduced conventional cigarette smoking with concomitant use of e-cigarettes.

Campagna et al⁵⁵ found no beneficial health effects in smokers who partially substituted conventional cigarettes for e-cigarettes.

Many studies found that smokers use e-cigarettes to maintain their habit instead of quitting entirely.⁵⁶ It has been suggested that any slight increase in effectiveness in smoking cessation by using e-cigarettes compared with other nicotine replacement products could be linked to satisfying of the habitual smoking actions, such as inhaling and bringing the hand to the mouth,²⁴ which are absent when using other nicotine replacement methods such as a nicotine patch.

As with safety information, long-term outcomes regarding the use of vape devices for smoking cessation have not been yet established, as this option is still relatively new.

 

 

VAPING AS A GATEWAY DRUG

Another worrisome trend involving electronic nicotine delivery systems is their marketing and branding, which appear to be aimed directly at adolescents and young adults. Juul and other similar products cannot be sold to anyone under the age of 18 (or 21 in 18 states, including California, Massachusetts, New York, and now Ohio). Despite this, Juul and similar products continue to increase in popularity among middle school and high school students.⁵⁷

While smoking cessation and health improvement are cited as reasons for vaping among middle-aged and older adults, adolescents and young adults more often cite flavor, enjoyment, peer use, and curiosity as reasons for use.

Adolescents are more likely to report interest in trying a vape product flavored with menthol or fruit than tobacco, and commonly hold the belief that fruit-flavored e-cigarettes are less harmful than tobacco-flavored e-cigarettes.⁵⁸ Harrell et al⁵⁹ polled youth and young adults who used flavored e-cigarettes, and 78% said they would no longer use the product if their preferred flavor were not available. In September 2019, Michigan became the first state to ban the sale of flavored e-cigarettes in stores and online. Similar bills have been introduced in California, Massachusetts, and New York.⁶⁰

Myths and misperceptions abound among youth regarding smoking vs vaping. Young people view regular cigarette smoking negatively, as causing cancer, bad breath, and asthma exacerbations. Meanwhile, they believe marijuana is safer and less addictive than traditional cigarette smoking.⁶¹ Youth exposed to e-cigarette advertisements viewed e-cigarettes as healthier, more enjoyable, “cool,” safe, and fun.⁶¹ The overall public health impact of increasing initiation of smoking, particularly among youth and young adults, should not be underestimated.

SECONDHAND VAPE AND OTHER EXPOSURE RISKS

Cigarette smoking has been banned in many public places, in view of a large body of scientific evidence about the harmful effects of secondhand smoke. Advocates for allowing vaping in public places say that vaping emissions do not harm bystanders, but evidence is insufficient to support this claim.⁶² One study showed that passive exposure to e-cigarette aerosol generated increases in serum levels of cotinine (a nicotine metabolite) similar to those with passive exposure to conventional cigarette smoke.⁵

Accidental nicotine poisoning in children as a result of ingesting e-cigarette liquid is also a major concern,⁶³ particularly with sweet flavors such as bubblegum or cheesecake that may be attractive to children.

Calls to US poison control centers with respect to e-cigarettes and vaping increased from 1 per month in September 2010 to 215 in February 2014, with 51% involving children under age 5.⁶⁴ This trend resulted in the Child Nicotine Poisoning Prevention Act, which passed in 2015 and went into effect in 2016, requiring packaging that is difficult to open for children under age 5.⁵

Device malfunctions or battery failures have led to explosions that have resulted in substantial injuries to users, as well as house and car fires.⁴⁹

HOW DO WE DISCOURAGE ADOLESCENT USE?

There are currently no established treatment approaches for adolescents who have become addicted to vaping. A review of the literature regarding treatment modalities used to address adolescent use of tobacco and marijuana provides insight that options such as nicotine replacement therapy and counseling modalities such as cognitive behavioral therapy may be helpful in treating teen vaping addiction. However, more research is needed to determine the effectiveness of these treatments in youth addicted to vaping.

Given that youth who vape even once are more likely to try other types of tobacco, we recommend that parents and healthcare providers start conversations by asking what the young person has seen or heard about vaping. Young people can also be asked what they think the school’s response should be: Do they think vaping should be banned in public places, as cigarettes have been banned? What about the carbon footprint? What are their thoughts on the plastic waste, batteries, and other toxins generated by the e-cigarette industry?

New US laws ban the sale of e-cigarettes and vaping devices to minors in stores and online. These policies are modeled in many cases on environmental control policies that have been previously employed to reduce tobacco use, particularly by youth. For example, changing laws to mandate sales only to individuals age 21 and older in all states can help to decrease access to these products among middle school and high school students.

As with tobacco cessation, education will not be enough. Support of legislation that bans vaping in public places, increases pricing to discourage adolescent use, and other measures used successfully to decrease conventional cigarette smoking can be deployed to decrease the public health impact of e-cigarettes. We recommend further regulation of specific harmful chemicals and clear, detailed ingredient labeling to increase consumer understanding of the risks associated with these products. Additionally, we recommend eliminating flavored e-cigarettes, which are the most appealing type for young users, and raising prices of e-cigarettes and similar products to discourage use by youth.

If current cigarette smokers want to use e-cigarettes to quit, we recommend that clinicians counsel them to eventually completely stop use of traditional cigarettes and switch to using e-cigarettes, instead of becoming a dual user of both types of products or using e-cigarettes indefinitely. After making that switch, they should then work to gradually taper usage and nicotine addiction by reducing the amount of nicotine in the e-liquid. Clinicians should ask patients about use of e-cigarettes and vaping devices specifically, and should counsel nonsmokers to avoid initiation of use.

EVIDENCE OF HARM CONTINUES TO EMERGE

Data about respiratory effects, secondhand exposure, and long-term smoking cessation efficacy are still limited, and it remains as yet unknown what combinations of solvents, flavorings, and nicotine in a given e-liquid will result in the most harmful or least harmful effects. In addition, while much of the information about the safety of these components has been obtained using in vitro or mouse models, increasing reports of serious respiratory illness and rising numbers of deaths linked to vaping make it clear that these findings likely translate to harmful effects in humans.

E-cigarettes may ultimately prove to be less harmful than traditional cigarettes, but it seems likely that with further time and research, serious health risks of e-cigarette use will continue to emerge.

Most tricyclic antidepressants (TCAs) have US Food and Drug Administration approval for treatment of depression and anxiety disorders, but they are also a viable off-label option that should be considered by clinicians in specialties beyond psychiatry, especially for treating pain syndromes. Given the ongoing epidemic of opioid use disorder, increasing attention has been drawn to alternative strategies for chronic pain management, renewing an interest in the use of TCAs.

This review summarizes the pharmacologic properties of TCAs, their potential indications in conditions other than depression, and safety considerations.

BRIEF HISTORY OF TRICYCLICS

TCAs were originally designed in the 1950s and marketed later for treating depression. Due to their adverse effects and lethality in overdose quantities, over time they have been largely replaced by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in depression management. However, TCAs have been applied to conditions other than depression with varying degrees of efficacy and safety.

TCA PHARMACOLOGY

TCAs are absorbed in the small intestine and undergo first-pass metabolism in the liver. They bind extensively to proteins, leading to interactions with other protein-bound drugs. They are widely distributed throughout the systemic circulation because they are highly lipophilic, resulting in systemic effects including central nervous system manifestations.

Peak plasma concentration is at about 2 to 6 hours, and elimination half-life is around 24 hours for most agents, providing a long duration of action. Clearance depends on cytochrome P450 oxidative enzymes.¹

MECHANISMS OF ACTION

TCAs inhibit reuptake of norepinephrine and serotonin, resulting in accumulation of these neurotransmitters in the presynaptic cleft. They also block postsynaptic histamine, alpha-adrenergic, and muscarinic-acetylcholine receptors, causing a variety of adverse effects, including dry mouth, confusion, cognitive impairment, hypotension, orthostasis, blurred vision, urinary retention, drowsiness, and sedation.¹

Research suggests that TCAs relieve pain centrally through a descending pathway that inhibits transmission of pain signals in the spinal cord, as well as peripherally through complex anti-neuroimmune actions.² Norepinephrine appears to play a more important role in this process than serotonin, although both are deemed necessary for the “dual action” often cited in pain management,¹ which is also the rationale for widespread use of SNRIs to control pain.

Table 1 compares neurotransmitter reuptake mechanisms, adverse effect profiles, and typical dosages for depression for commonly prescribed TCAs.

POTENTIAL USES

Headache and migraine

TCAs have been shown to be effective for managing and preventing chronic headache syndromes.^3,4 Amitriptyline has been the most studied of the TCAs for both chronic daily and episodic migraine headache, showing the most efficacy among diverse drug classes (angiotensin II receptor blockers, anticonvulsants, beta-blockers, SSRIs) compared with placebo. However, in head-to-head trials, amitriptyline was no more effective than SSRIs, venlafaxine, topiramate, or propranolol.⁴ Jackson et al⁴ suggested that prophylactic medication choices should be tailored to patient characteristics and expected adverse effects, and specifically recommended that TCAs—particularly amitriptyline—be reserved for patients who have both migraine and depression.

Neuropathic pain

Neuropathic pain is defined as pain secondary to a lesion or disease of the somatosensory nervous system⁵ and is the pathomechanistic component of a number of conditions, including postherpetic neuralgia,⁶ diabetic and nondiabetic painful polyneuropathy,⁷ posttraumatic or postsurgical neuropathic pain⁸ (including plexus avulsion and complex regional pain syndrome⁹), central poststroke pain,¹⁰ spinal cord injury pain,¹¹ and multiple sclerosis-associated pain.¹²

As a group, TCAs appear to have a role as first-line agents for managing these varied neuropathic pain syndromes. In a recent meta-analysis,¹³ 16 (89%) of 18 placebo-controlled trials of TCAs (mainly amitriptyline at 25–150 mg/day) for these pain conditions were positive, with a combined number needed to treat of 3.6, suggesting a role for TCAs in these conditions. Of note, the TCAs desipramine¹⁴ and nortriptyline¹⁵ have demonstrated little evidence of efficacy in neuropathic pain syndromes.

Chronic low back pain

Chronic low back pain is a leading cause of loss of work, excessive healthcare expenditure, and disability in the United States. It can be due to numerous spinal conditions, including degenerative disk disease, spinal stenosis, lumbar spondylosis, and spinal arthropathy.

TCAs have been used to treat chronic low back pain for decades and have been repeatedly shown to be more effective than placebo in reducing pain severity.^16,17 A double-blind controlled trial¹⁸ from 1999 compared the effects of the TCA maprotiline (up to 150 mg daily), the SSRI paroxetine (up to 30 mg daily), and placebo and found a statistically significant reduction in back pain with maprotiline compared with paroxetine and placebo. However, a 2008 meta-analysis suggested little evidence that TCAs were superior to placebo.¹⁹

Evidence of TCA efficacy for back pain was reported in 2018 with a well-designed 6-month double-blind randomized controlled trial²⁰ comparing low-dose amitriptyline (25 mg) with an active comparator (benztropine 1 mg). The authors reported that amitriptyline was effective in reducing pain and pain-related disability without incurring serious adverse effects. They suggested continued use of TCAs for chronic low back pain if complicated with pain-related disability, insomnia, depression, or other comorbidity, although they called for further large-scale studies. They also cautioned that patients started the trial with symptoms similar to the adverse effects of TCAs themselves; this has implications for monitoring of symptoms as well as TCA adverse effects while using these drugs.

 

 

Fibromyalgia and chronic widespread pain

Fibromyalgia is a common, frustrating, noninflammatory pain syndrome characterized by diffuse hyperalgesia and multiple comorbidities.²¹ Although sleep hygiene, exercise, cognitive-behavioral therapy, some gabapentinoids (pregabalin), and a combination of these therapies have demonstrated efficacy, TCAs also offer robust benefits.

A meta-analysis of 9 placebo-controlled TCA trials showed large effect sizes for pain reduction, fatigue reduction, improved sleep quality, and reduced stiffness and tenderness, with the most significant of these improvements being for sleep.²² A separate meta-analysis calculated that the number needed to treat with amitriptyline for a positive outcome is 4.9.²³ Recent systematic reviews have supported these findings, listing TCAs as second-line agents after pregabalin, duloxetine, and milnacipran.²⁴

Of note, TCA monotherapy rarely produces a complete response in patients with moderate to severe fibromyalgia, chronic widespread pain, or significant comorbidities (depression, anxiety). Supplementation with cognitive-behavioral therapy, physical therapy, functional restoration, and other modalities is strongly recommended.

Abdominal and gastrointestinal pain

TCAs have been applied to a number of gastrointestinal syndromes with or without pain. Patients with irritable bowel syndrome have long been known to benefit from TCAs; the number needed to treat for symptomatic benefit over placebo is 3.5.^25,26

Although there is no substantial evidence that TCAs are useful in reducing active inflammation in inflammatory bowel disease, a study involving 81 patients found that residual noninflammatory gastrointestinal symptoms (such as diarrhea and pain) responded to TCAs, including nortriptyline and amitriptyline, with greater benefit for ulcerative colitis than for Crohn disease.²⁷

TCAs have also shown prophylactic benefit in cyclic vomiting syndrome, with a clinical response in over 75% of patients in controlled cohort studies.²⁸

The efficacy of TCAs in other abdominal or gastrointestinal syndromes is unclear or modest at best.²⁹ However, few alternative treatments exist for these conditions. Amitriptyline may help symptoms of functional dyspepsia,³⁰ but nortriptyline has proven ineffective in gastroparesis.³¹ Nonetheless, some authors²⁹ suggest considering TCAs on an individualized basis, with proper monitoring, in many if not most functional gastrointestinal disorders, especially when paired with behavioral therapies.

Pelvic and urogynecologic symptoms

Chronic pelvic pain affects up to 24% of women³² and 5% to 10% of men.³³ TCAs have shown efficacy in treating chronic pelvic pain with or without comorbid depression.³⁴ Amitriptyline and to a lesser extent nortriptyline are the TCAs most often prescribed. Pain relief appears to be independent of antidepressant effects and may be achieved at low doses; initial dosing ranges from 10 to 25 mg at bedtime, which may be increased to 100 mg as tolerated.³⁴

Based on a randomized, double-blind trial,³⁵ amitriptyline was recommended as a treatment option for interstitial cystitis or bladder pain, with the greatest symptom improvement in patients tolerating a daily dose of 50 mg.

Another study³⁶ randomized 56 women with chronic pelvic pain to amitriptyline or  gabapentin, or a combination of the drugs for 24 months. Although each regimen resulted in significant reduction in pain, fewer adverse effects occurred with gabapentin than amitriptyline. Poor compliance and early discontinuation of amitriptyline were common due to anticholinergic effects.

In small uncontrolled studies,³⁷ about half of women with chronic pelvic pain became pain-free after 8 weeks of treatment with nortriptyline and imipramine.

Randomized controlled studies are needed to confirm potential benefits of TCAs in chronic urologic and pelvic pain.

Insomnia

Insomnia affects 23% to 56% of people in the United States, Europe, and Asia³⁸ and is the reason for more than 5.5 million primary care visits annually.³⁹ TCAs (especially doxepin, maprotiline, and amitriptyline⁴⁰) have been shown to be an effective treatment, with an 82% increase in somnolence compared with placebo, as well as measurably improved total sleep time, enhanced sleep efficiency, reduced latency to persistent sleep, and decreased wake times after sleep onset.³⁸

Dosing should be kept at a minimum to minimize harsh anticholinergic effects and avoid daytime sedation. Patients should be advised to take new doses or dose escalations earlier in the night to ensure less hangover sedation the next morning.

For patients with insomnia and comorbid depression, the American Academy of Sleep Medicine suggests the addition of a low dose (eg, 10–25 mg) of a TCA at nighttime to complement preexisting, full-dose, non-TCA antidepressants, while monitoring for serotonin syndrome and other potential but exceedingly rare drug-drug interactions.⁴¹

Psychiatric indications other than depression

Beyond the known benefits in major depressive disorder, TCAs have been shown to be effective for obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, bulimia nervosa, and childhood enuresis.⁴² Given the shortage of mental health clinicians and the high prevalence of these conditions, nonpsychiatrist physicians should be familiar with the therapeutic potential of TCAs for these indications.

ADVERSE EFFECTS

Adverse effects vary among TCAs. Common ones include blurred vision, dry mouth, constipation, urinary retention, hypotension, tachycardia, tremor, weight gain, and sexual dysfunction.⁴³ Tertiary amines are generally more sedating than secondary amines and cause more anticholinergic effects (Table 1).

Despite widespread perceptions that TCAs are less tolerable than newer antidepressants, studies repeatedly suggest that they have an adverse-effect burden similar to that of SSRIs and SNRIs, although SSRIs have a greater tendency to produce nausea, whereas TCAs are more likely to cause constipation.⁴⁴

Discontinuation syndrome

Abrupt discontinuation or unintentionally missed doses of TCAs have been associated with a discontinuation syndrome in about 40% of users.⁴⁵ Patients should be warned about this possibility and the syndrome’s potential effects: dizziness, insomnia, headaches, nausea, vomiting, flulike achiness, and restlessness. Rebound depression, anxiety, panic, or other psychiatric symptoms may also occur. Symptoms generally present within 2 to 5 days after dose discontinuation and last 7 to 14 days.⁴⁵

However, all TCAs have a long half-life, allowing for sufficient coverage with once-daily dosing and thus carry a lower risk of discontinuation syndrome than many other antidepressants (78% with venlafaxine; 55% with paroxetine).⁴⁵

To discontinue therapy safely, the dosage should be reduced gradually. As is pharmacologically expected, the greatest likelihood of discontinuation syndrome is associated with longer duration of continuous treatment.

CONTRAINDICATIONS

Cardiac conduction abnormalities

TCAs should not be prescribed to patients who have right bundle branch block, a severe electrolyte disturbance, or other cardiac conduction deficit or arrhythmia that can prolong the QTc interval and elevate the risk of lethal arrhythmia.^46,47 Cardiac effects from TCAs are largely dose-dependent. Nevertheless, a baseline electrocardiogram can be obtained to assess cardiac risk, and dose escalation can proceed if results are normal (eg, appropriate conduction intervals, QTc ≤ 450 ms).

Advanced age

For elderly patients, TCAs should be prescribed with caution and sometimes not at all,⁴⁸ because anticholinergic effects may worsen preexisting urinary retention (including benign prostatic hyperplasia), narrow-angle glaucoma, imbalance and gait issues, and cognitive impairment and dementia. Dehydration and orthostatic hypotension are contraindications for TCAs, as they may precipitate falls or hypotensive shock.

Epilepsy

TCAs should also be used with caution in patients with epilepsy, as they lower the seizure threshold.

Concomitant monoamine oxidase inhibitor treatment

Giving TCAs together with monoamine oxidase inhibitor antidepressants should be avoided, given the risk of hypertensive crisis.

Suicide risk

TCAs are dangerous and potentially lethal in overdose and so should not be prescribed to suicidal or otherwise impulsive patients.

Pregnancy

TCAs are in pregnancy risk category C (animal studies show adverse effects on fetus; no adequate or well-controlled studies in humans; potential benefits may warrant use despite risks). Using TCAs during pregnancy has very rarely led to neonatal withdrawal such as irritability, jitteriness, and convulsions, as well as fetal QTc interval prolongation.⁴⁹

The American College of Obstetricians and Gynecologists recommends that therapy for depression during pregnancy be individualized, incorporating the expertise of the patient’s mental health clinician, obstetrician, primary healthcare provider, and pediatrician. In general, they recommend that TCAs should be avoided if possible and that alternatives such as SSRIs or SNRIs should be considered.⁵⁰

TCAs are excreted in breast milk, but they have not been detected in the serum of nursing infants, and no adverse events have been reported.

OVERDOSE IS HIGHLY DANGEROUS

Severe morbidity and death are associated with TCA overdose, characterized by  convulsions, cardiac arrest, and coma (the “3 Cs”). These dangers occur at much higher rates with TCAs than with other antidepressants.⁴³ Signs and symptoms of toxicity develop rapidly, usually within the first hour of overdose. Manifestations of overdose include prolonged QTc, cardiac arrhythmias, tachycardia, hypertension, severe hypotension, agitation, seizures, central nervous system depression, hallucinations, seizures, and coma.

Overdose management includes activated charcoal, seizure control, cardioversion, hydration, electrolyte stabilization, and other intensive care.

OFF-LABEL TCA MANAGEMENT

Dosing recommendations for off-label use of TCAs vary based on the condition, the medication, and the suggestions of individual authors and researchers. In general, dosing ranges for pain and other nondepression indications may be lower than for severe depression (Table 2).¹

As with any pharmacologic titration, monitoring for rate-limiting adverse effects is recommended. We suggest caution, tailoring the approach to the patient, and routinely assessing for adverse effects and other safety considerations.

In addition, we strongly recommend supplementing TCA therapy with nonpharmacologic strategies such as lifestyle changes, dietary modifications, exercise, physical therapy, and mental health optimization.

Most tricyclic antidepressants (TCAs) have US Food and Drug Administration approval for treatment of depression and anxiety disorders, but they are also a viable off-label option that should be considered by clinicians in specialties beyond psychiatry, especially for treating pain syndromes. Given the ongoing epidemic of opioid use disorder, increasing attention has been drawn to alternative strategies for chronic pain management, renewing an interest in the use of TCAs.

This review summarizes the pharmacologic properties of TCAs, their potential indications in conditions other than depression, and safety considerations.

BRIEF HISTORY OF TRICYCLICS

TCAs were originally designed in the 1950s and marketed later for treating depression. Due to their adverse effects and lethality in overdose quantities, over time they have been largely replaced by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in depression management. However, TCAs have been applied to conditions other than depression with varying degrees of efficacy and safety.

TCA PHARMACOLOGY

TCAs are absorbed in the small intestine and undergo first-pass metabolism in the liver. They bind extensively to proteins, leading to interactions with other protein-bound drugs. They are widely distributed throughout the systemic circulation because they are highly lipophilic, resulting in systemic effects including central nervous system manifestations.

Peak plasma concentration is at about 2 to 6 hours, and elimination half-life is around 24 hours for most agents, providing a long duration of action. Clearance depends on cytochrome P450 oxidative enzymes.¹

MECHANISMS OF ACTION

TCAs inhibit reuptake of norepinephrine and serotonin, resulting in accumulation of these neurotransmitters in the presynaptic cleft. They also block postsynaptic histamine, alpha-adrenergic, and muscarinic-acetylcholine receptors, causing a variety of adverse effects, including dry mouth, confusion, cognitive impairment, hypotension, orthostasis, blurred vision, urinary retention, drowsiness, and sedation.¹

Research suggests that TCAs relieve pain centrally through a descending pathway that inhibits transmission of pain signals in the spinal cord, as well as peripherally through complex anti-neuroimmune actions.² Norepinephrine appears to play a more important role in this process than serotonin, although both are deemed necessary for the “dual action” often cited in pain management,¹ which is also the rationale for widespread use of SNRIs to control pain.

Table 1 compares neurotransmitter reuptake mechanisms, adverse effect profiles, and typical dosages for depression for commonly prescribed TCAs.

POTENTIAL USES

Headache and migraine

TCAs have been shown to be effective for managing and preventing chronic headache syndromes.^3,4 Amitriptyline has been the most studied of the TCAs for both chronic daily and episodic migraine headache, showing the most efficacy among diverse drug classes (angiotensin II receptor blockers, anticonvulsants, beta-blockers, SSRIs) compared with placebo. However, in head-to-head trials, amitriptyline was no more effective than SSRIs, venlafaxine, topiramate, or propranolol.⁴ Jackson et al⁴ suggested that prophylactic medication choices should be tailored to patient characteristics and expected adverse effects, and specifically recommended that TCAs—particularly amitriptyline—be reserved for patients who have both migraine and depression.

Neuropathic pain

Neuropathic pain is defined as pain secondary to a lesion or disease of the somatosensory nervous system⁵ and is the pathomechanistic component of a number of conditions, including postherpetic neuralgia,⁶ diabetic and nondiabetic painful polyneuropathy,⁷ posttraumatic or postsurgical neuropathic pain⁸ (including plexus avulsion and complex regional pain syndrome⁹), central poststroke pain,¹⁰ spinal cord injury pain,¹¹ and multiple sclerosis-associated pain.¹²

As a group, TCAs appear to have a role as first-line agents for managing these varied neuropathic pain syndromes. In a recent meta-analysis,¹³ 16 (89%) of 18 placebo-controlled trials of TCAs (mainly amitriptyline at 25–150 mg/day) for these pain conditions were positive, with a combined number needed to treat of 3.6, suggesting a role for TCAs in these conditions. Of note, the TCAs desipramine¹⁴ and nortriptyline¹⁵ have demonstrated little evidence of efficacy in neuropathic pain syndromes.

Chronic low back pain

Chronic low back pain is a leading cause of loss of work, excessive healthcare expenditure, and disability in the United States. It can be due to numerous spinal conditions, including degenerative disk disease, spinal stenosis, lumbar spondylosis, and spinal arthropathy.

TCAs have been used to treat chronic low back pain for decades and have been repeatedly shown to be more effective than placebo in reducing pain severity.^16,17 A double-blind controlled trial¹⁸ from 1999 compared the effects of the TCA maprotiline (up to 150 mg daily), the SSRI paroxetine (up to 30 mg daily), and placebo and found a statistically significant reduction in back pain with maprotiline compared with paroxetine and placebo. However, a 2008 meta-analysis suggested little evidence that TCAs were superior to placebo.¹⁹

Evidence of TCA efficacy for back pain was reported in 2018 with a well-designed 6-month double-blind randomized controlled trial²⁰ comparing low-dose amitriptyline (25 mg) with an active comparator (benztropine 1 mg). The authors reported that amitriptyline was effective in reducing pain and pain-related disability without incurring serious adverse effects. They suggested continued use of TCAs for chronic low back pain if complicated with pain-related disability, insomnia, depression, or other comorbidity, although they called for further large-scale studies. They also cautioned that patients started the trial with symptoms similar to the adverse effects of TCAs themselves; this has implications for monitoring of symptoms as well as TCA adverse effects while using these drugs.

 

 

Fibromyalgia and chronic widespread pain

Fibromyalgia is a common, frustrating, noninflammatory pain syndrome characterized by diffuse hyperalgesia and multiple comorbidities.²¹ Although sleep hygiene, exercise, cognitive-behavioral therapy, some gabapentinoids (pregabalin), and a combination of these therapies have demonstrated efficacy, TCAs also offer robust benefits.

A meta-analysis of 9 placebo-controlled TCA trials showed large effect sizes for pain reduction, fatigue reduction, improved sleep quality, and reduced stiffness and tenderness, with the most significant of these improvements being for sleep.²² A separate meta-analysis calculated that the number needed to treat with amitriptyline for a positive outcome is 4.9.²³ Recent systematic reviews have supported these findings, listing TCAs as second-line agents after pregabalin, duloxetine, and milnacipran.²⁴

Of note, TCA monotherapy rarely produces a complete response in patients with moderate to severe fibromyalgia, chronic widespread pain, or significant comorbidities (depression, anxiety). Supplementation with cognitive-behavioral therapy, physical therapy, functional restoration, and other modalities is strongly recommended.

Abdominal and gastrointestinal pain

TCAs have been applied to a number of gastrointestinal syndromes with or without pain. Patients with irritable bowel syndrome have long been known to benefit from TCAs; the number needed to treat for symptomatic benefit over placebo is 3.5.^25,26

Although there is no substantial evidence that TCAs are useful in reducing active inflammation in inflammatory bowel disease, a study involving 81 patients found that residual noninflammatory gastrointestinal symptoms (such as diarrhea and pain) responded to TCAs, including nortriptyline and amitriptyline, with greater benefit for ulcerative colitis than for Crohn disease.²⁷

TCAs have also shown prophylactic benefit in cyclic vomiting syndrome, with a clinical response in over 75% of patients in controlled cohort studies.²⁸

The efficacy of TCAs in other abdominal or gastrointestinal syndromes is unclear or modest at best.²⁹ However, few alternative treatments exist for these conditions. Amitriptyline may help symptoms of functional dyspepsia,³⁰ but nortriptyline has proven ineffective in gastroparesis.³¹ Nonetheless, some authors²⁹ suggest considering TCAs on an individualized basis, with proper monitoring, in many if not most functional gastrointestinal disorders, especially when paired with behavioral therapies.

Pelvic and urogynecologic symptoms

Chronic pelvic pain affects up to 24% of women³² and 5% to 10% of men.³³ TCAs have shown efficacy in treating chronic pelvic pain with or without comorbid depression.³⁴ Amitriptyline and to a lesser extent nortriptyline are the TCAs most often prescribed. Pain relief appears to be independent of antidepressant effects and may be achieved at low doses; initial dosing ranges from 10 to 25 mg at bedtime, which may be increased to 100 mg as tolerated.³⁴

Based on a randomized, double-blind trial,³⁵ amitriptyline was recommended as a treatment option for interstitial cystitis or bladder pain, with the greatest symptom improvement in patients tolerating a daily dose of 50 mg.

Another study³⁶ randomized 56 women with chronic pelvic pain to amitriptyline or  gabapentin, or a combination of the drugs for 24 months. Although each regimen resulted in significant reduction in pain, fewer adverse effects occurred with gabapentin than amitriptyline. Poor compliance and early discontinuation of amitriptyline were common due to anticholinergic effects.

In small uncontrolled studies,³⁷ about half of women with chronic pelvic pain became pain-free after 8 weeks of treatment with nortriptyline and imipramine.

Randomized controlled studies are needed to confirm potential benefits of TCAs in chronic urologic and pelvic pain.

Insomnia

Insomnia affects 23% to 56% of people in the United States, Europe, and Asia³⁸ and is the reason for more than 5.5 million primary care visits annually.³⁹ TCAs (especially doxepin, maprotiline, and amitriptyline⁴⁰) have been shown to be an effective treatment, with an 82% increase in somnolence compared with placebo, as well as measurably improved total sleep time, enhanced sleep efficiency, reduced latency to persistent sleep, and decreased wake times after sleep onset.³⁸

Dosing should be kept at a minimum to minimize harsh anticholinergic effects and avoid daytime sedation. Patients should be advised to take new doses or dose escalations earlier in the night to ensure less hangover sedation the next morning.

For patients with insomnia and comorbid depression, the American Academy of Sleep Medicine suggests the addition of a low dose (eg, 10–25 mg) of a TCA at nighttime to complement preexisting, full-dose, non-TCA antidepressants, while monitoring for serotonin syndrome and other potential but exceedingly rare drug-drug interactions.⁴¹

Psychiatric indications other than depression

Beyond the known benefits in major depressive disorder, TCAs have been shown to be effective for obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, bulimia nervosa, and childhood enuresis.⁴² Given the shortage of mental health clinicians and the high prevalence of these conditions, nonpsychiatrist physicians should be familiar with the therapeutic potential of TCAs for these indications.

ADVERSE EFFECTS

Adverse effects vary among TCAs. Common ones include blurred vision, dry mouth, constipation, urinary retention, hypotension, tachycardia, tremor, weight gain, and sexual dysfunction.⁴³ Tertiary amines are generally more sedating than secondary amines and cause more anticholinergic effects (Table 1).

Despite widespread perceptions that TCAs are less tolerable than newer antidepressants, studies repeatedly suggest that they have an adverse-effect burden similar to that of SSRIs and SNRIs, although SSRIs have a greater tendency to produce nausea, whereas TCAs are more likely to cause constipation.⁴⁴

Discontinuation syndrome

Abrupt discontinuation or unintentionally missed doses of TCAs have been associated with a discontinuation syndrome in about 40% of users.⁴⁵ Patients should be warned about this possibility and the syndrome’s potential effects: dizziness, insomnia, headaches, nausea, vomiting, flulike achiness, and restlessness. Rebound depression, anxiety, panic, or other psychiatric symptoms may also occur. Symptoms generally present within 2 to 5 days after dose discontinuation and last 7 to 14 days.⁴⁵

However, all TCAs have a long half-life, allowing for sufficient coverage with once-daily dosing and thus carry a lower risk of discontinuation syndrome than many other antidepressants (78% with venlafaxine; 55% with paroxetine).⁴⁵

To discontinue therapy safely, the dosage should be reduced gradually. As is pharmacologically expected, the greatest likelihood of discontinuation syndrome is associated with longer duration of continuous treatment.

CONTRAINDICATIONS

Cardiac conduction abnormalities

TCAs should not be prescribed to patients who have right bundle branch block, a severe electrolyte disturbance, or other cardiac conduction deficit or arrhythmia that can prolong the QTc interval and elevate the risk of lethal arrhythmia.^46,47 Cardiac effects from TCAs are largely dose-dependent. Nevertheless, a baseline electrocardiogram can be obtained to assess cardiac risk, and dose escalation can proceed if results are normal (eg, appropriate conduction intervals, QTc ≤ 450 ms).

Advanced age

For elderly patients, TCAs should be prescribed with caution and sometimes not at all,⁴⁸ because anticholinergic effects may worsen preexisting urinary retention (including benign prostatic hyperplasia), narrow-angle glaucoma, imbalance and gait issues, and cognitive impairment and dementia. Dehydration and orthostatic hypotension are contraindications for TCAs, as they may precipitate falls or hypotensive shock.

Epilepsy

TCAs should also be used with caution in patients with epilepsy, as they lower the seizure threshold.

Concomitant monoamine oxidase inhibitor treatment

Giving TCAs together with monoamine oxidase inhibitor antidepressants should be avoided, given the risk of hypertensive crisis.

Suicide risk

TCAs are dangerous and potentially lethal in overdose and so should not be prescribed to suicidal or otherwise impulsive patients.

Pregnancy

TCAs are in pregnancy risk category C (animal studies show adverse effects on fetus; no adequate or well-controlled studies in humans; potential benefits may warrant use despite risks). Using TCAs during pregnancy has very rarely led to neonatal withdrawal such as irritability, jitteriness, and convulsions, as well as fetal QTc interval prolongation.⁴⁹

The American College of Obstetricians and Gynecologists recommends that therapy for depression during pregnancy be individualized, incorporating the expertise of the patient’s mental health clinician, obstetrician, primary healthcare provider, and pediatrician. In general, they recommend that TCAs should be avoided if possible and that alternatives such as SSRIs or SNRIs should be considered.⁵⁰

TCAs are excreted in breast milk, but they have not been detected in the serum of nursing infants, and no adverse events have been reported.

OVERDOSE IS HIGHLY DANGEROUS

Severe morbidity and death are associated with TCA overdose, characterized by  convulsions, cardiac arrest, and coma (the “3 Cs”). These dangers occur at much higher rates with TCAs than with other antidepressants.⁴³ Signs and symptoms of toxicity develop rapidly, usually within the first hour of overdose. Manifestations of overdose include prolonged QTc, cardiac arrhythmias, tachycardia, hypertension, severe hypotension, agitation, seizures, central nervous system depression, hallucinations, seizures, and coma.

Overdose management includes activated charcoal, seizure control, cardioversion, hydration, electrolyte stabilization, and other intensive care.

OFF-LABEL TCA MANAGEMENT

Dosing recommendations for off-label use of TCAs vary based on the condition, the medication, and the suggestions of individual authors and researchers. In general, dosing ranges for pain and other nondepression indications may be lower than for severe depression (Table 2).¹

As with any pharmacologic titration, monitoring for rate-limiting adverse effects is recommended. We suggest caution, tailoring the approach to the patient, and routinely assessing for adverse effects and other safety considerations.

In addition, we strongly recommend supplementing TCA therapy with nonpharmacologic strategies such as lifestyle changes, dietary modifications, exercise, physical therapy, and mental health optimization.

Most tricyclic antidepressants (TCAs) have US Food and Drug Administration approval for treatment of depression and anxiety disorders, but they are also a viable off-label option that should be considered by clinicians in specialties beyond psychiatry, especially for treating pain syndromes. Given the ongoing epidemic of opioid use disorder, increasing attention has been drawn to alternative strategies for chronic pain management, renewing an interest in the use of TCAs.

This review summarizes the pharmacologic properties of TCAs, their potential indications in conditions other than depression, and safety considerations.

BRIEF HISTORY OF TRICYCLICS

TCAs were originally designed in the 1950s and marketed later for treating depression. Due to their adverse effects and lethality in overdose quantities, over time they have been largely replaced by selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) in depression management. However, TCAs have been applied to conditions other than depression with varying degrees of efficacy and safety.

TCA PHARMACOLOGY

TCAs are absorbed in the small intestine and undergo first-pass metabolism in the liver. They bind extensively to proteins, leading to interactions with other protein-bound drugs. They are widely distributed throughout the systemic circulation because they are highly lipophilic, resulting in systemic effects including central nervous system manifestations.

Peak plasma concentration is at about 2 to 6 hours, and elimination half-life is around 24 hours for most agents, providing a long duration of action. Clearance depends on cytochrome P450 oxidative enzymes.¹

MECHANISMS OF ACTION

TCAs inhibit reuptake of norepinephrine and serotonin, resulting in accumulation of these neurotransmitters in the presynaptic cleft. They also block postsynaptic histamine, alpha-adrenergic, and muscarinic-acetylcholine receptors, causing a variety of adverse effects, including dry mouth, confusion, cognitive impairment, hypotension, orthostasis, blurred vision, urinary retention, drowsiness, and sedation.¹

Research suggests that TCAs relieve pain centrally through a descending pathway that inhibits transmission of pain signals in the spinal cord, as well as peripherally through complex anti-neuroimmune actions.² Norepinephrine appears to play a more important role in this process than serotonin, although both are deemed necessary for the “dual action” often cited in pain management,¹ which is also the rationale for widespread use of SNRIs to control pain.

Table 1 compares neurotransmitter reuptake mechanisms, adverse effect profiles, and typical dosages for depression for commonly prescribed TCAs.

POTENTIAL USES

Headache and migraine

TCAs have been shown to be effective for managing and preventing chronic headache syndromes.^3,4 Amitriptyline has been the most studied of the TCAs for both chronic daily and episodic migraine headache, showing the most efficacy among diverse drug classes (angiotensin II receptor blockers, anticonvulsants, beta-blockers, SSRIs) compared with placebo. However, in head-to-head trials, amitriptyline was no more effective than SSRIs, venlafaxine, topiramate, or propranolol.⁴ Jackson et al⁴ suggested that prophylactic medication choices should be tailored to patient characteristics and expected adverse effects, and specifically recommended that TCAs—particularly amitriptyline—be reserved for patients who have both migraine and depression.

Neuropathic pain

Neuropathic pain is defined as pain secondary to a lesion or disease of the somatosensory nervous system⁵ and is the pathomechanistic component of a number of conditions, including postherpetic neuralgia,⁶ diabetic and nondiabetic painful polyneuropathy,⁷ posttraumatic or postsurgical neuropathic pain⁸ (including plexus avulsion and complex regional pain syndrome⁹), central poststroke pain,¹⁰ spinal cord injury pain,¹¹ and multiple sclerosis-associated pain.¹²

As a group, TCAs appear to have a role as first-line agents for managing these varied neuropathic pain syndromes. In a recent meta-analysis,¹³ 16 (89%) of 18 placebo-controlled trials of TCAs (mainly amitriptyline at 25–150 mg/day) for these pain conditions were positive, with a combined number needed to treat of 3.6, suggesting a role for TCAs in these conditions. Of note, the TCAs desipramine¹⁴ and nortriptyline¹⁵ have demonstrated little evidence of efficacy in neuropathic pain syndromes.

Chronic low back pain

Chronic low back pain is a leading cause of loss of work, excessive healthcare expenditure, and disability in the United States. It can be due to numerous spinal conditions, including degenerative disk disease, spinal stenosis, lumbar spondylosis, and spinal arthropathy.

TCAs have been used to treat chronic low back pain for decades and have been repeatedly shown to be more effective than placebo in reducing pain severity.^16,17 A double-blind controlled trial¹⁸ from 1999 compared the effects of the TCA maprotiline (up to 150 mg daily), the SSRI paroxetine (up to 30 mg daily), and placebo and found a statistically significant reduction in back pain with maprotiline compared with paroxetine and placebo. However, a 2008 meta-analysis suggested little evidence that TCAs were superior to placebo.¹⁹

Evidence of TCA efficacy for back pain was reported in 2018 with a well-designed 6-month double-blind randomized controlled trial²⁰ comparing low-dose amitriptyline (25 mg) with an active comparator (benztropine 1 mg). The authors reported that amitriptyline was effective in reducing pain and pain-related disability without incurring serious adverse effects. They suggested continued use of TCAs for chronic low back pain if complicated with pain-related disability, insomnia, depression, or other comorbidity, although they called for further large-scale studies. They also cautioned that patients started the trial with symptoms similar to the adverse effects of TCAs themselves; this has implications for monitoring of symptoms as well as TCA adverse effects while using these drugs.

 

 

Fibromyalgia and chronic widespread pain

Fibromyalgia is a common, frustrating, noninflammatory pain syndrome characterized by diffuse hyperalgesia and multiple comorbidities.²¹ Although sleep hygiene, exercise, cognitive-behavioral therapy, some gabapentinoids (pregabalin), and a combination of these therapies have demonstrated efficacy, TCAs also offer robust benefits.

A meta-analysis of 9 placebo-controlled TCA trials showed large effect sizes for pain reduction, fatigue reduction, improved sleep quality, and reduced stiffness and tenderness, with the most significant of these improvements being for sleep.²² A separate meta-analysis calculated that the number needed to treat with amitriptyline for a positive outcome is 4.9.²³ Recent systematic reviews have supported these findings, listing TCAs as second-line agents after pregabalin, duloxetine, and milnacipran.²⁴

Of note, TCA monotherapy rarely produces a complete response in patients with moderate to severe fibromyalgia, chronic widespread pain, or significant comorbidities (depression, anxiety). Supplementation with cognitive-behavioral therapy, physical therapy, functional restoration, and other modalities is strongly recommended.

Abdominal and gastrointestinal pain

TCAs have been applied to a number of gastrointestinal syndromes with or without pain. Patients with irritable bowel syndrome have long been known to benefit from TCAs; the number needed to treat for symptomatic benefit over placebo is 3.5.^25,26

Although there is no substantial evidence that TCAs are useful in reducing active inflammation in inflammatory bowel disease, a study involving 81 patients found that residual noninflammatory gastrointestinal symptoms (such as diarrhea and pain) responded to TCAs, including nortriptyline and amitriptyline, with greater benefit for ulcerative colitis than for Crohn disease.²⁷

TCAs have also shown prophylactic benefit in cyclic vomiting syndrome, with a clinical response in over 75% of patients in controlled cohort studies.²⁸

The efficacy of TCAs in other abdominal or gastrointestinal syndromes is unclear or modest at best.²⁹ However, few alternative treatments exist for these conditions. Amitriptyline may help symptoms of functional dyspepsia,³⁰ but nortriptyline has proven ineffective in gastroparesis.³¹ Nonetheless, some authors²⁹ suggest considering TCAs on an individualized basis, with proper monitoring, in many if not most functional gastrointestinal disorders, especially when paired with behavioral therapies.

Pelvic and urogynecologic symptoms

Chronic pelvic pain affects up to 24% of women³² and 5% to 10% of men.³³ TCAs have shown efficacy in treating chronic pelvic pain with or without comorbid depression.³⁴ Amitriptyline and to a lesser extent nortriptyline are the TCAs most often prescribed. Pain relief appears to be independent of antidepressant effects and may be achieved at low doses; initial dosing ranges from 10 to 25 mg at bedtime, which may be increased to 100 mg as tolerated.³⁴

Based on a randomized, double-blind trial,³⁵ amitriptyline was recommended as a treatment option for interstitial cystitis or bladder pain, with the greatest symptom improvement in patients tolerating a daily dose of 50 mg.

Another study³⁶ randomized 56 women with chronic pelvic pain to amitriptyline or  gabapentin, or a combination of the drugs for 24 months. Although each regimen resulted in significant reduction in pain, fewer adverse effects occurred with gabapentin than amitriptyline. Poor compliance and early discontinuation of amitriptyline were common due to anticholinergic effects.

In small uncontrolled studies,³⁷ about half of women with chronic pelvic pain became pain-free after 8 weeks of treatment with nortriptyline and imipramine.

Randomized controlled studies are needed to confirm potential benefits of TCAs in chronic urologic and pelvic pain.

Insomnia

Insomnia affects 23% to 56% of people in the United States, Europe, and Asia³⁸ and is the reason for more than 5.5 million primary care visits annually.³⁹ TCAs (especially doxepin, maprotiline, and amitriptyline⁴⁰) have been shown to be an effective treatment, with an 82% increase in somnolence compared with placebo, as well as measurably improved total sleep time, enhanced sleep efficiency, reduced latency to persistent sleep, and decreased wake times after sleep onset.³⁸

Dosing should be kept at a minimum to minimize harsh anticholinergic effects and avoid daytime sedation. Patients should be advised to take new doses or dose escalations earlier in the night to ensure less hangover sedation the next morning.

For patients with insomnia and comorbid depression, the American Academy of Sleep Medicine suggests the addition of a low dose (eg, 10–25 mg) of a TCA at nighttime to complement preexisting, full-dose, non-TCA antidepressants, while monitoring for serotonin syndrome and other potential but exceedingly rare drug-drug interactions.⁴¹

Psychiatric indications other than depression

Beyond the known benefits in major depressive disorder, TCAs have been shown to be effective for obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, bulimia nervosa, and childhood enuresis.⁴² Given the shortage of mental health clinicians and the high prevalence of these conditions, nonpsychiatrist physicians should be familiar with the therapeutic potential of TCAs for these indications.

ADVERSE EFFECTS

Adverse effects vary among TCAs. Common ones include blurred vision, dry mouth, constipation, urinary retention, hypotension, tachycardia, tremor, weight gain, and sexual dysfunction.⁴³ Tertiary amines are generally more sedating than secondary amines and cause more anticholinergic effects (Table 1).

Despite widespread perceptions that TCAs are less tolerable than newer antidepressants, studies repeatedly suggest that they have an adverse-effect burden similar to that of SSRIs and SNRIs, although SSRIs have a greater tendency to produce nausea, whereas TCAs are more likely to cause constipation.⁴⁴

Discontinuation syndrome

Abrupt discontinuation or unintentionally missed doses of TCAs have been associated with a discontinuation syndrome in about 40% of users.⁴⁵ Patients should be warned about this possibility and the syndrome’s potential effects: dizziness, insomnia, headaches, nausea, vomiting, flulike achiness, and restlessness. Rebound depression, anxiety, panic, or other psychiatric symptoms may also occur. Symptoms generally present within 2 to 5 days after dose discontinuation and last 7 to 14 days.⁴⁵

However, all TCAs have a long half-life, allowing for sufficient coverage with once-daily dosing and thus carry a lower risk of discontinuation syndrome than many other antidepressants (78% with venlafaxine; 55% with paroxetine).⁴⁵

To discontinue therapy safely, the dosage should be reduced gradually. As is pharmacologically expected, the greatest likelihood of discontinuation syndrome is associated with longer duration of continuous treatment.

CONTRAINDICATIONS

Cardiac conduction abnormalities

TCAs should not be prescribed to patients who have right bundle branch block, a severe electrolyte disturbance, or other cardiac conduction deficit or arrhythmia that can prolong the QTc interval and elevate the risk of lethal arrhythmia.^46,47 Cardiac effects from TCAs are largely dose-dependent. Nevertheless, a baseline electrocardiogram can be obtained to assess cardiac risk, and dose escalation can proceed if results are normal (eg, appropriate conduction intervals, QTc ≤ 450 ms).

Advanced age

For elderly patients, TCAs should be prescribed with caution and sometimes not at all,⁴⁸ because anticholinergic effects may worsen preexisting urinary retention (including benign prostatic hyperplasia), narrow-angle glaucoma, imbalance and gait issues, and cognitive impairment and dementia. Dehydration and orthostatic hypotension are contraindications for TCAs, as they may precipitate falls or hypotensive shock.

Epilepsy

TCAs should also be used with caution in patients with epilepsy, as they lower the seizure threshold.

Concomitant monoamine oxidase inhibitor treatment

Giving TCAs together with monoamine oxidase inhibitor antidepressants should be avoided, given the risk of hypertensive crisis.

Suicide risk

TCAs are dangerous and potentially lethal in overdose and so should not be prescribed to suicidal or otherwise impulsive patients.

Pregnancy

TCAs are in pregnancy risk category C (animal studies show adverse effects on fetus; no adequate or well-controlled studies in humans; potential benefits may warrant use despite risks). Using TCAs during pregnancy has very rarely led to neonatal withdrawal such as irritability, jitteriness, and convulsions, as well as fetal QTc interval prolongation.⁴⁹

The American College of Obstetricians and Gynecologists recommends that therapy for depression during pregnancy be individualized, incorporating the expertise of the patient’s mental health clinician, obstetrician, primary healthcare provider, and pediatrician. In general, they recommend that TCAs should be avoided if possible and that alternatives such as SSRIs or SNRIs should be considered.⁵⁰

TCAs are excreted in breast milk, but they have not been detected in the serum of nursing infants, and no adverse events have been reported.

OVERDOSE IS HIGHLY DANGEROUS

Severe morbidity and death are associated with TCA overdose, characterized by  convulsions, cardiac arrest, and coma (the “3 Cs”). These dangers occur at much higher rates with TCAs than with other antidepressants.⁴³ Signs and symptoms of toxicity develop rapidly, usually within the first hour of overdose. Manifestations of overdose include prolonged QTc, cardiac arrhythmias, tachycardia, hypertension, severe hypotension, agitation, seizures, central nervous system depression, hallucinations, seizures, and coma.

Overdose management includes activated charcoal, seizure control, cardioversion, hydration, electrolyte stabilization, and other intensive care.

OFF-LABEL TCA MANAGEMENT

Dosing recommendations for off-label use of TCAs vary based on the condition, the medication, and the suggestions of individual authors and researchers. In general, dosing ranges for pain and other nondepression indications may be lower than for severe depression (Table 2).¹

As with any pharmacologic titration, monitoring for rate-limiting adverse effects is recommended. We suggest caution, tailoring the approach to the patient, and routinely assessing for adverse effects and other safety considerations.

In addition, we strongly recommend supplementing TCA therapy with nonpharmacologic strategies such as lifestyle changes, dietary modifications, exercise, physical therapy, and mental health optimization.

Perceptions regarding the use of gabapentin for alcohol use disorder (AUD) have shifted over time.^1–4 Early on, the drug was deemed to be benign and effective.^4–6 But more and more, concerns are being raised about its recreational use to achieve euphoria,⁷ and the drug is often misused by vulnerable populations, particularly those with opioid use disorder.^7–9

Given the large number of gabapentin prescriptions written off-label for AUD, it is incumbent on providers to understand how to prescribe it responsibly.^7–9 To that end, this article focuses on the benefits—and concerns—of this treatment option. We describe the effects of gabapentin on the central nervous system and how it may mitigate alcohol withdrawal and increase the likelihood of abstinence. In addition, we review clinical trials that evaluated potential roles of gabapentin in AUD, discuss the drug’s misuse potential, and suggest a framework for its appropriate use in AUD management.

ALCOHOL USE DISORDER IS COMMON AND SERIOUS

AUD affects about 14% of US adults and represents a significant health burden,¹ often with severe clinical and social implications. It manifests as compulsive drinking and loss of control despite adverse consequences on various life domains.¹⁰ It is generally associated with cravings, tolerance, and withdrawal symptoms upon cessation. Alcohol withdrawal is characterized by tremors, anxiety, sweating, nausea, and tachycardia, and in severe cases, may involve hallucinations, seizures, and delirium tremens. Untreated, alcohol withdrawal can be fatal.¹⁰

Even though psychosocial treatments for AUD by themselves are associated with high relapse rates, pharmacotherapy is underutilized. Three drugs approved by the US Food and Drug Administration (FDA) are available to treat it, but they are often poorly accepted and have limited efficacy. For these reasons, there is considerable interest in finding alternatives. Gabapentin is one of several agents that have been studied (Table 1). The topic has been reviewed in depth by Soyka and Müller.¹¹

GABAPENTIN REDUCES EXCITATION

The anticonvulsant gabapentin is FDA-approved for treating epilepsy, postherpetic neuralgia, and restless leg syndrome.^8,12–14 It binds and selectively impedes voltage-sensitive calcium channels, the pores in cell membrane that permit calcium to enter a neuron in response to changes in electrical currents.¹⁵

Gabapentin is believed to decrease excitation of the central nervous system in multiple ways:

• It reduces the release of glutamate, a key component of the excitatory system¹⁶
• It increases the concentration of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain7
• By binding the alpha-2-delta type 1 subunit of voltage-sensitive calcium channels,^8,15–17 it inhibits excitatory synapse formation independent of calcium channel activity¹⁶
• By blocking excitatory neurotransmission, it also may indirectly increase the concentration of GABA in the central nervous system1^6,17
• It modulates action of glutamic acid decarboxylase (involved in the synthesis of GABA) and glutamate synthesizing enzyme to increase GABA and decrease glutamate.¹⁷

 

 

ALCOHOL’S ACTIONS

The actions of alcohol on the brain are also complex.¹⁸ Alpha-2-delta type 1 subunits of calcium channels are upregulated in the reward centers of the brain by addictive substances, including alcohol.¹⁶ Alcohol interacts with corticotropin-releasing factor and several neurotransmitters,¹⁸ and specifically affects neuropathways involving norepinephrine, GABA, and glutamate.¹⁹ Alcohol has reinforcing effects mediated by the release of dopamine in the nucleus accumbens.²⁰

Acutely, alcohol promotes GABA release and may also reduce GABA degradation, producing sedative and anxiolytic effects.²¹ Chronic alcohol use leads to a decrease in the number of GABAA receptors. Clinically, this downregulation manifests as tolerance to alcohol’s sedating effects.²¹

Alcohol affects the signaling of glutamatergic interaction with the N-methyl-d-aspartate (NMDA) receptor.²² Glutamate activates this receptor as well as the voltage-gated ion channels, modifying calcium influx and increasing neuronal excitability.^22,23 Acutely, alcohol has an antagonistic effect on the NMDA receptor, while chronic drinking upregulates (increases) the number of NMDA receptors and voltage-gated calcium channels.^22,23

Alcohol withdrawal increases excitatory effects

Patients experiencing alcohol withdrawal have decreased GABA-ergic functioning and increased glutamatergic action throughout the central nervous system.^19,24

Withdrawal can be subdivided into an acute phase (lasting up to about 5 days) and a protracted phase (of undetermined duration). During withdrawal, the brain activates its “stress system,” leading to overexpression of corticotropin-releasing factor in the amygdala. Protracted withdrawal dysregulates the prefrontal cortex, increasing cravings and worsening negative emotional states and sleep.¹⁶

GABAPENTIN FOR ALCOHOL WITHDRAWAL

Benzodiazepines are the standard treatment for alcohol withdrawal.^3,24 They relieve symptoms and can prevent seizures and delirium tremens,²⁴ but they are sedating and cause psychomotor impairments.³ Because of the potential for addiction, benzodiazepine use is limited to acute alcohol withdrawal.³

Gabapentin shows promise as an agent that can be used in withdrawal and continued through early abstinence without the highly addictive potential of benzodiazepines.¹⁶ It is thought to affect drinking behaviors during early abstinence by normalizing GABA and glutamate activity.^2,16

Early preclinical studies in mouse models found that gabapentin decreases anxiogenic and epileptic effects of alcohol withdrawal. Compared with other antidrinking medications, gabapentin has the benefits of lacking elimination via hepatic metabolism, few pharmacokinetic interactions, and good reported tolerability in this population.

Inpatient trials show no benefit over standard treatments

Bonnet et al²⁵ conducted a double-blind placebo-controlled trial in Germany in inpatients experiencing acute alcohol withdrawal to determine whether gabapentin might be an effective adjunct to clomethiazole, a GABAA modulator commonly used in Europe for alcohol withdrawal. Participants (N = 61) were randomized to receive placebo or gabapentin (400 mg every 6 hours) for 72 hours, with tapering over the next 3 days. All patients could receive rescue doses of clomethiazole, using a symptom-triggered protocol.

The study revealed no differences in the amount of clomethiazole administered between the 2 groups, suggesting that gabapentin had no adjunctive effect. Side effects (vertigo, nausea, dizziness, and ataxia) were mild and comparable between groups.

Nichols et al²⁶ conducted a retrospective cohort study in a South Carolina academic psychiatric hospital to assess the adjunctive effect of gabapentin on the as-needed use of benzodiazepines for alcohol withdrawal. The active group (n = 40) received gabapentin as well as a symptom-triggered alcohol withdrawal protocol of benzodiazepine. The control group (n = 43) received only the symptom-triggered alcohol withdrawal protocol without gabapentin.

No effect was found of gabapentin use for benzodiazepine treatment of alcohol withdrawal. It is notable that Bonnet et al and Nichols et al had similar findings despite their studies being conducted in different countries using distinct comparators and methods.

Bonnet et al,²⁷ in another study, tried a different design to investigate a possible role for gabapentin in inpatient alcohol withdrawal. The study included 37 patients with severe alcohol withdrawal (Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised [CIWA-Ar] > 15).

All participants received gabapentin 800 mg. Those whose CIWA-Ar score improved within 2 hours were considered “early responders” (n = 27) and next received 2 days of gabapentin 600 mg 4 times a day before starting a taper. The nonresponders whose CIWA-Ar score worsened (associated with greater anxiety and depressive symptoms; n = 10) were switched to standard treatment with clomethiazole (n = 4) or clonazepam (n = 6). Scores of 3 early responders subsequently worsened; 2 of these participants developed seizures and were switched to standard treatment.

The authors concluded that gabapentin in a dose of 3,200 mg in the first 24 hours is useful only for milder forms of alcohol withdrawal. Hence, subsequent efforts on the use of gabapentin for alcohol withdrawal have focused on outpatients.

Outpatient trials reveal benefits over benzodiazepines

Myrick et al³ compared gabapentin vs lorazepam in 100 outpatients seeking treatment for alcohol withdrawal. Participants were randomized to 1 of 4 groups: gabapentin 600 mg, 900 mg, or 1,200 mg, or lorazepam 6 mg, each tapering over 4 days. Alcohol withdrawal was measured by the CIWA-Ar score. Only 68 patients completed all follow-up appointments to day 12.

Gabapentin 600 mg was discontinued because of seizures in 2 patients, but it was generally well tolerated and was associated with diminished symptoms of alcohol withdrawal, especially at the 1,200 mg dose. The gabapentin groups experienced less anxiety and sedation and fewer cravings than the lorazepam group. Those treated with lorazepam fared worse for achieving early abstinence and were more likely to return to drinking when the intervention was discontinued. However, significant relapse by day 12 occurred in both groups.

The authors concluded that gabapentin was at least as effective as lorazepam in the outpatient treatment of alcohol withdrawal, with the 1,200-mg gabapentin dosage being more effective than 900 mg. At 1,200 mg, gabapentin was associated with better sleep, less anxiety, and better self-reported ability to work than lorazepam, and at the 900-mg dose it was associated with less depression than lorazepam.

Stock et al²⁸ conducted a randomized, double-blind study of gabapentin in acute alcohol withdrawal in 26 military veterans in an outpatient setting. Patients were ran­domized to one of the following:

• Gabapentin 1,200 mg orally for 3 days, followed by 900 mg, 600 mg, and 300 mg for 1 day each (n = 17)
• Chlordiazepoxide 100 mg orally for 3 days, followed by 75 mg, 50 mg, and 25 mg for 1 day each (n = 9).

Withdrawal scores improved similarly in both groups. Early on (days 1–4), neither cravings nor sleep differed significantly between groups; but later (days 5–7), the gabapentin group had superior scores for these measures. Gabapentin was also associated with significantly less sedation than chlordiazepoxide and trended to less alcohol craving.

 

 

Bottom line: Gabapentin is useful for mild withdrawal

Data suggest that gabapentin offers benefits for managing mild alcohol withdrawal. Improved residual craving and sleep measures are clinically important because they are risk factors for relapse. Mood and anxiety also improve with gabapentin, further indicating a therapeutic effect.

Gabapentin’s benefits for moderate and severe alcohol withdrawal have not been established. Seizures occurred during withdrawal despite gabapentin treatment, but whether from an insufficient dose, patient susceptibility, or lack of gabapentin efficacy is not clear. Best results occurred at the 1,200-mg daily dose, but benefits may not apply to patients with severe withdrawal. In addition, many studies were small, limiting the strength of conclusions.

Across most studies of gabapentin for alcohol withdrawal, advantages included a smoother transition into early abstinence due to improved sleep, mood, and anxiety, alleviating common triggers for a return to drinking. Gabapentin also carries less reinforcing potential than benzodiazepines. These qualities fueled interest in trying gabapentin to improve long-term abstinence.

GABAPENTIN FOR RELAPSE PREVENTION

Although naltrexone and acamprosate are the first-line treatments for relapse prevention, they do not help all patients and are more effective when combined with cognitive behavioral therapy.^1,29,30 For patients in whom standard treatments are not effective or tolerated, gabapentin may provide a reasonable alternative, and several randomized controlled trials have examined its use for this role.

Gabapentin alone is better than placebo

Furieri and Nakamura-Palacios⁴ assessed the use of gabapentin for relapse prevention in Brazilian outpatients (N = 60) who had averaged 27 years of drinking and consumed 17 drinks daily for the 90 days before baseline. After detoxification with diazepam and vitamins, patients were randomized to either gabapentin 300 mg twice daily or placebo for 4 weeks.

Compared with placebo, gabapentin significantly reduced cravings and lowered the percentage of heavy drinking days and the number of drinks per day, with a significant increase in the percentage of abstinent days. These self-reported measures correlated with decreases in gamma-glutamyl transferase, a biological marker for heavy drinking.

Brower et al³¹ investigated the use of gabapentin in 21 outpatients with AUD and insomnia who desired to remain abstinent. They were randomized to gabapentin (up to 1,500 mg at night) or placebo for 6 weeks. Just 14 participants completed the study; all but 2 were followed without treatment until week 12.

Gabapentin was associated with significantly lower relapse rates at 6 weeks (3 of 10 in the gabapentin group vs 9 of 11 in the placebo group) and at 12 weeks (6 of 10 in the gabapentin group vs 11 of 11 in the placebo group, assuming the 2 patients lost to follow-up relapsed). No difference between groups was detected for sleep measures in this small study. However, other studies have found that gabapentin for AUD improves measures of insomnia and daytime drowsiness—predictors of relapse—compared with other medications.¹⁶

High-dose gabapentin is better

Mason et al² randomized 150 outpatients with alcohol dependence to 12 weeks of daily treatment with either gabapentin (900 mg or 1,800 mg) or placebo after at least 3 days of abstinence. All participants received counseling. Drinking quantity and frequency were assessed by gamma-glutamyl transferase testing.

Patients taking gabapentin had better rates of abstinence and cessation of heavy drinking than those taking placebo. During the 12-week study, the 1,800-mg daily dose showed a substantially higher abstinence rate (17%) than either 900 mg  (11%) or placebo (4%). Significant dose-related improvements were also found for heavy drinking days, total drinking quantity, and frequency of alcohol withdrawal symptoms that predispose to early relapse, such as poor sleep, cravings, and poor mood. There were also significant linear dose effects on rates of abstinence and nondrinking days at the 24-week posttreatment follow-up.

Gabapentin plus naltrexone is better than naltrexone alone

Anton et al⁵ examined the efficacy of gabapentin combined with naltrexone during early abstinence. The study randomly assigned 150 people with AUD to one of the following groups:

• 16 weeks of naltrexone (50 mg/day) alone
• 6 weeks of naltrexone (50 mg/day) plus gabapentin (up to 1,200 mg/day), followed by 10 weeks of naltrexone alone
• Placebo.

All participants received medical management.

Over the first 6 weeks, those receiving naltrexone plus gabapentin had a longer interval to heavy drinking than those taking only naltrexone. By week 6, about half of those taking placebo or naltrexone alone had a heavy drinking day, compared with about 35% of those taking naltrexone plus gabapentin. Those receiving the combination also had fewer days of heavy drinking, fewer drinks per drinking day, and better sleep than the other groups. Participants in the naltrexone-alone group were more likely to drink heavily during periods in which they reported poor sleep. No significant group differences were found in measures of mood.

Gabapentin enacarbil is no better than placebo

Falk et al,³² in a 2019 preliminary analysis, examined data from a trial of gabapentin enacarbil, a prodrug formulation of gabapentin. In this 6-month double-blind study, 346 people with moderate AUD at 10 sites were randomized to gabapentin enacarbil extended-release 600 mg twice a day or placebo. All subjects received a computerized behavioral intervention.

No significant differences between groups were found in drinking measures or alcohol cravings, sleep problems, depression, or anxiety symptoms. However, a dose-response analysis found significantly less drinking for higher doses of the drug.

Bottom line: Evidence of benefits mixed but risk low

The efficacy of gabapentin as a treatment for AUD has varied across studies as a function of dosing and formulation. Daily doses have ranged from 600 mg to 1,800 mg, with the highest dose showing advantages in one study for cravings, insomnia, anxiety, dysphoria, and relapse.² Thus far, gabapentin immediate-release has performed better than gabapentin enacarbil extended-release. All forms of gabapentin have been well-tolerated in AUD trials.

The 2018 American Psychiatric Association guidelines stated that gabapentin had a small positive effect on drinking outcomes, but the harm of treatment was deemed minimal, especially relative to the harms of chronic drinking.³³ The guidelines endorse the use of gabapentin in patients with moderate to severe AUD who select gabapentin from the available options, or for those who are nonresponsive to or cannot tolerate naltrexone or acamprosate, as long as no contraindications exist. It was also noted that even small effects may be clinically important, considering the significant morbidity associated with AUD.

 

 

POTENTIAL FOR MISUSE

The use of gabapentin has become controversial owing to the growing recognition that it may not be as benign as initially thought.^7–9,34 A review of US legislative actions reflects concerns about its misuse.³⁵ In July 2017, Kentucky classified it as a schedule V controlled substance with prescription drug monitoring,³⁵ as did Tennessee in 2018³⁶ and Michigan in January 2019.³⁷ Currently, 8 other states (Massachusetts, Minnesota, Nebraska, North Dakota, Ohio, Virginia, Wyoming, and West Virginia) require prescription drug monitoring of gabapentin, and other states are considering it.³⁵

Efforts to understand gabapentin misuse derive largely from people with drug use disorders. A review of postmortem toxicology reports in fatal drug overdoses found gabapentin present in 22%.³⁸ Although it was not necessarily a cause of death, its high rate of detection suggests wide misuse among drug users.

Among a cohort of 503 prescription opioid misusers in Appalachian Kentucky, 15% reported using gabapentin “to get high.” Those who reported misusing gabapentin were 6 times more likely than nonusers to be abusing opioids and benzodiazepines. The main sources of gabapentin were doctors (52%) and dealers (36%). The average cost of gabapentin on the street was less than $1.00 per pill.³⁹

Gabapentin misuse by methadone clinic patients is also reported. Baird et al⁴⁰ surveyed patients in 6 addiction clinics in the United Kingdom for gabapentin and pregabalin abuse and found that 22% disclosed misusing these medications. Of these, 38% said they did so to enhance the methadone high.

In a review article, Quintero⁴¹ also cited enhancement of methadone euphoria and treatment of opioid withdrawal as motivations for misuse. Opioid-dependent gabapentin misusers consumed doses of gabapentin 3 to 20 times higher than clinically recommended and in combination with multiple drugs.⁴ Such use can cause dissociative and psychedelic effects.

Gabapentin also potentiates the sedative effects of opioids, thus increasing the risk of falls, accidents, and other adverse events.^34,35 Risk of opioid-related deaths was increased with coprescription of gabapentin and with moderate to high gabapentin doses.³⁴

Are people with AUD at higher risk of gabapentin abuse?

Despite concerns, patients in clinical trials of gabapentin treatment for AUD were not identified as at high risk for misuse of the drug.^2,4,5,16 Further, no such trials reported serious drug-related adverse events resulting in gabapentin discontinuation or side effects that differed from placebo in frequency or severity.^2,4,5,16

Clinical laboratory studies also have found no significant interactions between alcohol and gabapentin.^42,43 In fact, they showed no influence of gabapentin on the pharmacokinetics of alcohol or on alcohol’s subjective effects. Relative to placebo, gabapentin did not affect blood alcohol levels, the degree of intoxication, sedation, craving, or alcohol self-administration.

Smith et al⁹ reported estimates that only 1% of the general population misuse gabapentin. Another review concluded that gabapentin is seldom a drug of choice.¹⁷ Most patients prescribed gabapentin do not experience cravings or loss of control, which are hallmarks of addiction. Hence, with adequate precautions, the off-label use of gabapentin for AUD is reasonable.

CLINICAL IMPLICATIONS OF GABAPENTIN PRESCRIBING

Overall, evidence for the benefit of gabapentin in AUD is mixed. Subgroups of alcoholic patients, such as those who do not respond to or tolerate standard therapies, may particularly benefit, as may those with comorbid insomnia or neuropathic pain.⁴⁴ Clinicians should prescribe gabapentin only when it is likely to be helpful and should carefully document its efficacy.^2,45

At each visit, an open and honest assessment of the benefits and risks serves to promote shared decision-making regarding initiating, continuing, or discontinuing gabapentin.

For alcohol withdrawal

Before gabapentin is prescribed for alcohol withdrawal, potential benefits (reduction of withdrawal symptoms), side effects (sedation, fatigue), and risks (falls) should be discussed with the patient.⁴⁶ Patients should also be informed that benzodiazepines are the gold standard for alcohol withdrawal and that gabapentin is not effective for severe withdrawal.⁴⁶

For relapse prevention

When initiating treatment for relapse prevention, the patient and the prescriber should agree on specific goals (eg, reduction of drinking, anxiety, and insomnia).^2,16 Ongoing monitoring is essential and includes assessing and documenting improvement with respect to these goals.

In the AUD studies, gabapentin was well tolerated.¹⁶ Frequently observed side effects including headache, insomnia, fatigue, muscle aches, and gastrointestinal distress did not occur at a statistically different rate from placebo. However, patients in studies are selected samples, and their experience may not be generalizable to clinical practice. Thus, it is necessary to exercise caution and check for comorbidities that may put patients at risk of complications.⁴⁷ Older patients and those on hemodialysis are more susceptible to gabapentin side effects such as sedation, dizziness, ataxia, and mental status changes,³⁴ and prescribers should be alert for signs of toxicity (eg, ataxia, mental status changes).^47,48

Gabapentin misuse was not observed in AUD studies,^2,4,5,16 but evidence indicates that patients with opioid use disorder, prisoners, and polydrug users are at high risk for gabapentin misuse.^39–41 In all cases, clinicians should monitor for red flags that may indicate abuse, such as missed appointments, early refill requests, demands for increased dosage, and simultaneous opiate and benzodiazepine use.⁴⁹

Acknowledgment: The authors wish to thank Nick Mulligan for his invaluable assistance with formatting and grammar.

Perceptions regarding the use of gabapentin for alcohol use disorder (AUD) have shifted over time.^1–4 Early on, the drug was deemed to be benign and effective.^4–6 But more and more, concerns are being raised about its recreational use to achieve euphoria,⁷ and the drug is often misused by vulnerable populations, particularly those with opioid use disorder.^7–9

Given the large number of gabapentin prescriptions written off-label for AUD, it is incumbent on providers to understand how to prescribe it responsibly.^7–9 To that end, this article focuses on the benefits—and concerns—of this treatment option. We describe the effects of gabapentin on the central nervous system and how it may mitigate alcohol withdrawal and increase the likelihood of abstinence. In addition, we review clinical trials that evaluated potential roles of gabapentin in AUD, discuss the drug’s misuse potential, and suggest a framework for its appropriate use in AUD management.

ALCOHOL USE DISORDER IS COMMON AND SERIOUS

AUD affects about 14% of US adults and represents a significant health burden,¹ often with severe clinical and social implications. It manifests as compulsive drinking and loss of control despite adverse consequences on various life domains.¹⁰ It is generally associated with cravings, tolerance, and withdrawal symptoms upon cessation. Alcohol withdrawal is characterized by tremors, anxiety, sweating, nausea, and tachycardia, and in severe cases, may involve hallucinations, seizures, and delirium tremens. Untreated, alcohol withdrawal can be fatal.¹⁰

Even though psychosocial treatments for AUD by themselves are associated with high relapse rates, pharmacotherapy is underutilized. Three drugs approved by the US Food and Drug Administration (FDA) are available to treat it, but they are often poorly accepted and have limited efficacy. For these reasons, there is considerable interest in finding alternatives. Gabapentin is one of several agents that have been studied (Table 1). The topic has been reviewed in depth by Soyka and Müller.¹¹

GABAPENTIN REDUCES EXCITATION

The anticonvulsant gabapentin is FDA-approved for treating epilepsy, postherpetic neuralgia, and restless leg syndrome.^8,12–14 It binds and selectively impedes voltage-sensitive calcium channels, the pores in cell membrane that permit calcium to enter a neuron in response to changes in electrical currents.¹⁵

Gabapentin is believed to decrease excitation of the central nervous system in multiple ways:

• It reduces the release of glutamate, a key component of the excitatory system¹⁶
• It increases the concentration of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain7
• By binding the alpha-2-delta type 1 subunit of voltage-sensitive calcium channels,^8,15–17 it inhibits excitatory synapse formation independent of calcium channel activity¹⁶
• By blocking excitatory neurotransmission, it also may indirectly increase the concentration of GABA in the central nervous system1^6,17
• It modulates action of glutamic acid decarboxylase (involved in the synthesis of GABA) and glutamate synthesizing enzyme to increase GABA and decrease glutamate.¹⁷

 

 

ALCOHOL’S ACTIONS

The actions of alcohol on the brain are also complex.¹⁸ Alpha-2-delta type 1 subunits of calcium channels are upregulated in the reward centers of the brain by addictive substances, including alcohol.¹⁶ Alcohol interacts with corticotropin-releasing factor and several neurotransmitters,¹⁸ and specifically affects neuropathways involving norepinephrine, GABA, and glutamate.¹⁹ Alcohol has reinforcing effects mediated by the release of dopamine in the nucleus accumbens.²⁰

Acutely, alcohol promotes GABA release and may also reduce GABA degradation, producing sedative and anxiolytic effects.²¹ Chronic alcohol use leads to a decrease in the number of GABAA receptors. Clinically, this downregulation manifests as tolerance to alcohol’s sedating effects.²¹

Alcohol affects the signaling of glutamatergic interaction with the N-methyl-d-aspartate (NMDA) receptor.²² Glutamate activates this receptor as well as the voltage-gated ion channels, modifying calcium influx and increasing neuronal excitability.^22,23 Acutely, alcohol has an antagonistic effect on the NMDA receptor, while chronic drinking upregulates (increases) the number of NMDA receptors and voltage-gated calcium channels.^22,23

Alcohol withdrawal increases excitatory effects

Patients experiencing alcohol withdrawal have decreased GABA-ergic functioning and increased glutamatergic action throughout the central nervous system.^19,24

Withdrawal can be subdivided into an acute phase (lasting up to about 5 days) and a protracted phase (of undetermined duration). During withdrawal, the brain activates its “stress system,” leading to overexpression of corticotropin-releasing factor in the amygdala. Protracted withdrawal dysregulates the prefrontal cortex, increasing cravings and worsening negative emotional states and sleep.¹⁶

GABAPENTIN FOR ALCOHOL WITHDRAWAL

Benzodiazepines are the standard treatment for alcohol withdrawal.^3,24 They relieve symptoms and can prevent seizures and delirium tremens,²⁴ but they are sedating and cause psychomotor impairments.³ Because of the potential for addiction, benzodiazepine use is limited to acute alcohol withdrawal.³

Gabapentin shows promise as an agent that can be used in withdrawal and continued through early abstinence without the highly addictive potential of benzodiazepines.¹⁶ It is thought to affect drinking behaviors during early abstinence by normalizing GABA and glutamate activity.^2,16

Early preclinical studies in mouse models found that gabapentin decreases anxiogenic and epileptic effects of alcohol withdrawal. Compared with other antidrinking medications, gabapentin has the benefits of lacking elimination via hepatic metabolism, few pharmacokinetic interactions, and good reported tolerability in this population.

Inpatient trials show no benefit over standard treatments

Bonnet et al²⁵ conducted a double-blind placebo-controlled trial in Germany in inpatients experiencing acute alcohol withdrawal to determine whether gabapentin might be an effective adjunct to clomethiazole, a GABAA modulator commonly used in Europe for alcohol withdrawal. Participants (N = 61) were randomized to receive placebo or gabapentin (400 mg every 6 hours) for 72 hours, with tapering over the next 3 days. All patients could receive rescue doses of clomethiazole, using a symptom-triggered protocol.

The study revealed no differences in the amount of clomethiazole administered between the 2 groups, suggesting that gabapentin had no adjunctive effect. Side effects (vertigo, nausea, dizziness, and ataxia) were mild and comparable between groups.

Nichols et al²⁶ conducted a retrospective cohort study in a South Carolina academic psychiatric hospital to assess the adjunctive effect of gabapentin on the as-needed use of benzodiazepines for alcohol withdrawal. The active group (n = 40) received gabapentin as well as a symptom-triggered alcohol withdrawal protocol of benzodiazepine. The control group (n = 43) received only the symptom-triggered alcohol withdrawal protocol without gabapentin.

No effect was found of gabapentin use for benzodiazepine treatment of alcohol withdrawal. It is notable that Bonnet et al and Nichols et al had similar findings despite their studies being conducted in different countries using distinct comparators and methods.

Bonnet et al,²⁷ in another study, tried a different design to investigate a possible role for gabapentin in inpatient alcohol withdrawal. The study included 37 patients with severe alcohol withdrawal (Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised [CIWA-Ar] > 15).

All participants received gabapentin 800 mg. Those whose CIWA-Ar score improved within 2 hours were considered “early responders” (n = 27) and next received 2 days of gabapentin 600 mg 4 times a day before starting a taper. The nonresponders whose CIWA-Ar score worsened (associated with greater anxiety and depressive symptoms; n = 10) were switched to standard treatment with clomethiazole (n = 4) or clonazepam (n = 6). Scores of 3 early responders subsequently worsened; 2 of these participants developed seizures and were switched to standard treatment.

The authors concluded that gabapentin in a dose of 3,200 mg in the first 24 hours is useful only for milder forms of alcohol withdrawal. Hence, subsequent efforts on the use of gabapentin for alcohol withdrawal have focused on outpatients.

Outpatient trials reveal benefits over benzodiazepines

Myrick et al³ compared gabapentin vs lorazepam in 100 outpatients seeking treatment for alcohol withdrawal. Participants were randomized to 1 of 4 groups: gabapentin 600 mg, 900 mg, or 1,200 mg, or lorazepam 6 mg, each tapering over 4 days. Alcohol withdrawal was measured by the CIWA-Ar score. Only 68 patients completed all follow-up appointments to day 12.

Gabapentin 600 mg was discontinued because of seizures in 2 patients, but it was generally well tolerated and was associated with diminished symptoms of alcohol withdrawal, especially at the 1,200 mg dose. The gabapentin groups experienced less anxiety and sedation and fewer cravings than the lorazepam group. Those treated with lorazepam fared worse for achieving early abstinence and were more likely to return to drinking when the intervention was discontinued. However, significant relapse by day 12 occurred in both groups.

The authors concluded that gabapentin was at least as effective as lorazepam in the outpatient treatment of alcohol withdrawal, with the 1,200-mg gabapentin dosage being more effective than 900 mg. At 1,200 mg, gabapentin was associated with better sleep, less anxiety, and better self-reported ability to work than lorazepam, and at the 900-mg dose it was associated with less depression than lorazepam.

Stock et al²⁸ conducted a randomized, double-blind study of gabapentin in acute alcohol withdrawal in 26 military veterans in an outpatient setting. Patients were ran­domized to one of the following:

• Gabapentin 1,200 mg orally for 3 days, followed by 900 mg, 600 mg, and 300 mg for 1 day each (n = 17)
• Chlordiazepoxide 100 mg orally for 3 days, followed by 75 mg, 50 mg, and 25 mg for 1 day each (n = 9).

Withdrawal scores improved similarly in both groups. Early on (days 1–4), neither cravings nor sleep differed significantly between groups; but later (days 5–7), the gabapentin group had superior scores for these measures. Gabapentin was also associated with significantly less sedation than chlordiazepoxide and trended to less alcohol craving.

 

 

Bottom line: Gabapentin is useful for mild withdrawal

Data suggest that gabapentin offers benefits for managing mild alcohol withdrawal. Improved residual craving and sleep measures are clinically important because they are risk factors for relapse. Mood and anxiety also improve with gabapentin, further indicating a therapeutic effect.

Gabapentin’s benefits for moderate and severe alcohol withdrawal have not been established. Seizures occurred during withdrawal despite gabapentin treatment, but whether from an insufficient dose, patient susceptibility, or lack of gabapentin efficacy is not clear. Best results occurred at the 1,200-mg daily dose, but benefits may not apply to patients with severe withdrawal. In addition, many studies were small, limiting the strength of conclusions.

Across most studies of gabapentin for alcohol withdrawal, advantages included a smoother transition into early abstinence due to improved sleep, mood, and anxiety, alleviating common triggers for a return to drinking. Gabapentin also carries less reinforcing potential than benzodiazepines. These qualities fueled interest in trying gabapentin to improve long-term abstinence.

GABAPENTIN FOR RELAPSE PREVENTION

Although naltrexone and acamprosate are the first-line treatments for relapse prevention, they do not help all patients and are more effective when combined with cognitive behavioral therapy.^1,29,30 For patients in whom standard treatments are not effective or tolerated, gabapentin may provide a reasonable alternative, and several randomized controlled trials have examined its use for this role.

Gabapentin alone is better than placebo

Furieri and Nakamura-Palacios⁴ assessed the use of gabapentin for relapse prevention in Brazilian outpatients (N = 60) who had averaged 27 years of drinking and consumed 17 drinks daily for the 90 days before baseline. After detoxification with diazepam and vitamins, patients were randomized to either gabapentin 300 mg twice daily or placebo for 4 weeks.

Compared with placebo, gabapentin significantly reduced cravings and lowered the percentage of heavy drinking days and the number of drinks per day, with a significant increase in the percentage of abstinent days. These self-reported measures correlated with decreases in gamma-glutamyl transferase, a biological marker for heavy drinking.

Brower et al³¹ investigated the use of gabapentin in 21 outpatients with AUD and insomnia who desired to remain abstinent. They were randomized to gabapentin (up to 1,500 mg at night) or placebo for 6 weeks. Just 14 participants completed the study; all but 2 were followed without treatment until week 12.

Gabapentin was associated with significantly lower relapse rates at 6 weeks (3 of 10 in the gabapentin group vs 9 of 11 in the placebo group) and at 12 weeks (6 of 10 in the gabapentin group vs 11 of 11 in the placebo group, assuming the 2 patients lost to follow-up relapsed). No difference between groups was detected for sleep measures in this small study. However, other studies have found that gabapentin for AUD improves measures of insomnia and daytime drowsiness—predictors of relapse—compared with other medications.¹⁶

High-dose gabapentin is better

Mason et al² randomized 150 outpatients with alcohol dependence to 12 weeks of daily treatment with either gabapentin (900 mg or 1,800 mg) or placebo after at least 3 days of abstinence. All participants received counseling. Drinking quantity and frequency were assessed by gamma-glutamyl transferase testing.

Patients taking gabapentin had better rates of abstinence and cessation of heavy drinking than those taking placebo. During the 12-week study, the 1,800-mg daily dose showed a substantially higher abstinence rate (17%) than either 900 mg  (11%) or placebo (4%). Significant dose-related improvements were also found for heavy drinking days, total drinking quantity, and frequency of alcohol withdrawal symptoms that predispose to early relapse, such as poor sleep, cravings, and poor mood. There were also significant linear dose effects on rates of abstinence and nondrinking days at the 24-week posttreatment follow-up.

Gabapentin plus naltrexone is better than naltrexone alone

Anton et al⁵ examined the efficacy of gabapentin combined with naltrexone during early abstinence. The study randomly assigned 150 people with AUD to one of the following groups:

• 16 weeks of naltrexone (50 mg/day) alone
• 6 weeks of naltrexone (50 mg/day) plus gabapentin (up to 1,200 mg/day), followed by 10 weeks of naltrexone alone
• Placebo.

All participants received medical management.

Over the first 6 weeks, those receiving naltrexone plus gabapentin had a longer interval to heavy drinking than those taking only naltrexone. By week 6, about half of those taking placebo or naltrexone alone had a heavy drinking day, compared with about 35% of those taking naltrexone plus gabapentin. Those receiving the combination also had fewer days of heavy drinking, fewer drinks per drinking day, and better sleep than the other groups. Participants in the naltrexone-alone group were more likely to drink heavily during periods in which they reported poor sleep. No significant group differences were found in measures of mood.

Gabapentin enacarbil is no better than placebo

Falk et al,³² in a 2019 preliminary analysis, examined data from a trial of gabapentin enacarbil, a prodrug formulation of gabapentin. In this 6-month double-blind study, 346 people with moderate AUD at 10 sites were randomized to gabapentin enacarbil extended-release 600 mg twice a day or placebo. All subjects received a computerized behavioral intervention.

No significant differences between groups were found in drinking measures or alcohol cravings, sleep problems, depression, or anxiety symptoms. However, a dose-response analysis found significantly less drinking for higher doses of the drug.

Bottom line: Evidence of benefits mixed but risk low

The efficacy of gabapentin as a treatment for AUD has varied across studies as a function of dosing and formulation. Daily doses have ranged from 600 mg to 1,800 mg, with the highest dose showing advantages in one study for cravings, insomnia, anxiety, dysphoria, and relapse.² Thus far, gabapentin immediate-release has performed better than gabapentin enacarbil extended-release. All forms of gabapentin have been well-tolerated in AUD trials.

The 2018 American Psychiatric Association guidelines stated that gabapentin had a small positive effect on drinking outcomes, but the harm of treatment was deemed minimal, especially relative to the harms of chronic drinking.³³ The guidelines endorse the use of gabapentin in patients with moderate to severe AUD who select gabapentin from the available options, or for those who are nonresponsive to or cannot tolerate naltrexone or acamprosate, as long as no contraindications exist. It was also noted that even small effects may be clinically important, considering the significant morbidity associated with AUD.

 

 

POTENTIAL FOR MISUSE

The use of gabapentin has become controversial owing to the growing recognition that it may not be as benign as initially thought.^7–9,34 A review of US legislative actions reflects concerns about its misuse.³⁵ In July 2017, Kentucky classified it as a schedule V controlled substance with prescription drug monitoring,³⁵ as did Tennessee in 2018³⁶ and Michigan in January 2019.³⁷ Currently, 8 other states (Massachusetts, Minnesota, Nebraska, North Dakota, Ohio, Virginia, Wyoming, and West Virginia) require prescription drug monitoring of gabapentin, and other states are considering it.³⁵

Efforts to understand gabapentin misuse derive largely from people with drug use disorders. A review of postmortem toxicology reports in fatal drug overdoses found gabapentin present in 22%.³⁸ Although it was not necessarily a cause of death, its high rate of detection suggests wide misuse among drug users.

Among a cohort of 503 prescription opioid misusers in Appalachian Kentucky, 15% reported using gabapentin “to get high.” Those who reported misusing gabapentin were 6 times more likely than nonusers to be abusing opioids and benzodiazepines. The main sources of gabapentin were doctors (52%) and dealers (36%). The average cost of gabapentin on the street was less than $1.00 per pill.³⁹

Gabapentin misuse by methadone clinic patients is also reported. Baird et al⁴⁰ surveyed patients in 6 addiction clinics in the United Kingdom for gabapentin and pregabalin abuse and found that 22% disclosed misusing these medications. Of these, 38% said they did so to enhance the methadone high.

In a review article, Quintero⁴¹ also cited enhancement of methadone euphoria and treatment of opioid withdrawal as motivations for misuse. Opioid-dependent gabapentin misusers consumed doses of gabapentin 3 to 20 times higher than clinically recommended and in combination with multiple drugs.⁴ Such use can cause dissociative and psychedelic effects.

Gabapentin also potentiates the sedative effects of opioids, thus increasing the risk of falls, accidents, and other adverse events.^34,35 Risk of opioid-related deaths was increased with coprescription of gabapentin and with moderate to high gabapentin doses.³⁴

Are people with AUD at higher risk of gabapentin abuse?

Despite concerns, patients in clinical trials of gabapentin treatment for AUD were not identified as at high risk for misuse of the drug.^2,4,5,16 Further, no such trials reported serious drug-related adverse events resulting in gabapentin discontinuation or side effects that differed from placebo in frequency or severity.^2,4,5,16

Clinical laboratory studies also have found no significant interactions between alcohol and gabapentin.^42,43 In fact, they showed no influence of gabapentin on the pharmacokinetics of alcohol or on alcohol’s subjective effects. Relative to placebo, gabapentin did not affect blood alcohol levels, the degree of intoxication, sedation, craving, or alcohol self-administration.

Smith et al⁹ reported estimates that only 1% of the general population misuse gabapentin. Another review concluded that gabapentin is seldom a drug of choice.¹⁷ Most patients prescribed gabapentin do not experience cravings or loss of control, which are hallmarks of addiction. Hence, with adequate precautions, the off-label use of gabapentin for AUD is reasonable.

CLINICAL IMPLICATIONS OF GABAPENTIN PRESCRIBING

Overall, evidence for the benefit of gabapentin in AUD is mixed. Subgroups of alcoholic patients, such as those who do not respond to or tolerate standard therapies, may particularly benefit, as may those with comorbid insomnia or neuropathic pain.⁴⁴ Clinicians should prescribe gabapentin only when it is likely to be helpful and should carefully document its efficacy.^2,45

At each visit, an open and honest assessment of the benefits and risks serves to promote shared decision-making regarding initiating, continuing, or discontinuing gabapentin.

For alcohol withdrawal

Before gabapentin is prescribed for alcohol withdrawal, potential benefits (reduction of withdrawal symptoms), side effects (sedation, fatigue), and risks (falls) should be discussed with the patient.⁴⁶ Patients should also be informed that benzodiazepines are the gold standard for alcohol withdrawal and that gabapentin is not effective for severe withdrawal.⁴⁶

For relapse prevention

When initiating treatment for relapse prevention, the patient and the prescriber should agree on specific goals (eg, reduction of drinking, anxiety, and insomnia).^2,16 Ongoing monitoring is essential and includes assessing and documenting improvement with respect to these goals.

In the AUD studies, gabapentin was well tolerated.¹⁶ Frequently observed side effects including headache, insomnia, fatigue, muscle aches, and gastrointestinal distress did not occur at a statistically different rate from placebo. However, patients in studies are selected samples, and their experience may not be generalizable to clinical practice. Thus, it is necessary to exercise caution and check for comorbidities that may put patients at risk of complications.⁴⁷ Older patients and those on hemodialysis are more susceptible to gabapentin side effects such as sedation, dizziness, ataxia, and mental status changes,³⁴ and prescribers should be alert for signs of toxicity (eg, ataxia, mental status changes).^47,48

Gabapentin misuse was not observed in AUD studies,^2,4,5,16 but evidence indicates that patients with opioid use disorder, prisoners, and polydrug users are at high risk for gabapentin misuse.^39–41 In all cases, clinicians should monitor for red flags that may indicate abuse, such as missed appointments, early refill requests, demands for increased dosage, and simultaneous opiate and benzodiazepine use.⁴⁹

Acknowledgment: The authors wish to thank Nick Mulligan for his invaluable assistance with formatting and grammar.

Perceptions regarding the use of gabapentin for alcohol use disorder (AUD) have shifted over time.^1–4 Early on, the drug was deemed to be benign and effective.^4–6 But more and more, concerns are being raised about its recreational use to achieve euphoria,⁷ and the drug is often misused by vulnerable populations, particularly those with opioid use disorder.^7–9

Given the large number of gabapentin prescriptions written off-label for AUD, it is incumbent on providers to understand how to prescribe it responsibly.^7–9 To that end, this article focuses on the benefits—and concerns—of this treatment option. We describe the effects of gabapentin on the central nervous system and how it may mitigate alcohol withdrawal and increase the likelihood of abstinence. In addition, we review clinical trials that evaluated potential roles of gabapentin in AUD, discuss the drug’s misuse potential, and suggest a framework for its appropriate use in AUD management.

ALCOHOL USE DISORDER IS COMMON AND SERIOUS

AUD affects about 14% of US adults and represents a significant health burden,¹ often with severe clinical and social implications. It manifests as compulsive drinking and loss of control despite adverse consequences on various life domains.¹⁰ It is generally associated with cravings, tolerance, and withdrawal symptoms upon cessation. Alcohol withdrawal is characterized by tremors, anxiety, sweating, nausea, and tachycardia, and in severe cases, may involve hallucinations, seizures, and delirium tremens. Untreated, alcohol withdrawal can be fatal.¹⁰

Even though psychosocial treatments for AUD by themselves are associated with high relapse rates, pharmacotherapy is underutilized. Three drugs approved by the US Food and Drug Administration (FDA) are available to treat it, but they are often poorly accepted and have limited efficacy. For these reasons, there is considerable interest in finding alternatives. Gabapentin is one of several agents that have been studied (Table 1). The topic has been reviewed in depth by Soyka and Müller.¹¹

GABAPENTIN REDUCES EXCITATION

The anticonvulsant gabapentin is FDA-approved for treating epilepsy, postherpetic neuralgia, and restless leg syndrome.^8,12–14 It binds and selectively impedes voltage-sensitive calcium channels, the pores in cell membrane that permit calcium to enter a neuron in response to changes in electrical currents.¹⁵

Gabapentin is believed to decrease excitation of the central nervous system in multiple ways:

• It reduces the release of glutamate, a key component of the excitatory system¹⁶
• It increases the concentration of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain7
• By binding the alpha-2-delta type 1 subunit of voltage-sensitive calcium channels,^8,15–17 it inhibits excitatory synapse formation independent of calcium channel activity¹⁶
• By blocking excitatory neurotransmission, it also may indirectly increase the concentration of GABA in the central nervous system1^6,17
• It modulates action of glutamic acid decarboxylase (involved in the synthesis of GABA) and glutamate synthesizing enzyme to increase GABA and decrease glutamate.¹⁷

 

 

ALCOHOL’S ACTIONS

The actions of alcohol on the brain are also complex.¹⁸ Alpha-2-delta type 1 subunits of calcium channels are upregulated in the reward centers of the brain by addictive substances, including alcohol.¹⁶ Alcohol interacts with corticotropin-releasing factor and several neurotransmitters,¹⁸ and specifically affects neuropathways involving norepinephrine, GABA, and glutamate.¹⁹ Alcohol has reinforcing effects mediated by the release of dopamine in the nucleus accumbens.²⁰

Acutely, alcohol promotes GABA release and may also reduce GABA degradation, producing sedative and anxiolytic effects.²¹ Chronic alcohol use leads to a decrease in the number of GABAA receptors. Clinically, this downregulation manifests as tolerance to alcohol’s sedating effects.²¹

Alcohol affects the signaling of glutamatergic interaction with the N-methyl-d-aspartate (NMDA) receptor.²² Glutamate activates this receptor as well as the voltage-gated ion channels, modifying calcium influx and increasing neuronal excitability.^22,23 Acutely, alcohol has an antagonistic effect on the NMDA receptor, while chronic drinking upregulates (increases) the number of NMDA receptors and voltage-gated calcium channels.^22,23

Alcohol withdrawal increases excitatory effects

Patients experiencing alcohol withdrawal have decreased GABA-ergic functioning and increased glutamatergic action throughout the central nervous system.^19,24

Withdrawal can be subdivided into an acute phase (lasting up to about 5 days) and a protracted phase (of undetermined duration). During withdrawal, the brain activates its “stress system,” leading to overexpression of corticotropin-releasing factor in the amygdala. Protracted withdrawal dysregulates the prefrontal cortex, increasing cravings and worsening negative emotional states and sleep.¹⁶

GABAPENTIN FOR ALCOHOL WITHDRAWAL

Benzodiazepines are the standard treatment for alcohol withdrawal.^3,24 They relieve symptoms and can prevent seizures and delirium tremens,²⁴ but they are sedating and cause psychomotor impairments.³ Because of the potential for addiction, benzodiazepine use is limited to acute alcohol withdrawal.³

Gabapentin shows promise as an agent that can be used in withdrawal and continued through early abstinence without the highly addictive potential of benzodiazepines.¹⁶ It is thought to affect drinking behaviors during early abstinence by normalizing GABA and glutamate activity.^2,16

Early preclinical studies in mouse models found that gabapentin decreases anxiogenic and epileptic effects of alcohol withdrawal. Compared with other antidrinking medications, gabapentin has the benefits of lacking elimination via hepatic metabolism, few pharmacokinetic interactions, and good reported tolerability in this population.

Inpatient trials show no benefit over standard treatments

Bonnet et al²⁵ conducted a double-blind placebo-controlled trial in Germany in inpatients experiencing acute alcohol withdrawal to determine whether gabapentin might be an effective adjunct to clomethiazole, a GABAA modulator commonly used in Europe for alcohol withdrawal. Participants (N = 61) were randomized to receive placebo or gabapentin (400 mg every 6 hours) for 72 hours, with tapering over the next 3 days. All patients could receive rescue doses of clomethiazole, using a symptom-triggered protocol.

The study revealed no differences in the amount of clomethiazole administered between the 2 groups, suggesting that gabapentin had no adjunctive effect. Side effects (vertigo, nausea, dizziness, and ataxia) were mild and comparable between groups.

Nichols et al²⁶ conducted a retrospective cohort study in a South Carolina academic psychiatric hospital to assess the adjunctive effect of gabapentin on the as-needed use of benzodiazepines for alcohol withdrawal. The active group (n = 40) received gabapentin as well as a symptom-triggered alcohol withdrawal protocol of benzodiazepine. The control group (n = 43) received only the symptom-triggered alcohol withdrawal protocol without gabapentin.

No effect was found of gabapentin use for benzodiazepine treatment of alcohol withdrawal. It is notable that Bonnet et al and Nichols et al had similar findings despite their studies being conducted in different countries using distinct comparators and methods.

Bonnet et al,²⁷ in another study, tried a different design to investigate a possible role for gabapentin in inpatient alcohol withdrawal. The study included 37 patients with severe alcohol withdrawal (Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised [CIWA-Ar] > 15).

All participants received gabapentin 800 mg. Those whose CIWA-Ar score improved within 2 hours were considered “early responders” (n = 27) and next received 2 days of gabapentin 600 mg 4 times a day before starting a taper. The nonresponders whose CIWA-Ar score worsened (associated with greater anxiety and depressive symptoms; n = 10) were switched to standard treatment with clomethiazole (n = 4) or clonazepam (n = 6). Scores of 3 early responders subsequently worsened; 2 of these participants developed seizures and were switched to standard treatment.

The authors concluded that gabapentin in a dose of 3,200 mg in the first 24 hours is useful only for milder forms of alcohol withdrawal. Hence, subsequent efforts on the use of gabapentin for alcohol withdrawal have focused on outpatients.

Outpatient trials reveal benefits over benzodiazepines

Myrick et al³ compared gabapentin vs lorazepam in 100 outpatients seeking treatment for alcohol withdrawal. Participants were randomized to 1 of 4 groups: gabapentin 600 mg, 900 mg, or 1,200 mg, or lorazepam 6 mg, each tapering over 4 days. Alcohol withdrawal was measured by the CIWA-Ar score. Only 68 patients completed all follow-up appointments to day 12.

Gabapentin 600 mg was discontinued because of seizures in 2 patients, but it was generally well tolerated and was associated with diminished symptoms of alcohol withdrawal, especially at the 1,200 mg dose. The gabapentin groups experienced less anxiety and sedation and fewer cravings than the lorazepam group. Those treated with lorazepam fared worse for achieving early abstinence and were more likely to return to drinking when the intervention was discontinued. However, significant relapse by day 12 occurred in both groups.

The authors concluded that gabapentin was at least as effective as lorazepam in the outpatient treatment of alcohol withdrawal, with the 1,200-mg gabapentin dosage being more effective than 900 mg. At 1,200 mg, gabapentin was associated with better sleep, less anxiety, and better self-reported ability to work than lorazepam, and at the 900-mg dose it was associated with less depression than lorazepam.

Stock et al²⁸ conducted a randomized, double-blind study of gabapentin in acute alcohol withdrawal in 26 military veterans in an outpatient setting. Patients were ran­domized to one of the following:

• Gabapentin 1,200 mg orally for 3 days, followed by 900 mg, 600 mg, and 300 mg for 1 day each (n = 17)
• Chlordiazepoxide 100 mg orally for 3 days, followed by 75 mg, 50 mg, and 25 mg for 1 day each (n = 9).

Withdrawal scores improved similarly in both groups. Early on (days 1–4), neither cravings nor sleep differed significantly between groups; but later (days 5–7), the gabapentin group had superior scores for these measures. Gabapentin was also associated with significantly less sedation than chlordiazepoxide and trended to less alcohol craving.

 

 

Bottom line: Gabapentin is useful for mild withdrawal

Data suggest that gabapentin offers benefits for managing mild alcohol withdrawal. Improved residual craving and sleep measures are clinically important because they are risk factors for relapse. Mood and anxiety also improve with gabapentin, further indicating a therapeutic effect.

Gabapentin’s benefits for moderate and severe alcohol withdrawal have not been established. Seizures occurred during withdrawal despite gabapentin treatment, but whether from an insufficient dose, patient susceptibility, or lack of gabapentin efficacy is not clear. Best results occurred at the 1,200-mg daily dose, but benefits may not apply to patients with severe withdrawal. In addition, many studies were small, limiting the strength of conclusions.

Across most studies of gabapentin for alcohol withdrawal, advantages included a smoother transition into early abstinence due to improved sleep, mood, and anxiety, alleviating common triggers for a return to drinking. Gabapentin also carries less reinforcing potential than benzodiazepines. These qualities fueled interest in trying gabapentin to improve long-term abstinence.

GABAPENTIN FOR RELAPSE PREVENTION

Although naltrexone and acamprosate are the first-line treatments for relapse prevention, they do not help all patients and are more effective when combined with cognitive behavioral therapy.^1,29,30 For patients in whom standard treatments are not effective or tolerated, gabapentin may provide a reasonable alternative, and several randomized controlled trials have examined its use for this role.

Gabapentin alone is better than placebo

Furieri and Nakamura-Palacios⁴ assessed the use of gabapentin for relapse prevention in Brazilian outpatients (N = 60) who had averaged 27 years of drinking and consumed 17 drinks daily for the 90 days before baseline. After detoxification with diazepam and vitamins, patients were randomized to either gabapentin 300 mg twice daily or placebo for 4 weeks.

Compared with placebo, gabapentin significantly reduced cravings and lowered the percentage of heavy drinking days and the number of drinks per day, with a significant increase in the percentage of abstinent days. These self-reported measures correlated with decreases in gamma-glutamyl transferase, a biological marker for heavy drinking.

Brower et al³¹ investigated the use of gabapentin in 21 outpatients with AUD and insomnia who desired to remain abstinent. They were randomized to gabapentin (up to 1,500 mg at night) or placebo for 6 weeks. Just 14 participants completed the study; all but 2 were followed without treatment until week 12.

Gabapentin was associated with significantly lower relapse rates at 6 weeks (3 of 10 in the gabapentin group vs 9 of 11 in the placebo group) and at 12 weeks (6 of 10 in the gabapentin group vs 11 of 11 in the placebo group, assuming the 2 patients lost to follow-up relapsed). No difference between groups was detected for sleep measures in this small study. However, other studies have found that gabapentin for AUD improves measures of insomnia and daytime drowsiness—predictors of relapse—compared with other medications.¹⁶

High-dose gabapentin is better

Mason et al² randomized 150 outpatients with alcohol dependence to 12 weeks of daily treatment with either gabapentin (900 mg or 1,800 mg) or placebo after at least 3 days of abstinence. All participants received counseling. Drinking quantity and frequency were assessed by gamma-glutamyl transferase testing.

Patients taking gabapentin had better rates of abstinence and cessation of heavy drinking than those taking placebo. During the 12-week study, the 1,800-mg daily dose showed a substantially higher abstinence rate (17%) than either 900 mg  (11%) or placebo (4%). Significant dose-related improvements were also found for heavy drinking days, total drinking quantity, and frequency of alcohol withdrawal symptoms that predispose to early relapse, such as poor sleep, cravings, and poor mood. There were also significant linear dose effects on rates of abstinence and nondrinking days at the 24-week posttreatment follow-up.

Gabapentin plus naltrexone is better than naltrexone alone

Anton et al⁵ examined the efficacy of gabapentin combined with naltrexone during early abstinence. The study randomly assigned 150 people with AUD to one of the following groups:

• 16 weeks of naltrexone (50 mg/day) alone
• 6 weeks of naltrexone (50 mg/day) plus gabapentin (up to 1,200 mg/day), followed by 10 weeks of naltrexone alone
• Placebo.

All participants received medical management.

Over the first 6 weeks, those receiving naltrexone plus gabapentin had a longer interval to heavy drinking than those taking only naltrexone. By week 6, about half of those taking placebo or naltrexone alone had a heavy drinking day, compared with about 35% of those taking naltrexone plus gabapentin. Those receiving the combination also had fewer days of heavy drinking, fewer drinks per drinking day, and better sleep than the other groups. Participants in the naltrexone-alone group were more likely to drink heavily during periods in which they reported poor sleep. No significant group differences were found in measures of mood.

Gabapentin enacarbil is no better than placebo

Falk et al,³² in a 2019 preliminary analysis, examined data from a trial of gabapentin enacarbil, a prodrug formulation of gabapentin. In this 6-month double-blind study, 346 people with moderate AUD at 10 sites were randomized to gabapentin enacarbil extended-release 600 mg twice a day or placebo. All subjects received a computerized behavioral intervention.

No significant differences between groups were found in drinking measures or alcohol cravings, sleep problems, depression, or anxiety symptoms. However, a dose-response analysis found significantly less drinking for higher doses of the drug.

Bottom line: Evidence of benefits mixed but risk low

The efficacy of gabapentin as a treatment for AUD has varied across studies as a function of dosing and formulation. Daily doses have ranged from 600 mg to 1,800 mg, with the highest dose showing advantages in one study for cravings, insomnia, anxiety, dysphoria, and relapse.² Thus far, gabapentin immediate-release has performed better than gabapentin enacarbil extended-release. All forms of gabapentin have been well-tolerated in AUD trials.

The 2018 American Psychiatric Association guidelines stated that gabapentin had a small positive effect on drinking outcomes, but the harm of treatment was deemed minimal, especially relative to the harms of chronic drinking.³³ The guidelines endorse the use of gabapentin in patients with moderate to severe AUD who select gabapentin from the available options, or for those who are nonresponsive to or cannot tolerate naltrexone or acamprosate, as long as no contraindications exist. It was also noted that even small effects may be clinically important, considering the significant morbidity associated with AUD.

 

 

POTENTIAL FOR MISUSE

The use of gabapentin has become controversial owing to the growing recognition that it may not be as benign as initially thought.^7–9,34 A review of US legislative actions reflects concerns about its misuse.³⁵ In July 2017, Kentucky classified it as a schedule V controlled substance with prescription drug monitoring,³⁵ as did Tennessee in 2018³⁶ and Michigan in January 2019.³⁷ Currently, 8 other states (Massachusetts, Minnesota, Nebraska, North Dakota, Ohio, Virginia, Wyoming, and West Virginia) require prescription drug monitoring of gabapentin, and other states are considering it.³⁵

Efforts to understand gabapentin misuse derive largely from people with drug use disorders. A review of postmortem toxicology reports in fatal drug overdoses found gabapentin present in 22%.³⁸ Although it was not necessarily a cause of death, its high rate of detection suggests wide misuse among drug users.

Among a cohort of 503 prescription opioid misusers in Appalachian Kentucky, 15% reported using gabapentin “to get high.” Those who reported misusing gabapentin were 6 times more likely than nonusers to be abusing opioids and benzodiazepines. The main sources of gabapentin were doctors (52%) and dealers (36%). The average cost of gabapentin on the street was less than $1.00 per pill.³⁹

Gabapentin misuse by methadone clinic patients is also reported. Baird et al⁴⁰ surveyed patients in 6 addiction clinics in the United Kingdom for gabapentin and pregabalin abuse and found that 22% disclosed misusing these medications. Of these, 38% said they did so to enhance the methadone high.

In a review article, Quintero⁴¹ also cited enhancement of methadone euphoria and treatment of opioid withdrawal as motivations for misuse. Opioid-dependent gabapentin misusers consumed doses of gabapentin 3 to 20 times higher than clinically recommended and in combination with multiple drugs.⁴ Such use can cause dissociative and psychedelic effects.

Gabapentin also potentiates the sedative effects of opioids, thus increasing the risk of falls, accidents, and other adverse events.^34,35 Risk of opioid-related deaths was increased with coprescription of gabapentin and with moderate to high gabapentin doses.³⁴

Are people with AUD at higher risk of gabapentin abuse?

Despite concerns, patients in clinical trials of gabapentin treatment for AUD were not identified as at high risk for misuse of the drug.^2,4,5,16 Further, no such trials reported serious drug-related adverse events resulting in gabapentin discontinuation or side effects that differed from placebo in frequency or severity.^2,4,5,16

Clinical laboratory studies also have found no significant interactions between alcohol and gabapentin.^42,43 In fact, they showed no influence of gabapentin on the pharmacokinetics of alcohol or on alcohol’s subjective effects. Relative to placebo, gabapentin did not affect blood alcohol levels, the degree of intoxication, sedation, craving, or alcohol self-administration.

Smith et al⁹ reported estimates that only 1% of the general population misuse gabapentin. Another review concluded that gabapentin is seldom a drug of choice.¹⁷ Most patients prescribed gabapentin do not experience cravings or loss of control, which are hallmarks of addiction. Hence, with adequate precautions, the off-label use of gabapentin for AUD is reasonable.

CLINICAL IMPLICATIONS OF GABAPENTIN PRESCRIBING

Overall, evidence for the benefit of gabapentin in AUD is mixed. Subgroups of alcoholic patients, such as those who do not respond to or tolerate standard therapies, may particularly benefit, as may those with comorbid insomnia or neuropathic pain.⁴⁴ Clinicians should prescribe gabapentin only when it is likely to be helpful and should carefully document its efficacy.^2,45

At each visit, an open and honest assessment of the benefits and risks serves to promote shared decision-making regarding initiating, continuing, or discontinuing gabapentin.

For alcohol withdrawal

Before gabapentin is prescribed for alcohol withdrawal, potential benefits (reduction of withdrawal symptoms), side effects (sedation, fatigue), and risks (falls) should be discussed with the patient.⁴⁶ Patients should also be informed that benzodiazepines are the gold standard for alcohol withdrawal and that gabapentin is not effective for severe withdrawal.⁴⁶

For relapse prevention

When initiating treatment for relapse prevention, the patient and the prescriber should agree on specific goals (eg, reduction of drinking, anxiety, and insomnia).^2,16 Ongoing monitoring is essential and includes assessing and documenting improvement with respect to these goals.

In the AUD studies, gabapentin was well tolerated.¹⁶ Frequently observed side effects including headache, insomnia, fatigue, muscle aches, and gastrointestinal distress did not occur at a statistically different rate from placebo. However, patients in studies are selected samples, and their experience may not be generalizable to clinical practice. Thus, it is necessary to exercise caution and check for comorbidities that may put patients at risk of complications.⁴⁷ Older patients and those on hemodialysis are more susceptible to gabapentin side effects such as sedation, dizziness, ataxia, and mental status changes,³⁴ and prescribers should be alert for signs of toxicity (eg, ataxia, mental status changes).^47,48

Gabapentin misuse was not observed in AUD studies,^2,4,5,16 but evidence indicates that patients with opioid use disorder, prisoners, and polydrug users are at high risk for gabapentin misuse.^39–41 In all cases, clinicians should monitor for red flags that may indicate abuse, such as missed appointments, early refill requests, demands for increased dosage, and simultaneous opiate and benzodiazepine use.⁴⁹

Acknowledgment: The authors wish to thank Nick Mulligan for his invaluable assistance with formatting and grammar.

The benefits of influenza vaccination are clear to those in the medical community. Yet misinformation and unfounded fears continue to discourage some people from getting a flu shot. During the 2018–2019 influenza season, only 45% of US adults and 63% of children were vaccinated.¹

‘IT DOESN’T WORK FOR MANY PEOPLE’

Multiple studies have shown that the flu vaccine prevents millions of flu cases and flu-related doctor’s visits each year. During the 2016–2017 flu season, flu vaccine prevented an estimated 5.3 million influenza cases, 2.6 million influenza-associated medical visits, and 85,000 influenza-associated hospitalizations.²

Several viral and host factors affect vaccine effectiveness. In seasons when the vaccine viruses have matched circulating strains, flu vaccine has been shown to reduce the following:

• The risk of having to go to the doctor with flu by 40% to 60%
• Children’s risk of flu-related death and intensive care unit (ICU) admission by 74%
• The risk in adults of flu-associated hospitalizations by 40% and ICU admission by 82%
• The rate of cardiac events in people with heart disease
• Hospitalizations in people with diabetes or underlying chronic lung disease.³

In people hospitalized with influenza despite receiving the flu vaccine for the season, studies have shown that receiving the flu vaccine shortens the average duration of hospitalization, reduces the chance of ICU admission by 59%, shortens the duration of ICU stay by 4 days, and reduces deaths.³

‘IT TARGETS THE WRONG VIRUS’

Selecting an effective influenza vaccine is a challenge. Every year, the World Health Organization and the CDC decide on the influenza strains expected to circulate in the upcoming flu season in the Northern Hemisphere, based on data for circulating strains in the Southern Hemisphere. This decision takes place about 7 months before the expected onset of the flu season. Flu viruses may mutate between the time the decision is made and the time the vaccine is administered (as well as after the flu season starts). Also, vaccine production in eggs needs time, which is why this decision must be made several months ahead of the flu season.

Vaccine effectiveness varies by virus serotype. Vaccines are typically less effective against influenza A H3N2 viruses than against influenza A H1N1 and influenza B viruses. Effectiveness also varies from season to season depending on how close the vaccine serotypes match the circulating serotypes, but some effectiveness is retained even in seasons when some of the serotypes don’t match circulating viruses. For example, in the 2017–2018 season, when the influenza A H3N2 vaccine serotype did not match the circulating serotype, the overall effectiveness in preventing medically attended, laboratory-confirmed influenza virus infection was 36%.⁵

A universal flu vaccine that does not need to be updated annually is the ultimate solution, but according to the National Institute of Allergy and Infectious Diseases, such a vaccine is likely several years away.⁶

‘IT MAKES PEOPLE SICK’

Pain at the injection site of a flu shot occurs in 10% to 65% of people, lasts less than 2 days, and does not usually interfere with daily activities.⁷

Systemic symptoms such as fever, malaise, and myalgia may occur in people who have had no previous exposure to the influenza virus antigens in the vaccine, particularly in children. In adults, the frequency of systemic symptoms after the flu shot is similar to that with placebo.

The Vaccine Adverse Event Reporting System, which has been capturing data since 1990, shows that the influenza vaccine accounted for 5.7% of people who developed malaise after receiving any vaccine.⁸

The injectable inactivated influenza vaccine cannot biologically cause an influenza virus-related illness, since the inactivated vaccine viruses can elicit a protective immune response but cannot replicate. The nasal live-attenuated flu vaccine can in theory cause acute illness in the person receiving it, but because it is cold-adapted, it multiplies only in the colder environment of the nasal epithelium, not in the lower airways where the temperature is higher. Consequently, the vaccine virus triggers immunity by multiplying in the nose, but doesn’t infect the lungs.

From 10% to 50% of people who receive the nasal live-attenuated vaccine develop runny nose, wheezing, headache, vomiting, muscle aches, fever, sore throat, or cough shortly after receiving the vaccine, but these symptoms are usually mild and short-lived.

The most common reactions people have to flu vaccines are considerably less severe than the symptoms caused by actual flu illness.

While influenza illness results in natural immunity to the specific viral serotype causing it, this illness results in hospitalization in 2% and is fatal in 0.16% of people. Influenza vaccine results in immunity to the serotypes included in the vaccine, and multiple studies have not found a causal relationship between vaccination and death.⁹

 

 

‘IT CAUSES GUILLAIN-BARRÉ SYNDROME’

In the United States, 3,000 to 6,000 people per year develop Guillain-Barré syndrome, or 1 to 2 of every 100,000, which translates to 80 to 160 cases per week.¹⁰ While the exact cause of Guillain-Barré syndrome is unknown, about two-thirds of people have an acute diarrheal or respiratory illness within 3 months before the onset of symptoms. In 1976, the estimated attributable risk of influenza vaccine-related Guillain-Barré syndrome in the US adult population was 1 case per 100,000 in the 6 weeks after vaccination.¹¹ Studies in subsequent influenza seasons have not shown similar findings.¹² In fact, one study showed that the risk of developing Guillain-Barré syndrome was 15 times higher after influenza illness than after influenza vaccination.¹³

Since 5% to 15% of the US population develop symptomatic influenza annually,¹⁴ the decision to vaccinate with respect to the risk of Guillain-Barré syndrome should be obvious: vaccinate. The correct question to ask before influenza vaccination should be, “Have you previously developed Guillain-Barré syndrome within 6 weeks after receiving the flu vaccine?” If the answer is yes, the CDC considers this a caution, not a contraindication against receiving the influenza vaccine, since the benefit may still outweigh the risk.

‘I GOT THE FLU SHOT AND STILL GOT SICK’

The flu vaccine does not prevent illnesses caused by other viruses or bacteria that can make people sick during flu season. Influenza, the common cold, and streptococcal pharyngitis can have similar symptoms that make it difficult for patients—and, frequently, even healthcare providers—to distinguish between these illnesses with certainty.

One study suggested that influenza vaccine recipients had an increased risk of virologically confirmed noninfluenza respiratory viral infections,¹⁵ citing the phenomenon of virus interference that was described in the 1940s¹⁶ as a potential explanation. In essence, people protected against influenza by the vaccine may lack temporary nonspecific immunity against other respiratory viruses. However, these findings have not been replicated in subsequent studies.¹⁷

Viral gastroenteritis, mistakenly called “stomach flu,” is also not prevented by influenza vaccination.

‘I’M ALLERGIC TO EGGS’

The prevalence of egg allergy in US children is 0.5% to 2.5%.¹⁸ Most outgrow it by school age, but in one-third, the allergy persists into adulthood.

In general, people who can eat lightly cooked eggs (eg, scrambled eggs) without a reaction are unlikely to be allergic. On the other hand, the fact that egg-allergic people may tolerate egg included in baked products does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reaction to eggs and egg-containing foods, in addition to skin or blood testing for immunoglobulin E directed against egg proteins.¹⁹

Most currently available influenza vaccines are prepared by propagation of virus in embryonated eggs and so may contain trace amounts of egg proteins such as ovalbumin, with the exception of the inactivated quadri­valent recombinant influenza vaccine (Flublok) and the inactivated quadrivalent cell culture-based vaccine (Flucelvax).

The ACIP recommends that persons with a history of urticaria (hives) after exposure to eggs should receive any licensed, recommended influenza vaccine that is otherwise appropriate for their age and health status. Persons who report having angioedema, respiratory distress, lightheadedness, or recurrent vomiting, or who required epinephrine or another emergency medical intervention after exposure to eggs, should receive the influenza vaccine in an inpatient or outpatient medical setting under the supervision of a healthcare provider who is able to recognize and manage severe allergic reactions.

A history of severe allergic reaction such as anaphylaxis to a previous dose of any influenza vaccine, regardless of the vaccine component (including eggs) suspected of being responsible for the reaction, is a contraindication to influenza vaccination. The ACIP recommends that vaccine providers consider observing patients for 15 minutes after administration of any vaccine (regardless of history of egg allergy) to decrease the risk of injury should syncope occur.²⁰

‘I DON’T WANT TO PUT POISONOUS MERCURY IN MY BODY’

A process of biomagnification of methylmercury occurs when humans eat large fish that have eaten smaller fish. Thus, larger fish such as shark can be hazardous for women who are or may become pregnant, for nursing mothers, and for young children, while smaller fish such as herring are relatively safe.

As a precautionary measure, thimerosal was taken out of childhood vaccines in the United States in 2001. Thimerosal-free influenza vaccine formulations include the nasal live-attenuated flu vaccine, the inactivated quadrivalent recombinant influenza vaccine, and the inactivated quadrivalent cell culture-based vaccine.

‘I DON’T LIKE NEEDLES’

At least 10% of US adults have aichmophobia, the fear of sharp objects including needles.²² Vasovagal syncope is the most common manifestation. Behavioral therapy, topical anesthetics, and systemic anxiolytics have variable efficacy in treating needle phobia. For those who are absolutely averse to needles, the nasal flu vaccine is an appropriate alternative.

‘I DON’T WANT TO TAKE ANYTHING THAT CAN MESS WITH MY OTHER MEDICATIONS’

Some immunosuppressive medications may decrease influenza vaccine immunogenicity. Concomitant administration of the inactivated influenza vaccine with other vaccines is safe and does not alter immunogenicity of other vaccines.¹ The live-attenuated influenza vaccine is contraindicated in children and adolescents taking aspirin or other salicylates due to the risk of Reye syndrome.

 

 

‘I’M AFRAID IT WILL TRIGGER AN IMMUNE RESPONSE THAT WILL MAKE MY ASTHMA WORSE’

A recent systematic review and meta-analysis showed that the inactivated influenza vaccine is not associated with asthma exacerbation.²³ However, the nasal live-attenuated influenza vaccine is contraindicated in children 2 to 4 years old who have asthma and should be used with caution in persons with asthma 5 years old and older. In the systematic review, influenza vaccine prevented 59% to 78% of asthma attacks leading to emergency visits or hospitalization.²³ In other immune-mediated diseases such as rheumatoid arthritis, influenza vaccine does not precipitate exacerbations.²⁴

‘I HAD AN ORGAN TRANSPLANT, AND I’M AFRAID THE FLU SHOT WILL CAUSE ORGAN REJECTION’

A study of 51,730 kidney transplant recipients found that receipt of the inactivated influenza vaccine in the first year after transplant was associated with a lower risk of subsequent allograft loss (adjusted hazard ratio 0.77; 95% confidence interval 0.69–0.85; P < .001) and death (adjusted hazard ratio 0.82; 95% confidence interval 0.76–0.89; P < .001).²⁵ In the same study, although acute rejection in the first year was not associated with influenza vaccination, influenza infection in the first year was associated with rejection (odds ratio 1.58; 95% confidence interval 1.10–2.26; P < 0.001), but not with graft loss or death. Solid organ transplant recipients should receive the inactivated influenza vaccine starting 3 months after transplant.²⁶

Influenza vaccination has not been shown to precipitate graft-vs-host disease in hematopoietic stem cell transplant recipients. These patients should also receive the inactivated influenza vaccine starting 3 to 6 months after transplant.²⁷

The nasal live-attenuated influenza vaccine is contraindicated in these immunocompromised patients.

‘I’M PREGNANT, AND I DON’T WANT TO EXPOSE MY UNBORN BABY TO ANYTHING POTENTIALLY HARMFUL’

The morbidity and mortality risk from influenza is high in children under 2 years old because of low immunogenicity to flu vaccine. This is particularly true in children younger than 6 months, but the vaccine is not recommended in this population. The best way to protect infants is for all household members to be vaccinated against the flu.

Equally important, morbidity and mortality risk from influenza is much higher in pregnant women than in the general population. Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants. A recently published study showed that 18% of infants who developed influenza required hospitalization.²⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively. Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.²⁹ A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.³⁰

Healthcare providers should try to understand the public’s misconceptions³¹ about seasonal influenza and influenza vaccines in order to best address them.

The benefits of influenza vaccination are clear to those in the medical community. Yet misinformation and unfounded fears continue to discourage some people from getting a flu shot. During the 2018–2019 influenza season, only 45% of US adults and 63% of children were vaccinated.¹

‘IT DOESN’T WORK FOR MANY PEOPLE’

Multiple studies have shown that the flu vaccine prevents millions of flu cases and flu-related doctor’s visits each year. During the 2016–2017 flu season, flu vaccine prevented an estimated 5.3 million influenza cases, 2.6 million influenza-associated medical visits, and 85,000 influenza-associated hospitalizations.²

Several viral and host factors affect vaccine effectiveness. In seasons when the vaccine viruses have matched circulating strains, flu vaccine has been shown to reduce the following:

• The risk of having to go to the doctor with flu by 40% to 60%
• Children’s risk of flu-related death and intensive care unit (ICU) admission by 74%
• The risk in adults of flu-associated hospitalizations by 40% and ICU admission by 82%
• The rate of cardiac events in people with heart disease
• Hospitalizations in people with diabetes or underlying chronic lung disease.³

In people hospitalized with influenza despite receiving the flu vaccine for the season, studies have shown that receiving the flu vaccine shortens the average duration of hospitalization, reduces the chance of ICU admission by 59%, shortens the duration of ICU stay by 4 days, and reduces deaths.³

‘IT TARGETS THE WRONG VIRUS’

Selecting an effective influenza vaccine is a challenge. Every year, the World Health Organization and the CDC decide on the influenza strains expected to circulate in the upcoming flu season in the Northern Hemisphere, based on data for circulating strains in the Southern Hemisphere. This decision takes place about 7 months before the expected onset of the flu season. Flu viruses may mutate between the time the decision is made and the time the vaccine is administered (as well as after the flu season starts). Also, vaccine production in eggs needs time, which is why this decision must be made several months ahead of the flu season.

Vaccine effectiveness varies by virus serotype. Vaccines are typically less effective against influenza A H3N2 viruses than against influenza A H1N1 and influenza B viruses. Effectiveness also varies from season to season depending on how close the vaccine serotypes match the circulating serotypes, but some effectiveness is retained even in seasons when some of the serotypes don’t match circulating viruses. For example, in the 2017–2018 season, when the influenza A H3N2 vaccine serotype did not match the circulating serotype, the overall effectiveness in preventing medically attended, laboratory-confirmed influenza virus infection was 36%.⁵

A universal flu vaccine that does not need to be updated annually is the ultimate solution, but according to the National Institute of Allergy and Infectious Diseases, such a vaccine is likely several years away.⁶

‘IT MAKES PEOPLE SICK’

Pain at the injection site of a flu shot occurs in 10% to 65% of people, lasts less than 2 days, and does not usually interfere with daily activities.⁷

Systemic symptoms such as fever, malaise, and myalgia may occur in people who have had no previous exposure to the influenza virus antigens in the vaccine, particularly in children. In adults, the frequency of systemic symptoms after the flu shot is similar to that with placebo.

The Vaccine Adverse Event Reporting System, which has been capturing data since 1990, shows that the influenza vaccine accounted for 5.7% of people who developed malaise after receiving any vaccine.⁸

The injectable inactivated influenza vaccine cannot biologically cause an influenza virus-related illness, since the inactivated vaccine viruses can elicit a protective immune response but cannot replicate. The nasal live-attenuated flu vaccine can in theory cause acute illness in the person receiving it, but because it is cold-adapted, it multiplies only in the colder environment of the nasal epithelium, not in the lower airways where the temperature is higher. Consequently, the vaccine virus triggers immunity by multiplying in the nose, but doesn’t infect the lungs.

From 10% to 50% of people who receive the nasal live-attenuated vaccine develop runny nose, wheezing, headache, vomiting, muscle aches, fever, sore throat, or cough shortly after receiving the vaccine, but these symptoms are usually mild and short-lived.

The most common reactions people have to flu vaccines are considerably less severe than the symptoms caused by actual flu illness.

While influenza illness results in natural immunity to the specific viral serotype causing it, this illness results in hospitalization in 2% and is fatal in 0.16% of people. Influenza vaccine results in immunity to the serotypes included in the vaccine, and multiple studies have not found a causal relationship between vaccination and death.⁹

 

 

‘IT CAUSES GUILLAIN-BARRÉ SYNDROME’

In the United States, 3,000 to 6,000 people per year develop Guillain-Barré syndrome, or 1 to 2 of every 100,000, which translates to 80 to 160 cases per week.¹⁰ While the exact cause of Guillain-Barré syndrome is unknown, about two-thirds of people have an acute diarrheal or respiratory illness within 3 months before the onset of symptoms. In 1976, the estimated attributable risk of influenza vaccine-related Guillain-Barré syndrome in the US adult population was 1 case per 100,000 in the 6 weeks after vaccination.¹¹ Studies in subsequent influenza seasons have not shown similar findings.¹² In fact, one study showed that the risk of developing Guillain-Barré syndrome was 15 times higher after influenza illness than after influenza vaccination.¹³

Since 5% to 15% of the US population develop symptomatic influenza annually,¹⁴ the decision to vaccinate with respect to the risk of Guillain-Barré syndrome should be obvious: vaccinate. The correct question to ask before influenza vaccination should be, “Have you previously developed Guillain-Barré syndrome within 6 weeks after receiving the flu vaccine?” If the answer is yes, the CDC considers this a caution, not a contraindication against receiving the influenza vaccine, since the benefit may still outweigh the risk.

‘I GOT THE FLU SHOT AND STILL GOT SICK’

The flu vaccine does not prevent illnesses caused by other viruses or bacteria that can make people sick during flu season. Influenza, the common cold, and streptococcal pharyngitis can have similar symptoms that make it difficult for patients—and, frequently, even healthcare providers—to distinguish between these illnesses with certainty.

One study suggested that influenza vaccine recipients had an increased risk of virologically confirmed noninfluenza respiratory viral infections,¹⁵ citing the phenomenon of virus interference that was described in the 1940s¹⁶ as a potential explanation. In essence, people protected against influenza by the vaccine may lack temporary nonspecific immunity against other respiratory viruses. However, these findings have not been replicated in subsequent studies.¹⁷

Viral gastroenteritis, mistakenly called “stomach flu,” is also not prevented by influenza vaccination.

‘I’M ALLERGIC TO EGGS’

The prevalence of egg allergy in US children is 0.5% to 2.5%.¹⁸ Most outgrow it by school age, but in one-third, the allergy persists into adulthood.

In general, people who can eat lightly cooked eggs (eg, scrambled eggs) without a reaction are unlikely to be allergic. On the other hand, the fact that egg-allergic people may tolerate egg included in baked products does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reaction to eggs and egg-containing foods, in addition to skin or blood testing for immunoglobulin E directed against egg proteins.¹⁹

Most currently available influenza vaccines are prepared by propagation of virus in embryonated eggs and so may contain trace amounts of egg proteins such as ovalbumin, with the exception of the inactivated quadri­valent recombinant influenza vaccine (Flublok) and the inactivated quadrivalent cell culture-based vaccine (Flucelvax).

The ACIP recommends that persons with a history of urticaria (hives) after exposure to eggs should receive any licensed, recommended influenza vaccine that is otherwise appropriate for their age and health status. Persons who report having angioedema, respiratory distress, lightheadedness, or recurrent vomiting, or who required epinephrine or another emergency medical intervention after exposure to eggs, should receive the influenza vaccine in an inpatient or outpatient medical setting under the supervision of a healthcare provider who is able to recognize and manage severe allergic reactions.

A history of severe allergic reaction such as anaphylaxis to a previous dose of any influenza vaccine, regardless of the vaccine component (including eggs) suspected of being responsible for the reaction, is a contraindication to influenza vaccination. The ACIP recommends that vaccine providers consider observing patients for 15 minutes after administration of any vaccine (regardless of history of egg allergy) to decrease the risk of injury should syncope occur.²⁰

‘I DON’T WANT TO PUT POISONOUS MERCURY IN MY BODY’

A process of biomagnification of methylmercury occurs when humans eat large fish that have eaten smaller fish. Thus, larger fish such as shark can be hazardous for women who are or may become pregnant, for nursing mothers, and for young children, while smaller fish such as herring are relatively safe.

As a precautionary measure, thimerosal was taken out of childhood vaccines in the United States in 2001. Thimerosal-free influenza vaccine formulations include the nasal live-attenuated flu vaccine, the inactivated quadrivalent recombinant influenza vaccine, and the inactivated quadrivalent cell culture-based vaccine.

‘I DON’T LIKE NEEDLES’

At least 10% of US adults have aichmophobia, the fear of sharp objects including needles.²² Vasovagal syncope is the most common manifestation. Behavioral therapy, topical anesthetics, and systemic anxiolytics have variable efficacy in treating needle phobia. For those who are absolutely averse to needles, the nasal flu vaccine is an appropriate alternative.

‘I DON’T WANT TO TAKE ANYTHING THAT CAN MESS WITH MY OTHER MEDICATIONS’

Some immunosuppressive medications may decrease influenza vaccine immunogenicity. Concomitant administration of the inactivated influenza vaccine with other vaccines is safe and does not alter immunogenicity of other vaccines.¹ The live-attenuated influenza vaccine is contraindicated in children and adolescents taking aspirin or other salicylates due to the risk of Reye syndrome.

 

 

‘I’M AFRAID IT WILL TRIGGER AN IMMUNE RESPONSE THAT WILL MAKE MY ASTHMA WORSE’

A recent systematic review and meta-analysis showed that the inactivated influenza vaccine is not associated with asthma exacerbation.²³ However, the nasal live-attenuated influenza vaccine is contraindicated in children 2 to 4 years old who have asthma and should be used with caution in persons with asthma 5 years old and older. In the systematic review, influenza vaccine prevented 59% to 78% of asthma attacks leading to emergency visits or hospitalization.²³ In other immune-mediated diseases such as rheumatoid arthritis, influenza vaccine does not precipitate exacerbations.²⁴

‘I HAD AN ORGAN TRANSPLANT, AND I’M AFRAID THE FLU SHOT WILL CAUSE ORGAN REJECTION’

A study of 51,730 kidney transplant recipients found that receipt of the inactivated influenza vaccine in the first year after transplant was associated with a lower risk of subsequent allograft loss (adjusted hazard ratio 0.77; 95% confidence interval 0.69–0.85; P < .001) and death (adjusted hazard ratio 0.82; 95% confidence interval 0.76–0.89; P < .001).²⁵ In the same study, although acute rejection in the first year was not associated with influenza vaccination, influenza infection in the first year was associated with rejection (odds ratio 1.58; 95% confidence interval 1.10–2.26; P < 0.001), but not with graft loss or death. Solid organ transplant recipients should receive the inactivated influenza vaccine starting 3 months after transplant.²⁶

Influenza vaccination has not been shown to precipitate graft-vs-host disease in hematopoietic stem cell transplant recipients. These patients should also receive the inactivated influenza vaccine starting 3 to 6 months after transplant.²⁷

The nasal live-attenuated influenza vaccine is contraindicated in these immunocompromised patients.

‘I’M PREGNANT, AND I DON’T WANT TO EXPOSE MY UNBORN BABY TO ANYTHING POTENTIALLY HARMFUL’

The morbidity and mortality risk from influenza is high in children under 2 years old because of low immunogenicity to flu vaccine. This is particularly true in children younger than 6 months, but the vaccine is not recommended in this population. The best way to protect infants is for all household members to be vaccinated against the flu.

Equally important, morbidity and mortality risk from influenza is much higher in pregnant women than in the general population. Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants. A recently published study showed that 18% of infants who developed influenza required hospitalization.²⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively. Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.²⁹ A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.³⁰

Healthcare providers should try to understand the public’s misconceptions³¹ about seasonal influenza and influenza vaccines in order to best address them.

The benefits of influenza vaccination are clear to those in the medical community. Yet misinformation and unfounded fears continue to discourage some people from getting a flu shot. During the 2018–2019 influenza season, only 45% of US adults and 63% of children were vaccinated.¹

‘IT DOESN’T WORK FOR MANY PEOPLE’

Multiple studies have shown that the flu vaccine prevents millions of flu cases and flu-related doctor’s visits each year. During the 2016–2017 flu season, flu vaccine prevented an estimated 5.3 million influenza cases, 2.6 million influenza-associated medical visits, and 85,000 influenza-associated hospitalizations.²

Several viral and host factors affect vaccine effectiveness. In seasons when the vaccine viruses have matched circulating strains, flu vaccine has been shown to reduce the following:

• The risk of having to go to the doctor with flu by 40% to 60%
• Children’s risk of flu-related death and intensive care unit (ICU) admission by 74%
• The risk in adults of flu-associated hospitalizations by 40% and ICU admission by 82%
• The rate of cardiac events in people with heart disease
• Hospitalizations in people with diabetes or underlying chronic lung disease.³

In people hospitalized with influenza despite receiving the flu vaccine for the season, studies have shown that receiving the flu vaccine shortens the average duration of hospitalization, reduces the chance of ICU admission by 59%, shortens the duration of ICU stay by 4 days, and reduces deaths.³

‘IT TARGETS THE WRONG VIRUS’

Selecting an effective influenza vaccine is a challenge. Every year, the World Health Organization and the CDC decide on the influenza strains expected to circulate in the upcoming flu season in the Northern Hemisphere, based on data for circulating strains in the Southern Hemisphere. This decision takes place about 7 months before the expected onset of the flu season. Flu viruses may mutate between the time the decision is made and the time the vaccine is administered (as well as after the flu season starts). Also, vaccine production in eggs needs time, which is why this decision must be made several months ahead of the flu season.

Vaccine effectiveness varies by virus serotype. Vaccines are typically less effective against influenza A H3N2 viruses than against influenza A H1N1 and influenza B viruses. Effectiveness also varies from season to season depending on how close the vaccine serotypes match the circulating serotypes, but some effectiveness is retained even in seasons when some of the serotypes don’t match circulating viruses. For example, in the 2017–2018 season, when the influenza A H3N2 vaccine serotype did not match the circulating serotype, the overall effectiveness in preventing medically attended, laboratory-confirmed influenza virus infection was 36%.⁵

A universal flu vaccine that does not need to be updated annually is the ultimate solution, but according to the National Institute of Allergy and Infectious Diseases, such a vaccine is likely several years away.⁶

‘IT MAKES PEOPLE SICK’

Pain at the injection site of a flu shot occurs in 10% to 65% of people, lasts less than 2 days, and does not usually interfere with daily activities.⁷

Systemic symptoms such as fever, malaise, and myalgia may occur in people who have had no previous exposure to the influenza virus antigens in the vaccine, particularly in children. In adults, the frequency of systemic symptoms after the flu shot is similar to that with placebo.

The Vaccine Adverse Event Reporting System, which has been capturing data since 1990, shows that the influenza vaccine accounted for 5.7% of people who developed malaise after receiving any vaccine.⁸

The injectable inactivated influenza vaccine cannot biologically cause an influenza virus-related illness, since the inactivated vaccine viruses can elicit a protective immune response but cannot replicate. The nasal live-attenuated flu vaccine can in theory cause acute illness in the person receiving it, but because it is cold-adapted, it multiplies only in the colder environment of the nasal epithelium, not in the lower airways where the temperature is higher. Consequently, the vaccine virus triggers immunity by multiplying in the nose, but doesn’t infect the lungs.

From 10% to 50% of people who receive the nasal live-attenuated vaccine develop runny nose, wheezing, headache, vomiting, muscle aches, fever, sore throat, or cough shortly after receiving the vaccine, but these symptoms are usually mild and short-lived.

The most common reactions people have to flu vaccines are considerably less severe than the symptoms caused by actual flu illness.

While influenza illness results in natural immunity to the specific viral serotype causing it, this illness results in hospitalization in 2% and is fatal in 0.16% of people. Influenza vaccine results in immunity to the serotypes included in the vaccine, and multiple studies have not found a causal relationship between vaccination and death.⁹

 

 

‘IT CAUSES GUILLAIN-BARRÉ SYNDROME’

In the United States, 3,000 to 6,000 people per year develop Guillain-Barré syndrome, or 1 to 2 of every 100,000, which translates to 80 to 160 cases per week.¹⁰ While the exact cause of Guillain-Barré syndrome is unknown, about two-thirds of people have an acute diarrheal or respiratory illness within 3 months before the onset of symptoms. In 1976, the estimated attributable risk of influenza vaccine-related Guillain-Barré syndrome in the US adult population was 1 case per 100,000 in the 6 weeks after vaccination.¹¹ Studies in subsequent influenza seasons have not shown similar findings.¹² In fact, one study showed that the risk of developing Guillain-Barré syndrome was 15 times higher after influenza illness than after influenza vaccination.¹³

Since 5% to 15% of the US population develop symptomatic influenza annually,¹⁴ the decision to vaccinate with respect to the risk of Guillain-Barré syndrome should be obvious: vaccinate. The correct question to ask before influenza vaccination should be, “Have you previously developed Guillain-Barré syndrome within 6 weeks after receiving the flu vaccine?” If the answer is yes, the CDC considers this a caution, not a contraindication against receiving the influenza vaccine, since the benefit may still outweigh the risk.

‘I GOT THE FLU SHOT AND STILL GOT SICK’

The flu vaccine does not prevent illnesses caused by other viruses or bacteria that can make people sick during flu season. Influenza, the common cold, and streptococcal pharyngitis can have similar symptoms that make it difficult for patients—and, frequently, even healthcare providers—to distinguish between these illnesses with certainty.

One study suggested that influenza vaccine recipients had an increased risk of virologically confirmed noninfluenza respiratory viral infections,¹⁵ citing the phenomenon of virus interference that was described in the 1940s¹⁶ as a potential explanation. In essence, people protected against influenza by the vaccine may lack temporary nonspecific immunity against other respiratory viruses. However, these findings have not been replicated in subsequent studies.¹⁷

Viral gastroenteritis, mistakenly called “stomach flu,” is also not prevented by influenza vaccination.

‘I’M ALLERGIC TO EGGS’

The prevalence of egg allergy in US children is 0.5% to 2.5%.¹⁸ Most outgrow it by school age, but in one-third, the allergy persists into adulthood.

In general, people who can eat lightly cooked eggs (eg, scrambled eggs) without a reaction are unlikely to be allergic. On the other hand, the fact that egg-allergic people may tolerate egg included in baked products does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reaction to eggs and egg-containing foods, in addition to skin or blood testing for immunoglobulin E directed against egg proteins.¹⁹

Most currently available influenza vaccines are prepared by propagation of virus in embryonated eggs and so may contain trace amounts of egg proteins such as ovalbumin, with the exception of the inactivated quadri­valent recombinant influenza vaccine (Flublok) and the inactivated quadrivalent cell culture-based vaccine (Flucelvax).

The ACIP recommends that persons with a history of urticaria (hives) after exposure to eggs should receive any licensed, recommended influenza vaccine that is otherwise appropriate for their age and health status. Persons who report having angioedema, respiratory distress, lightheadedness, or recurrent vomiting, or who required epinephrine or another emergency medical intervention after exposure to eggs, should receive the influenza vaccine in an inpatient or outpatient medical setting under the supervision of a healthcare provider who is able to recognize and manage severe allergic reactions.

A history of severe allergic reaction such as anaphylaxis to a previous dose of any influenza vaccine, regardless of the vaccine component (including eggs) suspected of being responsible for the reaction, is a contraindication to influenza vaccination. The ACIP recommends that vaccine providers consider observing patients for 15 minutes after administration of any vaccine (regardless of history of egg allergy) to decrease the risk of injury should syncope occur.²⁰

‘I DON’T WANT TO PUT POISONOUS MERCURY IN MY BODY’

A process of biomagnification of methylmercury occurs when humans eat large fish that have eaten smaller fish. Thus, larger fish such as shark can be hazardous for women who are or may become pregnant, for nursing mothers, and for young children, while smaller fish such as herring are relatively safe.

As a precautionary measure, thimerosal was taken out of childhood vaccines in the United States in 2001. Thimerosal-free influenza vaccine formulations include the nasal live-attenuated flu vaccine, the inactivated quadrivalent recombinant influenza vaccine, and the inactivated quadrivalent cell culture-based vaccine.

‘I DON’T LIKE NEEDLES’

At least 10% of US adults have aichmophobia, the fear of sharp objects including needles.²² Vasovagal syncope is the most common manifestation. Behavioral therapy, topical anesthetics, and systemic anxiolytics have variable efficacy in treating needle phobia. For those who are absolutely averse to needles, the nasal flu vaccine is an appropriate alternative.

‘I DON’T WANT TO TAKE ANYTHING THAT CAN MESS WITH MY OTHER MEDICATIONS’

Some immunosuppressive medications may decrease influenza vaccine immunogenicity. Concomitant administration of the inactivated influenza vaccine with other vaccines is safe and does not alter immunogenicity of other vaccines.¹ The live-attenuated influenza vaccine is contraindicated in children and adolescents taking aspirin or other salicylates due to the risk of Reye syndrome.

 

 

‘I’M AFRAID IT WILL TRIGGER AN IMMUNE RESPONSE THAT WILL MAKE MY ASTHMA WORSE’

A recent systematic review and meta-analysis showed that the inactivated influenza vaccine is not associated with asthma exacerbation.²³ However, the nasal live-attenuated influenza vaccine is contraindicated in children 2 to 4 years old who have asthma and should be used with caution in persons with asthma 5 years old and older. In the systematic review, influenza vaccine prevented 59% to 78% of asthma attacks leading to emergency visits or hospitalization.²³ In other immune-mediated diseases such as rheumatoid arthritis, influenza vaccine does not precipitate exacerbations.²⁴

‘I HAD AN ORGAN TRANSPLANT, AND I’M AFRAID THE FLU SHOT WILL CAUSE ORGAN REJECTION’

A study of 51,730 kidney transplant recipients found that receipt of the inactivated influenza vaccine in the first year after transplant was associated with a lower risk of subsequent allograft loss (adjusted hazard ratio 0.77; 95% confidence interval 0.69–0.85; P < .001) and death (adjusted hazard ratio 0.82; 95% confidence interval 0.76–0.89; P < .001).²⁵ In the same study, although acute rejection in the first year was not associated with influenza vaccination, influenza infection in the first year was associated with rejection (odds ratio 1.58; 95% confidence interval 1.10–2.26; P < 0.001), but not with graft loss or death. Solid organ transplant recipients should receive the inactivated influenza vaccine starting 3 months after transplant.²⁶

Influenza vaccination has not been shown to precipitate graft-vs-host disease in hematopoietic stem cell transplant recipients. These patients should also receive the inactivated influenza vaccine starting 3 to 6 months after transplant.²⁷

The nasal live-attenuated influenza vaccine is contraindicated in these immunocompromised patients.

‘I’M PREGNANT, AND I DON’T WANT TO EXPOSE MY UNBORN BABY TO ANYTHING POTENTIALLY HARMFUL’

The morbidity and mortality risk from influenza is high in children under 2 years old because of low immunogenicity to flu vaccine. This is particularly true in children younger than 6 months, but the vaccine is not recommended in this population. The best way to protect infants is for all household members to be vaccinated against the flu.

Equally important, morbidity and mortality risk from influenza is much higher in pregnant women than in the general population. Many studies have shown the value of influenza vaccination during pregnancy for both mothers and their infants. A recently published study showed that 18% of infants who developed influenza required hospitalization.²⁸ In that study, prenatal and postpartum maternal influenza vaccination decreased the odds of influenza in infants by 61% and 53%, respectively. Another study showed that vaccine effectiveness did not vary by gestational age at vaccination.²⁹ A post hoc analysis of an influenza vaccination study in pregnant women suggested that the vaccine was also associated with decreased rates of pertussis in these women.³⁰

Healthcare providers should try to understand the public’s misconceptions³¹ about seasonal influenza and influenza vaccines in order to best address them.