THE CASE

A 4-year-old girl was triaged to the Pediatric Emergency Department (PED) Fast Track, complaining of pain and limited movement in both arms. For an unknown reason, she had attempted to lift a heavy, 3-person sofa several hours earlier.

Her prior medical history included left nursemaid elbow (NME) at both 15 months and 33 months of age. Neither event had a known mechanism of injury. In both episodes, it was noted in the medical record that the child was not using her arm, “was holding it funny,” and was complaining of pain. Each time, she presented about 24 hours after symptom onset.

During the physical exam in the PED, the patient showed no signs of acute distress. She held both arms close to her body, with a slight flexion at the elbows, and her hands were pronated. She could not pinpoint the location of her discomfort and described diffuse pain in her forearms, elbows, and upper arms. Examination revealed no localized pain or tenderness in her hands, wrists, or clavicles. Radial pulses were easily palpated, and capillary refill was less than 2 seconds. There was no swelling or bruising. The rest of her physical exam was normal.

DIAGNOSIS

The patient was given a diagnosis of self-inflicted bilateral nursemaid elbows (BNME). Reductions were performed by individually stabilizing the elbows and hyper-pronating the forearms, with palpable clicks felt at the proximal radius. Even though a palpable click was felt, this motion was immediately followed by supination of the forearm and flexion at the elbow. The patient tolerated the procedures well and was using both arms normally within 10 minutes. She was discharged home shortly thereafter.

DISCUSSION

BNME is an uncommon diagnosis; a literature review of reported cases indicates none were self-inflicted.^1-4 However, NME is a common injury and is easily reduced. The classic mechanism of injury for NME involves the elbow in extension, while the forearm is pronated, and a sudden brisk axial traction is applied. This combination of motions causes the annular ligament to slip over the head of the radius and become displaced downward into the radiohumeral joint, where it becomes entrapped. In this case, the patient apparently exerted enough longitudinal traction while trying to lift the couch to produce the injury.

NME occurs most commonly in the left arm of girls between the ages of 4 months and 7 years and peaks at around the age of 2 years.⁵ A 2014 study by Irie et al⁶ corroborated the findings on left-side predominance and increased incidence with age, noting that frequency of injury peaked at 6 months in those younger than 1 year of age and at 2 years for those 1 year or older. However, the researchers found no significant sex difference.⁶

NME is radiographically indistinguishable from a healthy elbow.⁷ To prevent unnecessary expense and radiation exposure in young children, prereduction radiographs should only be used to rule out the possibility of fracture or other injury.⁷ Krul et al⁸ recommend restricting x-ray use to cases with an unclear history or those that are due to trauma other than an arm pull.

Continue to: Methods of reduction

Methods of reduction. Once NME is diagnosed, there are 2 methods of reduction: hyper-pronation and supination-flexion. Reduction is best performed with the child sitting in the parent’s lap with the injured arm facing the examiner.

Nursemaid’s elbow is radiographically indistinguishable from a healthy elbow.

Success rates for both methods of NME reduction are statistically similar; however, first-attempt success rates are significantly higher with the hyper-pronation method than with supination-flexion.⁹ Furthermore, physicians have deemed the hyper-­pronation method significantly easier to perform than supination-flexion.⁹ A Cochrane review by Krul et al¹⁰ concluded that the hyper-­pronation method may result in lower failure rates than supination-flexion, but due to limited evidence, the researchers were unable to draw any conclusions on other outcomes, such as pain. Green et al¹¹ noted that hyper-pronation is perceived by parents of children with NME as being less painful. For these reasons, hyper-pronation should be utilized as the first method of reduction, followed by supination-flexion if the former does not work.¹²

Additional management. In a limited study of 50 children with pulled-elbow injuries, ultrasound revealed that 78% had an intact yet interposed radial annular ligament and 22% had a tear in the radial annular ligament.¹³ The authors propose that if, after appropriate reduction methods are attempted, no pop is felt, or there is no prompt clinical improvement, and ultrasound is not available to assess the integrity of the annular ligament, the child should be placed in a splint for 7 days and referred for orthopedic intervention.¹³

Our patient returned to the PED 3 days later, complaining of pain and an inability to move her left arm after her older sibling pulled her by her outstretched arms. She was once again diagnosed with NME, the injury was reduced, and she was using the arm within minutes. She has not presented to either the PED or the pediatric clinic with a similar complaint since. Discarding outliers, NME recurrence rates fall within a range of 23.7% to 32.9%.^14,15

THE TAKEAWAY

Pre-reduction x-rays are not warranted in cases of NME unless there is suspicion for fracture or another injury. The 2 reduction methods, hyper-pronation and supination-flexion, are easily mastered. Any reduction should be quick, easy, and as painless as possible. Hyper-pronation should be utilized first, as this maneuver seems to be the more successful and is perceived by parents as being less painful. However, it is always most helpful to be proficient in both methods. If, after appropriate attempts at reduction, the child has not regained the use of the arm, 7 days of splinting is recommended, along with an orthopedic referral.

CORRESPONDENCE
Robert N. Anderson, DNP, APRN, (F)NP-C, ENP-BC, Vanderbilt Health, 512 Autumn Springs Court, Suite 100 C, Franklin, TN 37067; bob.anderson@vumc.org

THE CASE

A 4-year-old girl was triaged to the Pediatric Emergency Department (PED) Fast Track, complaining of pain and limited movement in both arms. For an unknown reason, she had attempted to lift a heavy, 3-person sofa several hours earlier.

Her prior medical history included left nursemaid elbow (NME) at both 15 months and 33 months of age. Neither event had a known mechanism of injury. In both episodes, it was noted in the medical record that the child was not using her arm, “was holding it funny,” and was complaining of pain. Each time, she presented about 24 hours after symptom onset.

During the physical exam in the PED, the patient showed no signs of acute distress. She held both arms close to her body, with a slight flexion at the elbows, and her hands were pronated. She could not pinpoint the location of her discomfort and described diffuse pain in her forearms, elbows, and upper arms. Examination revealed no localized pain or tenderness in her hands, wrists, or clavicles. Radial pulses were easily palpated, and capillary refill was less than 2 seconds. There was no swelling or bruising. The rest of her physical exam was normal.

DIAGNOSIS

The patient was given a diagnosis of self-inflicted bilateral nursemaid elbows (BNME). Reductions were performed by individually stabilizing the elbows and hyper-pronating the forearms, with palpable clicks felt at the proximal radius. Even though a palpable click was felt, this motion was immediately followed by supination of the forearm and flexion at the elbow. The patient tolerated the procedures well and was using both arms normally within 10 minutes. She was discharged home shortly thereafter.

DISCUSSION

BNME is an uncommon diagnosis; a literature review of reported cases indicates none were self-inflicted.^1-4 However, NME is a common injury and is easily reduced. The classic mechanism of injury for NME involves the elbow in extension, while the forearm is pronated, and a sudden brisk axial traction is applied. This combination of motions causes the annular ligament to slip over the head of the radius and become displaced downward into the radiohumeral joint, where it becomes entrapped. In this case, the patient apparently exerted enough longitudinal traction while trying to lift the couch to produce the injury.

NME occurs most commonly in the left arm of girls between the ages of 4 months and 7 years and peaks at around the age of 2 years.⁵ A 2014 study by Irie et al⁶ corroborated the findings on left-side predominance and increased incidence with age, noting that frequency of injury peaked at 6 months in those younger than 1 year of age and at 2 years for those 1 year or older. However, the researchers found no significant sex difference.⁶

NME is radiographically indistinguishable from a healthy elbow.⁷ To prevent unnecessary expense and radiation exposure in young children, prereduction radiographs should only be used to rule out the possibility of fracture or other injury.⁷ Krul et al⁸ recommend restricting x-ray use to cases with an unclear history or those that are due to trauma other than an arm pull.

Continue to: Methods of reduction

Methods of reduction. Once NME is diagnosed, there are 2 methods of reduction: hyper-pronation and supination-flexion. Reduction is best performed with the child sitting in the parent’s lap with the injured arm facing the examiner.

Nursemaid’s elbow is radiographically indistinguishable from a healthy elbow.

Success rates for both methods of NME reduction are statistically similar; however, first-attempt success rates are significantly higher with the hyper-pronation method than with supination-flexion.⁹ Furthermore, physicians have deemed the hyper-­pronation method significantly easier to perform than supination-flexion.⁹ A Cochrane review by Krul et al¹⁰ concluded that the hyper-­pronation method may result in lower failure rates than supination-flexion, but due to limited evidence, the researchers were unable to draw any conclusions on other outcomes, such as pain. Green et al¹¹ noted that hyper-pronation is perceived by parents of children with NME as being less painful. For these reasons, hyper-pronation should be utilized as the first method of reduction, followed by supination-flexion if the former does not work.¹²

Additional management. In a limited study of 50 children with pulled-elbow injuries, ultrasound revealed that 78% had an intact yet interposed radial annular ligament and 22% had a tear in the radial annular ligament.¹³ The authors propose that if, after appropriate reduction methods are attempted, no pop is felt, or there is no prompt clinical improvement, and ultrasound is not available to assess the integrity of the annular ligament, the child should be placed in a splint for 7 days and referred for orthopedic intervention.¹³

Our patient returned to the PED 3 days later, complaining of pain and an inability to move her left arm after her older sibling pulled her by her outstretched arms. She was once again diagnosed with NME, the injury was reduced, and she was using the arm within minutes. She has not presented to either the PED or the pediatric clinic with a similar complaint since. Discarding outliers, NME recurrence rates fall within a range of 23.7% to 32.9%.^14,15

THE TAKEAWAY

Pre-reduction x-rays are not warranted in cases of NME unless there is suspicion for fracture or another injury. The 2 reduction methods, hyper-pronation and supination-flexion, are easily mastered. Any reduction should be quick, easy, and as painless as possible. Hyper-pronation should be utilized first, as this maneuver seems to be the more successful and is perceived by parents as being less painful. However, it is always most helpful to be proficient in both methods. If, after appropriate attempts at reduction, the child has not regained the use of the arm, 7 days of splinting is recommended, along with an orthopedic referral.

CORRESPONDENCE
Robert N. Anderson, DNP, APRN, (F)NP-C, ENP-BC, Vanderbilt Health, 512 Autumn Springs Court, Suite 100 C, Franklin, TN 37067; bob.anderson@vumc.org

THE CASE

A 4-year-old girl was triaged to the Pediatric Emergency Department (PED) Fast Track, complaining of pain and limited movement in both arms. For an unknown reason, she had attempted to lift a heavy, 3-person sofa several hours earlier.

Her prior medical history included left nursemaid elbow (NME) at both 15 months and 33 months of age. Neither event had a known mechanism of injury. In both episodes, it was noted in the medical record that the child was not using her arm, “was holding it funny,” and was complaining of pain. Each time, she presented about 24 hours after symptom onset.

During the physical exam in the PED, the patient showed no signs of acute distress. She held both arms close to her body, with a slight flexion at the elbows, and her hands were pronated. She could not pinpoint the location of her discomfort and described diffuse pain in her forearms, elbows, and upper arms. Examination revealed no localized pain or tenderness in her hands, wrists, or clavicles. Radial pulses were easily palpated, and capillary refill was less than 2 seconds. There was no swelling or bruising. The rest of her physical exam was normal.

DIAGNOSIS

The patient was given a diagnosis of self-inflicted bilateral nursemaid elbows (BNME). Reductions were performed by individually stabilizing the elbows and hyper-pronating the forearms, with palpable clicks felt at the proximal radius. Even though a palpable click was felt, this motion was immediately followed by supination of the forearm and flexion at the elbow. The patient tolerated the procedures well and was using both arms normally within 10 minutes. She was discharged home shortly thereafter.

DISCUSSION

BNME is an uncommon diagnosis; a literature review of reported cases indicates none were self-inflicted.^1-4 However, NME is a common injury and is easily reduced. The classic mechanism of injury for NME involves the elbow in extension, while the forearm is pronated, and a sudden brisk axial traction is applied. This combination of motions causes the annular ligament to slip over the head of the radius and become displaced downward into the radiohumeral joint, where it becomes entrapped. In this case, the patient apparently exerted enough longitudinal traction while trying to lift the couch to produce the injury.

NME occurs most commonly in the left arm of girls between the ages of 4 months and 7 years and peaks at around the age of 2 years.⁵ A 2014 study by Irie et al⁶ corroborated the findings on left-side predominance and increased incidence with age, noting that frequency of injury peaked at 6 months in those younger than 1 year of age and at 2 years for those 1 year or older. However, the researchers found no significant sex difference.⁶

NME is radiographically indistinguishable from a healthy elbow.⁷ To prevent unnecessary expense and radiation exposure in young children, prereduction radiographs should only be used to rule out the possibility of fracture or other injury.⁷ Krul et al⁸ recommend restricting x-ray use to cases with an unclear history or those that are due to trauma other than an arm pull.

Continue to: Methods of reduction

Methods of reduction. Once NME is diagnosed, there are 2 methods of reduction: hyper-pronation and supination-flexion. Reduction is best performed with the child sitting in the parent’s lap with the injured arm facing the examiner.

Nursemaid’s elbow is radiographically indistinguishable from a healthy elbow.

Success rates for both methods of NME reduction are statistically similar; however, first-attempt success rates are significantly higher with the hyper-pronation method than with supination-flexion.⁹ Furthermore, physicians have deemed the hyper-­pronation method significantly easier to perform than supination-flexion.⁹ A Cochrane review by Krul et al¹⁰ concluded that the hyper-­pronation method may result in lower failure rates than supination-flexion, but due to limited evidence, the researchers were unable to draw any conclusions on other outcomes, such as pain. Green et al¹¹ noted that hyper-pronation is perceived by parents of children with NME as being less painful. For these reasons, hyper-pronation should be utilized as the first method of reduction, followed by supination-flexion if the former does not work.¹²

Additional management. In a limited study of 50 children with pulled-elbow injuries, ultrasound revealed that 78% had an intact yet interposed radial annular ligament and 22% had a tear in the radial annular ligament.¹³ The authors propose that if, after appropriate reduction methods are attempted, no pop is felt, or there is no prompt clinical improvement, and ultrasound is not available to assess the integrity of the annular ligament, the child should be placed in a splint for 7 days and referred for orthopedic intervention.¹³

Our patient returned to the PED 3 days later, complaining of pain and an inability to move her left arm after her older sibling pulled her by her outstretched arms. She was once again diagnosed with NME, the injury was reduced, and she was using the arm within minutes. She has not presented to either the PED or the pediatric clinic with a similar complaint since. Discarding outliers, NME recurrence rates fall within a range of 23.7% to 32.9%.^14,15

THE TAKEAWAY

Pre-reduction x-rays are not warranted in cases of NME unless there is suspicion for fracture or another injury. The 2 reduction methods, hyper-pronation and supination-flexion, are easily mastered. Any reduction should be quick, easy, and as painless as possible. Hyper-pronation should be utilized first, as this maneuver seems to be the more successful and is perceived by parents as being less painful. However, it is always most helpful to be proficient in both methods. If, after appropriate attempts at reduction, the child has not regained the use of the arm, 7 days of splinting is recommended, along with an orthopedic referral.

CORRESPONDENCE
Robert N. Anderson, DNP, APRN, (F)NP-C, ENP-BC, Vanderbilt Health, 512 Autumn Springs Court, Suite 100 C, Franklin, TN 37067; bob.anderson@vumc.org

Since the early 1990s, modern treatments have steadily reduced overall cancer mortality from primary tumors.¹ Consequently, more people are at risk of metastatic bone disease, with subsequent pain and pathologic fractures^1,2 and death from metastasis.³ Patients who have bone metastases present with a variety of signs and symptoms including pain, fractures, and metabolic derangements. The primary care approach to work-up and diagnosis described in this article enables prompt treatment, either surgical or nonsurgical, to maintain a high quality of life for patients.

Primary tumors determine types of metastases and prognosis

Metastasis, a complex pathologic process in which cancerous cells migrate to distant organs, implant, and grow,³ is a poor prognostic indicator in cancer patients. Bone is the third most common site of metastasis, behind the liver and lungs.⁴ While the true prevalence of metastatic bone cancer is unknown, studies have estimated it to be > 280,000 cases in the United States.⁵

Bone metastases interfere with normal bone metabolism and turnover in several different characteristic patterns. These changes—radiographically defined as osteoblastic, osteolytic, or mixed lesions—are determined by the primary tumor type.

• Osteoblastic lesions, comprised of new, disorganized bone formation, often occur secondary to prostate cancer, small cell lung cancer, and carcinoid malignancies, among others.
• Osteolytic lesions, in which bone is destroyed, are more common with breast cancer, renal cell carcinoma, melanoma, and multiple myeloma.
• Mixed lesions, in which areas of bone destruction and growth are simultaneously found, occur with some GI cancers and a few breast cancers.^6,7

Most bone metastases result from carcinomas, of which up to 50% eventually spread to bone, although this process can take 10 to 15 years.^8,9 The likelihood of bone metastasis depends on the primary tumor and its stage. Breast and prostate cancer account for most skeletal metastases, although these lesions are often asymptomatic.^6,9 Other malignancies, such as ovarian and gastrointestinal, metastasize to bone much less frequently.^7,10 Virtually any cancer at an advanced stage can spread to bone. These metastases are usually multifocal and incurable, with the patient’s prognosis varying from a few months to years.^6,11,12

Factors that influence prognosis. Metastatic bone disease arising from melanoma and lung cancers has the shortest life expectancy of roughly 6 months from initial diagnosis; metastasis following prostate, breast, and thyroid cancers has the longest, usually 2 to 4 years.¹¹TABLE 1¹³ shows survival estimates from a large Danish population at various time points following bone metastasis diagnosis for several primary cancer types.

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer—even if such a history is remote. It’s important.

When surgical intervention for bony metastasis is required, prognosis is generally poorer, likely due to more advanced disease. The overall 1-year survival following surgery varies, but several large studies have found a rate of around 40% when considering all primary tumors.^14,15 The most common metastases, from breast and prostate cancers, have 1-year survivals of around 50% and 30%, respectively, following surgical intervention.^16-18

What you’re likely to see on presentation

Bone metastases are one of the leading causes of morbidity in cancer patients from resultant pain, pathologic fractures, metabolic derangements, and reduced activities of daily living.^8,19 The most common cause of cancer pain is bone involvement.⁶ Patients report pain that is usually worse at night, poorly localized, and not alleviated with rest. They often mistakenly relate the pain to an injury.²⁰ The pathophysiology of bone pain is not completely understood but is likely multifactorial and includes inflammatory and mechanical processes.^7,21 Spine involvement can lead to stenosis or nerve root compression, with symptoms dependent on level and severity of nerve or cord compromise.²⁰ Overall, the most common site of bone metastasis is the thoracic spine, followed by the ribs, pelvis, and proximal long bones.²⁰

Continue to: Pathologic fractures

Pathologic fractures occur frequently in cancer patients. Bone destruction leads to a loss of mechanical support which, in turn, causes microfractures and pain. These microfractures can proliferate and coalesce, causing a pathologic fracture, often in weight-bearing bones.⁶ Breast cancer with lytic lesions is the single leading cause of all pathologic fractures.²² Lung cancer with its short survival time and prostate cancer with blastic lesions are less common causes.²³ In the appendicular skeleton, the vast majority of these fractures occur in the femur and humerus.¹¹

Symptomatic metabolic derangements. The most common metabolic disorder is hypercalcemia, found predominantly in patients with hematologic malignancies, squamous cell lung cancer, renal cell cancer, and breast cancer.^6,7,12,24 The clinical presentation is nonspecific and can include polyuria, polydipsia, fatigue, constipation, and confusion. The prevalence is estimated to be 13% in breast cancer, 4% in lung cancers, and 1% in prostate cancer, although results in individual studies vary.¹² The pathophysiology is multifactorial and often includes osteolytic lesions and an increased circulating level of parathyroid hormone–related peptide, although other mechanisms contribute.^25,26 Ultimately, severe hypercalcemia may be fatal secondary to renal failure and cardiac arrhythmias.^6,7,12 Paraneoplastic hypercalcemia independently decreases survival; 1 study found the median survival to be 10 to 12 weeks.¹¹

Primary care work-up and diagnosis

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer. Even if such a history is remote, it is important—­particularly so if the patient received chemotherapy or radiation, which can lead to secondary cancers such as leukemia or sarcoma.²⁰ If a primary site of malignancy is unknown, pursue a general review of systems. Clues to the primary site of disease could be a history of chest pain, shortness of breath, hemoptysis, heat/cold intolerance, or changes in bowel/bladder habits. Also ask about risk factors such as smoking, chemical exposure, and sun exposure.

Pointers on radiographic imaging. If you suspect a destructive bone lesion, order appropriate radiographic imaging. Arrange for plain radiographs with at least 2 views of the specific area of interest that include the entire bone along with the joints above and below. Importantly, the entire bone must be imaged before any surgical procedure to avoid periprosthetic fractures from undetected bone metastases around hardware.²⁰ Keep in mind that plain films can miss early lesions, and computed tomography (CT) or magnetic resonance imaging (MRI) may be needed if suspicion of a pathologic process is still strong and especially if a primary malignancy is known.²⁷

Working back to a primary diagnosis

If imaging confirms a suspicious lesion and the patient has no known primary tumor, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan, and refer the patient to an oncologist. If the bone lesion is painful, initiate protected weight-bearing and additionally refer the patient to an orthopedic surgeon.

Continue to: Appropriate laboratory evaluation

Appropriate laboratory evaluation entails a complete blood count; metabolic panel that includes serum calcium and phosphorus, vitamin D, alkaline phosphatase, thyroid-stimulating hormone, and parathyroid hormone; and serum protein electrophoresis to rule out multiple myeloma.^7,11 Tumor markers are useful to monitor a patient’s response to cancer treatment or to determine recurrence, but they play only a limited role in the initial work-up of an unknown bone tumor.²⁸

Further imaging. A CT scan with intravenous contrast of the chest, abdomen, and pelvis is done to screen for visceral malignancy; however, 15% of bone lesions in patients with an unknown primary lesion never have a source identified.²⁹ Bone scans can be useful in identifying the extent of a single lesion seen on plain films and to assess for additional asymptomatic lesions. Additional imaging—eg, CT or MRI of the lesion, or positron emission tomography (PET)—can be left to the discretion of the oncologist or surgeon.

Order plain radiographs if you suspect a bone lesion. Request at least 2 views of the area that include the entire bone with the joints above and below.

CT scans have significantly higher sensitivity than radiographs and offer better visualization of bone quality, bone destruction, and soft-tissue extension.³⁰ MRI can be used to assess changes in bone marrow and soft-tissue involvement. PET scans, which detect tumors by quantifying metabolic activity, remain controversial. PET is superior to bone scans in detecting bone metastases from lung and breast cancers, but worse in renal and prostate cancers due to slow growth of metastases.^31-33

Caveat. Do not assume that a bone lesion is metastatic. Delayed diagnosis of a primary bone tumor can lead to significant changes in clinical course and patient outcome.³⁴ If any doubt exists as to the type of lesion, arrange for a biopsy using proper technique and delay bone fixation until a histologic diagnosis is complete.³⁵ Biopsy may be performed via image-guided fine-needle aspiration, core biopsy, or open incisional biopsy.

Treatment options

Metastatic bone disease is typically managed nonsurgically with radiation, chemo- or immunotherapies, hormone suppression, bone-modifying agents, or ablation.³⁶ An overview of the cancer treatment guidelines for bone metastasis from the 2017 National Comprehensive Cancer Network is shown in TABLE 2.³⁶

Continue to: Radiotherapy

Radiotherapy can take the form of external-beam or radioisotope radiation. With localized irradiation, most patients who have painful lesions experience at least partial relief, often within a few weeks.^12,37 It may be used postoperatively, as well, to decrease the chances of disease progession.²⁰

Systemic therapies include chemo- and hormone therapies. Chemotherapy effectiveness is highly dependent on the primary tumor type. For example, renal cell carcinoma and melanoma are often resistant, while lymphoma and germ-cell tumors may be eliminated and sometimes even cured.⁷ Hormone therapy can be highly effective in selective cancers, primarily breast and prostate cancers. Immunotherapy options may also be used to specifically target bone metastasis sites.

Bone-modifying agents include bisphosphonates and denosumab (Prolia, Xgeva). These are generally initiated at the discretion of the oncologist, but primary care physicians should be familiar with their use. Bisphosphonates, which includes zoledronic acid, pamidronate, and other agents, are analogues of pyrophosphate that inhibit bone demineralization.³⁸ These agents target bone resorption through incorporation into osteoclasts and have been effective in the treatment of hypercalcemia and bone lesions.^6,12,39 Not only do they reduce the incidence of all skeleton-related events, including pathologic fractures and pain, they also appear to have antitumor activity with prolonged survival in certain cancers.^7,12

Denosumab, which has a much shorter half-life than bisphosphonates, is a monoclonal antibody that targets the gene RANKL, a key activator of osteoclasts, and thereby prevents the development of osteoclasts and related bone resorption.⁴⁰

Radiofrequency ablation or cryoablation, using image-guided needle placement, specifically targets individual bone lesions, destroying tumor cells with extreme heat or cold, respectively. This has been shown to reduce pain and opioid consumption.⁴¹

Continue to: Managing pain

 

 

Managing pain

Pain management can be difficult, especially as patients live longer and undergo additional treatments such as surgery, radiation, and chemotherapy, each with the potential to produce chronic pain.⁴² A multidisciplinary team with a stepwise and multimodal approach can improve the patient’s function and comfort while decreasing drug adverse effects.⁴³

For mild-to-moderate pain, nonsteroidal anti-inflammatory drugs, acetaminophen, and tramadol may provide effective relief. For more severe pain, narcotics are often required on a fixed-dose schedule along with breakthrough options such as short-acting hydromorphone, oxycodone, or transmucosal fentanyl.^42-44 Opioid adverse effects such as constipation and nausea/vomiting must be managed with laxatives and metoclopramide/antidopaminergics, respectively.

Other important non-narcotic therapies are corticosteroids, tricyclic antidepressants, gabapentin, neuroleptics, and nerve blocks.⁴⁵ Physical therapy and acupuncture may also be useful, depending on the patient’s needs and desires. Despite the wide range of options, most patients continue to have a significant amount of pain that can impact daily activities and even cause them to feel that their quality of life was not an important factor in physician decision making.⁴⁶

Surgery options

Surgical intervention for metastatic bone disease differs from its use in primary bone tumors in that clinical indications are not clearly defined. In general, surgery for metastatic disease is used in patients who have pathologic fractures, a risk of pathologic fracture, or uncontrolled cancer-induced bone pain. Keep in mind that the overarching goal of surgery is to reduce morbidity, not mortality, although exceptions exist. Metastatic renal cell carcinoma is one such exception: improved survival may be achieved via aggressive surgical resection for solitary or oligometastatic lesions.⁴⁷

Before deciding on surgery, engage the patient in goals-of-care discussions and take into account factors specific to the individual, as operative complications can be devasting. Risk of postoperative infection is high, given that these patients are often immunocompromised and that irradiated tissue is prone to wound healing issues.⁸ Complications may require a pause in chemotherapy and a subsequent decrease in life expectancy.

Continue to: Another factor in surgical decision making...

Another factor in surgical decision making is that newer systemic therapies are leading to longer survival for those with various types of metastatic cancer.⁴⁸ Older methods of fixation designed to last a few years may now fail during the patient’s prolonged ­lifespan. As novel therapies continue to improve survival and complicate surgical indications, it may be prudent for the surgical management of metastatic bone disease to be handled by fellowship-trained orthopedic oncologists.

Factors that affect timing. Surgical intervention ideally occurs before the development of a pathologic fracture. Outcomes research has shown that intervention before fracture leads to reduced blood loss and length of hospital stay with improved functional recovery and survival.^12,49 Despite these improved outcomes, an adequate scoring system to guide surgical intervention has yet to be developed. Mirels’ criteria are cited most often, yet this scoring system fails to account for many important considerations such as primary tumor type, life expectancy, and other factors.^50,51

If a patient with no known primary tumor has a confirmed bone lesion, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan.

Given the deleterious effects of fractures in cancer patients and the inadequacy of closed reduction and immobilization, surgical intervention is often warranted.⁵² Surgical technology has continued to progress; however, intramedullary nailing, plating, and endoprostheses are still the most commonly used methods.⁵³

Intramedullary nailing is commonly used in the prophylactic treatment of pathologic lesions and fractures of long bones in patients whose expected survival is as little as 6 to 12 weeks.⁵⁴ Plate and screw fixation is a viable alternative to intramedullary nailing when tumor resection is desired. Endoprostheses replacement is used when a tumor involves joint surfaces or if biological reconstruction cannot be achieved by nailing or plating.

Explicit communication with patients is critical

Of vital importance is your participation with patients and families in shared decision making throughout the diagnostic and treatment process, ensuring clear communication. Misunderstandings about cancer stages and prognoses are not uncommon and are sometimes due to insufficient explanation.^55,56 Additionally, expectations of survival and adverse effects of treatment often differ greatly between physicians and patients, which can lead to patient dissatisfaction.⁵⁷

Continue to: Finally, the long-term care...

Finally, the long-term care of patients with metastatic cancers necessarily involves multidisciplinary teams, which further complicates communication. To ensure that patients are receiving an appropriate course of treatment, evaluate their health literacy, confirm their understanding of the disease, and acknowledge their desires.

CORRESPONDENCE
Kyle Sweeney, MD, University of Kansas Medical Center, Department of Orthopedic Surgery, 3901 Rainbow Boulevard, MS 3017, Kansas City, KS 66160; ksweeney2@kumc.edu.

Since the early 1990s, modern treatments have steadily reduced overall cancer mortality from primary tumors.¹ Consequently, more people are at risk of metastatic bone disease, with subsequent pain and pathologic fractures^1,2 and death from metastasis.³ Patients who have bone metastases present with a variety of signs and symptoms including pain, fractures, and metabolic derangements. The primary care approach to work-up and diagnosis described in this article enables prompt treatment, either surgical or nonsurgical, to maintain a high quality of life for patients.

Primary tumors determine types of metastases and prognosis

Metastasis, a complex pathologic process in which cancerous cells migrate to distant organs, implant, and grow,³ is a poor prognostic indicator in cancer patients. Bone is the third most common site of metastasis, behind the liver and lungs.⁴ While the true prevalence of metastatic bone cancer is unknown, studies have estimated it to be > 280,000 cases in the United States.⁵

Bone metastases interfere with normal bone metabolism and turnover in several different characteristic patterns. These changes—radiographically defined as osteoblastic, osteolytic, or mixed lesions—are determined by the primary tumor type.

• Osteoblastic lesions, comprised of new, disorganized bone formation, often occur secondary to prostate cancer, small cell lung cancer, and carcinoid malignancies, among others.
• Osteolytic lesions, in which bone is destroyed, are more common with breast cancer, renal cell carcinoma, melanoma, and multiple myeloma.
• Mixed lesions, in which areas of bone destruction and growth are simultaneously found, occur with some GI cancers and a few breast cancers.^6,7

Most bone metastases result from carcinomas, of which up to 50% eventually spread to bone, although this process can take 10 to 15 years.^8,9 The likelihood of bone metastasis depends on the primary tumor and its stage. Breast and prostate cancer account for most skeletal metastases, although these lesions are often asymptomatic.^6,9 Other malignancies, such as ovarian and gastrointestinal, metastasize to bone much less frequently.^7,10 Virtually any cancer at an advanced stage can spread to bone. These metastases are usually multifocal and incurable, with the patient’s prognosis varying from a few months to years.^6,11,12

Factors that influence prognosis. Metastatic bone disease arising from melanoma and lung cancers has the shortest life expectancy of roughly 6 months from initial diagnosis; metastasis following prostate, breast, and thyroid cancers has the longest, usually 2 to 4 years.¹¹TABLE 1¹³ shows survival estimates from a large Danish population at various time points following bone metastasis diagnosis for several primary cancer types.

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer—even if such a history is remote. It’s important.

When surgical intervention for bony metastasis is required, prognosis is generally poorer, likely due to more advanced disease. The overall 1-year survival following surgery varies, but several large studies have found a rate of around 40% when considering all primary tumors.^14,15 The most common metastases, from breast and prostate cancers, have 1-year survivals of around 50% and 30%, respectively, following surgical intervention.^16-18

What you’re likely to see on presentation

Bone metastases are one of the leading causes of morbidity in cancer patients from resultant pain, pathologic fractures, metabolic derangements, and reduced activities of daily living.^8,19 The most common cause of cancer pain is bone involvement.⁶ Patients report pain that is usually worse at night, poorly localized, and not alleviated with rest. They often mistakenly relate the pain to an injury.²⁰ The pathophysiology of bone pain is not completely understood but is likely multifactorial and includes inflammatory and mechanical processes.^7,21 Spine involvement can lead to stenosis or nerve root compression, with symptoms dependent on level and severity of nerve or cord compromise.²⁰ Overall, the most common site of bone metastasis is the thoracic spine, followed by the ribs, pelvis, and proximal long bones.²⁰

Continue to: Pathologic fractures

Pathologic fractures occur frequently in cancer patients. Bone destruction leads to a loss of mechanical support which, in turn, causes microfractures and pain. These microfractures can proliferate and coalesce, causing a pathologic fracture, often in weight-bearing bones.⁶ Breast cancer with lytic lesions is the single leading cause of all pathologic fractures.²² Lung cancer with its short survival time and prostate cancer with blastic lesions are less common causes.²³ In the appendicular skeleton, the vast majority of these fractures occur in the femur and humerus.¹¹

Symptomatic metabolic derangements. The most common metabolic disorder is hypercalcemia, found predominantly in patients with hematologic malignancies, squamous cell lung cancer, renal cell cancer, and breast cancer.^6,7,12,24 The clinical presentation is nonspecific and can include polyuria, polydipsia, fatigue, constipation, and confusion. The prevalence is estimated to be 13% in breast cancer, 4% in lung cancers, and 1% in prostate cancer, although results in individual studies vary.¹² The pathophysiology is multifactorial and often includes osteolytic lesions and an increased circulating level of parathyroid hormone–related peptide, although other mechanisms contribute.^25,26 Ultimately, severe hypercalcemia may be fatal secondary to renal failure and cardiac arrhythmias.^6,7,12 Paraneoplastic hypercalcemia independently decreases survival; 1 study found the median survival to be 10 to 12 weeks.¹¹

Primary care work-up and diagnosis

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer. Even if such a history is remote, it is important—­particularly so if the patient received chemotherapy or radiation, which can lead to secondary cancers such as leukemia or sarcoma.²⁰ If a primary site of malignancy is unknown, pursue a general review of systems. Clues to the primary site of disease could be a history of chest pain, shortness of breath, hemoptysis, heat/cold intolerance, or changes in bowel/bladder habits. Also ask about risk factors such as smoking, chemical exposure, and sun exposure.

Pointers on radiographic imaging. If you suspect a destructive bone lesion, order appropriate radiographic imaging. Arrange for plain radiographs with at least 2 views of the specific area of interest that include the entire bone along with the joints above and below. Importantly, the entire bone must be imaged before any surgical procedure to avoid periprosthetic fractures from undetected bone metastases around hardware.²⁰ Keep in mind that plain films can miss early lesions, and computed tomography (CT) or magnetic resonance imaging (MRI) may be needed if suspicion of a pathologic process is still strong and especially if a primary malignancy is known.²⁷

Working back to a primary diagnosis

If imaging confirms a suspicious lesion and the patient has no known primary tumor, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan, and refer the patient to an oncologist. If the bone lesion is painful, initiate protected weight-bearing and additionally refer the patient to an orthopedic surgeon.

Continue to: Appropriate laboratory evaluation

Appropriate laboratory evaluation entails a complete blood count; metabolic panel that includes serum calcium and phosphorus, vitamin D, alkaline phosphatase, thyroid-stimulating hormone, and parathyroid hormone; and serum protein electrophoresis to rule out multiple myeloma.^7,11 Tumor markers are useful to monitor a patient’s response to cancer treatment or to determine recurrence, but they play only a limited role in the initial work-up of an unknown bone tumor.²⁸

Further imaging. A CT scan with intravenous contrast of the chest, abdomen, and pelvis is done to screen for visceral malignancy; however, 15% of bone lesions in patients with an unknown primary lesion never have a source identified.²⁹ Bone scans can be useful in identifying the extent of a single lesion seen on plain films and to assess for additional asymptomatic lesions. Additional imaging—eg, CT or MRI of the lesion, or positron emission tomography (PET)—can be left to the discretion of the oncologist or surgeon.

Order plain radiographs if you suspect a bone lesion. Request at least 2 views of the area that include the entire bone with the joints above and below.

CT scans have significantly higher sensitivity than radiographs and offer better visualization of bone quality, bone destruction, and soft-tissue extension.³⁰ MRI can be used to assess changes in bone marrow and soft-tissue involvement. PET scans, which detect tumors by quantifying metabolic activity, remain controversial. PET is superior to bone scans in detecting bone metastases from lung and breast cancers, but worse in renal and prostate cancers due to slow growth of metastases.^31-33

Caveat. Do not assume that a bone lesion is metastatic. Delayed diagnosis of a primary bone tumor can lead to significant changes in clinical course and patient outcome.³⁴ If any doubt exists as to the type of lesion, arrange for a biopsy using proper technique and delay bone fixation until a histologic diagnosis is complete.³⁵ Biopsy may be performed via image-guided fine-needle aspiration, core biopsy, or open incisional biopsy.

Treatment options

Metastatic bone disease is typically managed nonsurgically with radiation, chemo- or immunotherapies, hormone suppression, bone-modifying agents, or ablation.³⁶ An overview of the cancer treatment guidelines for bone metastasis from the 2017 National Comprehensive Cancer Network is shown in TABLE 2.³⁶

Continue to: Radiotherapy

Radiotherapy can take the form of external-beam or radioisotope radiation. With localized irradiation, most patients who have painful lesions experience at least partial relief, often within a few weeks.^12,37 It may be used postoperatively, as well, to decrease the chances of disease progession.²⁰

Systemic therapies include chemo- and hormone therapies. Chemotherapy effectiveness is highly dependent on the primary tumor type. For example, renal cell carcinoma and melanoma are often resistant, while lymphoma and germ-cell tumors may be eliminated and sometimes even cured.⁷ Hormone therapy can be highly effective in selective cancers, primarily breast and prostate cancers. Immunotherapy options may also be used to specifically target bone metastasis sites.

Bone-modifying agents include bisphosphonates and denosumab (Prolia, Xgeva). These are generally initiated at the discretion of the oncologist, but primary care physicians should be familiar with their use. Bisphosphonates, which includes zoledronic acid, pamidronate, and other agents, are analogues of pyrophosphate that inhibit bone demineralization.³⁸ These agents target bone resorption through incorporation into osteoclasts and have been effective in the treatment of hypercalcemia and bone lesions.^6,12,39 Not only do they reduce the incidence of all skeleton-related events, including pathologic fractures and pain, they also appear to have antitumor activity with prolonged survival in certain cancers.^7,12

Denosumab, which has a much shorter half-life than bisphosphonates, is a monoclonal antibody that targets the gene RANKL, a key activator of osteoclasts, and thereby prevents the development of osteoclasts and related bone resorption.⁴⁰

Radiofrequency ablation or cryoablation, using image-guided needle placement, specifically targets individual bone lesions, destroying tumor cells with extreme heat or cold, respectively. This has been shown to reduce pain and opioid consumption.⁴¹

Continue to: Managing pain

 

 

Managing pain

Pain management can be difficult, especially as patients live longer and undergo additional treatments such as surgery, radiation, and chemotherapy, each with the potential to produce chronic pain.⁴² A multidisciplinary team with a stepwise and multimodal approach can improve the patient’s function and comfort while decreasing drug adverse effects.⁴³

For mild-to-moderate pain, nonsteroidal anti-inflammatory drugs, acetaminophen, and tramadol may provide effective relief. For more severe pain, narcotics are often required on a fixed-dose schedule along with breakthrough options such as short-acting hydromorphone, oxycodone, or transmucosal fentanyl.^42-44 Opioid adverse effects such as constipation and nausea/vomiting must be managed with laxatives and metoclopramide/antidopaminergics, respectively.

Other important non-narcotic therapies are corticosteroids, tricyclic antidepressants, gabapentin, neuroleptics, and nerve blocks.⁴⁵ Physical therapy and acupuncture may also be useful, depending on the patient’s needs and desires. Despite the wide range of options, most patients continue to have a significant amount of pain that can impact daily activities and even cause them to feel that their quality of life was not an important factor in physician decision making.⁴⁶

Surgery options

Surgical intervention for metastatic bone disease differs from its use in primary bone tumors in that clinical indications are not clearly defined. In general, surgery for metastatic disease is used in patients who have pathologic fractures, a risk of pathologic fracture, or uncontrolled cancer-induced bone pain. Keep in mind that the overarching goal of surgery is to reduce morbidity, not mortality, although exceptions exist. Metastatic renal cell carcinoma is one such exception: improved survival may be achieved via aggressive surgical resection for solitary or oligometastatic lesions.⁴⁷

Before deciding on surgery, engage the patient in goals-of-care discussions and take into account factors specific to the individual, as operative complications can be devasting. Risk of postoperative infection is high, given that these patients are often immunocompromised and that irradiated tissue is prone to wound healing issues.⁸ Complications may require a pause in chemotherapy and a subsequent decrease in life expectancy.

Continue to: Another factor in surgical decision making...

Another factor in surgical decision making is that newer systemic therapies are leading to longer survival for those with various types of metastatic cancer.⁴⁸ Older methods of fixation designed to last a few years may now fail during the patient’s prolonged ­lifespan. As novel therapies continue to improve survival and complicate surgical indications, it may be prudent for the surgical management of metastatic bone disease to be handled by fellowship-trained orthopedic oncologists.

Factors that affect timing. Surgical intervention ideally occurs before the development of a pathologic fracture. Outcomes research has shown that intervention before fracture leads to reduced blood loss and length of hospital stay with improved functional recovery and survival.^12,49 Despite these improved outcomes, an adequate scoring system to guide surgical intervention has yet to be developed. Mirels’ criteria are cited most often, yet this scoring system fails to account for many important considerations such as primary tumor type, life expectancy, and other factors.^50,51

If a patient with no known primary tumor has a confirmed bone lesion, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan.

Given the deleterious effects of fractures in cancer patients and the inadequacy of closed reduction and immobilization, surgical intervention is often warranted.⁵² Surgical technology has continued to progress; however, intramedullary nailing, plating, and endoprostheses are still the most commonly used methods.⁵³

Intramedullary nailing is commonly used in the prophylactic treatment of pathologic lesions and fractures of long bones in patients whose expected survival is as little as 6 to 12 weeks.⁵⁴ Plate and screw fixation is a viable alternative to intramedullary nailing when tumor resection is desired. Endoprostheses replacement is used when a tumor involves joint surfaces or if biological reconstruction cannot be achieved by nailing or plating.

Explicit communication with patients is critical

Of vital importance is your participation with patients and families in shared decision making throughout the diagnostic and treatment process, ensuring clear communication. Misunderstandings about cancer stages and prognoses are not uncommon and are sometimes due to insufficient explanation.^55,56 Additionally, expectations of survival and adverse effects of treatment often differ greatly between physicians and patients, which can lead to patient dissatisfaction.⁵⁷

Continue to: Finally, the long-term care...

Finally, the long-term care of patients with metastatic cancers necessarily involves multidisciplinary teams, which further complicates communication. To ensure that patients are receiving an appropriate course of treatment, evaluate their health literacy, confirm their understanding of the disease, and acknowledge their desires.

CORRESPONDENCE
Kyle Sweeney, MD, University of Kansas Medical Center, Department of Orthopedic Surgery, 3901 Rainbow Boulevard, MS 3017, Kansas City, KS 66160; ksweeney2@kumc.edu.

Since the early 1990s, modern treatments have steadily reduced overall cancer mortality from primary tumors.¹ Consequently, more people are at risk of metastatic bone disease, with subsequent pain and pathologic fractures^1,2 and death from metastasis.³ Patients who have bone metastases present with a variety of signs and symptoms including pain, fractures, and metabolic derangements. The primary care approach to work-up and diagnosis described in this article enables prompt treatment, either surgical or nonsurgical, to maintain a high quality of life for patients.

Primary tumors determine types of metastases and prognosis

Metastasis, a complex pathologic process in which cancerous cells migrate to distant organs, implant, and grow,³ is a poor prognostic indicator in cancer patients. Bone is the third most common site of metastasis, behind the liver and lungs.⁴ While the true prevalence of metastatic bone cancer is unknown, studies have estimated it to be > 280,000 cases in the United States.⁵

Bone metastases interfere with normal bone metabolism and turnover in several different characteristic patterns. These changes—radiographically defined as osteoblastic, osteolytic, or mixed lesions—are determined by the primary tumor type.

• Osteoblastic lesions, comprised of new, disorganized bone formation, often occur secondary to prostate cancer, small cell lung cancer, and carcinoid malignancies, among others.
• Osteolytic lesions, in which bone is destroyed, are more common with breast cancer, renal cell carcinoma, melanoma, and multiple myeloma.
• Mixed lesions, in which areas of bone destruction and growth are simultaneously found, occur with some GI cancers and a few breast cancers.^6,7

Most bone metastases result from carcinomas, of which up to 50% eventually spread to bone, although this process can take 10 to 15 years.^8,9 The likelihood of bone metastasis depends on the primary tumor and its stage. Breast and prostate cancer account for most skeletal metastases, although these lesions are often asymptomatic.^6,9 Other malignancies, such as ovarian and gastrointestinal, metastasize to bone much less frequently.^7,10 Virtually any cancer at an advanced stage can spread to bone. These metastases are usually multifocal and incurable, with the patient’s prognosis varying from a few months to years.^6,11,12

Factors that influence prognosis. Metastatic bone disease arising from melanoma and lung cancers has the shortest life expectancy of roughly 6 months from initial diagnosis; metastasis following prostate, breast, and thyroid cancers has the longest, usually 2 to 4 years.¹¹TABLE 1¹³ shows survival estimates from a large Danish population at various time points following bone metastasis diagnosis for several primary cancer types.

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer—even if such a history is remote. It’s important.

When surgical intervention for bony metastasis is required, prognosis is generally poorer, likely due to more advanced disease. The overall 1-year survival following surgery varies, but several large studies have found a rate of around 40% when considering all primary tumors.^14,15 The most common metastases, from breast and prostate cancers, have 1-year survivals of around 50% and 30%, respectively, following surgical intervention.^16-18

What you’re likely to see on presentation

Bone metastases are one of the leading causes of morbidity in cancer patients from resultant pain, pathologic fractures, metabolic derangements, and reduced activities of daily living.^8,19 The most common cause of cancer pain is bone involvement.⁶ Patients report pain that is usually worse at night, poorly localized, and not alleviated with rest. They often mistakenly relate the pain to an injury.²⁰ The pathophysiology of bone pain is not completely understood but is likely multifactorial and includes inflammatory and mechanical processes.^7,21 Spine involvement can lead to stenosis or nerve root compression, with symptoms dependent on level and severity of nerve or cord compromise.²⁰ Overall, the most common site of bone metastasis is the thoracic spine, followed by the ribs, pelvis, and proximal long bones.²⁰

Continue to: Pathologic fractures

Pathologic fractures occur frequently in cancer patients. Bone destruction leads to a loss of mechanical support which, in turn, causes microfractures and pain. These microfractures can proliferate and coalesce, causing a pathologic fracture, often in weight-bearing bones.⁶ Breast cancer with lytic lesions is the single leading cause of all pathologic fractures.²² Lung cancer with its short survival time and prostate cancer with blastic lesions are less common causes.²³ In the appendicular skeleton, the vast majority of these fractures occur in the femur and humerus.¹¹

Symptomatic metabolic derangements. The most common metabolic disorder is hypercalcemia, found predominantly in patients with hematologic malignancies, squamous cell lung cancer, renal cell cancer, and breast cancer.^6,7,12,24 The clinical presentation is nonspecific and can include polyuria, polydipsia, fatigue, constipation, and confusion. The prevalence is estimated to be 13% in breast cancer, 4% in lung cancers, and 1% in prostate cancer, although results in individual studies vary.¹² The pathophysiology is multifactorial and often includes osteolytic lesions and an increased circulating level of parathyroid hormone–related peptide, although other mechanisms contribute.^25,26 Ultimately, severe hypercalcemia may be fatal secondary to renal failure and cardiac arrhythmias.^6,7,12 Paraneoplastic hypercalcemia independently decreases survival; 1 study found the median survival to be 10 to 12 weeks.¹¹

Primary care work-up and diagnosis

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer. Even if such a history is remote, it is important—­particularly so if the patient received chemotherapy or radiation, which can lead to secondary cancers such as leukemia or sarcoma.²⁰ If a primary site of malignancy is unknown, pursue a general review of systems. Clues to the primary site of disease could be a history of chest pain, shortness of breath, hemoptysis, heat/cold intolerance, or changes in bowel/bladder habits. Also ask about risk factors such as smoking, chemical exposure, and sun exposure.

Pointers on radiographic imaging. If you suspect a destructive bone lesion, order appropriate radiographic imaging. Arrange for plain radiographs with at least 2 views of the specific area of interest that include the entire bone along with the joints above and below. Importantly, the entire bone must be imaged before any surgical procedure to avoid periprosthetic fractures from undetected bone metastases around hardware.²⁰ Keep in mind that plain films can miss early lesions, and computed tomography (CT) or magnetic resonance imaging (MRI) may be needed if suspicion of a pathologic process is still strong and especially if a primary malignancy is known.²⁷

Working back to a primary diagnosis

If imaging confirms a suspicious lesion and the patient has no known primary tumor, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan, and refer the patient to an oncologist. If the bone lesion is painful, initiate protected weight-bearing and additionally refer the patient to an orthopedic surgeon.

Continue to: Appropriate laboratory evaluation

Appropriate laboratory evaluation entails a complete blood count; metabolic panel that includes serum calcium and phosphorus, vitamin D, alkaline phosphatase, thyroid-stimulating hormone, and parathyroid hormone; and serum protein electrophoresis to rule out multiple myeloma.^7,11 Tumor markers are useful to monitor a patient’s response to cancer treatment or to determine recurrence, but they play only a limited role in the initial work-up of an unknown bone tumor.²⁸

Further imaging. A CT scan with intravenous contrast of the chest, abdomen, and pelvis is done to screen for visceral malignancy; however, 15% of bone lesions in patients with an unknown primary lesion never have a source identified.²⁹ Bone scans can be useful in identifying the extent of a single lesion seen on plain films and to assess for additional asymptomatic lesions. Additional imaging—eg, CT or MRI of the lesion, or positron emission tomography (PET)—can be left to the discretion of the oncologist or surgeon.

Order plain radiographs if you suspect a bone lesion. Request at least 2 views of the area that include the entire bone with the joints above and below.

CT scans have significantly higher sensitivity than radiographs and offer better visualization of bone quality, bone destruction, and soft-tissue extension.³⁰ MRI can be used to assess changes in bone marrow and soft-tissue involvement. PET scans, which detect tumors by quantifying metabolic activity, remain controversial. PET is superior to bone scans in detecting bone metastases from lung and breast cancers, but worse in renal and prostate cancers due to slow growth of metastases.^31-33

Caveat. Do not assume that a bone lesion is metastatic. Delayed diagnosis of a primary bone tumor can lead to significant changes in clinical course and patient outcome.³⁴ If any doubt exists as to the type of lesion, arrange for a biopsy using proper technique and delay bone fixation until a histologic diagnosis is complete.³⁵ Biopsy may be performed via image-guided fine-needle aspiration, core biopsy, or open incisional biopsy.

Treatment options

Metastatic bone disease is typically managed nonsurgically with radiation, chemo- or immunotherapies, hormone suppression, bone-modifying agents, or ablation.³⁶ An overview of the cancer treatment guidelines for bone metastasis from the 2017 National Comprehensive Cancer Network is shown in TABLE 2.³⁶

Continue to: Radiotherapy

Radiotherapy can take the form of external-beam or radioisotope radiation. With localized irradiation, most patients who have painful lesions experience at least partial relief, often within a few weeks.^12,37 It may be used postoperatively, as well, to decrease the chances of disease progession.²⁰

Systemic therapies include chemo- and hormone therapies. Chemotherapy effectiveness is highly dependent on the primary tumor type. For example, renal cell carcinoma and melanoma are often resistant, while lymphoma and germ-cell tumors may be eliminated and sometimes even cured.⁷ Hormone therapy can be highly effective in selective cancers, primarily breast and prostate cancers. Immunotherapy options may also be used to specifically target bone metastasis sites.

Bone-modifying agents include bisphosphonates and denosumab (Prolia, Xgeva). These are generally initiated at the discretion of the oncologist, but primary care physicians should be familiar with their use. Bisphosphonates, which includes zoledronic acid, pamidronate, and other agents, are analogues of pyrophosphate that inhibit bone demineralization.³⁸ These agents target bone resorption through incorporation into osteoclasts and have been effective in the treatment of hypercalcemia and bone lesions.^6,12,39 Not only do they reduce the incidence of all skeleton-related events, including pathologic fractures and pain, they also appear to have antitumor activity with prolonged survival in certain cancers.^7,12

Denosumab, which has a much shorter half-life than bisphosphonates, is a monoclonal antibody that targets the gene RANKL, a key activator of osteoclasts, and thereby prevents the development of osteoclasts and related bone resorption.⁴⁰

Radiofrequency ablation or cryoablation, using image-guided needle placement, specifically targets individual bone lesions, destroying tumor cells with extreme heat or cold, respectively. This has been shown to reduce pain and opioid consumption.⁴¹

Continue to: Managing pain

 

 

Managing pain

Pain management can be difficult, especially as patients live longer and undergo additional treatments such as surgery, radiation, and chemotherapy, each with the potential to produce chronic pain.⁴² A multidisciplinary team with a stepwise and multimodal approach can improve the patient’s function and comfort while decreasing drug adverse effects.⁴³

For mild-to-moderate pain, nonsteroidal anti-inflammatory drugs, acetaminophen, and tramadol may provide effective relief. For more severe pain, narcotics are often required on a fixed-dose schedule along with breakthrough options such as short-acting hydromorphone, oxycodone, or transmucosal fentanyl.^42-44 Opioid adverse effects such as constipation and nausea/vomiting must be managed with laxatives and metoclopramide/antidopaminergics, respectively.

Other important non-narcotic therapies are corticosteroids, tricyclic antidepressants, gabapentin, neuroleptics, and nerve blocks.⁴⁵ Physical therapy and acupuncture may also be useful, depending on the patient’s needs and desires. Despite the wide range of options, most patients continue to have a significant amount of pain that can impact daily activities and even cause them to feel that their quality of life was not an important factor in physician decision making.⁴⁶

Surgery options

Surgical intervention for metastatic bone disease differs from its use in primary bone tumors in that clinical indications are not clearly defined. In general, surgery for metastatic disease is used in patients who have pathologic fractures, a risk of pathologic fracture, or uncontrolled cancer-induced bone pain. Keep in mind that the overarching goal of surgery is to reduce morbidity, not mortality, although exceptions exist. Metastatic renal cell carcinoma is one such exception: improved survival may be achieved via aggressive surgical resection for solitary or oligometastatic lesions.⁴⁷

Before deciding on surgery, engage the patient in goals-of-care discussions and take into account factors specific to the individual, as operative complications can be devasting. Risk of postoperative infection is high, given that these patients are often immunocompromised and that irradiated tissue is prone to wound healing issues.⁸ Complications may require a pause in chemotherapy and a subsequent decrease in life expectancy.

Continue to: Another factor in surgical decision making...

Another factor in surgical decision making is that newer systemic therapies are leading to longer survival for those with various types of metastatic cancer.⁴⁸ Older methods of fixation designed to last a few years may now fail during the patient’s prolonged ­lifespan. As novel therapies continue to improve survival and complicate surgical indications, it may be prudent for the surgical management of metastatic bone disease to be handled by fellowship-trained orthopedic oncologists.

Factors that affect timing. Surgical intervention ideally occurs before the development of a pathologic fracture. Outcomes research has shown that intervention before fracture leads to reduced blood loss and length of hospital stay with improved functional recovery and survival.^12,49 Despite these improved outcomes, an adequate scoring system to guide surgical intervention has yet to be developed. Mirels’ criteria are cited most often, yet this scoring system fails to account for many important considerations such as primary tumor type, life expectancy, and other factors.^50,51

If a patient with no known primary tumor has a confirmed bone lesion, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan.

Given the deleterious effects of fractures in cancer patients and the inadequacy of closed reduction and immobilization, surgical intervention is often warranted.⁵² Surgical technology has continued to progress; however, intramedullary nailing, plating, and endoprostheses are still the most commonly used methods.⁵³

Intramedullary nailing is commonly used in the prophylactic treatment of pathologic lesions and fractures of long bones in patients whose expected survival is as little as 6 to 12 weeks.⁵⁴ Plate and screw fixation is a viable alternative to intramedullary nailing when tumor resection is desired. Endoprostheses replacement is used when a tumor involves joint surfaces or if biological reconstruction cannot be achieved by nailing or plating.

Explicit communication with patients is critical

Of vital importance is your participation with patients and families in shared decision making throughout the diagnostic and treatment process, ensuring clear communication. Misunderstandings about cancer stages and prognoses are not uncommon and are sometimes due to insufficient explanation.^55,56 Additionally, expectations of survival and adverse effects of treatment often differ greatly between physicians and patients, which can lead to patient dissatisfaction.⁵⁷

Continue to: Finally, the long-term care...

Finally, the long-term care of patients with metastatic cancers necessarily involves multidisciplinary teams, which further complicates communication. To ensure that patients are receiving an appropriate course of treatment, evaluate their health literacy, confirm their understanding of the disease, and acknowledge their desires.

CORRESPONDENCE
Kyle Sweeney, MD, University of Kansas Medical Center, Department of Orthopedic Surgery, 3901 Rainbow Boulevard, MS 3017, Kansas City, KS 66160; ksweeney2@kumc.edu.

A new review offers fresh guidance to help stem the mental health toll of the COVID-19 pandemic on frontline clinicians.

Investigators gathered practice guidelines and resources from a wide range of health care organizations and professional societies to develop a conceptual framework of mental health support for health care professionals (HCPs) caring for COVID-19 patients.

An opportune moment

Coauthor Rebecca Margolis, DO, director of well-being in the division of medical education and faculty development, Children’s Hospital of Los Angeles, said that this is “an opportune moment to look at how we treat frontline providers in this country.”

Studies of previous pandemics have shown heightened distress in HCPs, even years after the pandemic, and the unique challenges posed by the COVID-19 pandemic surpass those of previous pandemics, Dr. Margolis said in an interview.

Dr. Schwartz, Dr. Margolis, and coauthors Uma Anand, PhD, LP, and Jina Sinskey, MD, met through the Collaborative for Healing and Renewal in Medicine network, a group of medical educators, leaders in academic medicine, experts in burnout research and interventions, and trainees working together to promote well-being among trainees and practicing physicians.

“We were brought together on a conference call in March, when things were particularly bad in New York, and started looking to see what resources we could get to frontline providers who were suffering. It was great to lean on each other and stand on the shoulders of colleagues in New York, who were the ones we learned from on these calls,” said Dr. Margolis.

The authors recommended addressing clinicians’ basic practical needs, including ensuring essentials like meals and transportation, establishing a “well-being area” within hospitals for staff to rest, and providing well-stocked living quarters so clinicians can safely quarantine from family, as well as personal protective equipment and child care.

Clinicians are often asked to “assume new professional roles to meet evolving needs” during a pandemic, which can increase stress. The authors recommended targeted training, assessment of clinician skills before redeployment to a new clinical role, and clear communication practices around redeployment.

Recognition from hospital and government leaders improves morale and supports clinicians’ ability to continue delivering care. Leadership should “leverage communication strategies to provide clinicians with up-to-date information and reassurance,” they wrote.
 

‘Uniquely isolated’

Dr. Margolis noted that clinicians “are uniquely isolated, especially those with children” because many parents do not want their children mingling with children of HCPs.

“My colleagues feel a sense of moral injury, putting their lives on the line at work, performing the most perilous job, and their kids can’t hang out with other kids, which just puts salt on the wound,” she said.

Additional sources of moral injury are deciding which patients should receive life support in the event of inadequate resources and bearing witness to, or enforcing, policies that lead to patients dying alone.

Leaders should encourage clinicians to “seek informal support from colleagues, managers, or chaplains” and to “provide rapid access to professional help,” the authors noted.

Furthermore, they contended that leaders should “proactively and routinely monitor the psychological well-being of their teams,” since guilt and shame often prevent clinicians from disclosing feelings of moral injury.

“Being provided with routine mental health support should be normalized and it should be part of the job – not only during COVID-19 but in general,” Dr. Schwartz said.
 

‘Battle buddies’

Dr. Margolis recommended the “battle buddy” model for mutual peer support.

Dr. Anand, a mental health clinician at Mayo Medical School, Rochester, Minn., elaborated.

Self-care critical

Marcus S. Shaker, MD, MSc, associate professor of pediatrics, medicine, and community and family medicine, Children’s Hospital at Dartmouth-Hitchcock in Lebanon, N.H., and Geisel School of Medicine at Dartmouth, Hanover, N.H., said the study was “a much appreciated, timely reminder of the importance of clinician wellness.”

Moreover, “without self-care, our ability to help our patients withers. This article provides a useful conceptual framework for individuals and organizations to provide the right care at the right time in these unprecedented times,” said Dr. Shaker, who was not involved with the study.

The authors agreed, stating that clinicians “require proactive psychological protection specifically because they are a population known for putting others’ needs before their own.”

They recommended several resources for HCPs, including the Physician Support Line; Headspace, a mindfulness Web-based app for reducing stress and anxiety; the National Suicide Prevention Lifeline; and the Crisis Text Line.

The authors and Dr. Shaker disclosed no relevant financial relationships.

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

A new review offers fresh guidance to help stem the mental health toll of the COVID-19 pandemic on frontline clinicians.

Investigators gathered practice guidelines and resources from a wide range of health care organizations and professional societies to develop a conceptual framework of mental health support for health care professionals (HCPs) caring for COVID-19 patients.

An opportune moment

Coauthor Rebecca Margolis, DO, director of well-being in the division of medical education and faculty development, Children’s Hospital of Los Angeles, said that this is “an opportune moment to look at how we treat frontline providers in this country.”

Studies of previous pandemics have shown heightened distress in HCPs, even years after the pandemic, and the unique challenges posed by the COVID-19 pandemic surpass those of previous pandemics, Dr. Margolis said in an interview.

Dr. Schwartz, Dr. Margolis, and coauthors Uma Anand, PhD, LP, and Jina Sinskey, MD, met through the Collaborative for Healing and Renewal in Medicine network, a group of medical educators, leaders in academic medicine, experts in burnout research and interventions, and trainees working together to promote well-being among trainees and practicing physicians.

“We were brought together on a conference call in March, when things were particularly bad in New York, and started looking to see what resources we could get to frontline providers who were suffering. It was great to lean on each other and stand on the shoulders of colleagues in New York, who were the ones we learned from on these calls,” said Dr. Margolis.

The authors recommended addressing clinicians’ basic practical needs, including ensuring essentials like meals and transportation, establishing a “well-being area” within hospitals for staff to rest, and providing well-stocked living quarters so clinicians can safely quarantine from family, as well as personal protective equipment and child care.

Clinicians are often asked to “assume new professional roles to meet evolving needs” during a pandemic, which can increase stress. The authors recommended targeted training, assessment of clinician skills before redeployment to a new clinical role, and clear communication practices around redeployment.

Recognition from hospital and government leaders improves morale and supports clinicians’ ability to continue delivering care. Leadership should “leverage communication strategies to provide clinicians with up-to-date information and reassurance,” they wrote.
 

‘Uniquely isolated’

Dr. Margolis noted that clinicians “are uniquely isolated, especially those with children” because many parents do not want their children mingling with children of HCPs.

“My colleagues feel a sense of moral injury, putting their lives on the line at work, performing the most perilous job, and their kids can’t hang out with other kids, which just puts salt on the wound,” she said.

Additional sources of moral injury are deciding which patients should receive life support in the event of inadequate resources and bearing witness to, or enforcing, policies that lead to patients dying alone.

Leaders should encourage clinicians to “seek informal support from colleagues, managers, or chaplains” and to “provide rapid access to professional help,” the authors noted.

Furthermore, they contended that leaders should “proactively and routinely monitor the psychological well-being of their teams,” since guilt and shame often prevent clinicians from disclosing feelings of moral injury.

“Being provided with routine mental health support should be normalized and it should be part of the job – not only during COVID-19 but in general,” Dr. Schwartz said.
 

‘Battle buddies’

Dr. Margolis recommended the “battle buddy” model for mutual peer support.

Dr. Anand, a mental health clinician at Mayo Medical School, Rochester, Minn., elaborated.

Self-care critical

Marcus S. Shaker, MD, MSc, associate professor of pediatrics, medicine, and community and family medicine, Children’s Hospital at Dartmouth-Hitchcock in Lebanon, N.H., and Geisel School of Medicine at Dartmouth, Hanover, N.H., said the study was “a much appreciated, timely reminder of the importance of clinician wellness.”

Moreover, “without self-care, our ability to help our patients withers. This article provides a useful conceptual framework for individuals and organizations to provide the right care at the right time in these unprecedented times,” said Dr. Shaker, who was not involved with the study.

The authors agreed, stating that clinicians “require proactive psychological protection specifically because they are a population known for putting others’ needs before their own.”

They recommended several resources for HCPs, including the Physician Support Line; Headspace, a mindfulness Web-based app for reducing stress and anxiety; the National Suicide Prevention Lifeline; and the Crisis Text Line.

The authors and Dr. Shaker disclosed no relevant financial relationships.

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

A new review offers fresh guidance to help stem the mental health toll of the COVID-19 pandemic on frontline clinicians.

Investigators gathered practice guidelines and resources from a wide range of health care organizations and professional societies to develop a conceptual framework of mental health support for health care professionals (HCPs) caring for COVID-19 patients.

An opportune moment

Coauthor Rebecca Margolis, DO, director of well-being in the division of medical education and faculty development, Children’s Hospital of Los Angeles, said that this is “an opportune moment to look at how we treat frontline providers in this country.”

Studies of previous pandemics have shown heightened distress in HCPs, even years after the pandemic, and the unique challenges posed by the COVID-19 pandemic surpass those of previous pandemics, Dr. Margolis said in an interview.

Dr. Schwartz, Dr. Margolis, and coauthors Uma Anand, PhD, LP, and Jina Sinskey, MD, met through the Collaborative for Healing and Renewal in Medicine network, a group of medical educators, leaders in academic medicine, experts in burnout research and interventions, and trainees working together to promote well-being among trainees and practicing physicians.

“We were brought together on a conference call in March, when things were particularly bad in New York, and started looking to see what resources we could get to frontline providers who were suffering. It was great to lean on each other and stand on the shoulders of colleagues in New York, who were the ones we learned from on these calls,” said Dr. Margolis.

The authors recommended addressing clinicians’ basic practical needs, including ensuring essentials like meals and transportation, establishing a “well-being area” within hospitals for staff to rest, and providing well-stocked living quarters so clinicians can safely quarantine from family, as well as personal protective equipment and child care.

Clinicians are often asked to “assume new professional roles to meet evolving needs” during a pandemic, which can increase stress. The authors recommended targeted training, assessment of clinician skills before redeployment to a new clinical role, and clear communication practices around redeployment.

Recognition from hospital and government leaders improves morale and supports clinicians’ ability to continue delivering care. Leadership should “leverage communication strategies to provide clinicians with up-to-date information and reassurance,” they wrote.
 

‘Uniquely isolated’

Dr. Margolis noted that clinicians “are uniquely isolated, especially those with children” because many parents do not want their children mingling with children of HCPs.

“My colleagues feel a sense of moral injury, putting their lives on the line at work, performing the most perilous job, and their kids can’t hang out with other kids, which just puts salt on the wound,” she said.

Additional sources of moral injury are deciding which patients should receive life support in the event of inadequate resources and bearing witness to, or enforcing, policies that lead to patients dying alone.

Leaders should encourage clinicians to “seek informal support from colleagues, managers, or chaplains” and to “provide rapid access to professional help,” the authors noted.

Furthermore, they contended that leaders should “proactively and routinely monitor the psychological well-being of their teams,” since guilt and shame often prevent clinicians from disclosing feelings of moral injury.

“Being provided with routine mental health support should be normalized and it should be part of the job – not only during COVID-19 but in general,” Dr. Schwartz said.
 

‘Battle buddies’

Dr. Margolis recommended the “battle buddy” model for mutual peer support.

Dr. Anand, a mental health clinician at Mayo Medical School, Rochester, Minn., elaborated.

Self-care critical

Marcus S. Shaker, MD, MSc, associate professor of pediatrics, medicine, and community and family medicine, Children’s Hospital at Dartmouth-Hitchcock in Lebanon, N.H., and Geisel School of Medicine at Dartmouth, Hanover, N.H., said the study was “a much appreciated, timely reminder of the importance of clinician wellness.”

Moreover, “without self-care, our ability to help our patients withers. This article provides a useful conceptual framework for individuals and organizations to provide the right care at the right time in these unprecedented times,” said Dr. Shaker, who was not involved with the study.

The authors agreed, stating that clinicians “require proactive psychological protection specifically because they are a population known for putting others’ needs before their own.”

They recommended several resources for HCPs, including the Physician Support Line; Headspace, a mindfulness Web-based app for reducing stress and anxiety; the National Suicide Prevention Lifeline; and the Crisis Text Line.

The authors and Dr. Shaker disclosed no relevant financial relationships.

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

In this issue of JFP, there is an extraordinarily valuable PURL (Priority Updates from the Research Literature) for you. PURLs^® are written by academic family physicians who comb through volumes of research to identify and then summarize for JFP important studies we believe should change your practice. After reading a PURL, you may find that you have already implemented this new evidence into your practice. In that case, the PURL confirms that you are doing the right thing.

We should all tell our patients to take their BP medication in the evening from now on. What could be an easier way to reduce CV morbidity and mortality?

Here is the good news from this month’s PURL: Having patients take their blood pressure (BP) medication in the evening, rather than in the morning, leads not only to better BP control but also to a reduction in cardiovascular events.¹ How large is this effect? This simple intervention nearly cut in half the number of major cardiovascular events—including myocardial infarction, stroke, and congestive heart failure—and the risk for death from a cardiovascular event was reduced 56%. The number needed to treat to prevent 1 major cardiovascular event over the course of 6.3 years was 20. That means this intervention is more powerful than taking a statin!

The investigators, who call this intervention “chronotherapy” since it takes into account the body’s circadian rhythms, have been studying the effect of this simple intervention for many years, and this large randomized trial provides very strong evidence that it’s effective. Despite the excellent trial design and execution, some cardiovascular researchers have questioned the integrity of the trial and believe patients should continue to take their antihypertensives in the morning.² The main investigator of the study, however, has provided a very strong rebuttal in print.³

I am delighted to see the positive results of this definitive trial of chronotherapy for hypertension. When these investigators published their first randomized trial of chronotherapy in 2010,⁴ which demonstrated a significant BP reduction with evening dosing of antihypertensives, I began telling all of my patients to take at least 1 of their antihypertensive meds in the evening. Maybe I was jumping the gun at that time, but we should all tell our patients to take their BP medication in the evening from now on. What could be an easier way to reduce cardiovascular morbidity and mortality?

In this issue of JFP, there is an extraordinarily valuable PURL (Priority Updates from the Research Literature) for you. PURLs^® are written by academic family physicians who comb through volumes of research to identify and then summarize for JFP important studies we believe should change your practice. After reading a PURL, you may find that you have already implemented this new evidence into your practice. In that case, the PURL confirms that you are doing the right thing.

We should all tell our patients to take their BP medication in the evening from now on. What could be an easier way to reduce CV morbidity and mortality?

Here is the good news from this month’s PURL: Having patients take their blood pressure (BP) medication in the evening, rather than in the morning, leads not only to better BP control but also to a reduction in cardiovascular events.¹ How large is this effect? This simple intervention nearly cut in half the number of major cardiovascular events—including myocardial infarction, stroke, and congestive heart failure—and the risk for death from a cardiovascular event was reduced 56%. The number needed to treat to prevent 1 major cardiovascular event over the course of 6.3 years was 20. That means this intervention is more powerful than taking a statin!

The investigators, who call this intervention “chronotherapy” since it takes into account the body’s circadian rhythms, have been studying the effect of this simple intervention for many years, and this large randomized trial provides very strong evidence that it’s effective. Despite the excellent trial design and execution, some cardiovascular researchers have questioned the integrity of the trial and believe patients should continue to take their antihypertensives in the morning.² The main investigator of the study, however, has provided a very strong rebuttal in print.³

I am delighted to see the positive results of this definitive trial of chronotherapy for hypertension. When these investigators published their first randomized trial of chronotherapy in 2010,⁴ which demonstrated a significant BP reduction with evening dosing of antihypertensives, I began telling all of my patients to take at least 1 of their antihypertensive meds in the evening. Maybe I was jumping the gun at that time, but we should all tell our patients to take their BP medication in the evening from now on. What could be an easier way to reduce cardiovascular morbidity and mortality?

In this issue of JFP, there is an extraordinarily valuable PURL (Priority Updates from the Research Literature) for you. PURLs^® are written by academic family physicians who comb through volumes of research to identify and then summarize for JFP important studies we believe should change your practice. After reading a PURL, you may find that you have already implemented this new evidence into your practice. In that case, the PURL confirms that you are doing the right thing.

We should all tell our patients to take their BP medication in the evening from now on. What could be an easier way to reduce CV morbidity and mortality?

Here is the good news from this month’s PURL: Having patients take their blood pressure (BP) medication in the evening, rather than in the morning, leads not only to better BP control but also to a reduction in cardiovascular events.¹ How large is this effect? This simple intervention nearly cut in half the number of major cardiovascular events—including myocardial infarction, stroke, and congestive heart failure—and the risk for death from a cardiovascular event was reduced 56%. The number needed to treat to prevent 1 major cardiovascular event over the course of 6.3 years was 20. That means this intervention is more powerful than taking a statin!

The investigators, who call this intervention “chronotherapy” since it takes into account the body’s circadian rhythms, have been studying the effect of this simple intervention for many years, and this large randomized trial provides very strong evidence that it’s effective. Despite the excellent trial design and execution, some cardiovascular researchers have questioned the integrity of the trial and believe patients should continue to take their antihypertensives in the morning.² The main investigator of the study, however, has provided a very strong rebuttal in print.³

I am delighted to see the positive results of this definitive trial of chronotherapy for hypertension. When these investigators published their first randomized trial of chronotherapy in 2010,⁴ which demonstrated a significant BP reduction with evening dosing of antihypertensives, I began telling all of my patients to take at least 1 of their antihypertensive meds in the evening. Maybe I was jumping the gun at that time, but we should all tell our patients to take their BP medication in the evening from now on. What could be an easier way to reduce cardiovascular morbidity and mortality?

ILLUSTRATIVE CASE

A 54-year-old White woman presents to your office with new-onset hypertension. As you are discussing options for treatment, she mentions she would prefer once-daily dosing to help her remember to take her medication. She also wants to know what the best time of day is to take her medication to reduce her risk of cardiovascular disease (CVD). What do you advise?

The burden of hypertension is significant and growing in the United States. The 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines reported that more than 108 million people were affected in 2015-2016—up from 87 million in 1999-2000.² Yet control of hypertension is improving among those receiving antihypertension pharmacotherapy. As reported in the ACC/AHA guidelines, data from the 2016 National Health and Nutrition Examination Survey (NHANES) indicate an increase of controlled hypertension among those receiving treatment from 25.6% (1999-2000) to 43.5% (2015-2016).²

Chronotherapy involves the administration of medication in coordination with the body’s circadian rhythms to maximize therapeutic effectiveness and/or minimize adverse effects. It is not a new concept as it applies to hypertension. Circadian rhythm–­dependent mechanisms influence the natural rise and fall of blood pressure (BP).¹ The ­renin-­angiotensin-aldosterone system, known to be most active at night, is a target mechanism for BP control.¹ Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are more effective (alone or in combination with other agents) at reducing BP during sleep and wakefulness when they are taken at night.^3,4 Additional prospective clinical trials and systematic reviews have documented improved BP during sleep and on 24-hour ambulatory monitoring when antihypertensives are taken at bedtime.^3-5

However, there have been few long-term studies assessing the effects of bedtime administration of antihypertensive medication on CVD risk reduction with patient-oriented outcomes.^6,7 Additionally, no studies have evaluated morning vs bedtime administration of antihypertensive medication for CVD risk reduction in a primary care setting. The 2019 ACC/AHA guideline on the primary prevention of CVD offers no recommendation regarding when to take antihypertensive medication.⁸ Timing of medication administration also is not addressed in the NHANES study of hypertension awareness, treatment, and control in US adults.⁹

This study sought to determine in a primary care setting whether taking antihypertensives at bedtime, as opposed to upon waking, more effectively reduces CVD risk.

STUDY SUMMARY

PM vs AM antihypertensive dosing reduces CV events

This prospective, randomized, open-label, blinded endpoint trial of antihypertensive medication administration timing was part of a large, multicenter Spanish study investigating ambulatory BP monitoring (ABPM) as a routine diagnostic tool.

A simple change in administration time has the potential to significantly improve the lives of our patients by reducing the risk for cardiovascular events and their medication burden.

Study participants were randomly assigned in a 1:1 ratio to 2 treatment arms; participants either took all of their BP medications in the morning upon waking (n = 9532) or right before bedtime (n = 9552). The study was conducted in a primary care clinical setting. It included adult participants (age ≥ 18 years) with hypertension (defined as having at least 1 of the following benchmarks: awake systolic BP [SBP] mean ≥ 135 mm Hg, awake diastolic BP (DBP) mean ≥ 85 mm Hg, asleep SBP mean ≥ 120 mm Hg, asleep DBP mean ≥ 70 mm Hg as corroborated by 48-hour ABPM) who were taking at least 1 antihypertensive medication.

Continue to: Any antihypertension medication...

Any antihypertension medication included in the Spanish national formulary was allowed (exact agents were not delineated, but the following classes were included: ARB, ACE inhibitor, calcium channel blocker [CCB], beta-blocker, and/or diuretic). All BP medications had to be dosed once daily for inclusion. Exclusion criteria included pregnancy, night or rotating-shift work, alcohol or other substance dependence, acquired immunodeficiency syndrome, preexisting CVD (unstable angina, heart failure, arrhythmia, kidney failure, and retinopathy), inability to tolerate ABPM, and inability to comply with required 1-year follow-up.

Upon enrollment and at every subsequent clinic visit (scheduled at least annually), participants underwent 48-hour ABPM. Those with uncontrolled BP or elevated CVD risk had scheduled follow-up and ABPM more frequently. The primary outcome was a composite of CVD events including new-onset myocardial infarction, coronary revascularization, heart failure, ischemic stroke, hemorrhagic stroke, and CVD death. Secondary endpoints were individually analyzed primary outcomes of CVD events. The typical patient at baseline was 60.5 years of age with a body mass index of 29.7, an almost 9-year duration of hypertension, and a baseline office BP of 149/86 mm Hg. The patient break-out by antihypertensive class (awakening vs bedtime groups) was as follows: ARB (53% vs 53%), ACE inhibitor (25% vs 23%), CCB (33% vs 37%), beta-blocker (22% vs 18%), and diuretic (47% vs 40%).

See “It’s time to change when BP meds are taken” for more on the controversy that surrounded the initial release of this study.

During the median 6.3-year patient follow-up period, 1752 participants experienced a total of 2454 CVD events. Patients in the bedtime administration group, compared with those in the morning group, showed significantly lower risk for a CVD event (hazard ratio [HR] = 0.55; 95% confidence interval [CI], 0.50-0.61; P < .001). Also, there was a lower risk for individual CVD events in the bedtime administration group: CVD death (HR = 0.44; 95% CI, 0.34-0.56), myocardial infarction (HR = 0.66; 95% CI, 0.52-0.84), coronary revascularization (HR = 0.60; 95% CI, 0.47-0.75), heart failure (HR = 0.58; 95% CI, 0.49-0.70), and stroke (HR = 0.51; 95% CI, 0.41-0.63). This difference remained after correction for multiple potential confounders. There were no differences in adverse events, such as sleep-time hypotension, between groups.

WHAT’S NEW

First RCT in primary care to show dosing time change reduces CV risk

This is the first randomized controlled trial (RCT) performed in a primary care setting to compare before-bedtime to upon-waking administration of antihypertensive medications using clinically significant endpoints. The study demonstrates that a simple change in administration time has the potential to significantly improve the lives of our patients by reducing the risk for cardiovascular events and their medication burden.

CAVEATS

Homogenous population and exclusions limit generalizability

Because the study population consisted of white Spanish men and women, the results may not be generalizable beyond that ethnic group. In addition, the study exclusions limit interpretation in night/rotating-shift employees, patients with secondary hypertension, and those with CVD, chronic kidney disease, or severe retinopathy looking to reduce their risk.

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

Nighttime urination could lead to nonadherence

Taking diuretics at bedtime may result in unwanted nighttime awakenings for visits to the bathroom, which could lead to nonadherence in some patients.

ACKNOWLEDGMENT

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

A 54-year-old White woman presents to your office with new-onset hypertension. As you are discussing options for treatment, she mentions she would prefer once-daily dosing to help her remember to take her medication. She also wants to know what the best time of day is to take her medication to reduce her risk of cardiovascular disease (CVD). What do you advise?

The burden of hypertension is significant and growing in the United States. The 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines reported that more than 108 million people were affected in 2015-2016—up from 87 million in 1999-2000.² Yet control of hypertension is improving among those receiving antihypertension pharmacotherapy. As reported in the ACC/AHA guidelines, data from the 2016 National Health and Nutrition Examination Survey (NHANES) indicate an increase of controlled hypertension among those receiving treatment from 25.6% (1999-2000) to 43.5% (2015-2016).²

Chronotherapy involves the administration of medication in coordination with the body’s circadian rhythms to maximize therapeutic effectiveness and/or minimize adverse effects. It is not a new concept as it applies to hypertension. Circadian rhythm–­dependent mechanisms influence the natural rise and fall of blood pressure (BP).¹ The ­renin-­angiotensin-aldosterone system, known to be most active at night, is a target mechanism for BP control.¹ Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are more effective (alone or in combination with other agents) at reducing BP during sleep and wakefulness when they are taken at night.^3,4 Additional prospective clinical trials and systematic reviews have documented improved BP during sleep and on 24-hour ambulatory monitoring when antihypertensives are taken at bedtime.^3-5

However, there have been few long-term studies assessing the effects of bedtime administration of antihypertensive medication on CVD risk reduction with patient-oriented outcomes.^6,7 Additionally, no studies have evaluated morning vs bedtime administration of antihypertensive medication for CVD risk reduction in a primary care setting. The 2019 ACC/AHA guideline on the primary prevention of CVD offers no recommendation regarding when to take antihypertensive medication.⁸ Timing of medication administration also is not addressed in the NHANES study of hypertension awareness, treatment, and control in US adults.⁹

This study sought to determine in a primary care setting whether taking antihypertensives at bedtime, as opposed to upon waking, more effectively reduces CVD risk.

STUDY SUMMARY

PM vs AM antihypertensive dosing reduces CV events

This prospective, randomized, open-label, blinded endpoint trial of antihypertensive medication administration timing was part of a large, multicenter Spanish study investigating ambulatory BP monitoring (ABPM) as a routine diagnostic tool.

A simple change in administration time has the potential to significantly improve the lives of our patients by reducing the risk for cardiovascular events and their medication burden.

Study participants were randomly assigned in a 1:1 ratio to 2 treatment arms; participants either took all of their BP medications in the morning upon waking (n = 9532) or right before bedtime (n = 9552). The study was conducted in a primary care clinical setting. It included adult participants (age ≥ 18 years) with hypertension (defined as having at least 1 of the following benchmarks: awake systolic BP [SBP] mean ≥ 135 mm Hg, awake diastolic BP (DBP) mean ≥ 85 mm Hg, asleep SBP mean ≥ 120 mm Hg, asleep DBP mean ≥ 70 mm Hg as corroborated by 48-hour ABPM) who were taking at least 1 antihypertensive medication.

Continue to: Any antihypertension medication...

Any antihypertension medication included in the Spanish national formulary was allowed (exact agents were not delineated, but the following classes were included: ARB, ACE inhibitor, calcium channel blocker [CCB], beta-blocker, and/or diuretic). All BP medications had to be dosed once daily for inclusion. Exclusion criteria included pregnancy, night or rotating-shift work, alcohol or other substance dependence, acquired immunodeficiency syndrome, preexisting CVD (unstable angina, heart failure, arrhythmia, kidney failure, and retinopathy), inability to tolerate ABPM, and inability to comply with required 1-year follow-up.

Upon enrollment and at every subsequent clinic visit (scheduled at least annually), participants underwent 48-hour ABPM. Those with uncontrolled BP or elevated CVD risk had scheduled follow-up and ABPM more frequently. The primary outcome was a composite of CVD events including new-onset myocardial infarction, coronary revascularization, heart failure, ischemic stroke, hemorrhagic stroke, and CVD death. Secondary endpoints were individually analyzed primary outcomes of CVD events. The typical patient at baseline was 60.5 years of age with a body mass index of 29.7, an almost 9-year duration of hypertension, and a baseline office BP of 149/86 mm Hg. The patient break-out by antihypertensive class (awakening vs bedtime groups) was as follows: ARB (53% vs 53%), ACE inhibitor (25% vs 23%), CCB (33% vs 37%), beta-blocker (22% vs 18%), and diuretic (47% vs 40%).

See “It’s time to change when BP meds are taken” for more on the controversy that surrounded the initial release of this study.

During the median 6.3-year patient follow-up period, 1752 participants experienced a total of 2454 CVD events. Patients in the bedtime administration group, compared with those in the morning group, showed significantly lower risk for a CVD event (hazard ratio [HR] = 0.55; 95% confidence interval [CI], 0.50-0.61; P < .001). Also, there was a lower risk for individual CVD events in the bedtime administration group: CVD death (HR = 0.44; 95% CI, 0.34-0.56), myocardial infarction (HR = 0.66; 95% CI, 0.52-0.84), coronary revascularization (HR = 0.60; 95% CI, 0.47-0.75), heart failure (HR = 0.58; 95% CI, 0.49-0.70), and stroke (HR = 0.51; 95% CI, 0.41-0.63). This difference remained after correction for multiple potential confounders. There were no differences in adverse events, such as sleep-time hypotension, between groups.

WHAT’S NEW

First RCT in primary care to show dosing time change reduces CV risk

This is the first randomized controlled trial (RCT) performed in a primary care setting to compare before-bedtime to upon-waking administration of antihypertensive medications using clinically significant endpoints. The study demonstrates that a simple change in administration time has the potential to significantly improve the lives of our patients by reducing the risk for cardiovascular events and their medication burden.

CAVEATS

Homogenous population and exclusions limit generalizability

Because the study population consisted of white Spanish men and women, the results may not be generalizable beyond that ethnic group. In addition, the study exclusions limit interpretation in night/rotating-shift employees, patients with secondary hypertension, and those with CVD, chronic kidney disease, or severe retinopathy looking to reduce their risk.

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

Nighttime urination could lead to nonadherence

Taking diuretics at bedtime may result in unwanted nighttime awakenings for visits to the bathroom, which could lead to nonadherence in some patients.

ACKNOWLEDGMENT

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

A 54-year-old White woman presents to your office with new-onset hypertension. As you are discussing options for treatment, she mentions she would prefer once-daily dosing to help her remember to take her medication. She also wants to know what the best time of day is to take her medication to reduce her risk of cardiovascular disease (CVD). What do you advise?

The burden of hypertension is significant and growing in the United States. The 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines reported that more than 108 million people were affected in 2015-2016—up from 87 million in 1999-2000.² Yet control of hypertension is improving among those receiving antihypertension pharmacotherapy. As reported in the ACC/AHA guidelines, data from the 2016 National Health and Nutrition Examination Survey (NHANES) indicate an increase of controlled hypertension among those receiving treatment from 25.6% (1999-2000) to 43.5% (2015-2016).²

Chronotherapy involves the administration of medication in coordination with the body’s circadian rhythms to maximize therapeutic effectiveness and/or minimize adverse effects. It is not a new concept as it applies to hypertension. Circadian rhythm–­dependent mechanisms influence the natural rise and fall of blood pressure (BP).¹ The ­renin-­angiotensin-aldosterone system, known to be most active at night, is a target mechanism for BP control.¹ Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are more effective (alone or in combination with other agents) at reducing BP during sleep and wakefulness when they are taken at night.^3,4 Additional prospective clinical trials and systematic reviews have documented improved BP during sleep and on 24-hour ambulatory monitoring when antihypertensives are taken at bedtime.^3-5

However, there have been few long-term studies assessing the effects of bedtime administration of antihypertensive medication on CVD risk reduction with patient-oriented outcomes.^6,7 Additionally, no studies have evaluated morning vs bedtime administration of antihypertensive medication for CVD risk reduction in a primary care setting. The 2019 ACC/AHA guideline on the primary prevention of CVD offers no recommendation regarding when to take antihypertensive medication.⁸ Timing of medication administration also is not addressed in the NHANES study of hypertension awareness, treatment, and control in US adults.⁹

This study sought to determine in a primary care setting whether taking antihypertensives at bedtime, as opposed to upon waking, more effectively reduces CVD risk.

STUDY SUMMARY

PM vs AM antihypertensive dosing reduces CV events

This prospective, randomized, open-label, blinded endpoint trial of antihypertensive medication administration timing was part of a large, multicenter Spanish study investigating ambulatory BP monitoring (ABPM) as a routine diagnostic tool.

A simple change in administration time has the potential to significantly improve the lives of our patients by reducing the risk for cardiovascular events and their medication burden.

Study participants were randomly assigned in a 1:1 ratio to 2 treatment arms; participants either took all of their BP medications in the morning upon waking (n = 9532) or right before bedtime (n = 9552). The study was conducted in a primary care clinical setting. It included adult participants (age ≥ 18 years) with hypertension (defined as having at least 1 of the following benchmarks: awake systolic BP [SBP] mean ≥ 135 mm Hg, awake diastolic BP (DBP) mean ≥ 85 mm Hg, asleep SBP mean ≥ 120 mm Hg, asleep DBP mean ≥ 70 mm Hg as corroborated by 48-hour ABPM) who were taking at least 1 antihypertensive medication.

Continue to: Any antihypertension medication...

Any antihypertension medication included in the Spanish national formulary was allowed (exact agents were not delineated, but the following classes were included: ARB, ACE inhibitor, calcium channel blocker [CCB], beta-blocker, and/or diuretic). All BP medications had to be dosed once daily for inclusion. Exclusion criteria included pregnancy, night or rotating-shift work, alcohol or other substance dependence, acquired immunodeficiency syndrome, preexisting CVD (unstable angina, heart failure, arrhythmia, kidney failure, and retinopathy), inability to tolerate ABPM, and inability to comply with required 1-year follow-up.

Upon enrollment and at every subsequent clinic visit (scheduled at least annually), participants underwent 48-hour ABPM. Those with uncontrolled BP or elevated CVD risk had scheduled follow-up and ABPM more frequently. The primary outcome was a composite of CVD events including new-onset myocardial infarction, coronary revascularization, heart failure, ischemic stroke, hemorrhagic stroke, and CVD death. Secondary endpoints were individually analyzed primary outcomes of CVD events. The typical patient at baseline was 60.5 years of age with a body mass index of 29.7, an almost 9-year duration of hypertension, and a baseline office BP of 149/86 mm Hg. The patient break-out by antihypertensive class (awakening vs bedtime groups) was as follows: ARB (53% vs 53%), ACE inhibitor (25% vs 23%), CCB (33% vs 37%), beta-blocker (22% vs 18%), and diuretic (47% vs 40%).

See “It’s time to change when BP meds are taken” for more on the controversy that surrounded the initial release of this study.

During the median 6.3-year patient follow-up period, 1752 participants experienced a total of 2454 CVD events. Patients in the bedtime administration group, compared with those in the morning group, showed significantly lower risk for a CVD event (hazard ratio [HR] = 0.55; 95% confidence interval [CI], 0.50-0.61; P < .001). Also, there was a lower risk for individual CVD events in the bedtime administration group: CVD death (HR = 0.44; 95% CI, 0.34-0.56), myocardial infarction (HR = 0.66; 95% CI, 0.52-0.84), coronary revascularization (HR = 0.60; 95% CI, 0.47-0.75), heart failure (HR = 0.58; 95% CI, 0.49-0.70), and stroke (HR = 0.51; 95% CI, 0.41-0.63). This difference remained after correction for multiple potential confounders. There were no differences in adverse events, such as sleep-time hypotension, between groups.

WHAT’S NEW

First RCT in primary care to show dosing time change reduces CV risk

This is the first randomized controlled trial (RCT) performed in a primary care setting to compare before-bedtime to upon-waking administration of antihypertensive medications using clinically significant endpoints. The study demonstrates that a simple change in administration time has the potential to significantly improve the lives of our patients by reducing the risk for cardiovascular events and their medication burden.

CAVEATS

Homogenous population and exclusions limit generalizability

Because the study population consisted of white Spanish men and women, the results may not be generalizable beyond that ethnic group. In addition, the study exclusions limit interpretation in night/rotating-shift employees, patients with secondary hypertension, and those with CVD, chronic kidney disease, or severe retinopathy looking to reduce their risk.

Continue to: CHALLENGES TO IMPLEMENTATION

 

 

CHALLENGES TO IMPLEMENTATION

Nighttime urination could lead to nonadherence

Taking diuretics at bedtime may result in unwanted nighttime awakenings for visits to the bathroom, which could lead to nonadherence in some patients.

ACKNOWLEDGMENT

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.

Click here to access August 2020 Advances in Precision Oncology

Table of Contents

• Foreword
• Introduction: Precision Oncology Changes the Game for VA Health Care
• VA National Precision Oncology Program
• Prostate Cancer Foundation-Department of Veterans Affairs Partnership: A Model to Advance Treatment and Care of Invasive Cancers
• The Precision Oncology Program for Cancer of the Prostate Network: A VA-Prostate Cancer Foundation Alliance
• Leveraging Veterans Health Administration Clinical and Research Resources to Accelerate Discovery and Testing in Precision Oncology
• Strategic Initiatives for Veterans With Lung Cancer
• Integrating Germline Genetics Into Precision Oncology Practice in the Veterans Health Administration: Challenges and Opportunities

Click here to access August 2020 Advances in Precision Oncology

Table of Contents

• Foreword
• Introduction: Precision Oncology Changes the Game for VA Health Care
• VA National Precision Oncology Program
• Prostate Cancer Foundation-Department of Veterans Affairs Partnership: A Model to Advance Treatment and Care of Invasive Cancers
• The Precision Oncology Program for Cancer of the Prostate Network: A VA-Prostate Cancer Foundation Alliance
• Leveraging Veterans Health Administration Clinical and Research Resources to Accelerate Discovery and Testing in Precision Oncology
• Strategic Initiatives for Veterans With Lung Cancer
• Integrating Germline Genetics Into Precision Oncology Practice in the Veterans Health Administration: Challenges and Opportunities

Click here to access August 2020 Advances in Precision Oncology

Table of Contents

• Foreword
• Introduction: Precision Oncology Changes the Game for VA Health Care
• VA National Precision Oncology Program
• Prostate Cancer Foundation-Department of Veterans Affairs Partnership: A Model to Advance Treatment and Care of Invasive Cancers
• The Precision Oncology Program for Cancer of the Prostate Network: A VA-Prostate Cancer Foundation Alliance
• Leveraging Veterans Health Administration Clinical and Research Resources to Accelerate Discovery and Testing in Precision Oncology
• Strategic Initiatives for Veterans With Lung Cancer
• Integrating Germline Genetics Into Precision Oncology Practice in the Veterans Health Administration: Challenges and Opportunities

One high school student out of every seven ever has either misused a prescription pain medicine or taken one without a prescription, according to an analysis from the Centers for Disease Control and Prevention.

That type of opioid use/misuse, reported by 14.3% of respondents to the 2019 Youth Risk Behavior Survey, was more common among females (16.1%) than males (12.4%) and even more prevalent among nonheterosexuals and those who are unsure about their sexual identity, Christopher M. Jones, PharmD, DrPH, and associates at the CDC said in the Morbidity and Mortality Weekly Report.

The YRBS data show that 18.5% of gay or lesbian students had, at some point in their lives, used a prescription opioid differently than a physician had told them to or taken one without a prescription. That figure was slightly higher (19.1%) for those unsure of their sexual identity, considerably higher (25.4%) for bisexuals, and lower for heterosexuals (12.7%), they reported.

The pattern for current use/misuse of opioids, defined as use one or more times in the 30 days before the survey, was similar to ever use but somewhat less pronounced in 2019. Prevalence was 7.2% for all students in grades 9-12, 8.3% for females, and 6.1% for males. By sexual identity, prevalence was 6.4% for heterosexuals, 7.6% for gays or lesbians, 11.5% for those unsure about their sexual identity, and 13.1% for bisexuals, based on the YRBS data.

This increased misuse of opioids among sexual minority youths, “even after controlling for other demographic and substance use characteristics ... emphasizes the importance of identifying tailored prevention strategies to address disparities among this vulnerable population,” the CDC researchers wrote.

rfranki@mdedge.com

SOURCE: Jones CM et al. MMWR Suppl. 2020 Aug 21;69(1):38-46.

One high school student out of every seven ever has either misused a prescription pain medicine or taken one without a prescription, according to an analysis from the Centers for Disease Control and Prevention.

That type of opioid use/misuse, reported by 14.3% of respondents to the 2019 Youth Risk Behavior Survey, was more common among females (16.1%) than males (12.4%) and even more prevalent among nonheterosexuals and those who are unsure about their sexual identity, Christopher M. Jones, PharmD, DrPH, and associates at the CDC said in the Morbidity and Mortality Weekly Report.

The YRBS data show that 18.5% of gay or lesbian students had, at some point in their lives, used a prescription opioid differently than a physician had told them to or taken one without a prescription. That figure was slightly higher (19.1%) for those unsure of their sexual identity, considerably higher (25.4%) for bisexuals, and lower for heterosexuals (12.7%), they reported.

The pattern for current use/misuse of opioids, defined as use one or more times in the 30 days before the survey, was similar to ever use but somewhat less pronounced in 2019. Prevalence was 7.2% for all students in grades 9-12, 8.3% for females, and 6.1% for males. By sexual identity, prevalence was 6.4% for heterosexuals, 7.6% for gays or lesbians, 11.5% for those unsure about their sexual identity, and 13.1% for bisexuals, based on the YRBS data.

This increased misuse of opioids among sexual minority youths, “even after controlling for other demographic and substance use characteristics ... emphasizes the importance of identifying tailored prevention strategies to address disparities among this vulnerable population,” the CDC researchers wrote.

rfranki@mdedge.com

SOURCE: Jones CM et al. MMWR Suppl. 2020 Aug 21;69(1):38-46.

One high school student out of every seven ever has either misused a prescription pain medicine or taken one without a prescription, according to an analysis from the Centers for Disease Control and Prevention.

That type of opioid use/misuse, reported by 14.3% of respondents to the 2019 Youth Risk Behavior Survey, was more common among females (16.1%) than males (12.4%) and even more prevalent among nonheterosexuals and those who are unsure about their sexual identity, Christopher M. Jones, PharmD, DrPH, and associates at the CDC said in the Morbidity and Mortality Weekly Report.

The YRBS data show that 18.5% of gay or lesbian students had, at some point in their lives, used a prescription opioid differently than a physician had told them to or taken one without a prescription. That figure was slightly higher (19.1%) for those unsure of their sexual identity, considerably higher (25.4%) for bisexuals, and lower for heterosexuals (12.7%), they reported.

The pattern for current use/misuse of opioids, defined as use one or more times in the 30 days before the survey, was similar to ever use but somewhat less pronounced in 2019. Prevalence was 7.2% for all students in grades 9-12, 8.3% for females, and 6.1% for males. By sexual identity, prevalence was 6.4% for heterosexuals, 7.6% for gays or lesbians, 11.5% for those unsure about their sexual identity, and 13.1% for bisexuals, based on the YRBS data.

This increased misuse of opioids among sexual minority youths, “even after controlling for other demographic and substance use characteristics ... emphasizes the importance of identifying tailored prevention strategies to address disparities among this vulnerable population,” the CDC researchers wrote.

rfranki@mdedge.com

SOURCE: Jones CM et al. MMWR Suppl. 2020 Aug 21;69(1):38-46.

The emergence of the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) in December 2019, has resulted in a global pandemic that has challenged the medical community and will continue to represent a public health emergency for the next several months.¹ It has rapidly spread globally, infecting many individuals in an unprecedented rate of infection and worldwide reach. On March 11, 2020, the World Health Organization designated COVID-19 as a pandemic. While the majority of infected individuals are asymptomatic or develop only mild symptoms, some have an unfortunate clinical course resulting in multi-organ failure and death.²

It is accepted that the virus mainly spreads during close contact and via respiratory droplets.³ The average time from infection to onset of symptoms ranges from 2 to 14 days, with an average of 5 days.⁴ Recommended measures to prevent the spread of the infection include social distancing (at least 6 feet from others), meticulous hand hygiene, and wearing a mask covering the mouth and nose when in public.⁵ Aiming to mitigate the risk of viral dissemination for patients and health care providers, and to preserve hospital resources, all nonessential medical interventions were initially suspended. Recently, the American College of Surgeons in a joint statement with 9 women’s health care societies have provided recommendations on how to resume clinical activities as we recover from the pandemic.⁶

As we reinitiate clinical activities, gynecologists have been alerted of the potential risk of viral dissemination during gynecologic minimally invasive surgical procedures due to the presence of the virus in blood, stool, and the potential risk of aerosolization of the virus, especially when using smoke-generating devices.^7,8 This risk is not limited to intubation and extubation of the airway during anesthesia; the risk also presents itself during other aerosol-generating procedures, such as laparoscopy or robotic surgery.^9,10

Hysteroscopy is considered the gold standard procedure for the diagnosis and management of intrauterine pathologies.¹¹ It is frequently performed in an office setting without the use of anesthesia.^11,12 It is usually well tolerated, with only a few patients reporting discomfort.¹² It allows for immediate treatment (using the “see and treat” approach) while avoiding not only the risk of anesthesia, as stated, but also the need for intubation—which has a high risk of droplet contamination in COVID-19–infected individuals.¹³

Is there risk of viral dissemination during hysteroscopic procedures?

The novel and rapidly changing nature of the COVID-19 pandemic present many challenges to the gynecologist. Significant concerns have been raised regarding potential risk of viral dissemination during laparoscopic surgery due to aerosolization of viral particles and the presence of the virus in blood and the gastrointestinal tract of infected patients.⁷ Diagnostic, and some simple, hysteroscopic procedures are commonly performed in an outpatient setting, with the patient awake. Complex hysteroscopic interventions, however, are generally performed in the operating room, typically with the use of general anesthesia. Hysteroscopy has the theoretical risks of viral dissemination when performed in COVID-19–positive patients. Two important questions must be addressed to better understand the potential risk of COVID-19 viral dissemination during hysteroscopic procedures.

Continue to: 1. Is the virus present in the vaginal fluid of women infected with COVID-19?...

1. Is the virus present in the vaginal fluid of women infected with COVID-19?

Recent studies have confirmed the presence of viral particles in urine, feces, blood, and tears in addition to the respiratory tract in patients infected with COVID-19.^3,14,15 The presence of the SARS-CoV-2 virus in the female genital system is currently unknown. Previous studies, of other epidemic viral infections, have demonstrated the presence of the virus in the female genital tract in affected patients of Zika virus and Ebola.^16,17 However, 2 recent studies have failed to demonstrate the presence of the SARS-CoV-2 virus in the vaginal fluid of pregnant¹⁴ and not pregnant¹⁸ women with severe COVID-19 infection.

2. Is there risk of viral dissemination during hysteroscopy if using electrosurgery?

There are significant concerns with possible risk of COVID-19 transmission to health care providers in direct contact with infected patients during minimally invasive gynecologic procedures due to direct contamination and aerosolization of the virus.^10,19 Current data on COVID-19 transmission during surgery are limited. However, it is important to recognize that viral aerosolization has been documented with other viral diseases, such as human papillomavirus and hepatitis B.²⁰ A recent report called for awareness in the surgical community about the potential risks of COVID-19 viral dissemination during laparoscopic surgery. Among other recommendations, international experts advised minimizing the use of electrosurgery to reduce the creation of surgical plume, decreasing the pneumoperitoneum pressure to minimum levels, and using suction devices in a closed system.²¹ Although these preventive measures apply to laparoscopic surgery, it is important to consider that hysteroscopy is performed in a unique environment.

During hysteroscopy the uterine cavity is distended with a liquid medium (normal saline or electrolyte-free solutions); this is opposed to gynecologic laparoscopy, in which the peritoneal cavity is distended with carbon dioxide.²² The smoke produced with the use of hysteroscopic electrosurgical instruments generates bubbles that are immediately cooled down to the temperature of the distention media and subsequently dissolve into it. Therefore, there are no bubbles generated during hysteroscopic surgery that are subsequently released into the air. This results in a low risk for viral dissemination during hysteroscopic procedures. Nevertheless, the necessary precautions to minimize the risk of COVID-19 transmission during hysteroscopic intervention are extremely important.

Recommendations for hysteroscopic procedures during the COVID-19 pandemic

We provide our overall recommendations for hysteroscopy, as well as those specific to the office and hospital setting.

Recommendations: General

Limit hysteroscopic procedures to COVID-19–negative patients and to those patients in whom delaying the procedure could result in adverse clinical outcomes.²³

Universally screen for potential COVID-19 infection. When possible, a phone interview to triage patients based on their symptoms and infection exposure status should take place before the patient arrives to the health care center. Patients with suspected or confirmed COVID-19 infection who require immediate evaluation should be directed to COVID-19–designated emergency areas.

Universally test for SARS-CoV-2 before procedures performed in the operating room (OR). Using nasopharyngeal swabs for the detection of viral RNA, employing molecular methods such as polymerase chain reaction (PCR), within 48 to 72 hours prior to all OR hysteroscopic procedures is strongly recommended. Adopting this testing strategy will aid to identify asymptomatic SARS-CoV-2‒infected patients, allowing to defer the procedure, if possible, among patients testing positive. If tests are limited, testing only patients scheduled for hysteroscopic procedures in which general or regional anesthesia will be required is acceptable.

Universal SARS-CoV-2 testing of patients undergoing in-office hysteroscopic diagnostic or minor operative procedures without the use of anesthesia is not required.

Limit the presence of a companion. It is understood that visitor policies may vary at the discretion of each institution’s guidelines. Children and individuals over the age of 60 years should not be granted access to the center. Companions will be subjected to the same screening criteria as patients.

Provide for social distancing and other precautionary measures. If more than one patient is scheduled to be at the facility at the same time, ensure that the facility provides adequate space to allow the appropriate social distancing recommendations between patients. Hand sanitizers and facemasks should be available for patients and companions.

Provide PPE for clinicians. All health care providers in close contact with the patient must wear personal protective equipment (PPE), which includes an apron and gown, a surgical mask, eye protection, and gloves. Health care providers should wear PPE deemed appropriate by their regulatory institutions following their local and national guidelines during clinical patient interactions.

Restrict surgical attendees to vital personnel. The participation of learners by physical presence in the office or operating room should be restricted.

Continue to: Recommendations: Office setting...

 

 

Recommendations: Office setting

Preprocedural recommendations

• Advise patients to come to the office alone. If the patient requires a companion, a maximum of one adult companion under the age of 60 should be accepted.
• Limit the number of health care team members present in the procedure room.

Intraprocedural recommendations

• Choose the appropriate device(s) that will allow for an effective and fast procedure.
• Use the recommended PPE for all clinicians.
• Limit the movement of staff members in and out of the procedure room.

Postprocedure recommendations

• When more than one case is scheduled to be performed in the same procedure room, allow enough time in between cases to grant a thorough OR decontamination.
• Allow for patients to recover from the procedure in the same room as the procedure took place in order to avoid potential contamination of multiple rooms.
• Expedite patient discharge.
• Follow up after the procedure by phone or telemedicine.
• Use standard endoscope disinfection procedures, as they are effective and should not be modified.

Continue to: Recommendations: Operating room setting...

 

 

Recommendations: Operating room setting

Preprocedural recommendations

• Perform adequate patient screening for potential COVID-19 infection. (Screening should be independent of symptoms and not be limited to those with clinical symptoms.)
• Limit the number of health care team members in the operating procedure room.
• To minimize unnecessary staff exposure, have surgeons and staff not needed for intubation remain outside the OR until intubation is completed and leave the OR before extubation.

Intraprocedure recommendations

• Limit personnel in the OR to a minimum.
• Staff should not enter or leave the room during the procedure.
• When possible, use conscious sedation or regional anesthesia to avoid the risk of viral dissemination at the time of intubation/extubation.
• Choose the device that will allow an effective and fast procedure.
• Favor non–smoke-generating devices, such as hysteroscopic scissors, graspers, and tissue retrieval systems.
• Connect active suction to the outflow, especially when using smoke-generating instruments, to facilitate the extraction of surgical smoke.

Postprocedure recommendations

• When more than one case is scheduled to be performed in the same room, allow enough time in between cases to grant a thorough OR decontamination.
• Expedite postprocedure recovery and patient discharge.
• After completion of the procedure, staff should remove scrubs and change into clean clothing.
• Use standard endoscope disinfection procedures, as they are effective and should not be modified.

Conclusions

The COVID-19 pandemic has caused a global health emergency. Our knowledge of this devastating virus is constantly evolving as we continue to fight this overwhelming disease. Theoretical risk of “viral” dissemination is considered extremely low, or negligible, during hysterosocopy. Hysteroscopic procedures in COVID-19–positive patients with life-threatening conditions or in patients in whom delaying the procedure could worsen outcomes should be performed taking appropriate measures. Patients who test negative for COVID-19 (confirmed by PCR) and require hysteroscopic procedures, should be treated using universal precautions. ●

The emergence of the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) in December 2019, has resulted in a global pandemic that has challenged the medical community and will continue to represent a public health emergency for the next several months.¹ It has rapidly spread globally, infecting many individuals in an unprecedented rate of infection and worldwide reach. On March 11, 2020, the World Health Organization designated COVID-19 as a pandemic. While the majority of infected individuals are asymptomatic or develop only mild symptoms, some have an unfortunate clinical course resulting in multi-organ failure and death.²

It is accepted that the virus mainly spreads during close contact and via respiratory droplets.³ The average time from infection to onset of symptoms ranges from 2 to 14 days, with an average of 5 days.⁴ Recommended measures to prevent the spread of the infection include social distancing (at least 6 feet from others), meticulous hand hygiene, and wearing a mask covering the mouth and nose when in public.⁵ Aiming to mitigate the risk of viral dissemination for patients and health care providers, and to preserve hospital resources, all nonessential medical interventions were initially suspended. Recently, the American College of Surgeons in a joint statement with 9 women’s health care societies have provided recommendations on how to resume clinical activities as we recover from the pandemic.⁶

As we reinitiate clinical activities, gynecologists have been alerted of the potential risk of viral dissemination during gynecologic minimally invasive surgical procedures due to the presence of the virus in blood, stool, and the potential risk of aerosolization of the virus, especially when using smoke-generating devices.^7,8 This risk is not limited to intubation and extubation of the airway during anesthesia; the risk also presents itself during other aerosol-generating procedures, such as laparoscopy or robotic surgery.^9,10

Hysteroscopy is considered the gold standard procedure for the diagnosis and management of intrauterine pathologies.¹¹ It is frequently performed in an office setting without the use of anesthesia.^11,12 It is usually well tolerated, with only a few patients reporting discomfort.¹² It allows for immediate treatment (using the “see and treat” approach) while avoiding not only the risk of anesthesia, as stated, but also the need for intubation—which has a high risk of droplet contamination in COVID-19–infected individuals.¹³

Is there risk of viral dissemination during hysteroscopic procedures?

The novel and rapidly changing nature of the COVID-19 pandemic present many challenges to the gynecologist. Significant concerns have been raised regarding potential risk of viral dissemination during laparoscopic surgery due to aerosolization of viral particles and the presence of the virus in blood and the gastrointestinal tract of infected patients.⁷ Diagnostic, and some simple, hysteroscopic procedures are commonly performed in an outpatient setting, with the patient awake. Complex hysteroscopic interventions, however, are generally performed in the operating room, typically with the use of general anesthesia. Hysteroscopy has the theoretical risks of viral dissemination when performed in COVID-19–positive patients. Two important questions must be addressed to better understand the potential risk of COVID-19 viral dissemination during hysteroscopic procedures.

Continue to: 1. Is the virus present in the vaginal fluid of women infected with COVID-19?...

1. Is the virus present in the vaginal fluid of women infected with COVID-19?

Recent studies have confirmed the presence of viral particles in urine, feces, blood, and tears in addition to the respiratory tract in patients infected with COVID-19.^3,14,15 The presence of the SARS-CoV-2 virus in the female genital system is currently unknown. Previous studies, of other epidemic viral infections, have demonstrated the presence of the virus in the female genital tract in affected patients of Zika virus and Ebola.^16,17 However, 2 recent studies have failed to demonstrate the presence of the SARS-CoV-2 virus in the vaginal fluid of pregnant¹⁴ and not pregnant¹⁸ women with severe COVID-19 infection.

2. Is there risk of viral dissemination during hysteroscopy if using electrosurgery?

There are significant concerns with possible risk of COVID-19 transmission to health care providers in direct contact with infected patients during minimally invasive gynecologic procedures due to direct contamination and aerosolization of the virus.^10,19 Current data on COVID-19 transmission during surgery are limited. However, it is important to recognize that viral aerosolization has been documented with other viral diseases, such as human papillomavirus and hepatitis B.²⁰ A recent report called for awareness in the surgical community about the potential risks of COVID-19 viral dissemination during laparoscopic surgery. Among other recommendations, international experts advised minimizing the use of electrosurgery to reduce the creation of surgical plume, decreasing the pneumoperitoneum pressure to minimum levels, and using suction devices in a closed system.²¹ Although these preventive measures apply to laparoscopic surgery, it is important to consider that hysteroscopy is performed in a unique environment.

During hysteroscopy the uterine cavity is distended with a liquid medium (normal saline or electrolyte-free solutions); this is opposed to gynecologic laparoscopy, in which the peritoneal cavity is distended with carbon dioxide.²² The smoke produced with the use of hysteroscopic electrosurgical instruments generates bubbles that are immediately cooled down to the temperature of the distention media and subsequently dissolve into it. Therefore, there are no bubbles generated during hysteroscopic surgery that are subsequently released into the air. This results in a low risk for viral dissemination during hysteroscopic procedures. Nevertheless, the necessary precautions to minimize the risk of COVID-19 transmission during hysteroscopic intervention are extremely important.

Recommendations for hysteroscopic procedures during the COVID-19 pandemic

We provide our overall recommendations for hysteroscopy, as well as those specific to the office and hospital setting.

Recommendations: General

Limit hysteroscopic procedures to COVID-19–negative patients and to those patients in whom delaying the procedure could result in adverse clinical outcomes.²³

Universally screen for potential COVID-19 infection. When possible, a phone interview to triage patients based on their symptoms and infection exposure status should take place before the patient arrives to the health care center. Patients with suspected or confirmed COVID-19 infection who require immediate evaluation should be directed to COVID-19–designated emergency areas.

Universally test for SARS-CoV-2 before procedures performed in the operating room (OR). Using nasopharyngeal swabs for the detection of viral RNA, employing molecular methods such as polymerase chain reaction (PCR), within 48 to 72 hours prior to all OR hysteroscopic procedures is strongly recommended. Adopting this testing strategy will aid to identify asymptomatic SARS-CoV-2‒infected patients, allowing to defer the procedure, if possible, among patients testing positive. If tests are limited, testing only patients scheduled for hysteroscopic procedures in which general or regional anesthesia will be required is acceptable.

Universal SARS-CoV-2 testing of patients undergoing in-office hysteroscopic diagnostic or minor operative procedures without the use of anesthesia is not required.

Limit the presence of a companion. It is understood that visitor policies may vary at the discretion of each institution’s guidelines. Children and individuals over the age of 60 years should not be granted access to the center. Companions will be subjected to the same screening criteria as patients.

Provide for social distancing and other precautionary measures. If more than one patient is scheduled to be at the facility at the same time, ensure that the facility provides adequate space to allow the appropriate social distancing recommendations between patients. Hand sanitizers and facemasks should be available for patients and companions.

Provide PPE for clinicians. All health care providers in close contact with the patient must wear personal protective equipment (PPE), which includes an apron and gown, a surgical mask, eye protection, and gloves. Health care providers should wear PPE deemed appropriate by their regulatory institutions following their local and national guidelines during clinical patient interactions.

Restrict surgical attendees to vital personnel. The participation of learners by physical presence in the office or operating room should be restricted.

Continue to: Recommendations: Office setting...

 

 

Recommendations: Office setting

Preprocedural recommendations

• Advise patients to come to the office alone. If the patient requires a companion, a maximum of one adult companion under the age of 60 should be accepted.
• Limit the number of health care team members present in the procedure room.

Intraprocedural recommendations

• Choose the appropriate device(s) that will allow for an effective and fast procedure.
• Use the recommended PPE for all clinicians.
• Limit the movement of staff members in and out of the procedure room.

Postprocedure recommendations

• When more than one case is scheduled to be performed in the same procedure room, allow enough time in between cases to grant a thorough OR decontamination.
• Allow for patients to recover from the procedure in the same room as the procedure took place in order to avoid potential contamination of multiple rooms.
• Expedite patient discharge.
• Follow up after the procedure by phone or telemedicine.
• Use standard endoscope disinfection procedures, as they are effective and should not be modified.

Continue to: Recommendations: Operating room setting...

 

 

Recommendations: Operating room setting

Preprocedural recommendations

• Perform adequate patient screening for potential COVID-19 infection. (Screening should be independent of symptoms and not be limited to those with clinical symptoms.)
• Limit the number of health care team members in the operating procedure room.
• To minimize unnecessary staff exposure, have surgeons and staff not needed for intubation remain outside the OR until intubation is completed and leave the OR before extubation.

Intraprocedure recommendations

• Limit personnel in the OR to a minimum.
• Staff should not enter or leave the room during the procedure.
• When possible, use conscious sedation or regional anesthesia to avoid the risk of viral dissemination at the time of intubation/extubation.
• Choose the device that will allow an effective and fast procedure.
• Favor non–smoke-generating devices, such as hysteroscopic scissors, graspers, and tissue retrieval systems.
• Connect active suction to the outflow, especially when using smoke-generating instruments, to facilitate the extraction of surgical smoke.

Postprocedure recommendations

• When more than one case is scheduled to be performed in the same room, allow enough time in between cases to grant a thorough OR decontamination.
• Expedite postprocedure recovery and patient discharge.
• After completion of the procedure, staff should remove scrubs and change into clean clothing.
• Use standard endoscope disinfection procedures, as they are effective and should not be modified.

Conclusions

The COVID-19 pandemic has caused a global health emergency. Our knowledge of this devastating virus is constantly evolving as we continue to fight this overwhelming disease. Theoretical risk of “viral” dissemination is considered extremely low, or negligible, during hysterosocopy. Hysteroscopic procedures in COVID-19–positive patients with life-threatening conditions or in patients in whom delaying the procedure could worsen outcomes should be performed taking appropriate measures. Patients who test negative for COVID-19 (confirmed by PCR) and require hysteroscopic procedures, should be treated using universal precautions. ●

The emergence of the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) in December 2019, has resulted in a global pandemic that has challenged the medical community and will continue to represent a public health emergency for the next several months.¹ It has rapidly spread globally, infecting many individuals in an unprecedented rate of infection and worldwide reach. On March 11, 2020, the World Health Organization designated COVID-19 as a pandemic. While the majority of infected individuals are asymptomatic or develop only mild symptoms, some have an unfortunate clinical course resulting in multi-organ failure and death.²

It is accepted that the virus mainly spreads during close contact and via respiratory droplets.³ The average time from infection to onset of symptoms ranges from 2 to 14 days, with an average of 5 days.⁴ Recommended measures to prevent the spread of the infection include social distancing (at least 6 feet from others), meticulous hand hygiene, and wearing a mask covering the mouth and nose when in public.⁵ Aiming to mitigate the risk of viral dissemination for patients and health care providers, and to preserve hospital resources, all nonessential medical interventions were initially suspended. Recently, the American College of Surgeons in a joint statement with 9 women’s health care societies have provided recommendations on how to resume clinical activities as we recover from the pandemic.⁶

As we reinitiate clinical activities, gynecologists have been alerted of the potential risk of viral dissemination during gynecologic minimally invasive surgical procedures due to the presence of the virus in blood, stool, and the potential risk of aerosolization of the virus, especially when using smoke-generating devices.^7,8 This risk is not limited to intubation and extubation of the airway during anesthesia; the risk also presents itself during other aerosol-generating procedures, such as laparoscopy or robotic surgery.^9,10

Hysteroscopy is considered the gold standard procedure for the diagnosis and management of intrauterine pathologies.¹¹ It is frequently performed in an office setting without the use of anesthesia.^11,12 It is usually well tolerated, with only a few patients reporting discomfort.¹² It allows for immediate treatment (using the “see and treat” approach) while avoiding not only the risk of anesthesia, as stated, but also the need for intubation—which has a high risk of droplet contamination in COVID-19–infected individuals.¹³

Is there risk of viral dissemination during hysteroscopic procedures?

The novel and rapidly changing nature of the COVID-19 pandemic present many challenges to the gynecologist. Significant concerns have been raised regarding potential risk of viral dissemination during laparoscopic surgery due to aerosolization of viral particles and the presence of the virus in blood and the gastrointestinal tract of infected patients.⁷ Diagnostic, and some simple, hysteroscopic procedures are commonly performed in an outpatient setting, with the patient awake. Complex hysteroscopic interventions, however, are generally performed in the operating room, typically with the use of general anesthesia. Hysteroscopy has the theoretical risks of viral dissemination when performed in COVID-19–positive patients. Two important questions must be addressed to better understand the potential risk of COVID-19 viral dissemination during hysteroscopic procedures.

Continue to: 1. Is the virus present in the vaginal fluid of women infected with COVID-19?...

1. Is the virus present in the vaginal fluid of women infected with COVID-19?

Recent studies have confirmed the presence of viral particles in urine, feces, blood, and tears in addition to the respiratory tract in patients infected with COVID-19.^3,14,15 The presence of the SARS-CoV-2 virus in the female genital system is currently unknown. Previous studies, of other epidemic viral infections, have demonstrated the presence of the virus in the female genital tract in affected patients of Zika virus and Ebola.^16,17 However, 2 recent studies have failed to demonstrate the presence of the SARS-CoV-2 virus in the vaginal fluid of pregnant¹⁴ and not pregnant¹⁸ women with severe COVID-19 infection.

2. Is there risk of viral dissemination during hysteroscopy if using electrosurgery?

There are significant concerns with possible risk of COVID-19 transmission to health care providers in direct contact with infected patients during minimally invasive gynecologic procedures due to direct contamination and aerosolization of the virus.^10,19 Current data on COVID-19 transmission during surgery are limited. However, it is important to recognize that viral aerosolization has been documented with other viral diseases, such as human papillomavirus and hepatitis B.²⁰ A recent report called for awareness in the surgical community about the potential risks of COVID-19 viral dissemination during laparoscopic surgery. Among other recommendations, international experts advised minimizing the use of electrosurgery to reduce the creation of surgical plume, decreasing the pneumoperitoneum pressure to minimum levels, and using suction devices in a closed system.²¹ Although these preventive measures apply to laparoscopic surgery, it is important to consider that hysteroscopy is performed in a unique environment.

During hysteroscopy the uterine cavity is distended with a liquid medium (normal saline or electrolyte-free solutions); this is opposed to gynecologic laparoscopy, in which the peritoneal cavity is distended with carbon dioxide.²² The smoke produced with the use of hysteroscopic electrosurgical instruments generates bubbles that are immediately cooled down to the temperature of the distention media and subsequently dissolve into it. Therefore, there are no bubbles generated during hysteroscopic surgery that are subsequently released into the air. This results in a low risk for viral dissemination during hysteroscopic procedures. Nevertheless, the necessary precautions to minimize the risk of COVID-19 transmission during hysteroscopic intervention are extremely important.

Recommendations for hysteroscopic procedures during the COVID-19 pandemic

We provide our overall recommendations for hysteroscopy, as well as those specific to the office and hospital setting.

Recommendations: General

Limit hysteroscopic procedures to COVID-19–negative patients and to those patients in whom delaying the procedure could result in adverse clinical outcomes.²³

Universally screen for potential COVID-19 infection. When possible, a phone interview to triage patients based on their symptoms and infection exposure status should take place before the patient arrives to the health care center. Patients with suspected or confirmed COVID-19 infection who require immediate evaluation should be directed to COVID-19–designated emergency areas.

Universally test for SARS-CoV-2 before procedures performed in the operating room (OR). Using nasopharyngeal swabs for the detection of viral RNA, employing molecular methods such as polymerase chain reaction (PCR), within 48 to 72 hours prior to all OR hysteroscopic procedures is strongly recommended. Adopting this testing strategy will aid to identify asymptomatic SARS-CoV-2‒infected patients, allowing to defer the procedure, if possible, among patients testing positive. If tests are limited, testing only patients scheduled for hysteroscopic procedures in which general or regional anesthesia will be required is acceptable.

Universal SARS-CoV-2 testing of patients undergoing in-office hysteroscopic diagnostic or minor operative procedures without the use of anesthesia is not required.

Limit the presence of a companion. It is understood that visitor policies may vary at the discretion of each institution’s guidelines. Children and individuals over the age of 60 years should not be granted access to the center. Companions will be subjected to the same screening criteria as patients.

Provide for social distancing and other precautionary measures. If more than one patient is scheduled to be at the facility at the same time, ensure that the facility provides adequate space to allow the appropriate social distancing recommendations between patients. Hand sanitizers and facemasks should be available for patients and companions.

Provide PPE for clinicians. All health care providers in close contact with the patient must wear personal protective equipment (PPE), which includes an apron and gown, a surgical mask, eye protection, and gloves. Health care providers should wear PPE deemed appropriate by their regulatory institutions following their local and national guidelines during clinical patient interactions.

Restrict surgical attendees to vital personnel. The participation of learners by physical presence in the office or operating room should be restricted.

Continue to: Recommendations: Office setting...

 

 

Recommendations: Office setting

Preprocedural recommendations

• Advise patients to come to the office alone. If the patient requires a companion, a maximum of one adult companion under the age of 60 should be accepted.
• Limit the number of health care team members present in the procedure room.

Intraprocedural recommendations

• Choose the appropriate device(s) that will allow for an effective and fast procedure.
• Use the recommended PPE for all clinicians.
• Limit the movement of staff members in and out of the procedure room.

Postprocedure recommendations

• When more than one case is scheduled to be performed in the same procedure room, allow enough time in between cases to grant a thorough OR decontamination.
• Allow for patients to recover from the procedure in the same room as the procedure took place in order to avoid potential contamination of multiple rooms.
• Expedite patient discharge.
• Follow up after the procedure by phone or telemedicine.
• Use standard endoscope disinfection procedures, as they are effective and should not be modified.

Continue to: Recommendations: Operating room setting...

 

 

Recommendations: Operating room setting

Preprocedural recommendations

• Perform adequate patient screening for potential COVID-19 infection. (Screening should be independent of symptoms and not be limited to those with clinical symptoms.)
• Limit the number of health care team members in the operating procedure room.
• To minimize unnecessary staff exposure, have surgeons and staff not needed for intubation remain outside the OR until intubation is completed and leave the OR before extubation.

Intraprocedure recommendations

• Limit personnel in the OR to a minimum.
• Staff should not enter or leave the room during the procedure.
• When possible, use conscious sedation or regional anesthesia to avoid the risk of viral dissemination at the time of intubation/extubation.
• Choose the device that will allow an effective and fast procedure.
• Favor non–smoke-generating devices, such as hysteroscopic scissors, graspers, and tissue retrieval systems.
• Connect active suction to the outflow, especially when using smoke-generating instruments, to facilitate the extraction of surgical smoke.

Postprocedure recommendations

• When more than one case is scheduled to be performed in the same room, allow enough time in between cases to grant a thorough OR decontamination.
• Expedite postprocedure recovery and patient discharge.
• After completion of the procedure, staff should remove scrubs and change into clean clothing.
• Use standard endoscope disinfection procedures, as they are effective and should not be modified.

Conclusions

The COVID-19 pandemic has caused a global health emergency. Our knowledge of this devastating virus is constantly evolving as we continue to fight this overwhelming disease. Theoretical risk of “viral” dissemination is considered extremely low, or negligible, during hysterosocopy. Hysteroscopic procedures in COVID-19–positive patients with life-threatening conditions or in patients in whom delaying the procedure could worsen outcomes should be performed taking appropriate measures. Patients who test negative for COVID-19 (confirmed by PCR) and require hysteroscopic procedures, should be treated using universal precautions. ●

A novel biomarker could help identify progression in Parkinson’s disease, distinguish it from other neurodegenerative disorders, and monitor response to treatments. Although the biomarker, neurofilament light chain (NfL), is not especially specific, it is the first blood-based biomarker for Parkinson’s disease.

Neurofilaments are components of the neural cytoskeleton, where they maintain structure along with other functions. Following axonal damage, NfL gets released into extracellular fluids. Previously, NfL has been detected in cerebrospinal fluid (CSF) in patients with multiple sclerosis and neurodegenerative dementias. NfL in the CSF can distinguish Parkinson’s disease (PD) from multiple system atrophy and progressive supranuclear palsy.

That’s useful, but a serum marker would open new doors. “An easily accessible biomarker that will serve as an indicator of diagnosis, disease state, and progression, as well as a marker of response to therapeutic intervention is needed. A biomarker will strengthen the ability to select patients for inclusion or stratification within clinical trials,” commented Okeanis Vaou, MD, director of the movement disorders program at St. Elizabeth’s Medical Center in Brighton, Mass. Dr. Vaou was not involved in the study, which was published Aug. 15 in Movement Disorders.
 

A potential biomarker?

To determine if serum NfL levels would correlate with CSF values and had potential as a biomarker, a large, multi-institutional team of researchers led by Brit Mollenhauer, MD, of the University Medical Center Goettingen (Germany), and Danielle Graham, MD, of Biogen, drew data from a prospective, longitudinal, single-center project called the De Novo Parkinson’s disease (DeNoPa) cohort.

The researchers analyzed data from 176 subjects, including drug-naive patients with newly diagnosed PD; age, sex, and education matched healthy controls; and patients who were initially diagnosed with Parkinson’s disease but had their diagnoses changed to a cognate or neurodegenerative disorder (OND). The researchers also drew 514 serum samples from the prospective longitudinal, observational, international multicenter study Parkinson’s Progression Marker Initiative (PPMI) cohort.

In the DeNoPa cohort, OND patients had the highest median CSF NfL levels at baseline (839 pg/mL) followed by PD patients (562 pg/mL) and healthy controls (494 pg/mL; P = .01). There was a strong correlation between CSF and serum NfL levels in a cross-sectional exploratory study with the PPMI cohort.

Age and sex covariates in the PPMI cohort explained 51% of NfL variability. After adjustment for age and sex, baseline median blood NfL levels were highest in the OND group (16.23 pg/mL), followed by the genetic PD group (13.36 pg/mL), prodromal participants (12.20 pg/mL), PD patients (11.73 pg/mL), unaffected mutation carriers (11.63 pg/mL), and healthy controls (11.05 pg/mL; F test P < .0001). Median serum NfL increased by 3.35% per year of age (P < .0001), and median serum NfL was 6.79% higher in women (P = .0002).

Doubling of adjusted serum NfL levels were associated with a median increase in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale total score of 3.45 points (false-discovery rate–adjusted P = .0115), a median decrease in Symbol Digit Modality Test total score of 1.39 (FDR P = .026), a median decrease in Hopkins Verbal Learning Tests with discrimination recognition score of 0.3 (FDR P = .03), and a median decrease in Hopkins Verbal Learning Tests with retention score of 0.029 (FDR P = .04).
 

More specific markers needed

The findings are intriguing, said Dr Vaou, but “we need to acknowledge that increased NfL levels are not specific enough to Parkinson’s disease and reflect neuronal and axonal damage. Therefore, there is a need for more specific markers to support diagnostic accuracy, rate of progression, and ultimate prognosis. A serum NfL assay may be useful to clinicians evaluating patients with PD or OND diagnosis and mitigate the misdiagnosis of atypical PD. NfL may be particularly useful in differentiating PD from cognate disorders such as multiple system atrophy, progressive supranuclear palsy, and dementia with Lewy bodies.”

The current success is the result of large patient databases containing phenotypic data, imaging, and tests of tissue, blood, and cerebrospinal fluid, along with collaborations between advocacy groups, academia, and industry, according to Dr. Vaou. As that work continues, it could uncover more specific biomarkers “that will allow us not only to help with diagnosis and treatment but with disease progression, inclusion, recruitment and stratification in clinical studies, as well as (be an) indicator of response to therapeutic intervention of an investigational drug.”

The study was funded by the Michael J. Fox Foundation for Parkinson’s Research. Dr. Vaou had no relevant financial disclosures.

SOURCE: Mollenhauer B et al. Mov Disord. 2020 Aug 15. doi: 10.1002/mds.28206.

A novel biomarker could help identify progression in Parkinson’s disease, distinguish it from other neurodegenerative disorders, and monitor response to treatments. Although the biomarker, neurofilament light chain (NfL), is not especially specific, it is the first blood-based biomarker for Parkinson’s disease.

Neurofilaments are components of the neural cytoskeleton, where they maintain structure along with other functions. Following axonal damage, NfL gets released into extracellular fluids. Previously, NfL has been detected in cerebrospinal fluid (CSF) in patients with multiple sclerosis and neurodegenerative dementias. NfL in the CSF can distinguish Parkinson’s disease (PD) from multiple system atrophy and progressive supranuclear palsy.

That’s useful, but a serum marker would open new doors. “An easily accessible biomarker that will serve as an indicator of diagnosis, disease state, and progression, as well as a marker of response to therapeutic intervention is needed. A biomarker will strengthen the ability to select patients for inclusion or stratification within clinical trials,” commented Okeanis Vaou, MD, director of the movement disorders program at St. Elizabeth’s Medical Center in Brighton, Mass. Dr. Vaou was not involved in the study, which was published Aug. 15 in Movement Disorders.
 

A potential biomarker?

To determine if serum NfL levels would correlate with CSF values and had potential as a biomarker, a large, multi-institutional team of researchers led by Brit Mollenhauer, MD, of the University Medical Center Goettingen (Germany), and Danielle Graham, MD, of Biogen, drew data from a prospective, longitudinal, single-center project called the De Novo Parkinson’s disease (DeNoPa) cohort.

The researchers analyzed data from 176 subjects, including drug-naive patients with newly diagnosed PD; age, sex, and education matched healthy controls; and patients who were initially diagnosed with Parkinson’s disease but had their diagnoses changed to a cognate or neurodegenerative disorder (OND). The researchers also drew 514 serum samples from the prospective longitudinal, observational, international multicenter study Parkinson’s Progression Marker Initiative (PPMI) cohort.

In the DeNoPa cohort, OND patients had the highest median CSF NfL levels at baseline (839 pg/mL) followed by PD patients (562 pg/mL) and healthy controls (494 pg/mL; P = .01). There was a strong correlation between CSF and serum NfL levels in a cross-sectional exploratory study with the PPMI cohort.

Age and sex covariates in the PPMI cohort explained 51% of NfL variability. After adjustment for age and sex, baseline median blood NfL levels were highest in the OND group (16.23 pg/mL), followed by the genetic PD group (13.36 pg/mL), prodromal participants (12.20 pg/mL), PD patients (11.73 pg/mL), unaffected mutation carriers (11.63 pg/mL), and healthy controls (11.05 pg/mL; F test P < .0001). Median serum NfL increased by 3.35% per year of age (P < .0001), and median serum NfL was 6.79% higher in women (P = .0002).

Doubling of adjusted serum NfL levels were associated with a median increase in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale total score of 3.45 points (false-discovery rate–adjusted P = .0115), a median decrease in Symbol Digit Modality Test total score of 1.39 (FDR P = .026), a median decrease in Hopkins Verbal Learning Tests with discrimination recognition score of 0.3 (FDR P = .03), and a median decrease in Hopkins Verbal Learning Tests with retention score of 0.029 (FDR P = .04).
 

More specific markers needed

The findings are intriguing, said Dr Vaou, but “we need to acknowledge that increased NfL levels are not specific enough to Parkinson’s disease and reflect neuronal and axonal damage. Therefore, there is a need for more specific markers to support diagnostic accuracy, rate of progression, and ultimate prognosis. A serum NfL assay may be useful to clinicians evaluating patients with PD or OND diagnosis and mitigate the misdiagnosis of atypical PD. NfL may be particularly useful in differentiating PD from cognate disorders such as multiple system atrophy, progressive supranuclear palsy, and dementia with Lewy bodies.”

The current success is the result of large patient databases containing phenotypic data, imaging, and tests of tissue, blood, and cerebrospinal fluid, along with collaborations between advocacy groups, academia, and industry, according to Dr. Vaou. As that work continues, it could uncover more specific biomarkers “that will allow us not only to help with diagnosis and treatment but with disease progression, inclusion, recruitment and stratification in clinical studies, as well as (be an) indicator of response to therapeutic intervention of an investigational drug.”

The study was funded by the Michael J. Fox Foundation for Parkinson’s Research. Dr. Vaou had no relevant financial disclosures.

SOURCE: Mollenhauer B et al. Mov Disord. 2020 Aug 15. doi: 10.1002/mds.28206.

A novel biomarker could help identify progression in Parkinson’s disease, distinguish it from other neurodegenerative disorders, and monitor response to treatments. Although the biomarker, neurofilament light chain (NfL), is not especially specific, it is the first blood-based biomarker for Parkinson’s disease.

Neurofilaments are components of the neural cytoskeleton, where they maintain structure along with other functions. Following axonal damage, NfL gets released into extracellular fluids. Previously, NfL has been detected in cerebrospinal fluid (CSF) in patients with multiple sclerosis and neurodegenerative dementias. NfL in the CSF can distinguish Parkinson’s disease (PD) from multiple system atrophy and progressive supranuclear palsy.

That’s useful, but a serum marker would open new doors. “An easily accessible biomarker that will serve as an indicator of diagnosis, disease state, and progression, as well as a marker of response to therapeutic intervention is needed. A biomarker will strengthen the ability to select patients for inclusion or stratification within clinical trials,” commented Okeanis Vaou, MD, director of the movement disorders program at St. Elizabeth’s Medical Center in Brighton, Mass. Dr. Vaou was not involved in the study, which was published Aug. 15 in Movement Disorders.
 

A potential biomarker?

To determine if serum NfL levels would correlate with CSF values and had potential as a biomarker, a large, multi-institutional team of researchers led by Brit Mollenhauer, MD, of the University Medical Center Goettingen (Germany), and Danielle Graham, MD, of Biogen, drew data from a prospective, longitudinal, single-center project called the De Novo Parkinson’s disease (DeNoPa) cohort.

The researchers analyzed data from 176 subjects, including drug-naive patients with newly diagnosed PD; age, sex, and education matched healthy controls; and patients who were initially diagnosed with Parkinson’s disease but had their diagnoses changed to a cognate or neurodegenerative disorder (OND). The researchers also drew 514 serum samples from the prospective longitudinal, observational, international multicenter study Parkinson’s Progression Marker Initiative (PPMI) cohort.

In the DeNoPa cohort, OND patients had the highest median CSF NfL levels at baseline (839 pg/mL) followed by PD patients (562 pg/mL) and healthy controls (494 pg/mL; P = .01). There was a strong correlation between CSF and serum NfL levels in a cross-sectional exploratory study with the PPMI cohort.

Age and sex covariates in the PPMI cohort explained 51% of NfL variability. After adjustment for age and sex, baseline median blood NfL levels were highest in the OND group (16.23 pg/mL), followed by the genetic PD group (13.36 pg/mL), prodromal participants (12.20 pg/mL), PD patients (11.73 pg/mL), unaffected mutation carriers (11.63 pg/mL), and healthy controls (11.05 pg/mL; F test P < .0001). Median serum NfL increased by 3.35% per year of age (P < .0001), and median serum NfL was 6.79% higher in women (P = .0002).

Doubling of adjusted serum NfL levels were associated with a median increase in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale total score of 3.45 points (false-discovery rate–adjusted P = .0115), a median decrease in Symbol Digit Modality Test total score of 1.39 (FDR P = .026), a median decrease in Hopkins Verbal Learning Tests with discrimination recognition score of 0.3 (FDR P = .03), and a median decrease in Hopkins Verbal Learning Tests with retention score of 0.029 (FDR P = .04).
 

More specific markers needed

The findings are intriguing, said Dr Vaou, but “we need to acknowledge that increased NfL levels are not specific enough to Parkinson’s disease and reflect neuronal and axonal damage. Therefore, there is a need for more specific markers to support diagnostic accuracy, rate of progression, and ultimate prognosis. A serum NfL assay may be useful to clinicians evaluating patients with PD or OND diagnosis and mitigate the misdiagnosis of atypical PD. NfL may be particularly useful in differentiating PD from cognate disorders such as multiple system atrophy, progressive supranuclear palsy, and dementia with Lewy bodies.”

The current success is the result of large patient databases containing phenotypic data, imaging, and tests of tissue, blood, and cerebrospinal fluid, along with collaborations between advocacy groups, academia, and industry, according to Dr. Vaou. As that work continues, it could uncover more specific biomarkers “that will allow us not only to help with diagnosis and treatment but with disease progression, inclusion, recruitment and stratification in clinical studies, as well as (be an) indicator of response to therapeutic intervention of an investigational drug.”

The study was funded by the Michael J. Fox Foundation for Parkinson’s Research. Dr. Vaou had no relevant financial disclosures.

SOURCE: Mollenhauer B et al. Mov Disord. 2020 Aug 15. doi: 10.1002/mds.28206.

THE CASE

Sandra H,* a 24-year-old single woman with a history of asthma, presented to our family medicine clinic as a new patient. Ms. H said she lived at home with her mother. She completed high school but never attended college due to anxiety. She had held several jobs since high school and recently decided to apply to a local college, which prompted a desire to gain control over the anxiety that had been present since middle school. She reported feeling anxious, having difficulty breathing, shaking all over, having difficulty concentrating, and experiencing numbness and tingling in her fingers. She was often irritable at home, which she attributed partly to anxiety but mostly to disrupted sleep. We administered the 7-question Generalized Anxiety Disorder (GAD-7) questionnaire and she scored 15 (of a possible 21) points, indicative of severe anxiety.

● How would you proceed with this patient?

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

Approximately 1 in 5 patients presenting to primary care clinics have at least 1 anxiety disorder and 7.6% have generalized anxiety disorder (GAD).¹ Yet many go untreated. The lifetime prevalence of GAD is 3.7% worldwide and 7.8% in the United States.² Only 5% of cases emerge by age 13,² but incidence increases through adolescence and young adulthood, with a quarter of all cases occurring by age 25.² GAD occurs about twice as often in women as it does in men. It is typically recurrent, and many patients require ongoing treatment.²

GAD diagnostic criteria and differential considerations

Diagnosis of GAD requires at least 6 months of excessive worry or anxiety about a variety of circumstances, occurring on most days and for more than half the day.³ The worry or anxiety in GAD is difficult to control, disrupts meaningful areas of life, and surrounds everyday concerns, such as finances, health, or family-related issues. Among adolescents with GAD, worries typically include school performance and may often present as perfectionism.⁴ At least 3 of the following 6 symptoms result from chronic anxiety: restlessness, fatigue, poor concentration, irritability, muscle tension, and sleep disturbance.²

Rule out other conditions. Make sure symptoms of GAD are not better explained by another medical problem, including other mental disorders or substance use disorders.³ Complaints of anxiety in the context of mania, hypomania, or withdrawal from alcohol or a sedative hypnotic suggest a different underlying cause, thereby requiring a complete history with symptom chronology and collateral information. The pattern of anxiety seen in GAD also differs from the focused sources of anxiety found in disorders such as social anxiety disorder (SAD) and post-traumatic stress disorder. For example, SAD might center on embarrassment in a social setting rather than reflect a pattern of general worry.⁵

Consider comorbidities. Further complicating diagnosis and treatment, GAD has been linked to higher rates of comorbidity and higher health care utilization. About 90% of GAD patients experience psychiatric comorbidity, with major depressive disorder co-­occurring about 60% of the time.⁶ Substance use disorders co-occur with GAD more than 20% of the time.² Despite comorbidities, it is the somatic complaints in GAD that often drive patient requests for medical care.^7,8 GAD itself is an independent predictor of heart disease⁹ and is linked to increased risk of chronic or severe headaches¹⁰ and suicide.^11,12

Continue to: Work with patients and family toward a diagnosis

Work with patients and family toward a diagnosis

Despite the potential benefits of early identification and treatment of GAD,¹³ the average elapsed time from symptom onset to initial medication treatment is 7 years.¹⁴ Multiple factors likely account for this delay. Clinical presentations can be highly variable,⁶ with 1 patient presenting primarily with sleep complaints and another with gastrointestinal symptoms. Some medical conditions (TABLE 1)¹⁵ and substances (TABLE 2)^16-18 can cause secondary anxiety symptoms, and their presence should prompt a thorough ­evaluation.

Address the mind-body connection. Because uncertainty and ambiguity surrounding a diagnosis often drive worry,¹⁹ anxious patients or their family members commonly seek additional medical visits and tests in search of answers. In such instances, it helps to explain the physiologic connection between somatic complaints and anxiety.⁸ Describe how areas of the brain that manage fear and stress can also cause muscle tension, gastrointestinal complaints, hyperarousal, or sleep disturbance.

Despite the potential benefits of early identification and treatment of generalized anxiety disorder, the average elapsed time from symptom onset to initial medication treatment is 7 years.

Empathy and early psychoeducation on the reason anxiety is being considered can decrease stigma and enable appropriate follow-up and treatment. You might introduce the connection between health complaints and GAD specifically by exploring the amount of worry surrounding the presenting symptoms, followed by a question such as, “Sometimes your worry will fit the situation and sometimes it’ll be too much. Has anyone ever told you that you worry too much?” The patient’s response to such a question could signal a need to use the GAD-7 screening tool¹ as an aid to diagnosis and as a baseline measure for monitoring subsequent treatment progress.

Psycho- and pharmacotherapy aspects of management

Helping someone understand a GAD diagnosis and treatment options can test a clinician’s communication skills. Avoid trying to reason patients out of their worries or fears (TABLE 3). Instead, rely on psychoeducation about the mind-body connection and on focused counseling (TABLE 4) to help patients and their family members understand effective next steps.^8,20 At a minimum, ensure that everyone involved understands how anxiety is influenced by unhealthy lifestyle choices such as poor sleep hygiene and caffeine misuse.

Let patients choose from among various coping strategies. Be prepared to offer patients user-friendly handouts, reading material, or links to educational Web sites. Many patients are interested in using smartphone applications to learn and practice coping strategies. Although these apps can encourage the regular practice of coping skills, caution teens and parents about privacy issues and the lack of evidence supporting this approach as stand-alone therapy.²¹ Offering several choices (TABLE 4) can increase the sense of ownership an individual experiences when choosing the next step.

Continue to: For patients who remain focused...

For patients who remain focused on somatic complaints and resist adopting coping skills or treatment, pushing certain recommendations can actually increase resistance to proper treatment.²² Instead, explore their ambivalence, offer facts, express concern about the current course of the illness, and emphasize the need to revisit the discussion at a future appointment. Offer follow-up monitoring to assess the course of the illness and readiness for GAD treatment.

Initiate treatment in a stepwise manner¹³ for the patient who is ready for GAD treatment. This approach includes education and monitoring; low-intensity interventions (eg, treatment workbooks or group sessions); medication and/or referral for psychotherapy; referral for outpatient psychiatric care; and hospitalization for patients who pose a danger to self or others.¹³ Studies suggest that patients receiving both psychotherapy and pharmacotherapy benefit from the complementary targeting of symptoms, exhibit increased adherence, and report fewer adverse effects.²³

Patients are most likely to benefit from therapy when they have the capacity for introspection and forming friendships (ie, can form a therapeutic alliance). With such patients who have mild or moderate symptoms of GAD, offer cognitive behavioral therapy (CBT) or applied relaxation training. Consider a trial of medication when symptoms are severe, when psychotherapy is not a good option, or when response to psychotherapy is inadequate.¹³ Medications work by targeting primitive parts of the brain such as the amygdala (bottom up), while psychotherapy targets the cortex or more evolved part of the brain, teaching it to modulate the lower or more primitive structures (top down).²⁴

Medication considerations. Selective serotonin reuptake inhibitors (SSRIs) are considered first-line pharmacotherapy for adult and adolescent patients with GAD.²⁰ However, in adolescents, no SSRIs are approved by the US Food and Drug Administration (FDA) to treat anxiety disorders unassociated with obsessive-compulsive disorder. Use caution if prescribing an SSRI for off-label treatment in an adolescent; talk with the patient and family about the FDA’s black-box warning regarding the potential for suicidality in adolescents.

Say to the patient: “Sometimes your worry will fit the situation and sometimes it’ll be too much. Has anyone ever told you that you worry too much?”

For adults, selective norepinephrine reuptake inhibitors (SNRIs) are also considered a first-line treatment option.²³ SSRIs and SNRIs are well-studied, effective, safe, and better tolerated than earlier antidepressants. However, be aware that both SSRIs and SNRIs are often associated with headache, nausea, and sexual dysfunction. They are dosed once daily and have not been shown to cause dependence. Inform patients that onset of action is often delayed 4 to 8 weeks²³ and that there is a risk for anxiety-producing effects early in treatment. To minimize these effects, consider starting treatment at a lower dose and titrate upward more gradually than when treating depression.

Continue to: Continue treatment for 12 months...

Continue treatment for 12 months to reduce the risk of recurrence.²³ If response to treatment is insufficient after 2 adequate trials of an SSRI or SNRI, consider second-line agents such as azapirones or benzodiazepines for adults, keeping in mind the risk for dependence with benzodiazepines.¹³

Evidence supports GABAergic drugs such as gabapentin and pregabalin as off-label treatments for GAD in refractory adult cases.²⁵ In the European Union, pregabalin is approved for use in GAD. Caution is recommended with both drugs due to abuse potential. Next steps for an inadequate response should include referral to Psychiatry or for inpatient care when risk of harm to self or others is high.

CASE

Considering Ms. H’s ability to work and complete daily activities, we talked to her about CBT as a first step and referred her to a therapist in the community. One month after her initial visit with us, Ms. H returned for a follow-up visit and scored a 17 on her GAD-7, still in the severe range. After one CBT session, she had cancelled her second and third appointments due to work conflicts. She had missed some work from oversleeping after worried sleepless nights. Her worries concerned friendships, paying bills, physical appearance, not being able to exercise and therefore gaining weight, and troubles at work and with her mother. She also described several episodes of nightmares after breaking up with a boyfriend.

To minimize the anxiety-producing effects of SSRIs and SNRIs, consider starting treatment at a lower dose and titrate upward more gradually than when treating depression.

She agreed to try an SSRI, and we started her on fluoxetine 10 mg/d. We counseled her on SSRI risks and benefits, including the potential for increased suicidal ideation and how to respond if such thoughts developed. Three weeks after starting fluoxetine, Ms. H reported improvement with no adverse effects from the medication, except for decreased appetite and some weight loss, which she welcomed. She had registered for college courses, and her third score on the GAD-7 was an 8.

We increased her fluoxetine dose to 20 mg/d for maintenance. We encouraged her to return to her therapist for CBT and she scheduled that appointment. Therapy records noted a GAD-7 score of 5 at follow-up 8 weeks later. Ms. H reported improved sleep, reduced irritability at home, and better relationships with her mother and friends. She had begun college classes and was writing about her thoughts and worries as part of her CBT homework. She continued follow-up appointments with both her family physician and her therapist.

CORRESPONDENCE
Christopher A. Ebberwein, PhD, Wesley Family Medicine Residency, 850 North Hillside, Wichita, KS 67214; chris. ebberwein@wesleymc.com.

THE CASE

Sandra H,* a 24-year-old single woman with a history of asthma, presented to our family medicine clinic as a new patient. Ms. H said she lived at home with her mother. She completed high school but never attended college due to anxiety. She had held several jobs since high school and recently decided to apply to a local college, which prompted a desire to gain control over the anxiety that had been present since middle school. She reported feeling anxious, having difficulty breathing, shaking all over, having difficulty concentrating, and experiencing numbness and tingling in her fingers. She was often irritable at home, which she attributed partly to anxiety but mostly to disrupted sleep. We administered the 7-question Generalized Anxiety Disorder (GAD-7) questionnaire and she scored 15 (of a possible 21) points, indicative of severe anxiety.

● How would you proceed with this patient?

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

Approximately 1 in 5 patients presenting to primary care clinics have at least 1 anxiety disorder and 7.6% have generalized anxiety disorder (GAD).¹ Yet many go untreated. The lifetime prevalence of GAD is 3.7% worldwide and 7.8% in the United States.² Only 5% of cases emerge by age 13,² but incidence increases through adolescence and young adulthood, with a quarter of all cases occurring by age 25.² GAD occurs about twice as often in women as it does in men. It is typically recurrent, and many patients require ongoing treatment.²

GAD diagnostic criteria and differential considerations

Diagnosis of GAD requires at least 6 months of excessive worry or anxiety about a variety of circumstances, occurring on most days and for more than half the day.³ The worry or anxiety in GAD is difficult to control, disrupts meaningful areas of life, and surrounds everyday concerns, such as finances, health, or family-related issues. Among adolescents with GAD, worries typically include school performance and may often present as perfectionism.⁴ At least 3 of the following 6 symptoms result from chronic anxiety: restlessness, fatigue, poor concentration, irritability, muscle tension, and sleep disturbance.²

Rule out other conditions. Make sure symptoms of GAD are not better explained by another medical problem, including other mental disorders or substance use disorders.³ Complaints of anxiety in the context of mania, hypomania, or withdrawal from alcohol or a sedative hypnotic suggest a different underlying cause, thereby requiring a complete history with symptom chronology and collateral information. The pattern of anxiety seen in GAD also differs from the focused sources of anxiety found in disorders such as social anxiety disorder (SAD) and post-traumatic stress disorder. For example, SAD might center on embarrassment in a social setting rather than reflect a pattern of general worry.⁵

Consider comorbidities. Further complicating diagnosis and treatment, GAD has been linked to higher rates of comorbidity and higher health care utilization. About 90% of GAD patients experience psychiatric comorbidity, with major depressive disorder co-­occurring about 60% of the time.⁶ Substance use disorders co-occur with GAD more than 20% of the time.² Despite comorbidities, it is the somatic complaints in GAD that often drive patient requests for medical care.^7,8 GAD itself is an independent predictor of heart disease⁹ and is linked to increased risk of chronic or severe headaches¹⁰ and suicide.^11,12

Continue to: Work with patients and family toward a diagnosis

Work with patients and family toward a diagnosis

Despite the potential benefits of early identification and treatment of GAD,¹³ the average elapsed time from symptom onset to initial medication treatment is 7 years.¹⁴ Multiple factors likely account for this delay. Clinical presentations can be highly variable,⁶ with 1 patient presenting primarily with sleep complaints and another with gastrointestinal symptoms. Some medical conditions (TABLE 1)¹⁵ and substances (TABLE 2)^16-18 can cause secondary anxiety symptoms, and their presence should prompt a thorough ­evaluation.

Address the mind-body connection. Because uncertainty and ambiguity surrounding a diagnosis often drive worry,¹⁹ anxious patients or their family members commonly seek additional medical visits and tests in search of answers. In such instances, it helps to explain the physiologic connection between somatic complaints and anxiety.⁸ Describe how areas of the brain that manage fear and stress can also cause muscle tension, gastrointestinal complaints, hyperarousal, or sleep disturbance.

Despite the potential benefits of early identification and treatment of generalized anxiety disorder, the average elapsed time from symptom onset to initial medication treatment is 7 years.

Empathy and early psychoeducation on the reason anxiety is being considered can decrease stigma and enable appropriate follow-up and treatment. You might introduce the connection between health complaints and GAD specifically by exploring the amount of worry surrounding the presenting symptoms, followed by a question such as, “Sometimes your worry will fit the situation and sometimes it’ll be too much. Has anyone ever told you that you worry too much?” The patient’s response to such a question could signal a need to use the GAD-7 screening tool¹ as an aid to diagnosis and as a baseline measure for monitoring subsequent treatment progress.

Psycho- and pharmacotherapy aspects of management

Helping someone understand a GAD diagnosis and treatment options can test a clinician’s communication skills. Avoid trying to reason patients out of their worries or fears (TABLE 3). Instead, rely on psychoeducation about the mind-body connection and on focused counseling (TABLE 4) to help patients and their family members understand effective next steps.^8,20 At a minimum, ensure that everyone involved understands how anxiety is influenced by unhealthy lifestyle choices such as poor sleep hygiene and caffeine misuse.

Let patients choose from among various coping strategies. Be prepared to offer patients user-friendly handouts, reading material, or links to educational Web sites. Many patients are interested in using smartphone applications to learn and practice coping strategies. Although these apps can encourage the regular practice of coping skills, caution teens and parents about privacy issues and the lack of evidence supporting this approach as stand-alone therapy.²¹ Offering several choices (TABLE 4) can increase the sense of ownership an individual experiences when choosing the next step.

Continue to: For patients who remain focused...

For patients who remain focused on somatic complaints and resist adopting coping skills or treatment, pushing certain recommendations can actually increase resistance to proper treatment.²² Instead, explore their ambivalence, offer facts, express concern about the current course of the illness, and emphasize the need to revisit the discussion at a future appointment. Offer follow-up monitoring to assess the course of the illness and readiness for GAD treatment.

Initiate treatment in a stepwise manner¹³ for the patient who is ready for GAD treatment. This approach includes education and monitoring; low-intensity interventions (eg, treatment workbooks or group sessions); medication and/or referral for psychotherapy; referral for outpatient psychiatric care; and hospitalization for patients who pose a danger to self or others.¹³ Studies suggest that patients receiving both psychotherapy and pharmacotherapy benefit from the complementary targeting of symptoms, exhibit increased adherence, and report fewer adverse effects.²³

Patients are most likely to benefit from therapy when they have the capacity for introspection and forming friendships (ie, can form a therapeutic alliance). With such patients who have mild or moderate symptoms of GAD, offer cognitive behavioral therapy (CBT) or applied relaxation training. Consider a trial of medication when symptoms are severe, when psychotherapy is not a good option, or when response to psychotherapy is inadequate.¹³ Medications work by targeting primitive parts of the brain such as the amygdala (bottom up), while psychotherapy targets the cortex or more evolved part of the brain, teaching it to modulate the lower or more primitive structures (top down).²⁴

Medication considerations. Selective serotonin reuptake inhibitors (SSRIs) are considered first-line pharmacotherapy for adult and adolescent patients with GAD.²⁰ However, in adolescents, no SSRIs are approved by the US Food and Drug Administration (FDA) to treat anxiety disorders unassociated with obsessive-compulsive disorder. Use caution if prescribing an SSRI for off-label treatment in an adolescent; talk with the patient and family about the FDA’s black-box warning regarding the potential for suicidality in adolescents.

Say to the patient: “Sometimes your worry will fit the situation and sometimes it’ll be too much. Has anyone ever told you that you worry too much?”

For adults, selective norepinephrine reuptake inhibitors (SNRIs) are also considered a first-line treatment option.²³ SSRIs and SNRIs are well-studied, effective, safe, and better tolerated than earlier antidepressants. However, be aware that both SSRIs and SNRIs are often associated with headache, nausea, and sexual dysfunction. They are dosed once daily and have not been shown to cause dependence. Inform patients that onset of action is often delayed 4 to 8 weeks²³ and that there is a risk for anxiety-producing effects early in treatment. To minimize these effects, consider starting treatment at a lower dose and titrate upward more gradually than when treating depression.

Continue to: Continue treatment for 12 months...

Continue treatment for 12 months to reduce the risk of recurrence.²³ If response to treatment is insufficient after 2 adequate trials of an SSRI or SNRI, consider second-line agents such as azapirones or benzodiazepines for adults, keeping in mind the risk for dependence with benzodiazepines.¹³

Evidence supports GABAergic drugs such as gabapentin and pregabalin as off-label treatments for GAD in refractory adult cases.²⁵ In the European Union, pregabalin is approved for use in GAD. Caution is recommended with both drugs due to abuse potential. Next steps for an inadequate response should include referral to Psychiatry or for inpatient care when risk of harm to self or others is high.

CASE

Considering Ms. H’s ability to work and complete daily activities, we talked to her about CBT as a first step and referred her to a therapist in the community. One month after her initial visit with us, Ms. H returned for a follow-up visit and scored a 17 on her GAD-7, still in the severe range. After one CBT session, she had cancelled her second and third appointments due to work conflicts. She had missed some work from oversleeping after worried sleepless nights. Her worries concerned friendships, paying bills, physical appearance, not being able to exercise and therefore gaining weight, and troubles at work and with her mother. She also described several episodes of nightmares after breaking up with a boyfriend.

To minimize the anxiety-producing effects of SSRIs and SNRIs, consider starting treatment at a lower dose and titrate upward more gradually than when treating depression.

She agreed to try an SSRI, and we started her on fluoxetine 10 mg/d. We counseled her on SSRI risks and benefits, including the potential for increased suicidal ideation and how to respond if such thoughts developed. Three weeks after starting fluoxetine, Ms. H reported improvement with no adverse effects from the medication, except for decreased appetite and some weight loss, which she welcomed. She had registered for college courses, and her third score on the GAD-7 was an 8.

We increased her fluoxetine dose to 20 mg/d for maintenance. We encouraged her to return to her therapist for CBT and she scheduled that appointment. Therapy records noted a GAD-7 score of 5 at follow-up 8 weeks later. Ms. H reported improved sleep, reduced irritability at home, and better relationships with her mother and friends. She had begun college classes and was writing about her thoughts and worries as part of her CBT homework. She continued follow-up appointments with both her family physician and her therapist.

CORRESPONDENCE
Christopher A. Ebberwein, PhD, Wesley Family Medicine Residency, 850 North Hillside, Wichita, KS 67214; chris. ebberwein@wesleymc.com.

THE CASE

Sandra H,* a 24-year-old single woman with a history of asthma, presented to our family medicine clinic as a new patient. Ms. H said she lived at home with her mother. She completed high school but never attended college due to anxiety. She had held several jobs since high school and recently decided to apply to a local college, which prompted a desire to gain control over the anxiety that had been present since middle school. She reported feeling anxious, having difficulty breathing, shaking all over, having difficulty concentrating, and experiencing numbness and tingling in her fingers. She was often irritable at home, which she attributed partly to anxiety but mostly to disrupted sleep. We administered the 7-question Generalized Anxiety Disorder (GAD-7) questionnaire and she scored 15 (of a possible 21) points, indicative of severe anxiety.

● How would you proceed with this patient?

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

Approximately 1 in 5 patients presenting to primary care clinics have at least 1 anxiety disorder and 7.6% have generalized anxiety disorder (GAD).¹ Yet many go untreated. The lifetime prevalence of GAD is 3.7% worldwide and 7.8% in the United States.² Only 5% of cases emerge by age 13,² but incidence increases through adolescence and young adulthood, with a quarter of all cases occurring by age 25.² GAD occurs about twice as often in women as it does in men. It is typically recurrent, and many patients require ongoing treatment.²

GAD diagnostic criteria and differential considerations

Diagnosis of GAD requires at least 6 months of excessive worry or anxiety about a variety of circumstances, occurring on most days and for more than half the day.³ The worry or anxiety in GAD is difficult to control, disrupts meaningful areas of life, and surrounds everyday concerns, such as finances, health, or family-related issues. Among adolescents with GAD, worries typically include school performance and may often present as perfectionism.⁴ At least 3 of the following 6 symptoms result from chronic anxiety: restlessness, fatigue, poor concentration, irritability, muscle tension, and sleep disturbance.²

Rule out other conditions. Make sure symptoms of GAD are not better explained by another medical problem, including other mental disorders or substance use disorders.³ Complaints of anxiety in the context of mania, hypomania, or withdrawal from alcohol or a sedative hypnotic suggest a different underlying cause, thereby requiring a complete history with symptom chronology and collateral information. The pattern of anxiety seen in GAD also differs from the focused sources of anxiety found in disorders such as social anxiety disorder (SAD) and post-traumatic stress disorder. For example, SAD might center on embarrassment in a social setting rather than reflect a pattern of general worry.⁵

Consider comorbidities. Further complicating diagnosis and treatment, GAD has been linked to higher rates of comorbidity and higher health care utilization. About 90% of GAD patients experience psychiatric comorbidity, with major depressive disorder co-­occurring about 60% of the time.⁶ Substance use disorders co-occur with GAD more than 20% of the time.² Despite comorbidities, it is the somatic complaints in GAD that often drive patient requests for medical care.^7,8 GAD itself is an independent predictor of heart disease⁹ and is linked to increased risk of chronic or severe headaches¹⁰ and suicide.^11,12

Continue to: Work with patients and family toward a diagnosis

Work with patients and family toward a diagnosis

Despite the potential benefits of early identification and treatment of GAD,¹³ the average elapsed time from symptom onset to initial medication treatment is 7 years.¹⁴ Multiple factors likely account for this delay. Clinical presentations can be highly variable,⁶ with 1 patient presenting primarily with sleep complaints and another with gastrointestinal symptoms. Some medical conditions (TABLE 1)¹⁵ and substances (TABLE 2)^16-18 can cause secondary anxiety symptoms, and their presence should prompt a thorough ­evaluation.

Address the mind-body connection. Because uncertainty and ambiguity surrounding a diagnosis often drive worry,¹⁹ anxious patients or their family members commonly seek additional medical visits and tests in search of answers. In such instances, it helps to explain the physiologic connection between somatic complaints and anxiety.⁸ Describe how areas of the brain that manage fear and stress can also cause muscle tension, gastrointestinal complaints, hyperarousal, or sleep disturbance.

Despite the potential benefits of early identification and treatment of generalized anxiety disorder, the average elapsed time from symptom onset to initial medication treatment is 7 years.

Empathy and early psychoeducation on the reason anxiety is being considered can decrease stigma and enable appropriate follow-up and treatment. You might introduce the connection between health complaints and GAD specifically by exploring the amount of worry surrounding the presenting symptoms, followed by a question such as, “Sometimes your worry will fit the situation and sometimes it’ll be too much. Has anyone ever told you that you worry too much?” The patient’s response to such a question could signal a need to use the GAD-7 screening tool¹ as an aid to diagnosis and as a baseline measure for monitoring subsequent treatment progress.

Psycho- and pharmacotherapy aspects of management

Helping someone understand a GAD diagnosis and treatment options can test a clinician’s communication skills. Avoid trying to reason patients out of their worries or fears (TABLE 3). Instead, rely on psychoeducation about the mind-body connection and on focused counseling (TABLE 4) to help patients and their family members understand effective next steps.^8,20 At a minimum, ensure that everyone involved understands how anxiety is influenced by unhealthy lifestyle choices such as poor sleep hygiene and caffeine misuse.

Let patients choose from among various coping strategies. Be prepared to offer patients user-friendly handouts, reading material, or links to educational Web sites. Many patients are interested in using smartphone applications to learn and practice coping strategies. Although these apps can encourage the regular practice of coping skills, caution teens and parents about privacy issues and the lack of evidence supporting this approach as stand-alone therapy.²¹ Offering several choices (TABLE 4) can increase the sense of ownership an individual experiences when choosing the next step.

Continue to: For patients who remain focused...

For patients who remain focused on somatic complaints and resist adopting coping skills or treatment, pushing certain recommendations can actually increase resistance to proper treatment.²² Instead, explore their ambivalence, offer facts, express concern about the current course of the illness, and emphasize the need to revisit the discussion at a future appointment. Offer follow-up monitoring to assess the course of the illness and readiness for GAD treatment.

Initiate treatment in a stepwise manner¹³ for the patient who is ready for GAD treatment. This approach includes education and monitoring; low-intensity interventions (eg, treatment workbooks or group sessions); medication and/or referral for psychotherapy; referral for outpatient psychiatric care; and hospitalization for patients who pose a danger to self or others.¹³ Studies suggest that patients receiving both psychotherapy and pharmacotherapy benefit from the complementary targeting of symptoms, exhibit increased adherence, and report fewer adverse effects.²³

Patients are most likely to benefit from therapy when they have the capacity for introspection and forming friendships (ie, can form a therapeutic alliance). With such patients who have mild or moderate symptoms of GAD, offer cognitive behavioral therapy (CBT) or applied relaxation training. Consider a trial of medication when symptoms are severe, when psychotherapy is not a good option, or when response to psychotherapy is inadequate.¹³ Medications work by targeting primitive parts of the brain such as the amygdala (bottom up), while psychotherapy targets the cortex or more evolved part of the brain, teaching it to modulate the lower or more primitive structures (top down).²⁴

Medication considerations. Selective serotonin reuptake inhibitors (SSRIs) are considered first-line pharmacotherapy for adult and adolescent patients with GAD.²⁰ However, in adolescents, no SSRIs are approved by the US Food and Drug Administration (FDA) to treat anxiety disorders unassociated with obsessive-compulsive disorder. Use caution if prescribing an SSRI for off-label treatment in an adolescent; talk with the patient and family about the FDA’s black-box warning regarding the potential for suicidality in adolescents.

Say to the patient: “Sometimes your worry will fit the situation and sometimes it’ll be too much. Has anyone ever told you that you worry too much?”

For adults, selective norepinephrine reuptake inhibitors (SNRIs) are also considered a first-line treatment option.²³ SSRIs and SNRIs are well-studied, effective, safe, and better tolerated than earlier antidepressants. However, be aware that both SSRIs and SNRIs are often associated with headache, nausea, and sexual dysfunction. They are dosed once daily and have not been shown to cause dependence. Inform patients that onset of action is often delayed 4 to 8 weeks²³ and that there is a risk for anxiety-producing effects early in treatment. To minimize these effects, consider starting treatment at a lower dose and titrate upward more gradually than when treating depression.

Continue to: Continue treatment for 12 months...

Continue treatment for 12 months to reduce the risk of recurrence.²³ If response to treatment is insufficient after 2 adequate trials of an SSRI or SNRI, consider second-line agents such as azapirones or benzodiazepines for adults, keeping in mind the risk for dependence with benzodiazepines.¹³

Evidence supports GABAergic drugs such as gabapentin and pregabalin as off-label treatments for GAD in refractory adult cases.²⁵ In the European Union, pregabalin is approved for use in GAD. Caution is recommended with both drugs due to abuse potential. Next steps for an inadequate response should include referral to Psychiatry or for inpatient care when risk of harm to self or others is high.

CASE

Considering Ms. H’s ability to work and complete daily activities, we talked to her about CBT as a first step and referred her to a therapist in the community. One month after her initial visit with us, Ms. H returned for a follow-up visit and scored a 17 on her GAD-7, still in the severe range. After one CBT session, she had cancelled her second and third appointments due to work conflicts. She had missed some work from oversleeping after worried sleepless nights. Her worries concerned friendships, paying bills, physical appearance, not being able to exercise and therefore gaining weight, and troubles at work and with her mother. She also described several episodes of nightmares after breaking up with a boyfriend.

To minimize the anxiety-producing effects of SSRIs and SNRIs, consider starting treatment at a lower dose and titrate upward more gradually than when treating depression.

She agreed to try an SSRI, and we started her on fluoxetine 10 mg/d. We counseled her on SSRI risks and benefits, including the potential for increased suicidal ideation and how to respond if such thoughts developed. Three weeks after starting fluoxetine, Ms. H reported improvement with no adverse effects from the medication, except for decreased appetite and some weight loss, which she welcomed. She had registered for college courses, and her third score on the GAD-7 was an 8.

We increased her fluoxetine dose to 20 mg/d for maintenance. We encouraged her to return to her therapist for CBT and she scheduled that appointment. Therapy records noted a GAD-7 score of 5 at follow-up 8 weeks later. Ms. H reported improved sleep, reduced irritability at home, and better relationships with her mother and friends. She had begun college classes and was writing about her thoughts and worries as part of her CBT homework. She continued follow-up appointments with both her family physician and her therapist.

CORRESPONDENCE
Christopher A. Ebberwein, PhD, Wesley Family Medicine Residency, 850 North Hillside, Wichita, KS 67214; chris. ebberwein@wesleymc.com.