Leaders in health care and practicing physicians recognize the need for changes in how health care is delivered.^1-3 Despite this awareness, though, barriers to meaningful change persist and the current practice environment wherein physicians must routinely spend 2 hours on electronic health records (EHRs) and desk work for every hour of direct face time with patients⁴ is driving trainees away from ambulatory specialties and is contributing to physicians’ decisions to reduce their practices to part-time, retire early, or leave medicine altogether.^5,6 Those who persevere in this environment with heavy administrative burdens run the increasing risk of burnout.⁷

Some physicians and practices are responding by taking creative measures to reform the way patient care is delivered. Bellin Health—a 160-provider, multispecialty health system in northeast Wisconsin where one of the authors (JJ) works—introduced an advanced team-based care (aTBC) model between November 2014 and November 2018, starting with our primary care providers. The development and introduction of this new model arose from an iterative, multidisciplinary process driven by the desire to transform the Triple Aim—enhancing patient experience, improving population health, and reducing costs—into a Quadruple Aim⁸ by additionally focusing on improving the work life of health care providers, which, in turn, will help achieve the first 3 goals. In introducing an aTBC model, Bellin Health focused on 3 elements: office visit redesign, in-basket management redesign, and the use of extended care team members and system and community resources to assist in the care of complex and high-risk patients.

We trained certified medical assistants and licensed practical nurses to become care team coordinators and optimized the direct clinical support ratio for busier physicians.

Herein we describe the 3 components of our aTBC model,^1,9 identify the barriers that existed in the minds of multiple stakeholders (from patients to clinicians and Bellin executives), and describe the strategies that enabled us to overcome these barriers.

The impetus behind our move to aTBC

Bellin Health considered a move to an aTBC model to be critical in light of factors in the health care environment, in general, and at Bellin, in particular. The factors included

• an industry-wide shift to value-based payments, which requires new models for long-term financial viability.
• recognition that physician and medical staff burnout leads to lower productivity and, in some cases, workforce losses.^5,6 Replacing a physician in a practice can be difficult and expensive, with cost estimates of $500,000 to more than $1 million per physician.^10,11
• a belief that aTBC could help the Bellin Health leadership team meet its organizational goals of improved patient satisfaction, achieve gains in quality measures, enhance engagement and loyalty among patients and employees, and lower recruitment costs.

A 3-part aTBC initiative

■ Part 1: Redesign the office visit

We redesigned staffing and workflow for office visits to maximize the core skills of physicians, which required distributing ancillary tasks among support staff. We up-trained certified medical assistants (CMAs) and licensed practical nurses (LPNs) to take on the new role of care team coordinator (CTC) and optimized the direct clinical support ratio for busier physicians. For physicians who were seeing 15 to 19 patients a day, a ratio of 3 CTCs to 2 physicians was implemented; for those seeing 20 or more patients a day, we used a support ratio of 2:1.

The role of CTC was designed so that he or she would accompany a patient throughout the entire appointment. Responsibilities were broken out as follows:

Pre-visit. Before the physician enters the room, the CTC would now perform expanded rooming functions including pending orders, refill management, care gap closure using standing orders, agenda setting, and preliminary documentation.¹²

Visit. The CTC would now hand off the patient to the physician and stay in the room to document details of the visit and record new orders for consults, x-ray films, referrals, or prescriptions.¹³ This intensive EHR support was established to ensure that the physician could focus directly on the patient without the distraction of the computer.

Continue to: Post-visit

Post-visit. After a physician leaves a room, the CTC was now charged with finishing the pending orders, setting up the patient’s next appointment and pre-visit labs, reviewing details of the after-visit summary, and doing any basic health coaching with the patient. During this time, the physician would use the co-location space to review and edit the documentation, cosign the orders and prescriptions submitted by the CTC, and close the chart before going into the next room with the second CTC. The need to revisit these details after clinic hours was eliminated.

Another change … The role of our phone triage registered nurses (RN) was expanded. Care team RNs began providing diabetes counseling, blood pressure checks, annual wellness visits (AWV), and follow-up through the Centers for Medicare and Medicaid Services (CMS)'s Chronic Care Management and Transitional Care Management programs.

■ Part 2: Redesign between-visit in-basket management

Responding to an increasing number of inbox messages had become overwhelming for our physicians. Bellin Health’s management was aware that strategic delegation of inbox messages could save an hour or more of a physician’s time each day.¹⁴ Bellin implemented a procedure whereby inbox test results would be handled by the same CTC who saw the patient, thereby extending continuity. If the results were normal, the CTC would contact the patient. If the results were abnormal, the physician and the CTC would discuss them and develop a plan. Co-location of the RN, the CTC, and the physician would leverage face-to-face communication and make in-basket management more efficient.

■ Part 3: Redesign population health management

We developed an Extended Care Team (ECT), including social workers, clinical pharmacists, RN care coordinators, and diabetes educators, to assist with the care of patients with high-risk disorders or otherwise complex issues. These team members would work closely with the CTC, care team RN, and physician to review patients, develop plans of care, optimize management, and improve outcomes. Patients would be identified as candidates for potential ECT involvement based on the physician’s judgment in consultation with an EHR-based risk score for hospitalization or emergency department visit.

Team coordinators document details of the patient visit, thereby allowing the physician to focus directly on the patient.

As we developed new processes, such as screening for determinants of health, we engaged additional system and community resources to help meet the needs of our patients.

Continue to: A look at stakeholder concerns and overcoming the barriers

Critical to our success was being attentive to the concerns of our stakeholders and addressing them. Along the way, we gained valuable implementation insights, which we share here along with some specifics about how, exactly, we did things at Bellin.

Patients

Some patients expressed hesitation at having a person other than their physician in the exam room. They worried that the intimacy and privacy with their physician would be lost. In light of this, we gave patients the option not to have the CTC remain in the room. However, patients quickly saw the value of this team-based care approach and seldom asked to be seen without the CTC.

Throughout the process, we surveyed patients for feedback on their experiences. Comments indicated that the presence of the CTC in our team-based model led to positive patient experiences:

My physician is fully attentive. Patients appreciated that physicians were not distracted by the computer in the exam room. “I feel like I’ve got my doctor back” has been a common refrain.

The office staff is more responsive. The CTC, having been present during the appointment, has a deeper understanding of the care plan and can respond to calls or emails between visits, thereby reducing the time patients must wait for answers. One patient commented that, “I love [the doctor’s] team; his nurses are willing to answer every question I have.”

Continue to: I increasingly feel that I'm understood

I increasingly feel that I’m understood. We have seen patients develop meaningful relationships with other team members, confiding in them in ways that they hadn’t always done with physicians and advanced practice clinicians (APCs). Team members, in turn, have added valuable insights that help optimize patients’ care. In particular, the care of patients with multiple needs has been enhanced with the addition of ECT members who work with the core team and use their expertise to optimize the care of these patients.

Certified medical assistants and licensed practical nurses

Bellin’s leadership knew that team documentation could cause stress for the CMA, who, acting as a CTC, wanted to avoid misrepresenting details of the clinical encounter.¹³ Adding to the stress were other duties that would need to be learned, including agenda setting, refill management, care gap closure, and health coaching. With thorough training and preparation, many—but not all—of our CMAs and LPNs were able to successfully make the transition and flourish.

Implementation strategies

Provide thorough training. Our training process started 8 weeks before it was time to “go live.” There were weekly hour-long training sessions in population health basics, team culture and change management, documentation basics, and new roles and responsibilities. In the final week, the entire aTBC team sat together for 3 days of EHR training. All new teams shadowed existing teams to get a clear picture of the new processes.

Create a community of support. As our CMAs adapted to their new CTC roles, it was critical that they had support from experienced CTCs. Encouragement and patience from physicians were—and are—essential for CTCs to develop confidence in their new roles.

Enable ongoing feedback. We introduced weekly team meetings to enhance team communication and dynamics. Forums for all roles are held periodically to facilitate discussion, share learning, and enable support between teams.

Continue to: Use EHR tools to facilitate this work

Use EHR tools to facilitate this work. Using standard templates and documentation tools helped CTCs develop the confidence needed to thrive in their new role. Knowing these tools were available helped CTCs become effective in helping the team manage the between-visit work.

In our aTBC model, the percentage of patients receiving age- appropriate screening is higher now in every domain we measure, and metrics have improved in most quality measures.

Monitor workload. As we developed more workflows and processes, we took care to monitor the amount of additional work for those in this role. We offloaded work whenever possible. For example, coordinated refill management at time of service, coupled with a back-up centralized refill system, can significantly decrease the number of refill requests made to CTCs. We continue to adjust staffing, where appropriate, to provide adequate support for those in this valuable role.

Be prepared for turnover. As CTCs became empowered in their new roles, some decided to advance their training into other roles. We developed a plan for replacing and training new staff. Higher pay can also be used to help attract and retain these staff members. Bellin uses LPNs in this role to ensure adequate staffing. Other health systems have developed a tier system for CMAs to improve retention.

Registered nurses

Before our move to an aTBC model, our office RNs primarily managed phone triage. Now the nurses were enlisted to play a more active role in patient care and team leadership. Although it was a dramatic departure from prior responsibilities, the majority of Bellin’s RNs have found increased satisfaction in taking on direct patient care.

Implementation strategies

Define new roles and provide training. In addition to participating in acute patient visits, consider ways that care team RNs can expand responsibilities as they pertain to disease counseling, population health management, and team leadership.¹⁵ At Bellin, the expanded role of the RN is evident in diabetes education and Medicare AWVs. Specifically, RNs now provide diabetes education to appropriate patients following a warm handoff from the physician at the time of the visit. RNs now also complete Medicare AWVs, which frees up physicians for other tasks and helps ensure sustainability for the new RN roles. Rates of completed AWVs at Bellin are now more than 70%, compared with reported national rates of less than 30%.¹⁶

Continue to: Maximize co-location

Maximize co-location. It is helpful to have the team members whose work is closely related—such as the CTCs and the RN for the team—to be situated near each other, rather than down a hall or in separate offices. Since the RN is co-located with the core teams at Bellin, there is now greater opportunity for verbal interaction, rather than just electronic communications, for matters such as triage calls and results management. RNs also provide a valuable resource for CMAs and LPNs, as well as help oversee team management of the in-basket.

Evaluate sustainability. Additional roles for the RNs required additional RN staffing. We assessed the new workload duties and balanced that against potential revenue from RN visits. This analysis indicated that an optimal ratio was 1 RN to every 3000 patients. This would allow an adequate number of RNs to fulfill additional roles and was financially sustainable with the goal of 4 billable RN visits per day.

Physicians

Bellin’s leadership recognized that some physicians might perceive team-based care as eroding their primary responsibility for patients’ care. Physicians have historically been trained in a model based on the primacy of the individual physician and that can be a hurdle to embracing team culture as a new paradigm of care. Several strategies helped us and can help others, too.

Implementation strategies

Cultivate trust. Thorough training of CTCs and RNs is critical to helping physicians develop trust and reliance in the team. The physician retains final authority over the team for cosigning orders, editing and finalizing documentation, and overseeing results management. Physicians invested in training and educating their staff will reap the rewards of a highly functioning, more satisfied team.

Encourage leadership. This can be a cultural shift for physicians, yet it is critical that they take a leadership role in this transformation.¹⁷ Physicians and their team leaders attended training sessions in team culture and change management. Prior to the go-live date, team leaders also met with the physician individually to explore their concerns and discuss ways to effectively lead and support their teams.

Continue to: Urge acceptance of support

Urge acceptance of support. The complexity of patient care today makes it difficult for a physician to manage all of a patient’s needs single-handedly. Complexity arises from the variety of plan co-pays and deductibles, the number of patients with chronic diseases, and the increased emphasis on improving quality measures.¹⁸ Enhanced support during any office visit and the extra support of an ECT for complex patients improves the ability of the physician to more effectively meet the needs of the patient.

Emphasize the benefit of an empowered team. The demands of the EHR on physicians and the resultant frustrations are well chronicled.^4,19-22 Strategically delegating much of this work to other team members allows the physician to focus on the patient and perform physician-level work. At Bellin, we observed that our most successful care teams were those in which the physician fully accepted team-based care principles and empowered the staff to work at the top of their skill set.

Advanced practice clinicians

APCs in our system had traditionally practiced in 1 of 3 ways: independently handling defined panels with physician supervision; handling overflow or acute visits; or working collaboratively with a supervising physician to share a larger “team panel.” The third approach has become our preferred model. aTBC provides opportunities for APCs to thrive and collaborate with the physician to provide excellent care for patients.

Provider satisfaction has increased, with 83% of aTBC physicians at Bellin being moderately or very satisfied with their experience.

APCs underwent the same process changes as physicians, including appropriate CTC support. Implementation strategies for APCs were similar to those that were useful for physicians.

Risk management professionals

At Bellin, we found that risk-management professionals had concerns about the scope of practice assigned to various team members, particularly regarding documentation. CMS allows for elements of a patient visit to be documented by CMAs and other members of the care team in real time as authorized by the physician.^23,24 CTCs at Bellin also have other clinical duties in patient and EHR management. aTBC practices generally prefer the term team documentation over scribing, since it more accurately reflects the scope of the CTC’s work.

Continue to: Implementation strategies

Clarify regulatory issues. Extensive use of standing orders and protocols allowed us to increase involvement of various team members. State laws vary in what functions CMAs and LPNs are allowed to perform, so it is important to check your state guidelines.²⁵ There is a tendency for some risk managers to overinterpret regulations. Challenge them to provide exact documentation from regulatory agencies to support their decisions.

Give assurances of physician oversight and processes. The physician assumes responsibility for standing orders, protocols, and documentation. We made sure that we had clear and consistent processes in place and worked closely with our risk managers as we developed our model. aTBC provides checks and balances to ensure accurate records, since team members are able to contribute and check for accuracy. A recent study suggested that CMAs perform documentation that is of equal or higher quality than that performed by the physician.²⁶

Financial leadership

Like any organization adopting aTBC, Bellin’s leadership was concerned about the expense of adopting this approach. However, the leadership also recognized that the transition to aTBC could increase revenue by more than the increased staffing costs. In addition, we expected that capacity, access, continuity, and financial margins would increase.^2,3,27,28 We also anticipated a decrease in downstream services, such as unnecessary tests, emergency department visits, and hospitalizations—a benefit of accountable care payment models.

Our efforts have been successful from a financial point of view. We attribute the financial sustainability that we have experienced to 4 factors:

1. Increased productivity. We knew that the increased efficiency of team-based care enables physicians to see 1 to 2 more patients per half day, and sometimes more.^3,28,29 An increase of at least 1 patient visit per half-day was expected of our physicians and APCs on aTBC. In addition, they were expected to support the care team RN in achieving at least 4 billable visits per day. Our current level of RN visits is at 3.5 per nurse per day. There is significant variability in the increase of patients seen by a physician per day, ranging from 1 to 4 additional patients. These increased visits have helped us achieve financial viability, even in a predominantly fee-for-service environment.

2. More thorough service. The ability to keep patients in primary care and to focus on the patient’s full range of needs has led to higher levels of service and, consequently, to appropriately higher levels of billing codes. For example, Bellin’s revenue from billing increased by $724 per patient, related (in part) to higher rates of immunizations, cancer screenings with mammography, and colonoscopies.

Continue to: 3. New billable services

3. New billable services. Billing for RN blood pressure checks, AWVs, and extended care team services have helped make aTBC at Bellin financially feasible. Revenue from RN visits, for example, was $630,000 in 2018.

4. Improved access for patients. Of the 130 primary care providers now on aTBC, 15 (11.5%) had closed their practices to new patients before aTBC. Now, all of their practices are open to new patients, which has improved access to care. In a 2018 patient access survey, 96.6% of patients obtained an appointment as soon as they thought it was needed, compared with 70.7% of patients before the transition to aTBC.

Greater opportunity for financial sustainability. The combination of improved quality measures and decreased cost of care in the Bellin aTBC bodes well for future success in a value-based world. We have realized a significant increase in value-based payments for improved quality, and in our Next Gen Accountable Care Organization (ACO) patients, we have seen a decrease of $29 in per-member-per-month costs, likely due to the use of nonphysicians in expanded roles. In addition, hospital admissions have decreased by 5% due to the ability of ambulatory teams to manage more complex patients in the office setting. This model has also allowed physicians and APCs to increase their panel size, another key value-based metric. From 2016 to 2018, panel size for primary care providers increased by an average of 8%.

Enhanced ability to retain and recruit. Several of Bellin’s primary care recruits indicated that they had interviewed only at practices incorporating team-based care. This trend may increase as residencies transition to team-based models of care.

So how did we do?

Metrics of Bellin’s aTBC success

By the end of 2018, all 130 primary care physicians and APCs at Bellin had made the transition to this model, representing family medicine, internal medicine, and pediatrics. We have now begun the transition of our non-primary care specialties to team-based care.

Continue to: In the aTBC model...

In the aTBC model, the percentage of patients receiving age-appropriate screening is higher than before in every domain we measure (FIGURE 1). There has also been improvement in major quality metrics (FIGURE 2).

In a survey done in Spring 2018 by St. Norbert College Strategic Research Center, provider satisfaction increased, with 83% of physicians having made the transition to an aTBC practice moderately or very satisfied with their Bellin Health experience, compared with 70% in the traditional model. More recent 2019 survey data show a satisfaction rate of 90% for team-based care providers. Finally, in our aTBC model—in CMS’s Next-Gen ACO initiative—the cost per patient per month is significantly less than for those in a non-team-based care model ($796 vs $940).

CORRESPONDENCE
James Jerzak, MD, 1630 Commanche Ave, Green Bay, WI 54313; [email protected].

ACKNOWLEDGEMENTS
The authors would like to thank Lindsey E. Carlasare, MBA, from the American Medical Association, and Brad Wozney, MD, Kathy Kerscher, and Christopher Elfner from Bellin Health, for their contributions to the content and review of this manuscript.

Leaders in health care and practicing physicians recognize the need for changes in how health care is delivered.^1-3 Despite this awareness, though, barriers to meaningful change persist and the current practice environment wherein physicians must routinely spend 2 hours on electronic health records (EHRs) and desk work for every hour of direct face time with patients⁴ is driving trainees away from ambulatory specialties and is contributing to physicians’ decisions to reduce their practices to part-time, retire early, or leave medicine altogether.^5,6 Those who persevere in this environment with heavy administrative burdens run the increasing risk of burnout.⁷

Some physicians and practices are responding by taking creative measures to reform the way patient care is delivered. Bellin Health—a 160-provider, multispecialty health system in northeast Wisconsin where one of the authors (JJ) works—introduced an advanced team-based care (aTBC) model between November 2014 and November 2018, starting with our primary care providers. The development and introduction of this new model arose from an iterative, multidisciplinary process driven by the desire to transform the Triple Aim—enhancing patient experience, improving population health, and reducing costs—into a Quadruple Aim⁸ by additionally focusing on improving the work life of health care providers, which, in turn, will help achieve the first 3 goals. In introducing an aTBC model, Bellin Health focused on 3 elements: office visit redesign, in-basket management redesign, and the use of extended care team members and system and community resources to assist in the care of complex and high-risk patients.

We trained certified medical assistants and licensed practical nurses to become care team coordinators and optimized the direct clinical support ratio for busier physicians.

Herein we describe the 3 components of our aTBC model,^1,9 identify the barriers that existed in the minds of multiple stakeholders (from patients to clinicians and Bellin executives), and describe the strategies that enabled us to overcome these barriers.

The impetus behind our move to aTBC

Bellin Health considered a move to an aTBC model to be critical in light of factors in the health care environment, in general, and at Bellin, in particular. The factors included

• an industry-wide shift to value-based payments, which requires new models for long-term financial viability.
• recognition that physician and medical staff burnout leads to lower productivity and, in some cases, workforce losses.^5,6 Replacing a physician in a practice can be difficult and expensive, with cost estimates of $500,000 to more than $1 million per physician.^10,11
• a belief that aTBC could help the Bellin Health leadership team meet its organizational goals of improved patient satisfaction, achieve gains in quality measures, enhance engagement and loyalty among patients and employees, and lower recruitment costs.

A 3-part aTBC initiative

■ Part 1: Redesign the office visit

We redesigned staffing and workflow for office visits to maximize the core skills of physicians, which required distributing ancillary tasks among support staff. We up-trained certified medical assistants (CMAs) and licensed practical nurses (LPNs) to take on the new role of care team coordinator (CTC) and optimized the direct clinical support ratio for busier physicians. For physicians who were seeing 15 to 19 patients a day, a ratio of 3 CTCs to 2 physicians was implemented; for those seeing 20 or more patients a day, we used a support ratio of 2:1.

The role of CTC was designed so that he or she would accompany a patient throughout the entire appointment. Responsibilities were broken out as follows:

Pre-visit. Before the physician enters the room, the CTC would now perform expanded rooming functions including pending orders, refill management, care gap closure using standing orders, agenda setting, and preliminary documentation.¹²

Visit. The CTC would now hand off the patient to the physician and stay in the room to document details of the visit and record new orders for consults, x-ray films, referrals, or prescriptions.¹³ This intensive EHR support was established to ensure that the physician could focus directly on the patient without the distraction of the computer.

Continue to: Post-visit

Post-visit. After a physician leaves a room, the CTC was now charged with finishing the pending orders, setting up the patient’s next appointment and pre-visit labs, reviewing details of the after-visit summary, and doing any basic health coaching with the patient. During this time, the physician would use the co-location space to review and edit the documentation, cosign the orders and prescriptions submitted by the CTC, and close the chart before going into the next room with the second CTC. The need to revisit these details after clinic hours was eliminated.

Another change … The role of our phone triage registered nurses (RN) was expanded. Care team RNs began providing diabetes counseling, blood pressure checks, annual wellness visits (AWV), and follow-up through the Centers for Medicare and Medicaid Services (CMS)'s Chronic Care Management and Transitional Care Management programs.

■ Part 2: Redesign between-visit in-basket management

Responding to an increasing number of inbox messages had become overwhelming for our physicians. Bellin Health’s management was aware that strategic delegation of inbox messages could save an hour or more of a physician’s time each day.¹⁴ Bellin implemented a procedure whereby inbox test results would be handled by the same CTC who saw the patient, thereby extending continuity. If the results were normal, the CTC would contact the patient. If the results were abnormal, the physician and the CTC would discuss them and develop a plan. Co-location of the RN, the CTC, and the physician would leverage face-to-face communication and make in-basket management more efficient.

■ Part 3: Redesign population health management

We developed an Extended Care Team (ECT), including social workers, clinical pharmacists, RN care coordinators, and diabetes educators, to assist with the care of patients with high-risk disorders or otherwise complex issues. These team members would work closely with the CTC, care team RN, and physician to review patients, develop plans of care, optimize management, and improve outcomes. Patients would be identified as candidates for potential ECT involvement based on the physician’s judgment in consultation with an EHR-based risk score for hospitalization or emergency department visit.

Team coordinators document details of the patient visit, thereby allowing the physician to focus directly on the patient.

As we developed new processes, such as screening for determinants of health, we engaged additional system and community resources to help meet the needs of our patients.

Continue to: A look at stakeholder concerns and overcoming the barriers

Critical to our success was being attentive to the concerns of our stakeholders and addressing them. Along the way, we gained valuable implementation insights, which we share here along with some specifics about how, exactly, we did things at Bellin.

Patients

Some patients expressed hesitation at having a person other than their physician in the exam room. They worried that the intimacy and privacy with their physician would be lost. In light of this, we gave patients the option not to have the CTC remain in the room. However, patients quickly saw the value of this team-based care approach and seldom asked to be seen without the CTC.

Throughout the process, we surveyed patients for feedback on their experiences. Comments indicated that the presence of the CTC in our team-based model led to positive patient experiences:

My physician is fully attentive. Patients appreciated that physicians were not distracted by the computer in the exam room. “I feel like I’ve got my doctor back” has been a common refrain.

The office staff is more responsive. The CTC, having been present during the appointment, has a deeper understanding of the care plan and can respond to calls or emails between visits, thereby reducing the time patients must wait for answers. One patient commented that, “I love [the doctor’s] team; his nurses are willing to answer every question I have.”

Continue to: I increasingly feel that I'm understood

I increasingly feel that I’m understood. We have seen patients develop meaningful relationships with other team members, confiding in them in ways that they hadn’t always done with physicians and advanced practice clinicians (APCs). Team members, in turn, have added valuable insights that help optimize patients’ care. In particular, the care of patients with multiple needs has been enhanced with the addition of ECT members who work with the core team and use their expertise to optimize the care of these patients.

Certified medical assistants and licensed practical nurses

Bellin’s leadership knew that team documentation could cause stress for the CMA, who, acting as a CTC, wanted to avoid misrepresenting details of the clinical encounter.¹³ Adding to the stress were other duties that would need to be learned, including agenda setting, refill management, care gap closure, and health coaching. With thorough training and preparation, many—but not all—of our CMAs and LPNs were able to successfully make the transition and flourish.

Implementation strategies

Provide thorough training. Our training process started 8 weeks before it was time to “go live.” There were weekly hour-long training sessions in population health basics, team culture and change management, documentation basics, and new roles and responsibilities. In the final week, the entire aTBC team sat together for 3 days of EHR training. All new teams shadowed existing teams to get a clear picture of the new processes.

Create a community of support. As our CMAs adapted to their new CTC roles, it was critical that they had support from experienced CTCs. Encouragement and patience from physicians were—and are—essential for CTCs to develop confidence in their new roles.

Enable ongoing feedback. We introduced weekly team meetings to enhance team communication and dynamics. Forums for all roles are held periodically to facilitate discussion, share learning, and enable support between teams.

Continue to: Use EHR tools to facilitate this work

Use EHR tools to facilitate this work. Using standard templates and documentation tools helped CTCs develop the confidence needed to thrive in their new role. Knowing these tools were available helped CTCs become effective in helping the team manage the between-visit work.

In our aTBC model, the percentage of patients receiving age- appropriate screening is higher now in every domain we measure, and metrics have improved in most quality measures.

Monitor workload. As we developed more workflows and processes, we took care to monitor the amount of additional work for those in this role. We offloaded work whenever possible. For example, coordinated refill management at time of service, coupled with a back-up centralized refill system, can significantly decrease the number of refill requests made to CTCs. We continue to adjust staffing, where appropriate, to provide adequate support for those in this valuable role.

Be prepared for turnover. As CTCs became empowered in their new roles, some decided to advance their training into other roles. We developed a plan for replacing and training new staff. Higher pay can also be used to help attract and retain these staff members. Bellin uses LPNs in this role to ensure adequate staffing. Other health systems have developed a tier system for CMAs to improve retention.

Registered nurses

Before our move to an aTBC model, our office RNs primarily managed phone triage. Now the nurses were enlisted to play a more active role in patient care and team leadership. Although it was a dramatic departure from prior responsibilities, the majority of Bellin’s RNs have found increased satisfaction in taking on direct patient care.

Implementation strategies

Define new roles and provide training. In addition to participating in acute patient visits, consider ways that care team RNs can expand responsibilities as they pertain to disease counseling, population health management, and team leadership.¹⁵ At Bellin, the expanded role of the RN is evident in diabetes education and Medicare AWVs. Specifically, RNs now provide diabetes education to appropriate patients following a warm handoff from the physician at the time of the visit. RNs now also complete Medicare AWVs, which frees up physicians for other tasks and helps ensure sustainability for the new RN roles. Rates of completed AWVs at Bellin are now more than 70%, compared with reported national rates of less than 30%.¹⁶

Continue to: Maximize co-location

Maximize co-location. It is helpful to have the team members whose work is closely related—such as the CTCs and the RN for the team—to be situated near each other, rather than down a hall or in separate offices. Since the RN is co-located with the core teams at Bellin, there is now greater opportunity for verbal interaction, rather than just electronic communications, for matters such as triage calls and results management. RNs also provide a valuable resource for CMAs and LPNs, as well as help oversee team management of the in-basket.

Evaluate sustainability. Additional roles for the RNs required additional RN staffing. We assessed the new workload duties and balanced that against potential revenue from RN visits. This analysis indicated that an optimal ratio was 1 RN to every 3000 patients. This would allow an adequate number of RNs to fulfill additional roles and was financially sustainable with the goal of 4 billable RN visits per day.

Physicians

Bellin’s leadership recognized that some physicians might perceive team-based care as eroding their primary responsibility for patients’ care. Physicians have historically been trained in a model based on the primacy of the individual physician and that can be a hurdle to embracing team culture as a new paradigm of care. Several strategies helped us and can help others, too.

Implementation strategies

Cultivate trust. Thorough training of CTCs and RNs is critical to helping physicians develop trust and reliance in the team. The physician retains final authority over the team for cosigning orders, editing and finalizing documentation, and overseeing results management. Physicians invested in training and educating their staff will reap the rewards of a highly functioning, more satisfied team.

Encourage leadership. This can be a cultural shift for physicians, yet it is critical that they take a leadership role in this transformation.¹⁷ Physicians and their team leaders attended training sessions in team culture and change management. Prior to the go-live date, team leaders also met with the physician individually to explore their concerns and discuss ways to effectively lead and support their teams.

Continue to: Urge acceptance of support

Urge acceptance of support. The complexity of patient care today makes it difficult for a physician to manage all of a patient’s needs single-handedly. Complexity arises from the variety of plan co-pays and deductibles, the number of patients with chronic diseases, and the increased emphasis on improving quality measures.¹⁸ Enhanced support during any office visit and the extra support of an ECT for complex patients improves the ability of the physician to more effectively meet the needs of the patient.

Emphasize the benefit of an empowered team. The demands of the EHR on physicians and the resultant frustrations are well chronicled.^4,19-22 Strategically delegating much of this work to other team members allows the physician to focus on the patient and perform physician-level work. At Bellin, we observed that our most successful care teams were those in which the physician fully accepted team-based care principles and empowered the staff to work at the top of their skill set.

Advanced practice clinicians

APCs in our system had traditionally practiced in 1 of 3 ways: independently handling defined panels with physician supervision; handling overflow or acute visits; or working collaboratively with a supervising physician to share a larger “team panel.” The third approach has become our preferred model. aTBC provides opportunities for APCs to thrive and collaborate with the physician to provide excellent care for patients.

Provider satisfaction has increased, with 83% of aTBC physicians at Bellin being moderately or very satisfied with their experience.

APCs underwent the same process changes as physicians, including appropriate CTC support. Implementation strategies for APCs were similar to those that were useful for physicians.

Risk management professionals

At Bellin, we found that risk-management professionals had concerns about the scope of practice assigned to various team members, particularly regarding documentation. CMS allows for elements of a patient visit to be documented by CMAs and other members of the care team in real time as authorized by the physician.^23,24 CTCs at Bellin also have other clinical duties in patient and EHR management. aTBC practices generally prefer the term team documentation over scribing, since it more accurately reflects the scope of the CTC’s work.

Continue to: Implementation strategies

Clarify regulatory issues. Extensive use of standing orders and protocols allowed us to increase involvement of various team members. State laws vary in what functions CMAs and LPNs are allowed to perform, so it is important to check your state guidelines.²⁵ There is a tendency for some risk managers to overinterpret regulations. Challenge them to provide exact documentation from regulatory agencies to support their decisions.

Give assurances of physician oversight and processes. The physician assumes responsibility for standing orders, protocols, and documentation. We made sure that we had clear and consistent processes in place and worked closely with our risk managers as we developed our model. aTBC provides checks and balances to ensure accurate records, since team members are able to contribute and check for accuracy. A recent study suggested that CMAs perform documentation that is of equal or higher quality than that performed by the physician.²⁶

Financial leadership

Like any organization adopting aTBC, Bellin’s leadership was concerned about the expense of adopting this approach. However, the leadership also recognized that the transition to aTBC could increase revenue by more than the increased staffing costs. In addition, we expected that capacity, access, continuity, and financial margins would increase.^2,3,27,28 We also anticipated a decrease in downstream services, such as unnecessary tests, emergency department visits, and hospitalizations—a benefit of accountable care payment models.

Our efforts have been successful from a financial point of view. We attribute the financial sustainability that we have experienced to 4 factors:

1. Increased productivity. We knew that the increased efficiency of team-based care enables physicians to see 1 to 2 more patients per half day, and sometimes more.^3,28,29 An increase of at least 1 patient visit per half-day was expected of our physicians and APCs on aTBC. In addition, they were expected to support the care team RN in achieving at least 4 billable visits per day. Our current level of RN visits is at 3.5 per nurse per day. There is significant variability in the increase of patients seen by a physician per day, ranging from 1 to 4 additional patients. These increased visits have helped us achieve financial viability, even in a predominantly fee-for-service environment.

2. More thorough service. The ability to keep patients in primary care and to focus on the patient’s full range of needs has led to higher levels of service and, consequently, to appropriately higher levels of billing codes. For example, Bellin’s revenue from billing increased by $724 per patient, related (in part) to higher rates of immunizations, cancer screenings with mammography, and colonoscopies.

Continue to: 3. New billable services

3. New billable services. Billing for RN blood pressure checks, AWVs, and extended care team services have helped make aTBC at Bellin financially feasible. Revenue from RN visits, for example, was $630,000 in 2018.

4. Improved access for patients. Of the 130 primary care providers now on aTBC, 15 (11.5%) had closed their practices to new patients before aTBC. Now, all of their practices are open to new patients, which has improved access to care. In a 2018 patient access survey, 96.6% of patients obtained an appointment as soon as they thought it was needed, compared with 70.7% of patients before the transition to aTBC.

Greater opportunity for financial sustainability. The combination of improved quality measures and decreased cost of care in the Bellin aTBC bodes well for future success in a value-based world. We have realized a significant increase in value-based payments for improved quality, and in our Next Gen Accountable Care Organization (ACO) patients, we have seen a decrease of $29 in per-member-per-month costs, likely due to the use of nonphysicians in expanded roles. In addition, hospital admissions have decreased by 5% due to the ability of ambulatory teams to manage more complex patients in the office setting. This model has also allowed physicians and APCs to increase their panel size, another key value-based metric. From 2016 to 2018, panel size for primary care providers increased by an average of 8%.

Enhanced ability to retain and recruit. Several of Bellin’s primary care recruits indicated that they had interviewed only at practices incorporating team-based care. This trend may increase as residencies transition to team-based models of care.

So how did we do?

Metrics of Bellin’s aTBC success

By the end of 2018, all 130 primary care physicians and APCs at Bellin had made the transition to this model, representing family medicine, internal medicine, and pediatrics. We have now begun the transition of our non-primary care specialties to team-based care.

Continue to: In the aTBC model...

In the aTBC model, the percentage of patients receiving age-appropriate screening is higher than before in every domain we measure (FIGURE 1). There has also been improvement in major quality metrics (FIGURE 2).

In a survey done in Spring 2018 by St. Norbert College Strategic Research Center, provider satisfaction increased, with 83% of physicians having made the transition to an aTBC practice moderately or very satisfied with their Bellin Health experience, compared with 70% in the traditional model. More recent 2019 survey data show a satisfaction rate of 90% for team-based care providers. Finally, in our aTBC model—in CMS’s Next-Gen ACO initiative—the cost per patient per month is significantly less than for those in a non-team-based care model ($796 vs $940).

CORRESPONDENCE
James Jerzak, MD, 1630 Commanche Ave, Green Bay, WI 54313; [email protected].

ACKNOWLEDGEMENTS
The authors would like to thank Lindsey E. Carlasare, MBA, from the American Medical Association, and Brad Wozney, MD, Kathy Kerscher, and Christopher Elfner from Bellin Health, for their contributions to the content and review of this manuscript.

Leaders in health care and practicing physicians recognize the need for changes in how health care is delivered.^1-3 Despite this awareness, though, barriers to meaningful change persist and the current practice environment wherein physicians must routinely spend 2 hours on electronic health records (EHRs) and desk work for every hour of direct face time with patients⁴ is driving trainees away from ambulatory specialties and is contributing to physicians’ decisions to reduce their practices to part-time, retire early, or leave medicine altogether.^5,6 Those who persevere in this environment with heavy administrative burdens run the increasing risk of burnout.⁷

Some physicians and practices are responding by taking creative measures to reform the way patient care is delivered. Bellin Health—a 160-provider, multispecialty health system in northeast Wisconsin where one of the authors (JJ) works—introduced an advanced team-based care (aTBC) model between November 2014 and November 2018, starting with our primary care providers. The development and introduction of this new model arose from an iterative, multidisciplinary process driven by the desire to transform the Triple Aim—enhancing patient experience, improving population health, and reducing costs—into a Quadruple Aim⁸ by additionally focusing on improving the work life of health care providers, which, in turn, will help achieve the first 3 goals. In introducing an aTBC model, Bellin Health focused on 3 elements: office visit redesign, in-basket management redesign, and the use of extended care team members and system and community resources to assist in the care of complex and high-risk patients.

We trained certified medical assistants and licensed practical nurses to become care team coordinators and optimized the direct clinical support ratio for busier physicians.

Herein we describe the 3 components of our aTBC model,^1,9 identify the barriers that existed in the minds of multiple stakeholders (from patients to clinicians and Bellin executives), and describe the strategies that enabled us to overcome these barriers.

The impetus behind our move to aTBC

Bellin Health considered a move to an aTBC model to be critical in light of factors in the health care environment, in general, and at Bellin, in particular. The factors included

• an industry-wide shift to value-based payments, which requires new models for long-term financial viability.
• recognition that physician and medical staff burnout leads to lower productivity and, in some cases, workforce losses.^5,6 Replacing a physician in a practice can be difficult and expensive, with cost estimates of $500,000 to more than $1 million per physician.^10,11
• a belief that aTBC could help the Bellin Health leadership team meet its organizational goals of improved patient satisfaction, achieve gains in quality measures, enhance engagement and loyalty among patients and employees, and lower recruitment costs.

A 3-part aTBC initiative

■ Part 1: Redesign the office visit

We redesigned staffing and workflow for office visits to maximize the core skills of physicians, which required distributing ancillary tasks among support staff. We up-trained certified medical assistants (CMAs) and licensed practical nurses (LPNs) to take on the new role of care team coordinator (CTC) and optimized the direct clinical support ratio for busier physicians. For physicians who were seeing 15 to 19 patients a day, a ratio of 3 CTCs to 2 physicians was implemented; for those seeing 20 or more patients a day, we used a support ratio of 2:1.

The role of CTC was designed so that he or she would accompany a patient throughout the entire appointment. Responsibilities were broken out as follows:

Pre-visit. Before the physician enters the room, the CTC would now perform expanded rooming functions including pending orders, refill management, care gap closure using standing orders, agenda setting, and preliminary documentation.¹²

Visit. The CTC would now hand off the patient to the physician and stay in the room to document details of the visit and record new orders for consults, x-ray films, referrals, or prescriptions.¹³ This intensive EHR support was established to ensure that the physician could focus directly on the patient without the distraction of the computer.

Continue to: Post-visit

Post-visit. After a physician leaves a room, the CTC was now charged with finishing the pending orders, setting up the patient’s next appointment and pre-visit labs, reviewing details of the after-visit summary, and doing any basic health coaching with the patient. During this time, the physician would use the co-location space to review and edit the documentation, cosign the orders and prescriptions submitted by the CTC, and close the chart before going into the next room with the second CTC. The need to revisit these details after clinic hours was eliminated.

Another change … The role of our phone triage registered nurses (RN) was expanded. Care team RNs began providing diabetes counseling, blood pressure checks, annual wellness visits (AWV), and follow-up through the Centers for Medicare and Medicaid Services (CMS)'s Chronic Care Management and Transitional Care Management programs.

■ Part 2: Redesign between-visit in-basket management

Responding to an increasing number of inbox messages had become overwhelming for our physicians. Bellin Health’s management was aware that strategic delegation of inbox messages could save an hour or more of a physician’s time each day.¹⁴ Bellin implemented a procedure whereby inbox test results would be handled by the same CTC who saw the patient, thereby extending continuity. If the results were normal, the CTC would contact the patient. If the results were abnormal, the physician and the CTC would discuss them and develop a plan. Co-location of the RN, the CTC, and the physician would leverage face-to-face communication and make in-basket management more efficient.

■ Part 3: Redesign population health management

We developed an Extended Care Team (ECT), including social workers, clinical pharmacists, RN care coordinators, and diabetes educators, to assist with the care of patients with high-risk disorders or otherwise complex issues. These team members would work closely with the CTC, care team RN, and physician to review patients, develop plans of care, optimize management, and improve outcomes. Patients would be identified as candidates for potential ECT involvement based on the physician’s judgment in consultation with an EHR-based risk score for hospitalization or emergency department visit.

Team coordinators document details of the patient visit, thereby allowing the physician to focus directly on the patient.

As we developed new processes, such as screening for determinants of health, we engaged additional system and community resources to help meet the needs of our patients.

Continue to: A look at stakeholder concerns and overcoming the barriers

Critical to our success was being attentive to the concerns of our stakeholders and addressing them. Along the way, we gained valuable implementation insights, which we share here along with some specifics about how, exactly, we did things at Bellin.

Patients

Some patients expressed hesitation at having a person other than their physician in the exam room. They worried that the intimacy and privacy with their physician would be lost. In light of this, we gave patients the option not to have the CTC remain in the room. However, patients quickly saw the value of this team-based care approach and seldom asked to be seen without the CTC.

Throughout the process, we surveyed patients for feedback on their experiences. Comments indicated that the presence of the CTC in our team-based model led to positive patient experiences:

My physician is fully attentive. Patients appreciated that physicians were not distracted by the computer in the exam room. “I feel like I’ve got my doctor back” has been a common refrain.

The office staff is more responsive. The CTC, having been present during the appointment, has a deeper understanding of the care plan and can respond to calls or emails between visits, thereby reducing the time patients must wait for answers. One patient commented that, “I love [the doctor’s] team; his nurses are willing to answer every question I have.”

Continue to: I increasingly feel that I'm understood

I increasingly feel that I’m understood. We have seen patients develop meaningful relationships with other team members, confiding in them in ways that they hadn’t always done with physicians and advanced practice clinicians (APCs). Team members, in turn, have added valuable insights that help optimize patients’ care. In particular, the care of patients with multiple needs has been enhanced with the addition of ECT members who work with the core team and use their expertise to optimize the care of these patients.

Certified medical assistants and licensed practical nurses

Bellin’s leadership knew that team documentation could cause stress for the CMA, who, acting as a CTC, wanted to avoid misrepresenting details of the clinical encounter.¹³ Adding to the stress were other duties that would need to be learned, including agenda setting, refill management, care gap closure, and health coaching. With thorough training and preparation, many—but not all—of our CMAs and LPNs were able to successfully make the transition and flourish.

Implementation strategies

Provide thorough training. Our training process started 8 weeks before it was time to “go live.” There were weekly hour-long training sessions in population health basics, team culture and change management, documentation basics, and new roles and responsibilities. In the final week, the entire aTBC team sat together for 3 days of EHR training. All new teams shadowed existing teams to get a clear picture of the new processes.

Create a community of support. As our CMAs adapted to their new CTC roles, it was critical that they had support from experienced CTCs. Encouragement and patience from physicians were—and are—essential for CTCs to develop confidence in their new roles.

Enable ongoing feedback. We introduced weekly team meetings to enhance team communication and dynamics. Forums for all roles are held periodically to facilitate discussion, share learning, and enable support between teams.

Continue to: Use EHR tools to facilitate this work

Use EHR tools to facilitate this work. Using standard templates and documentation tools helped CTCs develop the confidence needed to thrive in their new role. Knowing these tools were available helped CTCs become effective in helping the team manage the between-visit work.

In our aTBC model, the percentage of patients receiving age- appropriate screening is higher now in every domain we measure, and metrics have improved in most quality measures.

Monitor workload. As we developed more workflows and processes, we took care to monitor the amount of additional work for those in this role. We offloaded work whenever possible. For example, coordinated refill management at time of service, coupled with a back-up centralized refill system, can significantly decrease the number of refill requests made to CTCs. We continue to adjust staffing, where appropriate, to provide adequate support for those in this valuable role.

Be prepared for turnover. As CTCs became empowered in their new roles, some decided to advance their training into other roles. We developed a plan for replacing and training new staff. Higher pay can also be used to help attract and retain these staff members. Bellin uses LPNs in this role to ensure adequate staffing. Other health systems have developed a tier system for CMAs to improve retention.

Registered nurses

Before our move to an aTBC model, our office RNs primarily managed phone triage. Now the nurses were enlisted to play a more active role in patient care and team leadership. Although it was a dramatic departure from prior responsibilities, the majority of Bellin’s RNs have found increased satisfaction in taking on direct patient care.

Implementation strategies

Define new roles and provide training. In addition to participating in acute patient visits, consider ways that care team RNs can expand responsibilities as they pertain to disease counseling, population health management, and team leadership.¹⁵ At Bellin, the expanded role of the RN is evident in diabetes education and Medicare AWVs. Specifically, RNs now provide diabetes education to appropriate patients following a warm handoff from the physician at the time of the visit. RNs now also complete Medicare AWVs, which frees up physicians for other tasks and helps ensure sustainability for the new RN roles. Rates of completed AWVs at Bellin are now more than 70%, compared with reported national rates of less than 30%.¹⁶

Continue to: Maximize co-location

Maximize co-location. It is helpful to have the team members whose work is closely related—such as the CTCs and the RN for the team—to be situated near each other, rather than down a hall or in separate offices. Since the RN is co-located with the core teams at Bellin, there is now greater opportunity for verbal interaction, rather than just electronic communications, for matters such as triage calls and results management. RNs also provide a valuable resource for CMAs and LPNs, as well as help oversee team management of the in-basket.

Evaluate sustainability. Additional roles for the RNs required additional RN staffing. We assessed the new workload duties and balanced that against potential revenue from RN visits. This analysis indicated that an optimal ratio was 1 RN to every 3000 patients. This would allow an adequate number of RNs to fulfill additional roles and was financially sustainable with the goal of 4 billable RN visits per day.

Physicians

Bellin’s leadership recognized that some physicians might perceive team-based care as eroding their primary responsibility for patients’ care. Physicians have historically been trained in a model based on the primacy of the individual physician and that can be a hurdle to embracing team culture as a new paradigm of care. Several strategies helped us and can help others, too.

Implementation strategies

Cultivate trust. Thorough training of CTCs and RNs is critical to helping physicians develop trust and reliance in the team. The physician retains final authority over the team for cosigning orders, editing and finalizing documentation, and overseeing results management. Physicians invested in training and educating their staff will reap the rewards of a highly functioning, more satisfied team.

Encourage leadership. This can be a cultural shift for physicians, yet it is critical that they take a leadership role in this transformation.¹⁷ Physicians and their team leaders attended training sessions in team culture and change management. Prior to the go-live date, team leaders also met with the physician individually to explore their concerns and discuss ways to effectively lead and support their teams.

Continue to: Urge acceptance of support

Urge acceptance of support. The complexity of patient care today makes it difficult for a physician to manage all of a patient’s needs single-handedly. Complexity arises from the variety of plan co-pays and deductibles, the number of patients with chronic diseases, and the increased emphasis on improving quality measures.¹⁸ Enhanced support during any office visit and the extra support of an ECT for complex patients improves the ability of the physician to more effectively meet the needs of the patient.

Emphasize the benefit of an empowered team. The demands of the EHR on physicians and the resultant frustrations are well chronicled.^4,19-22 Strategically delegating much of this work to other team members allows the physician to focus on the patient and perform physician-level work. At Bellin, we observed that our most successful care teams were those in which the physician fully accepted team-based care principles and empowered the staff to work at the top of their skill set.

Advanced practice clinicians

APCs in our system had traditionally practiced in 1 of 3 ways: independently handling defined panels with physician supervision; handling overflow or acute visits; or working collaboratively with a supervising physician to share a larger “team panel.” The third approach has become our preferred model. aTBC provides opportunities for APCs to thrive and collaborate with the physician to provide excellent care for patients.

Provider satisfaction has increased, with 83% of aTBC physicians at Bellin being moderately or very satisfied with their experience.

APCs underwent the same process changes as physicians, including appropriate CTC support. Implementation strategies for APCs were similar to those that were useful for physicians.

Risk management professionals

At Bellin, we found that risk-management professionals had concerns about the scope of practice assigned to various team members, particularly regarding documentation. CMS allows for elements of a patient visit to be documented by CMAs and other members of the care team in real time as authorized by the physician.^23,24 CTCs at Bellin also have other clinical duties in patient and EHR management. aTBC practices generally prefer the term team documentation over scribing, since it more accurately reflects the scope of the CTC’s work.

Continue to: Implementation strategies

Clarify regulatory issues. Extensive use of standing orders and protocols allowed us to increase involvement of various team members. State laws vary in what functions CMAs and LPNs are allowed to perform, so it is important to check your state guidelines.²⁵ There is a tendency for some risk managers to overinterpret regulations. Challenge them to provide exact documentation from regulatory agencies to support their decisions.

Give assurances of physician oversight and processes. The physician assumes responsibility for standing orders, protocols, and documentation. We made sure that we had clear and consistent processes in place and worked closely with our risk managers as we developed our model. aTBC provides checks and balances to ensure accurate records, since team members are able to contribute and check for accuracy. A recent study suggested that CMAs perform documentation that is of equal or higher quality than that performed by the physician.²⁶

Financial leadership

Like any organization adopting aTBC, Bellin’s leadership was concerned about the expense of adopting this approach. However, the leadership also recognized that the transition to aTBC could increase revenue by more than the increased staffing costs. In addition, we expected that capacity, access, continuity, and financial margins would increase.^2,3,27,28 We also anticipated a decrease in downstream services, such as unnecessary tests, emergency department visits, and hospitalizations—a benefit of accountable care payment models.

Our efforts have been successful from a financial point of view. We attribute the financial sustainability that we have experienced to 4 factors:

1. Increased productivity. We knew that the increased efficiency of team-based care enables physicians to see 1 to 2 more patients per half day, and sometimes more.^3,28,29 An increase of at least 1 patient visit per half-day was expected of our physicians and APCs on aTBC. In addition, they were expected to support the care team RN in achieving at least 4 billable visits per day. Our current level of RN visits is at 3.5 per nurse per day. There is significant variability in the increase of patients seen by a physician per day, ranging from 1 to 4 additional patients. These increased visits have helped us achieve financial viability, even in a predominantly fee-for-service environment.

2. More thorough service. The ability to keep patients in primary care and to focus on the patient’s full range of needs has led to higher levels of service and, consequently, to appropriately higher levels of billing codes. For example, Bellin’s revenue from billing increased by $724 per patient, related (in part) to higher rates of immunizations, cancer screenings with mammography, and colonoscopies.

Continue to: 3. New billable services

3. New billable services. Billing for RN blood pressure checks, AWVs, and extended care team services have helped make aTBC at Bellin financially feasible. Revenue from RN visits, for example, was $630,000 in 2018.

4. Improved access for patients. Of the 130 primary care providers now on aTBC, 15 (11.5%) had closed their practices to new patients before aTBC. Now, all of their practices are open to new patients, which has improved access to care. In a 2018 patient access survey, 96.6% of patients obtained an appointment as soon as they thought it was needed, compared with 70.7% of patients before the transition to aTBC.

Greater opportunity for financial sustainability. The combination of improved quality measures and decreased cost of care in the Bellin aTBC bodes well for future success in a value-based world. We have realized a significant increase in value-based payments for improved quality, and in our Next Gen Accountable Care Organization (ACO) patients, we have seen a decrease of $29 in per-member-per-month costs, likely due to the use of nonphysicians in expanded roles. In addition, hospital admissions have decreased by 5% due to the ability of ambulatory teams to manage more complex patients in the office setting. This model has also allowed physicians and APCs to increase their panel size, another key value-based metric. From 2016 to 2018, panel size for primary care providers increased by an average of 8%.

Enhanced ability to retain and recruit. Several of Bellin’s primary care recruits indicated that they had interviewed only at practices incorporating team-based care. This trend may increase as residencies transition to team-based models of care.

So how did we do?

Metrics of Bellin’s aTBC success

By the end of 2018, all 130 primary care physicians and APCs at Bellin had made the transition to this model, representing family medicine, internal medicine, and pediatrics. We have now begun the transition of our non-primary care specialties to team-based care.

Continue to: In the aTBC model...

In the aTBC model, the percentage of patients receiving age-appropriate screening is higher than before in every domain we measure (FIGURE 1). There has also been improvement in major quality metrics (FIGURE 2).

In a survey done in Spring 2018 by St. Norbert College Strategic Research Center, provider satisfaction increased, with 83% of physicians having made the transition to an aTBC practice moderately or very satisfied with their Bellin Health experience, compared with 70% in the traditional model. More recent 2019 survey data show a satisfaction rate of 90% for team-based care providers. Finally, in our aTBC model—in CMS’s Next-Gen ACO initiative—the cost per patient per month is significantly less than for those in a non-team-based care model ($796 vs $940).

CORRESPONDENCE
James Jerzak, MD, 1630 Commanche Ave, Green Bay, WI 54313; [email protected].

ACKNOWLEDGEMENTS
The authors would like to thank Lindsey E. Carlasare, MBA, from the American Medical Association, and Brad Wozney, MD, Kathy Kerscher, and Christopher Elfner from Bellin Health, for their contributions to the content and review of this manuscript.

EVIDENCE SUMMARY

All NSAIDs at maximum clinical doses reduced large joint OA pain more effectively than placebo and acetaminophen based on data from a network meta-analysis of 129 RCTs with 32,129 patients (TABLE 1).¹ When various doses of NSAIDs are ranked for efficacy based on their effect size compared to placebo, diclofenac 150 mg/d had the greatest treatment effect, followed by ibuprofen 2400 mg/d.² Lower doses of NSAIDs—including diclofenac 70 mg/d, naproxen 750 mg/d, and ibuprofen 1200 mg/d—were not statistically superior to placebo (TABLE 2).²

Selective vs nonselective. There was no statistical difference in pain relief between the selective COX-2 inhibitor celecoxib and the nonselective NSAIDs naproxen, diclofenac, and ibuprofen (TABLE 1).¹

Meloxicam. A systematic review of 16 RCTs and 22,886 patients found that meloxicam reduced pain more effectively than placebo (10-point visual analogue scale [VAS] score pain difference of –6.8; 95% CI, –9.3 to –4.2) but was marginally less effective than other NSAIDs (VAS score pain difference of 1.7; 95% CI, 0.8 to 2.7).³

Acetaminophen. Data from 6 RCTs involving 2083 adults with knee OA indicate acetaminophen did not achieve clinical significance compared to placebo (TABLE 1).¹ Another meta-analysis of 5 RCTs involving 1741 patients with hip or knee OA also demonstrated that acetaminophen failed to achieve a clinically significant effect on pain, defined as a reduction of 9 mm on a 0 to 100 mm VAS (–3.7; 95% CI, –5.5 to –1.9).⁴ Another network meta-analysis of 6 RCTs including 58,556 patients with knee or hip OA, with the primary outcome of pain (using a hierarchy of pain scores, with global pain score taking precedence) also found no clinically significant difference between acetaminophen at the highest dose (4000 mg/d) and placebo (–0.17; 95% credible interval [CrI], –0.27 to –0.6).²

RECOMMENDATIONS

In a systematic review of mixed evidence-based and expert opinion recommendations and guidelines on the management of OA, 10 of the 11 guidelines that included pharmacologic management recommended acetaminophen as a first-line agent, followed by topical NSAIDs, and then oral NSAIDs. The exception is the most recent American Academy of Orthopaedic Surgeons guideline, which continues to recommend NSAIDs but is now unable to recommend for or against acetaminophen.⁵

EVIDENCE SUMMARY

All NSAIDs at maximum clinical doses reduced large joint OA pain more effectively than placebo and acetaminophen based on data from a network meta-analysis of 129 RCTs with 32,129 patients (TABLE 1).¹ When various doses of NSAIDs are ranked for efficacy based on their effect size compared to placebo, diclofenac 150 mg/d had the greatest treatment effect, followed by ibuprofen 2400 mg/d.² Lower doses of NSAIDs—including diclofenac 70 mg/d, naproxen 750 mg/d, and ibuprofen 1200 mg/d—were not statistically superior to placebo (TABLE 2).²

Selective vs nonselective. There was no statistical difference in pain relief between the selective COX-2 inhibitor celecoxib and the nonselective NSAIDs naproxen, diclofenac, and ibuprofen (TABLE 1).¹

Meloxicam. A systematic review of 16 RCTs and 22,886 patients found that meloxicam reduced pain more effectively than placebo (10-point visual analogue scale [VAS] score pain difference of –6.8; 95% CI, –9.3 to –4.2) but was marginally less effective than other NSAIDs (VAS score pain difference of 1.7; 95% CI, 0.8 to 2.7).³

Acetaminophen. Data from 6 RCTs involving 2083 adults with knee OA indicate acetaminophen did not achieve clinical significance compared to placebo (TABLE 1).¹ Another meta-analysis of 5 RCTs involving 1741 patients with hip or knee OA also demonstrated that acetaminophen failed to achieve a clinically significant effect on pain, defined as a reduction of 9 mm on a 0 to 100 mm VAS (–3.7; 95% CI, –5.5 to –1.9).⁴ Another network meta-analysis of 6 RCTs including 58,556 patients with knee or hip OA, with the primary outcome of pain (using a hierarchy of pain scores, with global pain score taking precedence) also found no clinically significant difference between acetaminophen at the highest dose (4000 mg/d) and placebo (–0.17; 95% credible interval [CrI], –0.27 to –0.6).²

RECOMMENDATIONS

In a systematic review of mixed evidence-based and expert opinion recommendations and guidelines on the management of OA, 10 of the 11 guidelines that included pharmacologic management recommended acetaminophen as a first-line agent, followed by topical NSAIDs, and then oral NSAIDs. The exception is the most recent American Academy of Orthopaedic Surgeons guideline, which continues to recommend NSAIDs but is now unable to recommend for or against acetaminophen.⁵

EVIDENCE SUMMARY

All NSAIDs at maximum clinical doses reduced large joint OA pain more effectively than placebo and acetaminophen based on data from a network meta-analysis of 129 RCTs with 32,129 patients (TABLE 1).¹ When various doses of NSAIDs are ranked for efficacy based on their effect size compared to placebo, diclofenac 150 mg/d had the greatest treatment effect, followed by ibuprofen 2400 mg/d.² Lower doses of NSAIDs—including diclofenac 70 mg/d, naproxen 750 mg/d, and ibuprofen 1200 mg/d—were not statistically superior to placebo (TABLE 2).²

Selective vs nonselective. There was no statistical difference in pain relief between the selective COX-2 inhibitor celecoxib and the nonselective NSAIDs naproxen, diclofenac, and ibuprofen (TABLE 1).¹

Meloxicam. A systematic review of 16 RCTs and 22,886 patients found that meloxicam reduced pain more effectively than placebo (10-point visual analogue scale [VAS] score pain difference of –6.8; 95% CI, –9.3 to –4.2) but was marginally less effective than other NSAIDs (VAS score pain difference of 1.7; 95% CI, 0.8 to 2.7).³

Acetaminophen. Data from 6 RCTs involving 2083 adults with knee OA indicate acetaminophen did not achieve clinical significance compared to placebo (TABLE 1).¹ Another meta-analysis of 5 RCTs involving 1741 patients with hip or knee OA also demonstrated that acetaminophen failed to achieve a clinically significant effect on pain, defined as a reduction of 9 mm on a 0 to 100 mm VAS (–3.7; 95% CI, –5.5 to –1.9).⁴ Another network meta-analysis of 6 RCTs including 58,556 patients with knee or hip OA, with the primary outcome of pain (using a hierarchy of pain scores, with global pain score taking precedence) also found no clinically significant difference between acetaminophen at the highest dose (4000 mg/d) and placebo (–0.17; 95% credible interval [CrI], –0.27 to –0.6).²

RECOMMENDATIONS

In a systematic review of mixed evidence-based and expert opinion recommendations and guidelines on the management of OA, 10 of the 11 guidelines that included pharmacologic management recommended acetaminophen as a first-line agent, followed by topical NSAIDs, and then oral NSAIDs. The exception is the most recent American Academy of Orthopaedic Surgeons guideline, which continues to recommend NSAIDs but is now unable to recommend for or against acetaminophen.⁵

In this issue of JFP, Weinstein and Worster provide a wealth of information about prescribing marijuana. Medical marijuana (Cannabis) is now legal in the majority of states, so it’s likely that some of your patients are using marijuana for symptom relief. For those physicians who elect to prescribe marijuana, reading this review will help you avoid harming patients while maximizing potential benefits.

I say “potential benefits” because the research evidence to support benefit for most conditions and symptoms is weak at best. In addition to the JAMA meta-analysis cited by Weinstein and Worster,¹ several meta-analyses and systematic reviews published since January 2018 reach similar conclusions.^2-4

Marijuana can provide significant relief from chemotherapy-induced nausea and vomiting, and it is effective in reducing intractable seizures in 2 rare pediatric seizure disorders. There may be some benefit for treatment of spasticity, and there may be some therapeutic value for relief of neuropathic pain, although the evidence is not strong. Interestingly, there is some preliminary evidence that cannabis can improve gastrointestinal symptoms in patients with Crohn's disease and ulcerative colitis.^5,6

Why do people use marijuana as medicine? A meta-analysis found that pain (64%), anxiety (50%), and depression/mood (34%) were common reasons.⁷ People use marijuana for a plethora of other conditions and symptoms, which is reflected in the long list of “approved” conditions in most state medical marijuana laws. The problem I have with prescribing cannabis for non-neuropathic pain, anxiety, and depression is that there is no good randomized trial evidence of its effectiveness beyond a placebo effect (which is probably quite strong considering the psychotropic effects of marijuana). And, as Weinstein and Worster point out, there is evidence of increased mental health symptoms in chronic marijuana users.

It behooves us to be prepared to discuss the pros and cons of Cannabis use with our patients—even if we decide not to prescribe it.

Regardless of the scientific evidence, use of cannabis for symptom relief is unlikely to be a passing fad. Surveys show that about 70% of users believe they receive benefit from it.⁸ Therefore, it behooves us to be prepared to discuss the pros and cons of cannabis use with our patients—even if we decide not to prescribe it. Warn patients with anxiety and depression that it is unlikely to be effective and may make matters worse.

There is intense interest in medical marijuana and better research will likely change the way we use cannabis for medical purposes in the future. So, for now, our best approach is to stay informed as the research unfolds.

In this issue of JFP, Weinstein and Worster provide a wealth of information about prescribing marijuana. Medical marijuana (Cannabis) is now legal in the majority of states, so it’s likely that some of your patients are using marijuana for symptom relief. For those physicians who elect to prescribe marijuana, reading this review will help you avoid harming patients while maximizing potential benefits.

I say “potential benefits” because the research evidence to support benefit for most conditions and symptoms is weak at best. In addition to the JAMA meta-analysis cited by Weinstein and Worster,¹ several meta-analyses and systematic reviews published since January 2018 reach similar conclusions.^2-4

Marijuana can provide significant relief from chemotherapy-induced nausea and vomiting, and it is effective in reducing intractable seizures in 2 rare pediatric seizure disorders. There may be some benefit for treatment of spasticity, and there may be some therapeutic value for relief of neuropathic pain, although the evidence is not strong. Interestingly, there is some preliminary evidence that cannabis can improve gastrointestinal symptoms in patients with Crohn's disease and ulcerative colitis.^5,6

Why do people use marijuana as medicine? A meta-analysis found that pain (64%), anxiety (50%), and depression/mood (34%) were common reasons.⁷ People use marijuana for a plethora of other conditions and symptoms, which is reflected in the long list of “approved” conditions in most state medical marijuana laws. The problem I have with prescribing cannabis for non-neuropathic pain, anxiety, and depression is that there is no good randomized trial evidence of its effectiveness beyond a placebo effect (which is probably quite strong considering the psychotropic effects of marijuana). And, as Weinstein and Worster point out, there is evidence of increased mental health symptoms in chronic marijuana users.

It behooves us to be prepared to discuss the pros and cons of Cannabis use with our patients—even if we decide not to prescribe it.

Regardless of the scientific evidence, use of cannabis for symptom relief is unlikely to be a passing fad. Surveys show that about 70% of users believe they receive benefit from it.⁸ Therefore, it behooves us to be prepared to discuss the pros and cons of cannabis use with our patients—even if we decide not to prescribe it. Warn patients with anxiety and depression that it is unlikely to be effective and may make matters worse.

There is intense interest in medical marijuana and better research will likely change the way we use cannabis for medical purposes in the future. So, for now, our best approach is to stay informed as the research unfolds.

In this issue of JFP, Weinstein and Worster provide a wealth of information about prescribing marijuana. Medical marijuana (Cannabis) is now legal in the majority of states, so it’s likely that some of your patients are using marijuana for symptom relief. For those physicians who elect to prescribe marijuana, reading this review will help you avoid harming patients while maximizing potential benefits.

I say “potential benefits” because the research evidence to support benefit for most conditions and symptoms is weak at best. In addition to the JAMA meta-analysis cited by Weinstein and Worster,¹ several meta-analyses and systematic reviews published since January 2018 reach similar conclusions.^2-4

Marijuana can provide significant relief from chemotherapy-induced nausea and vomiting, and it is effective in reducing intractable seizures in 2 rare pediatric seizure disorders. There may be some benefit for treatment of spasticity, and there may be some therapeutic value for relief of neuropathic pain, although the evidence is not strong. Interestingly, there is some preliminary evidence that cannabis can improve gastrointestinal symptoms in patients with Crohn's disease and ulcerative colitis.^5,6

Why do people use marijuana as medicine? A meta-analysis found that pain (64%), anxiety (50%), and depression/mood (34%) were common reasons.⁷ People use marijuana for a plethora of other conditions and symptoms, which is reflected in the long list of “approved” conditions in most state medical marijuana laws. The problem I have with prescribing cannabis for non-neuropathic pain, anxiety, and depression is that there is no good randomized trial evidence of its effectiveness beyond a placebo effect (which is probably quite strong considering the psychotropic effects of marijuana). And, as Weinstein and Worster point out, there is evidence of increased mental health symptoms in chronic marijuana users.

It behooves us to be prepared to discuss the pros and cons of Cannabis use with our patients—even if we decide not to prescribe it.

Regardless of the scientific evidence, use of cannabis for symptom relief is unlikely to be a passing fad. Surveys show that about 70% of users believe they receive benefit from it.⁸ Therefore, it behooves us to be prepared to discuss the pros and cons of cannabis use with our patients—even if we decide not to prescribe it. Warn patients with anxiety and depression that it is unlikely to be effective and may make matters worse.

There is intense interest in medical marijuana and better research will likely change the way we use cannabis for medical purposes in the future. So, for now, our best approach is to stay informed as the research unfolds.

A 21-year-old woman presented with a rash on her right thigh of 3 to 4 months’ duration. She reported that the patch was asymptomatic. She was not taking any medications and otherwise was in good health. A review of systems was negative. The patient was a student who used her laptop frequently. On physical examination, a 10×5-cm reticulated, hyperpigmented patch was seen on her right thigh (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Erythema ab igne (EAI) is a common dermatosis caused by repeated exposure to infrared radiation, most commonly in the form of low-grade heat (43–47°C).¹ Common heat sources include heating pads, heaters, fire, and battery-charged devices. The distribution of the rash is dependent on the location of the heat source and appears as a hyperpigmented, reticulated rash. The pathophysiology is not well understood, but likely involves changes in dermal elastic fibers as well as the dermal venous plexus.² Though rare, chronic cases of EAI have been associated with cutaneous dysplasia.³

Inquire about possible heat sources in cases of suspected erythema ab igne.

Diagnosis of EAI is made by a combination of medical history and clinical features. Laboratory tests are not required. Additionally, clinicians should inquire about possible heat sources. In this case, we asked the patient whether she rested anything on her thighs, and she acknowledged that this was where she typically placed her laptop computer.

Differential includes other reticulated conditions

The differential diagnosis of a reticulated patch includes other entities likely sharing vascular pathology. The age, sex, and medical history of the patient offer additional diagnostic clues.

Livedo reticularis presents with reticulated erythema. It is unrelated to heat exposure, but may be associated with cold exposure. It can be physiologic or can be associated with vasculitis or another obstruction of blood flow.

Erythema infectiosum is a parvovirus B19 infection that usually presents in young children. It often results in a lacy reticulated exanthem on the face that resembles a slapped cheek in children. Adolescent and adult contacts often present with a more petechial rash in an acral to periflexural distribution.⁴

Continue to: Polyarteritis nodosa

Polyarteritis nodosa is a rare necrotizing vasculitis of small and medium arteries with an incidence of 4 to 16 cases per million.⁴ It usually is painful and can present with nodules, ulcers, or bullae and may be associated with livedo-like reticulated pigmentation.

Livedoid vasculitis is a hyalinization of blood vessels leading to the obstruction of vessels due to a hypercoagulable state. It can be acquired or congenital and usually manifests in middle-aged women.⁴

Management is straight-forward: Remove the heat source

EAI typically is asymptomatic, although there are reports of mild pruritus or a burning sensation. Management includes withdrawal of the heat source and patient education. Our patient’s rash went away when she stopped resting her laptop computer on her lap.

CORRESPONDENCE
Lorraine C. Young, MD, 200 UCLA, Medical Plaza Driveway, Suites 450 & 465, Los Angeles, CA 90095; [email protected]

A 21-year-old woman presented with a rash on her right thigh of 3 to 4 months’ duration. She reported that the patch was asymptomatic. She was not taking any medications and otherwise was in good health. A review of systems was negative. The patient was a student who used her laptop frequently. On physical examination, a 10×5-cm reticulated, hyperpigmented patch was seen on her right thigh (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Erythema ab igne (EAI) is a common dermatosis caused by repeated exposure to infrared radiation, most commonly in the form of low-grade heat (43–47°C).¹ Common heat sources include heating pads, heaters, fire, and battery-charged devices. The distribution of the rash is dependent on the location of the heat source and appears as a hyperpigmented, reticulated rash. The pathophysiology is not well understood, but likely involves changes in dermal elastic fibers as well as the dermal venous plexus.² Though rare, chronic cases of EAI have been associated with cutaneous dysplasia.³

Inquire about possible heat sources in cases of suspected erythema ab igne.

Diagnosis of EAI is made by a combination of medical history and clinical features. Laboratory tests are not required. Additionally, clinicians should inquire about possible heat sources. In this case, we asked the patient whether she rested anything on her thighs, and she acknowledged that this was where she typically placed her laptop computer.

Differential includes other reticulated conditions

The differential diagnosis of a reticulated patch includes other entities likely sharing vascular pathology. The age, sex, and medical history of the patient offer additional diagnostic clues.

Livedo reticularis presents with reticulated erythema. It is unrelated to heat exposure, but may be associated with cold exposure. It can be physiologic or can be associated with vasculitis or another obstruction of blood flow.

Erythema infectiosum is a parvovirus B19 infection that usually presents in young children. It often results in a lacy reticulated exanthem on the face that resembles a slapped cheek in children. Adolescent and adult contacts often present with a more petechial rash in an acral to periflexural distribution.⁴

Continue to: Polyarteritis nodosa

Polyarteritis nodosa is a rare necrotizing vasculitis of small and medium arteries with an incidence of 4 to 16 cases per million.⁴ It usually is painful and can present with nodules, ulcers, or bullae and may be associated with livedo-like reticulated pigmentation.

Livedoid vasculitis is a hyalinization of blood vessels leading to the obstruction of vessels due to a hypercoagulable state. It can be acquired or congenital and usually manifests in middle-aged women.⁴

Management is straight-forward: Remove the heat source

EAI typically is asymptomatic, although there are reports of mild pruritus or a burning sensation. Management includes withdrawal of the heat source and patient education. Our patient’s rash went away when she stopped resting her laptop computer on her lap.

CORRESPONDENCE
Lorraine C. Young, MD, 200 UCLA, Medical Plaza Driveway, Suites 450 & 465, Los Angeles, CA 90095; [email protected]

A 21-year-old woman presented with a rash on her right thigh of 3 to 4 months’ duration. She reported that the patch was asymptomatic. She was not taking any medications and otherwise was in good health. A review of systems was negative. The patient was a student who used her laptop frequently. On physical examination, a 10×5-cm reticulated, hyperpigmented patch was seen on her right thigh (FIGURE).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Erythema ab igne (EAI) is a common dermatosis caused by repeated exposure to infrared radiation, most commonly in the form of low-grade heat (43–47°C).¹ Common heat sources include heating pads, heaters, fire, and battery-charged devices. The distribution of the rash is dependent on the location of the heat source and appears as a hyperpigmented, reticulated rash. The pathophysiology is not well understood, but likely involves changes in dermal elastic fibers as well as the dermal venous plexus.² Though rare, chronic cases of EAI have been associated with cutaneous dysplasia.³

Inquire about possible heat sources in cases of suspected erythema ab igne.

Diagnosis of EAI is made by a combination of medical history and clinical features. Laboratory tests are not required. Additionally, clinicians should inquire about possible heat sources. In this case, we asked the patient whether she rested anything on her thighs, and she acknowledged that this was where she typically placed her laptop computer.

Differential includes other reticulated conditions

The differential diagnosis of a reticulated patch includes other entities likely sharing vascular pathology. The age, sex, and medical history of the patient offer additional diagnostic clues.

Livedo reticularis presents with reticulated erythema. It is unrelated to heat exposure, but may be associated with cold exposure. It can be physiologic or can be associated with vasculitis or another obstruction of blood flow.

Erythema infectiosum is a parvovirus B19 infection that usually presents in young children. It often results in a lacy reticulated exanthem on the face that resembles a slapped cheek in children. Adolescent and adult contacts often present with a more petechial rash in an acral to periflexural distribution.⁴

Continue to: Polyarteritis nodosa

Polyarteritis nodosa is a rare necrotizing vasculitis of small and medium arteries with an incidence of 4 to 16 cases per million.⁴ It usually is painful and can present with nodules, ulcers, or bullae and may be associated with livedo-like reticulated pigmentation.

Livedoid vasculitis is a hyalinization of blood vessels leading to the obstruction of vessels due to a hypercoagulable state. It can be acquired or congenital and usually manifests in middle-aged women.⁴

Management is straight-forward: Remove the heat source

EAI typically is asymptomatic, although there are reports of mild pruritus or a burning sensation. Management includes withdrawal of the heat source and patient education. Our patient’s rash went away when she stopped resting her laptop computer on her lap.

CORRESPONDENCE
Lorraine C. Young, MD, 200 UCLA, Medical Plaza Driveway, Suites 450 & 465, Los Angeles, CA 90095; [email protected]

THE CASE

An 8-year-old boy presented to his family physician (FP) with pharyngitis, nasal drainage, and a dry cough of 3 days’ duration. He denied any fever, chills, vomiting, or diarrhea. He had no sick contacts or prior history of streptococcal pharyngitis, but a rapid strep test was positive. No throat culture was performed at this time. The patient was started on amoxicillin 250 mg 3 times daily for 10 days.

On Day 7 of symptoms, the patient presented to the emergency department with elbow and knee pain, as well as mild swelling and purpura of his legs of 3 days’ duration. He was normotensive and reported no abdominal pain. A laboratory workup, including a complete blood cell count and differential, prothrombin time, partial thromboplastin time, comprehensive metabolic panel, creatinine kinase test, urinalysis, and chest radiograph, was normal, but his erythrocyte sedimentation rate (ESR) was mildly elevated at 22 mm/h (reference range, 0–20 mm/h). The patient was discharged on acetaminophen 15 mg/kg every 4 hours as needed for pain.

THE DIAGNOSIS

Based on the distinctive palpable purpura on the legs, arthralgia, upper respiratory infection, and lack of thrombocytopenia and coagulopathy, a presumptive diagnosis of Henoch-Schönlein purpura (HSP) was made.

On Day 9 of symptoms, the patient returned to his FP’s office because the arthralgia persisted in his ankles, knees, and hips. He had developed lower back pain, but the pharyngitis and upper respiratory symptoms had resolved. On physical examination, he was normotensive with a normal abdominal exam. The patient reported that it hurt to move his wrists, hands, elbows, shoulders, knees, and ankles. He also had mild swelling in his left wrist, hand, and ankle. The paraspinal muscles in the lower thoracic and lumbar back were mildly tender to palpation. A complete metabolic panel and urinalysis were normal. Dermatologic examination revealed discrete purpuric lesions ranging from 1 to 8 mm in diameter on the child’s shins, thighs, and buttocks. Urinalysis, blood urea nitrogen, and creatinine kinase were normal. His ESR remained mildly elevated at 24 mm/h. Since there was no evidence of glomerulonephritis, ibuprofen 10 mg/kg every 8 hours as needed was added for pain management.

The child was brought back to his FP on Day 18 for a scheduled follow-up visit. The parents reported that his arthralgia was improved during the day, but by the evening, his knees and ankles hurt so much that they had to carry him to the bathroom. On physical examination, he still had palpable purpura of the legs. There was no swelling, but his joints were still tender to palpation. His parents were reminded to give him ibuprofen after school to control evening pain. Over the next 2 weeks, the patient showed gradual improvement, and by Day 33 the rash and all of the associated symptoms had resolved.

DISCUSSION

Clinical presentation. HSP is an IgA immune complex vasculitis in which abnormal glycosylation of IgA creates large immune complexes that are deposited in the walls of the skin capillaries and arterioles. The primary clinical finding in HSP is a distinctive nonthrombocytopenic purpuric rash that is not associated with coagulopathy and is characterized by reddish purple macules that progress to palpable purpura with petechiae (Figure). Lesions generally are distributed on the legs or buttocks but also may appear on the torso or arms. Flu-like symptoms, such as fever, runny nose, and cough, are common.

A preceding upper respiratory infection has been found in 37% of patients,¹ and in patients with renal complications, 20% to 50% have been found to have a group A Streptococcus infection.² Other associations include food allergies, cold exposure, insect bites, and drug allergies.

Continue to: HSP vasculitis causes...

HSP vasculitis causes abdominal pain in 50% to 75% of patients due to proximal small-bowel submucosal hemorrhage and bowel wall edema.³ In children with HSP, 20% to 55% have been shown to develop renal disease,⁴ which can range in severity from microscopic hematuria to nephrotic syndrome.³ To ensure prompt treatment of renal manifestations, renal function should be monitored regularly via blood pressure and urinalysis during the course of HSP and after resolution. Renal disease associated with HSP can be acute or chronic.

This case was different because our patient did not exhibit all elements of the classic tetrad of HSP, which includes the characteristic rash, abdominal pain, renal involvement, and arthralgia.

Incidence. HSP is more common in children than adults, with average annual incidence rates of 20/100,000 and 70/100,000 in children in the United States and Asia, respectively.⁵ While 90% of HSP cases occur in children < 10 years, the peak incidence is at 6 years of age.⁶ Complications from HSP are more common in adults than in children.⁷ Caucasian and Asian populations have a 3- to 4-times higher prevalence of HSP than black populations. The male-to-female ratio is 2 to 1.⁶

The diagnosis of HSP is usually made clinically, based on the distinctive rash, which typically is symmetrical, involving the buttocks, lower legs, elbows, and/or knees. HSP also can be confirmed via skin biopsy and/or direct immunofluorescence, which can identify the presence of IgA in the vessel walls.

The presence of 3 or more of the following criteria also suggests HSP: palpable purpura, bowel angina, gastrointestinal (GI) bleeding, hematuria, ≤ 20 years of age at onset, and no medications prior to presentation of symptoms (87% of cases correctly classified). Fewer than 3 of these factors favor hypersensitivity vasculitis (74% of cases correctly classified).⁸

Continue to: The differential diagnosis

The differential diagnosis for HSP includes polyarteritis nodosa, a vasculitis with a different characteristic rash; acute abdomen, distinguished by the absence of purpura or arthralgia; meningococcemia, in which fever and meningeal signs may occur; hypersensitivity vasculitis, which arises due to prior exposure to medications or food allergens; and thrombocytopenic purpura, which is characterized by low platelet count.⁹

Treatment focuses on pain management

In the absence of renal disease, HSP commonly is treated with naproxen for pain management (dosage for children < 2 years of age: 5-7 mg/kg orally every 8-12 hours; dosage for children ≥ 2 years of age, adolescents, and adults: 10-20 mg/kg/d divided into 2 doses; maximum adolescent and adult dose is 1500 mg/d for 3 days followed by a maximum of 1000 mg/d thereafter).

For patients of all ages with severe pain and those with GI effects limiting oral intake of medication, use oral prednisone (1-2 mg/kg/d [maximum dose, 60-80 mg/d]) or intravenous methylprednisolone (0.8-1.6 mg/kg/d [maximum dose, 64 mg/d). Glucocorticoids may then be tapered slowly over 4 to 8 weeks to avoid rebound since they help with inflammation but do not shorten the course of disease. Steroids can ease GI and joint symptoms in HSP but will not improve the rash.

THE TAKEAWAY

The classic tetrad of HSP includes the characteristic rash, abdominal pain, renal involvement, and arthralgia. Diagnosis usually is made clinically, but skin biopsy and direct immunofluorescence can confirm small vessel vasculitis with IgA deposits. More severe manifestations of HSP such as renal disease, hemorrhage, severe anemia, signs of intestinal obstruction, or peritonitis require rapid subspecialty referral.

CORRESPONDENCE
Rachel Bramson, MD, Department of Primary Care, Baylor Scott and White Health, University Clinic, 1700 University Drive, College Station, TX 77840; [email protected]

THE CASE

An 8-year-old boy presented to his family physician (FP) with pharyngitis, nasal drainage, and a dry cough of 3 days’ duration. He denied any fever, chills, vomiting, or diarrhea. He had no sick contacts or prior history of streptococcal pharyngitis, but a rapid strep test was positive. No throat culture was performed at this time. The patient was started on amoxicillin 250 mg 3 times daily for 10 days.

On Day 7 of symptoms, the patient presented to the emergency department with elbow and knee pain, as well as mild swelling and purpura of his legs of 3 days’ duration. He was normotensive and reported no abdominal pain. A laboratory workup, including a complete blood cell count and differential, prothrombin time, partial thromboplastin time, comprehensive metabolic panel, creatinine kinase test, urinalysis, and chest radiograph, was normal, but his erythrocyte sedimentation rate (ESR) was mildly elevated at 22 mm/h (reference range, 0–20 mm/h). The patient was discharged on acetaminophen 15 mg/kg every 4 hours as needed for pain.

THE DIAGNOSIS

Based on the distinctive palpable purpura on the legs, arthralgia, upper respiratory infection, and lack of thrombocytopenia and coagulopathy, a presumptive diagnosis of Henoch-Schönlein purpura (HSP) was made.

On Day 9 of symptoms, the patient returned to his FP’s office because the arthralgia persisted in his ankles, knees, and hips. He had developed lower back pain, but the pharyngitis and upper respiratory symptoms had resolved. On physical examination, he was normotensive with a normal abdominal exam. The patient reported that it hurt to move his wrists, hands, elbows, shoulders, knees, and ankles. He also had mild swelling in his left wrist, hand, and ankle. The paraspinal muscles in the lower thoracic and lumbar back were mildly tender to palpation. A complete metabolic panel and urinalysis were normal. Dermatologic examination revealed discrete purpuric lesions ranging from 1 to 8 mm in diameter on the child’s shins, thighs, and buttocks. Urinalysis, blood urea nitrogen, and creatinine kinase were normal. His ESR remained mildly elevated at 24 mm/h. Since there was no evidence of glomerulonephritis, ibuprofen 10 mg/kg every 8 hours as needed was added for pain management.

The child was brought back to his FP on Day 18 for a scheduled follow-up visit. The parents reported that his arthralgia was improved during the day, but by the evening, his knees and ankles hurt so much that they had to carry him to the bathroom. On physical examination, he still had palpable purpura of the legs. There was no swelling, but his joints were still tender to palpation. His parents were reminded to give him ibuprofen after school to control evening pain. Over the next 2 weeks, the patient showed gradual improvement, and by Day 33 the rash and all of the associated symptoms had resolved.

DISCUSSION

Clinical presentation. HSP is an IgA immune complex vasculitis in which abnormal glycosylation of IgA creates large immune complexes that are deposited in the walls of the skin capillaries and arterioles. The primary clinical finding in HSP is a distinctive nonthrombocytopenic purpuric rash that is not associated with coagulopathy and is characterized by reddish purple macules that progress to palpable purpura with petechiae (Figure). Lesions generally are distributed on the legs or buttocks but also may appear on the torso or arms. Flu-like symptoms, such as fever, runny nose, and cough, are common.

A preceding upper respiratory infection has been found in 37% of patients,¹ and in patients with renal complications, 20% to 50% have been found to have a group A Streptococcus infection.² Other associations include food allergies, cold exposure, insect bites, and drug allergies.

Continue to: HSP vasculitis causes...

HSP vasculitis causes abdominal pain in 50% to 75% of patients due to proximal small-bowel submucosal hemorrhage and bowel wall edema.³ In children with HSP, 20% to 55% have been shown to develop renal disease,⁴ which can range in severity from microscopic hematuria to nephrotic syndrome.³ To ensure prompt treatment of renal manifestations, renal function should be monitored regularly via blood pressure and urinalysis during the course of HSP and after resolution. Renal disease associated with HSP can be acute or chronic.

This case was different because our patient did not exhibit all elements of the classic tetrad of HSP, which includes the characteristic rash, abdominal pain, renal involvement, and arthralgia.

Incidence. HSP is more common in children than adults, with average annual incidence rates of 20/100,000 and 70/100,000 in children in the United States and Asia, respectively.⁵ While 90% of HSP cases occur in children < 10 years, the peak incidence is at 6 years of age.⁶ Complications from HSP are more common in adults than in children.⁷ Caucasian and Asian populations have a 3- to 4-times higher prevalence of HSP than black populations. The male-to-female ratio is 2 to 1.⁶

The diagnosis of HSP is usually made clinically, based on the distinctive rash, which typically is symmetrical, involving the buttocks, lower legs, elbows, and/or knees. HSP also can be confirmed via skin biopsy and/or direct immunofluorescence, which can identify the presence of IgA in the vessel walls.

The presence of 3 or more of the following criteria also suggests HSP: palpable purpura, bowel angina, gastrointestinal (GI) bleeding, hematuria, ≤ 20 years of age at onset, and no medications prior to presentation of symptoms (87% of cases correctly classified). Fewer than 3 of these factors favor hypersensitivity vasculitis (74% of cases correctly classified).⁸

Continue to: The differential diagnosis

The differential diagnosis for HSP includes polyarteritis nodosa, a vasculitis with a different characteristic rash; acute abdomen, distinguished by the absence of purpura or arthralgia; meningococcemia, in which fever and meningeal signs may occur; hypersensitivity vasculitis, which arises due to prior exposure to medications or food allergens; and thrombocytopenic purpura, which is characterized by low platelet count.⁹

Treatment focuses on pain management

In the absence of renal disease, HSP commonly is treated with naproxen for pain management (dosage for children < 2 years of age: 5-7 mg/kg orally every 8-12 hours; dosage for children ≥ 2 years of age, adolescents, and adults: 10-20 mg/kg/d divided into 2 doses; maximum adolescent and adult dose is 1500 mg/d for 3 days followed by a maximum of 1000 mg/d thereafter).

For patients of all ages with severe pain and those with GI effects limiting oral intake of medication, use oral prednisone (1-2 mg/kg/d [maximum dose, 60-80 mg/d]) or intravenous methylprednisolone (0.8-1.6 mg/kg/d [maximum dose, 64 mg/d). Glucocorticoids may then be tapered slowly over 4 to 8 weeks to avoid rebound since they help with inflammation but do not shorten the course of disease. Steroids can ease GI and joint symptoms in HSP but will not improve the rash.

THE TAKEAWAY

The classic tetrad of HSP includes the characteristic rash, abdominal pain, renal involvement, and arthralgia. Diagnosis usually is made clinically, but skin biopsy and direct immunofluorescence can confirm small vessel vasculitis with IgA deposits. More severe manifestations of HSP such as renal disease, hemorrhage, severe anemia, signs of intestinal obstruction, or peritonitis require rapid subspecialty referral.

CORRESPONDENCE
Rachel Bramson, MD, Department of Primary Care, Baylor Scott and White Health, University Clinic, 1700 University Drive, College Station, TX 77840; [email protected]

THE CASE

An 8-year-old boy presented to his family physician (FP) with pharyngitis, nasal drainage, and a dry cough of 3 days’ duration. He denied any fever, chills, vomiting, or diarrhea. He had no sick contacts or prior history of streptococcal pharyngitis, but a rapid strep test was positive. No throat culture was performed at this time. The patient was started on amoxicillin 250 mg 3 times daily for 10 days.

On Day 7 of symptoms, the patient presented to the emergency department with elbow and knee pain, as well as mild swelling and purpura of his legs of 3 days’ duration. He was normotensive and reported no abdominal pain. A laboratory workup, including a complete blood cell count and differential, prothrombin time, partial thromboplastin time, comprehensive metabolic panel, creatinine kinase test, urinalysis, and chest radiograph, was normal, but his erythrocyte sedimentation rate (ESR) was mildly elevated at 22 mm/h (reference range, 0–20 mm/h). The patient was discharged on acetaminophen 15 mg/kg every 4 hours as needed for pain.

THE DIAGNOSIS

Based on the distinctive palpable purpura on the legs, arthralgia, upper respiratory infection, and lack of thrombocytopenia and coagulopathy, a presumptive diagnosis of Henoch-Schönlein purpura (HSP) was made.

On Day 9 of symptoms, the patient returned to his FP’s office because the arthralgia persisted in his ankles, knees, and hips. He had developed lower back pain, but the pharyngitis and upper respiratory symptoms had resolved. On physical examination, he was normotensive with a normal abdominal exam. The patient reported that it hurt to move his wrists, hands, elbows, shoulders, knees, and ankles. He also had mild swelling in his left wrist, hand, and ankle. The paraspinal muscles in the lower thoracic and lumbar back were mildly tender to palpation. A complete metabolic panel and urinalysis were normal. Dermatologic examination revealed discrete purpuric lesions ranging from 1 to 8 mm in diameter on the child’s shins, thighs, and buttocks. Urinalysis, blood urea nitrogen, and creatinine kinase were normal. His ESR remained mildly elevated at 24 mm/h. Since there was no evidence of glomerulonephritis, ibuprofen 10 mg/kg every 8 hours as needed was added for pain management.

The child was brought back to his FP on Day 18 for a scheduled follow-up visit. The parents reported that his arthralgia was improved during the day, but by the evening, his knees and ankles hurt so much that they had to carry him to the bathroom. On physical examination, he still had palpable purpura of the legs. There was no swelling, but his joints were still tender to palpation. His parents were reminded to give him ibuprofen after school to control evening pain. Over the next 2 weeks, the patient showed gradual improvement, and by Day 33 the rash and all of the associated symptoms had resolved.

DISCUSSION

Clinical presentation. HSP is an IgA immune complex vasculitis in which abnormal glycosylation of IgA creates large immune complexes that are deposited in the walls of the skin capillaries and arterioles. The primary clinical finding in HSP is a distinctive nonthrombocytopenic purpuric rash that is not associated with coagulopathy and is characterized by reddish purple macules that progress to palpable purpura with petechiae (Figure). Lesions generally are distributed on the legs or buttocks but also may appear on the torso or arms. Flu-like symptoms, such as fever, runny nose, and cough, are common.

A preceding upper respiratory infection has been found in 37% of patients,¹ and in patients with renal complications, 20% to 50% have been found to have a group A Streptococcus infection.² Other associations include food allergies, cold exposure, insect bites, and drug allergies.

Continue to: HSP vasculitis causes...

HSP vasculitis causes abdominal pain in 50% to 75% of patients due to proximal small-bowel submucosal hemorrhage and bowel wall edema.³ In children with HSP, 20% to 55% have been shown to develop renal disease,⁴ which can range in severity from microscopic hematuria to nephrotic syndrome.³ To ensure prompt treatment of renal manifestations, renal function should be monitored regularly via blood pressure and urinalysis during the course of HSP and after resolution. Renal disease associated with HSP can be acute or chronic.

This case was different because our patient did not exhibit all elements of the classic tetrad of HSP, which includes the characteristic rash, abdominal pain, renal involvement, and arthralgia.

Incidence. HSP is more common in children than adults, with average annual incidence rates of 20/100,000 and 70/100,000 in children in the United States and Asia, respectively.⁵ While 90% of HSP cases occur in children < 10 years, the peak incidence is at 6 years of age.⁶ Complications from HSP are more common in adults than in children.⁷ Caucasian and Asian populations have a 3- to 4-times higher prevalence of HSP than black populations. The male-to-female ratio is 2 to 1.⁶

The diagnosis of HSP is usually made clinically, based on the distinctive rash, which typically is symmetrical, involving the buttocks, lower legs, elbows, and/or knees. HSP also can be confirmed via skin biopsy and/or direct immunofluorescence, which can identify the presence of IgA in the vessel walls.

The presence of 3 or more of the following criteria also suggests HSP: palpable purpura, bowel angina, gastrointestinal (GI) bleeding, hematuria, ≤ 20 years of age at onset, and no medications prior to presentation of symptoms (87% of cases correctly classified). Fewer than 3 of these factors favor hypersensitivity vasculitis (74% of cases correctly classified).⁸

Continue to: The differential diagnosis

The differential diagnosis for HSP includes polyarteritis nodosa, a vasculitis with a different characteristic rash; acute abdomen, distinguished by the absence of purpura or arthralgia; meningococcemia, in which fever and meningeal signs may occur; hypersensitivity vasculitis, which arises due to prior exposure to medications or food allergens; and thrombocytopenic purpura, which is characterized by low platelet count.⁹

Treatment focuses on pain management

In the absence of renal disease, HSP commonly is treated with naproxen for pain management (dosage for children < 2 years of age: 5-7 mg/kg orally every 8-12 hours; dosage for children ≥ 2 years of age, adolescents, and adults: 10-20 mg/kg/d divided into 2 doses; maximum adolescent and adult dose is 1500 mg/d for 3 days followed by a maximum of 1000 mg/d thereafter).

For patients of all ages with severe pain and those with GI effects limiting oral intake of medication, use oral prednisone (1-2 mg/kg/d [maximum dose, 60-80 mg/d]) or intravenous methylprednisolone (0.8-1.6 mg/kg/d [maximum dose, 64 mg/d). Glucocorticoids may then be tapered slowly over 4 to 8 weeks to avoid rebound since they help with inflammation but do not shorten the course of disease. Steroids can ease GI and joint symptoms in HSP but will not improve the rash.

THE TAKEAWAY

The classic tetrad of HSP includes the characteristic rash, abdominal pain, renal involvement, and arthralgia. Diagnosis usually is made clinically, but skin biopsy and direct immunofluorescence can confirm small vessel vasculitis with IgA deposits. More severe manifestations of HSP such as renal disease, hemorrhage, severe anemia, signs of intestinal obstruction, or peritonitis require rapid subspecialty referral.

CORRESPONDENCE
Rachel Bramson, MD, Department of Primary Care, Baylor Scott and White Health, University Clinic, 1700 University Drive, College Station, TX 77840; [email protected]

ILLUSTRATIVE CASE

A 42-year-old woman with generalized anxiety disorder and panic attacks has been treated with sertraline 100 mg/d for the past 8 months. She has also engaged in cognitive behavioral therapy (CBT) for 6 months. Her Generalized Anxiety Disorder-7 score has decreased from 19 prior to treatment to 5 at present. Now she would like to stop her antidepressant medication because she feels better. Would you recommend that she discontinue her medication at this point?

Anxiety disorders are common, often chronic, and can cause significant morbidity and impairment.^2,3 First-line treatments for anxiety disorders include CBT and antidepressants, particularly selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.^4-6

There is limited evidence regarding duration of antidepressant therapy for anxiety disorders. Previous studies have shown a high risk of relapse after discontinuation of antidepressants.⁶ A review of current practice patterns regarding pharmacologic treatment of depression and anxiety indicates an uptick in longer term antidepressant use for up to 2 years.⁷ However, long-term studies to guide treatment decisions are lacking.

STUDY SUMMARY

Clear benefit of continuing treatment up to 1 year

This systematic review and meta-analysis evaluated studies that looked at relapse rates and time to relapse in patients treated for anxiety disorders.¹ The authors used PubMed, Cochrane, and Embase to identify studies involving patients treated for a variety of disorders, including generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), panic disorder (PD), obsessive-compulsive disorder (OCD), and social phobia. Eligible studies enrolled patients with anxiety disorders who had a positive response to an antidepressant and then randomized them in a double-blind fashion to either discontinuation of antidepressants and starting placebo (stopping group) or continuation of antidepressants (continuation group) for a duration of 8 to 52 weeks. The primary outcomes were relapse rate and time to relapse.

Twenty-eight studies met the inclusion criteria for the meta-analysis, with a total of 5233 patients (2625 patients in the antidepressant group and 2608 patients in the placebo group). A breakdown of the trials by indiication included OCD (7), PD (6), GAD (6), social phobia (5), and PTSD (4). The authors graded the overall risk of bias to be low but noted that attrition bias was present in most studies.

Results. Relapse was more likely in the stopping group (odds ratio [OR] = 3.11; 95% confidence interval [CI], 2.48-3.89; n = 28 studies). Heterogeneity for relapse rate was low (I² = 8.07%). Subgroup analyses by type of antidepressant, mode of discontinuation, and exclusion of patient comorbidities yielded similar results. Relapse prevalence was 16.4% in the antidepressant group and 36.4% in the stopping group. Additionally, time to relapse was shorter when antidepressants were discontinued (hazard ratio [HR] = 3.63; 95% CI, 2.58-5.10; n = 11 studies). Again, the heterogeneity for relapse rate was low (I² = 0%). The original publications did not consistently report medication tolerability or withdrawal symptoms, preventing analysis of these. Dropout rates were higher in the stopping group (OR = 1.31; 95% CI, 1.06-1.63; n = 27 studies).

WHAT’S NEW

No more guessing about how long to treat

Previously, there was limited evidence to guide decisions about the duration of antidepressant treatment for anxiety disorders. This study provides evidence that stopping antidepressant treatment before 1 year increases the risk of relapse.

Continue to: CAVEATS

Potential bias … bias … and more bias

While the authors used standard and appropriate methodologies for this type of study, some significant threats to validity remained. All but 2 studies in the analysis were industry funded. Publication bias is another potential issue, even though the authors identified and included 6 unpublished studies, 4 of which had negative results.

This study provides evidence that stopping antidepressant treatment for anxiety disorders before 1 year increases the risk of relapse.

Additionally, the authors graded 11 of 28 trials as having a high likelihood of selective reporting bias, meaning that important portions of the original studies’ results may not have been published. Most studies were at high risk for attrition bias, resulting in loss of information when patients dropped out of the study. While this happened more often in the stopping groups, it is still possible that there are unidentified harms or unexpected outcomes in the medication groups.

While PTSD and OCD are no longer considered anxiety disorders, subgroup analyses found no difference in relapse rates between these diagnoses and the others included in the studies. Finally, treatment duration longer than 52 weeks has not been studied, so the optimal treatment duration is unknown.

CHALLENGES TO IMPLEMENTATION

Patients may resist continuing treatment once symptoms abate

Some patients may want to discontinue antidepressant treatment if their anxiety symptoms improve prior to 1 year. It may be difficult to convince them that continuing treatment will prevent relapse of their condition. Providing patients with information about the increased relapse rate with stopping medication early (with an estimated number needed to treat of 5) may help patients make a more informed decision.

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 42-year-old woman with generalized anxiety disorder and panic attacks has been treated with sertraline 100 mg/d for the past 8 months. She has also engaged in cognitive behavioral therapy (CBT) for 6 months. Her Generalized Anxiety Disorder-7 score has decreased from 19 prior to treatment to 5 at present. Now she would like to stop her antidepressant medication because she feels better. Would you recommend that she discontinue her medication at this point?

Anxiety disorders are common, often chronic, and can cause significant morbidity and impairment.^2,3 First-line treatments for anxiety disorders include CBT and antidepressants, particularly selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.^4-6

There is limited evidence regarding duration of antidepressant therapy for anxiety disorders. Previous studies have shown a high risk of relapse after discontinuation of antidepressants.⁶ A review of current practice patterns regarding pharmacologic treatment of depression and anxiety indicates an uptick in longer term antidepressant use for up to 2 years.⁷ However, long-term studies to guide treatment decisions are lacking.

STUDY SUMMARY

Clear benefit of continuing treatment up to 1 year

This systematic review and meta-analysis evaluated studies that looked at relapse rates and time to relapse in patients treated for anxiety disorders.¹ The authors used PubMed, Cochrane, and Embase to identify studies involving patients treated for a variety of disorders, including generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), panic disorder (PD), obsessive-compulsive disorder (OCD), and social phobia. Eligible studies enrolled patients with anxiety disorders who had a positive response to an antidepressant and then randomized them in a double-blind fashion to either discontinuation of antidepressants and starting placebo (stopping group) or continuation of antidepressants (continuation group) for a duration of 8 to 52 weeks. The primary outcomes were relapse rate and time to relapse.

Twenty-eight studies met the inclusion criteria for the meta-analysis, with a total of 5233 patients (2625 patients in the antidepressant group and 2608 patients in the placebo group). A breakdown of the trials by indiication included OCD (7), PD (6), GAD (6), social phobia (5), and PTSD (4). The authors graded the overall risk of bias to be low but noted that attrition bias was present in most studies.

Results. Relapse was more likely in the stopping group (odds ratio [OR] = 3.11; 95% confidence interval [CI], 2.48-3.89; n = 28 studies). Heterogeneity for relapse rate was low (I² = 8.07%). Subgroup analyses by type of antidepressant, mode of discontinuation, and exclusion of patient comorbidities yielded similar results. Relapse prevalence was 16.4% in the antidepressant group and 36.4% in the stopping group. Additionally, time to relapse was shorter when antidepressants were discontinued (hazard ratio [HR] = 3.63; 95% CI, 2.58-5.10; n = 11 studies). Again, the heterogeneity for relapse rate was low (I² = 0%). The original publications did not consistently report medication tolerability or withdrawal symptoms, preventing analysis of these. Dropout rates were higher in the stopping group (OR = 1.31; 95% CI, 1.06-1.63; n = 27 studies).

WHAT’S NEW

No more guessing about how long to treat

Previously, there was limited evidence to guide decisions about the duration of antidepressant treatment for anxiety disorders. This study provides evidence that stopping antidepressant treatment before 1 year increases the risk of relapse.

Continue to: CAVEATS

Potential bias … bias … and more bias

While the authors used standard and appropriate methodologies for this type of study, some significant threats to validity remained. All but 2 studies in the analysis were industry funded. Publication bias is another potential issue, even though the authors identified and included 6 unpublished studies, 4 of which had negative results.

This study provides evidence that stopping antidepressant treatment for anxiety disorders before 1 year increases the risk of relapse.

Additionally, the authors graded 11 of 28 trials as having a high likelihood of selective reporting bias, meaning that important portions of the original studies’ results may not have been published. Most studies were at high risk for attrition bias, resulting in loss of information when patients dropped out of the study. While this happened more often in the stopping groups, it is still possible that there are unidentified harms or unexpected outcomes in the medication groups.

While PTSD and OCD are no longer considered anxiety disorders, subgroup analyses found no difference in relapse rates between these diagnoses and the others included in the studies. Finally, treatment duration longer than 52 weeks has not been studied, so the optimal treatment duration is unknown.

CHALLENGES TO IMPLEMENTATION

Patients may resist continuing treatment once symptoms abate

Some patients may want to discontinue antidepressant treatment if their anxiety symptoms improve prior to 1 year. It may be difficult to convince them that continuing treatment will prevent relapse of their condition. Providing patients with information about the increased relapse rate with stopping medication early (with an estimated number needed to treat of 5) may help patients make a more informed decision.

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 42-year-old woman with generalized anxiety disorder and panic attacks has been treated with sertraline 100 mg/d for the past 8 months. She has also engaged in cognitive behavioral therapy (CBT) for 6 months. Her Generalized Anxiety Disorder-7 score has decreased from 19 prior to treatment to 5 at present. Now she would like to stop her antidepressant medication because she feels better. Would you recommend that she discontinue her medication at this point?

Anxiety disorders are common, often chronic, and can cause significant morbidity and impairment.^2,3 First-line treatments for anxiety disorders include CBT and antidepressants, particularly selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.^4-6

There is limited evidence regarding duration of antidepressant therapy for anxiety disorders. Previous studies have shown a high risk of relapse after discontinuation of antidepressants.⁶ A review of current practice patterns regarding pharmacologic treatment of depression and anxiety indicates an uptick in longer term antidepressant use for up to 2 years.⁷ However, long-term studies to guide treatment decisions are lacking.

STUDY SUMMARY

Clear benefit of continuing treatment up to 1 year

This systematic review and meta-analysis evaluated studies that looked at relapse rates and time to relapse in patients treated for anxiety disorders.¹ The authors used PubMed, Cochrane, and Embase to identify studies involving patients treated for a variety of disorders, including generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), panic disorder (PD), obsessive-compulsive disorder (OCD), and social phobia. Eligible studies enrolled patients with anxiety disorders who had a positive response to an antidepressant and then randomized them in a double-blind fashion to either discontinuation of antidepressants and starting placebo (stopping group) or continuation of antidepressants (continuation group) for a duration of 8 to 52 weeks. The primary outcomes were relapse rate and time to relapse.

Twenty-eight studies met the inclusion criteria for the meta-analysis, with a total of 5233 patients (2625 patients in the antidepressant group and 2608 patients in the placebo group). A breakdown of the trials by indiication included OCD (7), PD (6), GAD (6), social phobia (5), and PTSD (4). The authors graded the overall risk of bias to be low but noted that attrition bias was present in most studies.

Results. Relapse was more likely in the stopping group (odds ratio [OR] = 3.11; 95% confidence interval [CI], 2.48-3.89; n = 28 studies). Heterogeneity for relapse rate was low (I² = 8.07%). Subgroup analyses by type of antidepressant, mode of discontinuation, and exclusion of patient comorbidities yielded similar results. Relapse prevalence was 16.4% in the antidepressant group and 36.4% in the stopping group. Additionally, time to relapse was shorter when antidepressants were discontinued (hazard ratio [HR] = 3.63; 95% CI, 2.58-5.10; n = 11 studies). Again, the heterogeneity for relapse rate was low (I² = 0%). The original publications did not consistently report medication tolerability or withdrawal symptoms, preventing analysis of these. Dropout rates were higher in the stopping group (OR = 1.31; 95% CI, 1.06-1.63; n = 27 studies).

WHAT’S NEW

No more guessing about how long to treat

Previously, there was limited evidence to guide decisions about the duration of antidepressant treatment for anxiety disorders. This study provides evidence that stopping antidepressant treatment before 1 year increases the risk of relapse.

Continue to: CAVEATS

Potential bias … bias … and more bias

While the authors used standard and appropriate methodologies for this type of study, some significant threats to validity remained. All but 2 studies in the analysis were industry funded. Publication bias is another potential issue, even though the authors identified and included 6 unpublished studies, 4 of which had negative results.

This study provides evidence that stopping antidepressant treatment for anxiety disorders before 1 year increases the risk of relapse.

Additionally, the authors graded 11 of 28 trials as having a high likelihood of selective reporting bias, meaning that important portions of the original studies’ results may not have been published. Most studies were at high risk for attrition bias, resulting in loss of information when patients dropped out of the study. While this happened more often in the stopping groups, it is still possible that there are unidentified harms or unexpected outcomes in the medication groups.

While PTSD and OCD are no longer considered anxiety disorders, subgroup analyses found no difference in relapse rates between these diagnoses and the others included in the studies. Finally, treatment duration longer than 52 weeks has not been studied, so the optimal treatment duration is unknown.

CHALLENGES TO IMPLEMENTATION

Patients may resist continuing treatment once symptoms abate

Some patients may want to discontinue antidepressant treatment if their anxiety symptoms improve prior to 1 year. It may be difficult to convince them that continuing treatment will prevent relapse of their condition. Providing patients with information about the increased relapse rate with stopping medication early (with an estimated number needed to treat of 5) may help patients make a more informed decision.

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.

THE CASE

Janice J* visits her family physician with complaints of chest pain, shortness of breath, and heart palpitations that are usually worse at night. Her medical history is significant for deep vein thrombosis secondary to an underlying hypercoagulability condition (rheumatoid arthritis) diagnosed 2 months earlier. She also has a history of opioid use disorder and has been on buprenorphine/naloxone therapy for 3 years. Her family medical history is unremarkable. She works full-time and lives with her 8-year-old son. On physical exam, she appears anxious; her cardiac and pulmonary exams are normal. A completed workup rules out cardiac or pulmonary problems.

• What is your diagnosis?
• How would you treat this patient?

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

CO-OCCURRING DISORDERS: SCOPE OF THE PROBLEM

Co-occurring disorders, previously called “dual diagnosis,” refers to the coexistence of a mental health disorder and a substance use disorder. The obsolete term, dual diagnosis, specified the presence of 2 co-occurring Axis I diagnoses or the presence of an Axis I diagnosis and an Axis II diagnosis (such as mental disability). The change in nomenclature more precisely describes the co-existing mental health and substance use disorders.

Currently the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, (DSM-5) includes no diagnostic criteria for this dual condition.¹ The criteria for mental health disorders and for substance use disorders comprise separate lists. Criteria for substance use disorder fall broadly into categories of “impaired [self] control, social impairment, risky behaviors, increased tolerance, and withdrawal symptoms.”¹ It is estimated that 8.5 million US adults have co-occurring disorders, per the 2017 National Survey on Drug Use and Health conducted by the Substance Abuse and Mental Health Services Administration.² Distinguishing which of the 2 conditions occurred first can be challenging. It has been suggested that the lifetime prevalence of a mental health disorder with a coexisting substance use disorder is greater than 40%^3,4 (TABLE 1^1,4-8). For patients with schizophrenia and bipolar disorder, these numbers may be higher.

The consequences of undiagnosed and untreated co-occurring disorders include poor medication adherence, physical comorbidities (and decreased overall health), diminished self-care, increased suicide risk or aggression, increased risky sexual behavior, and possible incarceration.⁹

WHEN SHOULD YOU SUSPECT CO-OCCURRING DISORDERS?

With some patients, only one diagnosis may be apparent at a given point, which could make it difficult to expeditiously recognize the onset of a co-occurring condition. For example, if a patient with anxiety has been treated successfully for years and then experiences a worsening of symptoms, it’s possible a physician might increase the dosage of anxiety medication without reevaluating for a substance use disorder. However, when both co-occurring disorders are present, the patient usually exhibits a greater number of symptoms and, if the full scope of the condition remains unrecognized, will likely respond poorly to therapy and have a prolonged course to resolution.^3,8-13 Consider a co-occurring substance use disorder if treatment resistance persists, or if a patient has a recurrence or an exacerbation of a previously well-treated psychiatric disorder.

The estimated lifetime prevalence of coexisting mental health and substance use disorders is > 40%.

Diagnosing a second condition can also be difficult when a patient’s symptoms are actually adverse effects of substances or prescribed medications. For example, a patient with worsening anxiety may also exhibit increasing blood pressure resistant to treatment. The cause of the patient’s fluctuating blood pressures may actually be the result of his or her use of alcohol to self-treat the anxiety. In addition to self-medication, other underlying factors may be at play, including genetic vulnerability, environment, and lifestyle.¹⁴ In the case we present, the patient’s conditions arose independently.

Anxiety disorders, with a lifetime risk of 28.8% in the US population,⁴ may be the primary mental health issue in many patients with co-occurring disorders, but this cannot be assumed in lieu of a complete workup.^2,8,9,15 Substance use disorders in the general population have a past-year and lifetime prevalence of 14.6%.^1,4,16,17 Because the causal and temporal association between anxiety and substance abuse is not always clear, it’s important to separate the diagnoses of the mental health and substance use disorders.

Continue to: MAKING THE DIAGNOSIS

To make an accurate diagnosis of co-occurring disorder, it is essential to take a complete history focusing on the timeline of symptoms, previous diagnoses and treatments, if any, and substance-free periods. Details gathered from these inquiries will help to separate symptoms of a primary mental health disorder from adverse effects of medication, withdrawal symptoms, or symptoms related to an underlying chronic medical condition.

Optimally, the diagnosis of a mental health disorder should be considered following a ­substance-free period. If this is not possible, a chart review may reveal a time when the patient did not have a substance use ­disorder.¹⁸

A diagnosis of substance use disorder requires that the patient manifest at least 2 of 11 behaviors listed in the DSM-5 over a 12-month period.¹ The criteria focus on the amount of substance used, the time spent securing the substance, risky behaviors associated with the substance, and tolerance to the substance.

DON'T DEFER MENTAL HEALTH Tx

It is necessary to treat co-occurring disorders simultaneously. The old idea of deferring treatment of a mental health issue until the substance use disorder is resolved no longer ­applies.^19,20 Treating substance use problems without addressing comorbid mental health ­issues can negatively impact treatment progress and increase risk for relapse. In a similar way, leaving substance use problems untreated is associated with nonadherence in mental health treatment, poor engagement, and dropout.^21,22

Integrated services. Due to this condition’s level of clinical complexity, the optimal treatment approach is an interdisciplinary one in which integrated services are offered at a single location by a team of medical, mental health, and substance use providers (see “The case for behavioral health integration into primary care” in the June issue). An evidence-based example of such an approach is the Integrated Dual Disorder Treatment (IDDT) model—a comprehensive, integrated method of treating severe mental health disorders, including substance use disorders.^21,22 IDDT combines coordinated services such as pharmacologic, psychological, educational, and social interventions to address the needs of patients and their family members. The IDDT model conceptualizes and treats co-occurring disorders within a biopsychosocial framework. Specific services may include medical detoxification, pharmacotherapy, patient and family education, behavioral and cognitive therapies, contingency management, self-help support groups, supported employment, residential/housing assistance, and case management services.^23,24

Continue to: Medications for the mental health component

Medications for the mental health component. For patients who prefer medication treatment to cognitive behavioral therapy (CBT), or for whom CBT is unavailable, treat the mental health disorder per customary practice for the diagnosis (TABLE 2^25-30). For psychotic disorders, use an antipsychotic, adding a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) as needed depending on the presence of negative symptoms.^25,31 For bipolar spectrum disorder, start a mood stabilizer³²; for depressive disorders initiate an SSRI or SNRI.²⁷ Anxiety disorders respond optimally when treated with SSRIs or SNRIs. Buspirone may be prescribed alone or as an adjunct for anxiety, and it does not cause mood-altering or withdrawal effects. Benzodiazepines in a controlled and monitored setting are an option in some antianxiety treatment plans. Consultation with a psychiatrist will help to determine the best treatment in these situations.

In all cases, treat the substance use disorder concurrently. Treatment options vary depending on the substance of choice. Although often overlooked, there can be simultaneous nicotine abuse. Oral or inhaled medications for nicotine abuse treatment are limited. The range of pharmacologic options for alcohol use disorder includes naltrexone, acamprosate, and disulfiram.^29,33 Pharmacologic treatment options for opioid use disorder include naltrexone, methadone, and a combination of naloxone and buprenorphine.³⁴

Consider a co-occurring substance use disorder if treatment resistance persists, or if a patient has a recurrence or an exacerbation of a previously well-treated psychiatric disorder.

Physicians who wish to prescribe buprenorphine must qualify for and complete a certified 8 hour waiver-training course, which is then approved by the Drug Enforcement Agency (under the DATA 2000 – Drug and Alcohol Act 2000). The physician obtains the designation of a data-waived physician and is assigned a special identification number to prescribe these medications.^35,36 Methadone may be provided only in a licensed methadone maintenance program. Regular and random drug urine screen requirements apply to all treatment programs.

Psychosocial and behavioral interventions are essential to the successful treatment of co-occurring disorders. Evidence-based behavioral and cognitive therapies are recommended for promoting adaptive coping skills and healthy lifestyle behaviors in co-occurring disorder populations.^23,24,37-40 Motivational interviewing enhances motivation and adherence when patients demonstrate resistance or ambivalence.^41,42 Mindfulness-based interventions have been shown to be effective and may be particularly beneficial for treating cravings/­urges and promoting relapse prevention.^{37,39,40,43-46}

Psychotropic medications, as with other treatment components, are most effective when used in combination with services that simultaneously address the patient’s biological, psychological, and social needs.

Continue to: The grassroots organization...

The grassroots organization National Alliance on Mental Illness (www.nami.org) recommends self-help and support groups, which include 12-step, faith-based and non-faith–based programs.²⁰

For any treatment method to be successful, there needs to be a level of customization and individualization. Some patients may respond to medication or nonmedication treatments only, and others may need a combination of treatments.

CASE

The physician recalls a past diagnosis of anxiety and asks Ms. J if there are any new stressors or changes causing concern. The patient expresses concern about an opioid use relapse secondary to her recent diagnosis of rheumatoid arthritis, which may be life altering or limiting.

Even though she has been doing well and has been adherent to her daily buprenorphine treatment, she worries for the well-being of her family and what would happen if she cannot work, becomes incapacitated, or dies at a young age. She has never considered herself an anxious person and is surprised that anxiety could cause such pronounced physical symptoms.

Consider a co-occurring substance use disorder if treatment resistance persists, or if a patient has a recurrence or an exacerbation of a previously well-treated psychiatric disorder.

The physician discusses different modalities of treatment, including counseling with an onsite psychologist, a trial of an anti-anxiety medication such as sertraline, or return office visits with the physician. They decide first to schedule an appointment with the psychologist, and Ms. J promises to find more time for self-wellness activities, such as exercise.

After 3 months of therapy, the patient decides to space out treatment to every 2 to 3 months and does not report any more episodes of chest pain or shortness of breath.

CORRESPONDENCE
Kristen Rundell, MD, Northwood-High Building, 2231 N. High Street, Suite 211, Columbus, OH 43201; [email protected].

THE CASE

Janice J* visits her family physician with complaints of chest pain, shortness of breath, and heart palpitations that are usually worse at night. Her medical history is significant for deep vein thrombosis secondary to an underlying hypercoagulability condition (rheumatoid arthritis) diagnosed 2 months earlier. She also has a history of opioid use disorder and has been on buprenorphine/naloxone therapy for 3 years. Her family medical history is unremarkable. She works full-time and lives with her 8-year-old son. On physical exam, she appears anxious; her cardiac and pulmonary exams are normal. A completed workup rules out cardiac or pulmonary problems.

• What is your diagnosis?
• How would you treat this patient?

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

CO-OCCURRING DISORDERS: SCOPE OF THE PROBLEM

Co-occurring disorders, previously called “dual diagnosis,” refers to the coexistence of a mental health disorder and a substance use disorder. The obsolete term, dual diagnosis, specified the presence of 2 co-occurring Axis I diagnoses or the presence of an Axis I diagnosis and an Axis II diagnosis (such as mental disability). The change in nomenclature more precisely describes the co-existing mental health and substance use disorders.

Currently the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, (DSM-5) includes no diagnostic criteria for this dual condition.¹ The criteria for mental health disorders and for substance use disorders comprise separate lists. Criteria for substance use disorder fall broadly into categories of “impaired [self] control, social impairment, risky behaviors, increased tolerance, and withdrawal symptoms.”¹ It is estimated that 8.5 million US adults have co-occurring disorders, per the 2017 National Survey on Drug Use and Health conducted by the Substance Abuse and Mental Health Services Administration.² Distinguishing which of the 2 conditions occurred first can be challenging. It has been suggested that the lifetime prevalence of a mental health disorder with a coexisting substance use disorder is greater than 40%^3,4 (TABLE 1^1,4-8). For patients with schizophrenia and bipolar disorder, these numbers may be higher.

The consequences of undiagnosed and untreated co-occurring disorders include poor medication adherence, physical comorbidities (and decreased overall health), diminished self-care, increased suicide risk or aggression, increased risky sexual behavior, and possible incarceration.⁹

WHEN SHOULD YOU SUSPECT CO-OCCURRING DISORDERS?

With some patients, only one diagnosis may be apparent at a given point, which could make it difficult to expeditiously recognize the onset of a co-occurring condition. For example, if a patient with anxiety has been treated successfully for years and then experiences a worsening of symptoms, it’s possible a physician might increase the dosage of anxiety medication without reevaluating for a substance use disorder. However, when both co-occurring disorders are present, the patient usually exhibits a greater number of symptoms and, if the full scope of the condition remains unrecognized, will likely respond poorly to therapy and have a prolonged course to resolution.^3,8-13 Consider a co-occurring substance use disorder if treatment resistance persists, or if a patient has a recurrence or an exacerbation of a previously well-treated psychiatric disorder.

The estimated lifetime prevalence of coexisting mental health and substance use disorders is > 40%.

Diagnosing a second condition can also be difficult when a patient’s symptoms are actually adverse effects of substances or prescribed medications. For example, a patient with worsening anxiety may also exhibit increasing blood pressure resistant to treatment. The cause of the patient’s fluctuating blood pressures may actually be the result of his or her use of alcohol to self-treat the anxiety. In addition to self-medication, other underlying factors may be at play, including genetic vulnerability, environment, and lifestyle.¹⁴ In the case we present, the patient’s conditions arose independently.

Anxiety disorders, with a lifetime risk of 28.8% in the US population,⁴ may be the primary mental health issue in many patients with co-occurring disorders, but this cannot be assumed in lieu of a complete workup.^2,8,9,15 Substance use disorders in the general population have a past-year and lifetime prevalence of 14.6%.^1,4,16,17 Because the causal and temporal association between anxiety and substance abuse is not always clear, it’s important to separate the diagnoses of the mental health and substance use disorders.

Continue to: MAKING THE DIAGNOSIS

To make an accurate diagnosis of co-occurring disorder, it is essential to take a complete history focusing on the timeline of symptoms, previous diagnoses and treatments, if any, and substance-free periods. Details gathered from these inquiries will help to separate symptoms of a primary mental health disorder from adverse effects of medication, withdrawal symptoms, or symptoms related to an underlying chronic medical condition.

Optimally, the diagnosis of a mental health disorder should be considered following a ­substance-free period. If this is not possible, a chart review may reveal a time when the patient did not have a substance use ­disorder.¹⁸

A diagnosis of substance use disorder requires that the patient manifest at least 2 of 11 behaviors listed in the DSM-5 over a 12-month period.¹ The criteria focus on the amount of substance used, the time spent securing the substance, risky behaviors associated with the substance, and tolerance to the substance.

DON'T DEFER MENTAL HEALTH Tx

It is necessary to treat co-occurring disorders simultaneously. The old idea of deferring treatment of a mental health issue until the substance use disorder is resolved no longer ­applies.^19,20 Treating substance use problems without addressing comorbid mental health ­issues can negatively impact treatment progress and increase risk for relapse. In a similar way, leaving substance use problems untreated is associated with nonadherence in mental health treatment, poor engagement, and dropout.^21,22

Integrated services. Due to this condition’s level of clinical complexity, the optimal treatment approach is an interdisciplinary one in which integrated services are offered at a single location by a team of medical, mental health, and substance use providers (see “The case for behavioral health integration into primary care” in the June issue). An evidence-based example of such an approach is the Integrated Dual Disorder Treatment (IDDT) model—a comprehensive, integrated method of treating severe mental health disorders, including substance use disorders.^21,22 IDDT combines coordinated services such as pharmacologic, psychological, educational, and social interventions to address the needs of patients and their family members. The IDDT model conceptualizes and treats co-occurring disorders within a biopsychosocial framework. Specific services may include medical detoxification, pharmacotherapy, patient and family education, behavioral and cognitive therapies, contingency management, self-help support groups, supported employment, residential/housing assistance, and case management services.^23,24

Continue to: Medications for the mental health component

Medications for the mental health component. For patients who prefer medication treatment to cognitive behavioral therapy (CBT), or for whom CBT is unavailable, treat the mental health disorder per customary practice for the diagnosis (TABLE 2^25-30). For psychotic disorders, use an antipsychotic, adding a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) as needed depending on the presence of negative symptoms.^25,31 For bipolar spectrum disorder, start a mood stabilizer³²; for depressive disorders initiate an SSRI or SNRI.²⁷ Anxiety disorders respond optimally when treated with SSRIs or SNRIs. Buspirone may be prescribed alone or as an adjunct for anxiety, and it does not cause mood-altering or withdrawal effects. Benzodiazepines in a controlled and monitored setting are an option in some antianxiety treatment plans. Consultation with a psychiatrist will help to determine the best treatment in these situations.

In all cases, treat the substance use disorder concurrently. Treatment options vary depending on the substance of choice. Although often overlooked, there can be simultaneous nicotine abuse. Oral or inhaled medications for nicotine abuse treatment are limited. The range of pharmacologic options for alcohol use disorder includes naltrexone, acamprosate, and disulfiram.^29,33 Pharmacologic treatment options for opioid use disorder include naltrexone, methadone, and a combination of naloxone and buprenorphine.³⁴

Consider a co-occurring substance use disorder if treatment resistance persists, or if a patient has a recurrence or an exacerbation of a previously well-treated psychiatric disorder.

Physicians who wish to prescribe buprenorphine must qualify for and complete a certified 8 hour waiver-training course, which is then approved by the Drug Enforcement Agency (under the DATA 2000 – Drug and Alcohol Act 2000). The physician obtains the designation of a data-waived physician and is assigned a special identification number to prescribe these medications.^35,36 Methadone may be provided only in a licensed methadone maintenance program. Regular and random drug urine screen requirements apply to all treatment programs.

Psychosocial and behavioral interventions are essential to the successful treatment of co-occurring disorders. Evidence-based behavioral and cognitive therapies are recommended for promoting adaptive coping skills and healthy lifestyle behaviors in co-occurring disorder populations.^23,24,37-40 Motivational interviewing enhances motivation and adherence when patients demonstrate resistance or ambivalence.^41,42 Mindfulness-based interventions have been shown to be effective and may be particularly beneficial for treating cravings/­urges and promoting relapse prevention.^{37,39,40,43-46}

Psychotropic medications, as with other treatment components, are most effective when used in combination with services that simultaneously address the patient’s biological, psychological, and social needs.

Continue to: The grassroots organization...

The grassroots organization National Alliance on Mental Illness (www.nami.org) recommends self-help and support groups, which include 12-step, faith-based and non-faith–based programs.²⁰

For any treatment method to be successful, there needs to be a level of customization and individualization. Some patients may respond to medication or nonmedication treatments only, and others may need a combination of treatments.

CASE

The physician recalls a past diagnosis of anxiety and asks Ms. J if there are any new stressors or changes causing concern. The patient expresses concern about an opioid use relapse secondary to her recent diagnosis of rheumatoid arthritis, which may be life altering or limiting.

Even though she has been doing well and has been adherent to her daily buprenorphine treatment, she worries for the well-being of her family and what would happen if she cannot work, becomes incapacitated, or dies at a young age. She has never considered herself an anxious person and is surprised that anxiety could cause such pronounced physical symptoms.

Consider a co-occurring substance use disorder if treatment resistance persists, or if a patient has a recurrence or an exacerbation of a previously well-treated psychiatric disorder.

The physician discusses different modalities of treatment, including counseling with an onsite psychologist, a trial of an anti-anxiety medication such as sertraline, or return office visits with the physician. They decide first to schedule an appointment with the psychologist, and Ms. J promises to find more time for self-wellness activities, such as exercise.

After 3 months of therapy, the patient decides to space out treatment to every 2 to 3 months and does not report any more episodes of chest pain or shortness of breath.

CORRESPONDENCE
Kristen Rundell, MD, Northwood-High Building, 2231 N. High Street, Suite 211, Columbus, OH 43201; [email protected].

THE CASE

Janice J* visits her family physician with complaints of chest pain, shortness of breath, and heart palpitations that are usually worse at night. Her medical history is significant for deep vein thrombosis secondary to an underlying hypercoagulability condition (rheumatoid arthritis) diagnosed 2 months earlier. She also has a history of opioid use disorder and has been on buprenorphine/naloxone therapy for 3 years. Her family medical history is unremarkable. She works full-time and lives with her 8-year-old son. On physical exam, she appears anxious; her cardiac and pulmonary exams are normal. A completed workup rules out cardiac or pulmonary problems.

• What is your diagnosis?
• How would you treat this patient?

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

CO-OCCURRING DISORDERS: SCOPE OF THE PROBLEM

Co-occurring disorders, previously called “dual diagnosis,” refers to the coexistence of a mental health disorder and a substance use disorder. The obsolete term, dual diagnosis, specified the presence of 2 co-occurring Axis I diagnoses or the presence of an Axis I diagnosis and an Axis II diagnosis (such as mental disability). The change in nomenclature more precisely describes the co-existing mental health and substance use disorders.

Currently the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, (DSM-5) includes no diagnostic criteria for this dual condition.¹ The criteria for mental health disorders and for substance use disorders comprise separate lists. Criteria for substance use disorder fall broadly into categories of “impaired [self] control, social impairment, risky behaviors, increased tolerance, and withdrawal symptoms.”¹ It is estimated that 8.5 million US adults have co-occurring disorders, per the 2017 National Survey on Drug Use and Health conducted by the Substance Abuse and Mental Health Services Administration.² Distinguishing which of the 2 conditions occurred first can be challenging. It has been suggested that the lifetime prevalence of a mental health disorder with a coexisting substance use disorder is greater than 40%^3,4 (TABLE 1^1,4-8). For patients with schizophrenia and bipolar disorder, these numbers may be higher.

The consequences of undiagnosed and untreated co-occurring disorders include poor medication adherence, physical comorbidities (and decreased overall health), diminished self-care, increased suicide risk or aggression, increased risky sexual behavior, and possible incarceration.⁹

WHEN SHOULD YOU SUSPECT CO-OCCURRING DISORDERS?

With some patients, only one diagnosis may be apparent at a given point, which could make it difficult to expeditiously recognize the onset of a co-occurring condition. For example, if a patient with anxiety has been treated successfully for years and then experiences a worsening of symptoms, it’s possible a physician might increase the dosage of anxiety medication without reevaluating for a substance use disorder. However, when both co-occurring disorders are present, the patient usually exhibits a greater number of symptoms and, if the full scope of the condition remains unrecognized, will likely respond poorly to therapy and have a prolonged course to resolution.^3,8-13 Consider a co-occurring substance use disorder if treatment resistance persists, or if a patient has a recurrence or an exacerbation of a previously well-treated psychiatric disorder.

The estimated lifetime prevalence of coexisting mental health and substance use disorders is > 40%.

Diagnosing a second condition can also be difficult when a patient’s symptoms are actually adverse effects of substances or prescribed medications. For example, a patient with worsening anxiety may also exhibit increasing blood pressure resistant to treatment. The cause of the patient’s fluctuating blood pressures may actually be the result of his or her use of alcohol to self-treat the anxiety. In addition to self-medication, other underlying factors may be at play, including genetic vulnerability, environment, and lifestyle.¹⁴ In the case we present, the patient’s conditions arose independently.

Anxiety disorders, with a lifetime risk of 28.8% in the US population,⁴ may be the primary mental health issue in many patients with co-occurring disorders, but this cannot be assumed in lieu of a complete workup.^2,8,9,15 Substance use disorders in the general population have a past-year and lifetime prevalence of 14.6%.^1,4,16,17 Because the causal and temporal association between anxiety and substance abuse is not always clear, it’s important to separate the diagnoses of the mental health and substance use disorders.

Continue to: MAKING THE DIAGNOSIS

To make an accurate diagnosis of co-occurring disorder, it is essential to take a complete history focusing on the timeline of symptoms, previous diagnoses and treatments, if any, and substance-free periods. Details gathered from these inquiries will help to separate symptoms of a primary mental health disorder from adverse effects of medication, withdrawal symptoms, or symptoms related to an underlying chronic medical condition.

Optimally, the diagnosis of a mental health disorder should be considered following a ­substance-free period. If this is not possible, a chart review may reveal a time when the patient did not have a substance use ­disorder.¹⁸

A diagnosis of substance use disorder requires that the patient manifest at least 2 of 11 behaviors listed in the DSM-5 over a 12-month period.¹ The criteria focus on the amount of substance used, the time spent securing the substance, risky behaviors associated with the substance, and tolerance to the substance.

DON'T DEFER MENTAL HEALTH Tx

It is necessary to treat co-occurring disorders simultaneously. The old idea of deferring treatment of a mental health issue until the substance use disorder is resolved no longer ­applies.^19,20 Treating substance use problems without addressing comorbid mental health ­issues can negatively impact treatment progress and increase risk for relapse. In a similar way, leaving substance use problems untreated is associated with nonadherence in mental health treatment, poor engagement, and dropout.^21,22

Integrated services. Due to this condition’s level of clinical complexity, the optimal treatment approach is an interdisciplinary one in which integrated services are offered at a single location by a team of medical, mental health, and substance use providers (see “The case for behavioral health integration into primary care” in the June issue). An evidence-based example of such an approach is the Integrated Dual Disorder Treatment (IDDT) model—a comprehensive, integrated method of treating severe mental health disorders, including substance use disorders.^21,22 IDDT combines coordinated services such as pharmacologic, psychological, educational, and social interventions to address the needs of patients and their family members. The IDDT model conceptualizes and treats co-occurring disorders within a biopsychosocial framework. Specific services may include medical detoxification, pharmacotherapy, patient and family education, behavioral and cognitive therapies, contingency management, self-help support groups, supported employment, residential/housing assistance, and case management services.^23,24

Continue to: Medications for the mental health component

Medications for the mental health component. For patients who prefer medication treatment to cognitive behavioral therapy (CBT), or for whom CBT is unavailable, treat the mental health disorder per customary practice for the diagnosis (TABLE 2^25-30). For psychotic disorders, use an antipsychotic, adding a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) as needed depending on the presence of negative symptoms.^25,31 For bipolar spectrum disorder, start a mood stabilizer³²; for depressive disorders initiate an SSRI or SNRI.²⁷ Anxiety disorders respond optimally when treated with SSRIs or SNRIs. Buspirone may be prescribed alone or as an adjunct for anxiety, and it does not cause mood-altering or withdrawal effects. Benzodiazepines in a controlled and monitored setting are an option in some antianxiety treatment plans. Consultation with a psychiatrist will help to determine the best treatment in these situations.

In all cases, treat the substance use disorder concurrently. Treatment options vary depending on the substance of choice. Although often overlooked, there can be simultaneous nicotine abuse. Oral or inhaled medications for nicotine abuse treatment are limited. The range of pharmacologic options for alcohol use disorder includes naltrexone, acamprosate, and disulfiram.^29,33 Pharmacologic treatment options for opioid use disorder include naltrexone, methadone, and a combination of naloxone and buprenorphine.³⁴

Consider a co-occurring substance use disorder if treatment resistance persists, or if a patient has a recurrence or an exacerbation of a previously well-treated psychiatric disorder.

Physicians who wish to prescribe buprenorphine must qualify for and complete a certified 8 hour waiver-training course, which is then approved by the Drug Enforcement Agency (under the DATA 2000 – Drug and Alcohol Act 2000). The physician obtains the designation of a data-waived physician and is assigned a special identification number to prescribe these medications.^35,36 Methadone may be provided only in a licensed methadone maintenance program. Regular and random drug urine screen requirements apply to all treatment programs.

Psychosocial and behavioral interventions are essential to the successful treatment of co-occurring disorders. Evidence-based behavioral and cognitive therapies are recommended for promoting adaptive coping skills and healthy lifestyle behaviors in co-occurring disorder populations.^23,24,37-40 Motivational interviewing enhances motivation and adherence when patients demonstrate resistance or ambivalence.^41,42 Mindfulness-based interventions have been shown to be effective and may be particularly beneficial for treating cravings/­urges and promoting relapse prevention.^{37,39,40,43-46}

Psychotropic medications, as with other treatment components, are most effective when used in combination with services that simultaneously address the patient’s biological, psychological, and social needs.

Continue to: The grassroots organization...

The grassroots organization National Alliance on Mental Illness (www.nami.org) recommends self-help and support groups, which include 12-step, faith-based and non-faith–based programs.²⁰

For any treatment method to be successful, there needs to be a level of customization and individualization. Some patients may respond to medication or nonmedication treatments only, and others may need a combination of treatments.

CASE

The physician recalls a past diagnosis of anxiety and asks Ms. J if there are any new stressors or changes causing concern. The patient expresses concern about an opioid use relapse secondary to her recent diagnosis of rheumatoid arthritis, which may be life altering or limiting.

Even though she has been doing well and has been adherent to her daily buprenorphine treatment, she worries for the well-being of her family and what would happen if she cannot work, becomes incapacitated, or dies at a young age. She has never considered herself an anxious person and is surprised that anxiety could cause such pronounced physical symptoms.

Consider a co-occurring substance use disorder if treatment resistance persists, or if a patient has a recurrence or an exacerbation of a previously well-treated psychiatric disorder.

The physician discusses different modalities of treatment, including counseling with an onsite psychologist, a trial of an anti-anxiety medication such as sertraline, or return office visits with the physician. They decide first to schedule an appointment with the psychologist, and Ms. J promises to find more time for self-wellness activities, such as exercise.

After 3 months of therapy, the patient decides to space out treatment to every 2 to 3 months and does not report any more episodes of chest pain or shortness of breath.

CORRESPONDENCE
Kristen Rundell, MD, Northwood-High Building, 2231 N. High Street, Suite 211, Columbus, OH 43201; [email protected].

CASE 1

Robin S is a 40-year-old woman who has never had children or been pregnant. She is in a relationship with a woman so does not use contraception. She has no family history of cancer. She presents with worsening bilateral breast pain that starts 10 days before the onset of her period. The pain has been present for about 4 years, but it has worsened over the last 6 months such that she is unable to wear a bra during these 10 days, finds lying in bed on her side too painful for sleep, and is unable to exercise. She has tried to eliminate caffeine from her diet and takes ibuprofen, but neither of these interventions has controlled her pain. Her breast exam is normal except for diffuse tenderness over both breasts.

CASE 2

Meg R is a 50-year-old healthy woman. She is a G2P2 who breastfed each of her children for 1 year. She does not smoke. She has no family history of breast cancer or other malignancies. She presents with 2 months of deep, left-sided breast pain. She describes the pain as constant, progressive, dull, and achy. She points to a spot in the upper outer quadrant of her left breast and describes the pain as being close to her ribs. She had a screening mammogram 3 weeks earlier that was normal, with findings of dense breasts. She did not tell the technician that she was having pain. Clinical breast examination of both breasts reveals tenderness to deep palpation of the left breast. She has dense breasts but a focal mass is not palpated.

Mastalgia, or breast pain, is one of the most common breast symptoms seen in primary care and a common reason for referrals to breast surgeons. Up to 70% of women will experience breast pain during their lifetime—most in their premenopausal years.^1,2

The most common type of breast pain is cyclic (ie, relating to the menstrual cycle); it accounts for up to 70% of all cases of breast pain in women.^1,3 The other 2 types of breast pain are noncyclic and extramammary. The cause of cyclic breast pain is unclear, but it is likely hormonally mediated and multifactorial. In the vast majority of women with breast pain, no distinct etiology is found, and there is a very low incidence of breast cancer.^2,4

Up to 70% of women will experience breast pain during their lifetime, most in their premenopausal years.

In this review, we describe how to proceed when a woman who is not breastfeeding presents with cyclic or noncyclic breast pain.

Evaluation: Focus on the pain, medications, and history

Evaluation of breast pain should begin with the patient describing the pain, including its quality, location, radiation, and relationship to the menstrual cycle. It’s important to inquire about recent trauma or aggravating activities and to order a pregnancy test for women of childbearing age.¹

Cyclic mastalgia is typically described as diffuse, either unilateral or bilateral, with an aching or heavy quality. The pain is often felt in the upper outer quadrant of the breast with radiation to the axilla. It most commonly occurs during the luteal phase of the menstrual cycle, improves with the onset of menses, and is thought to be related to the increased water content in breast stroma caused by increasing hormone levels during the luteal phase.^5-7

Continue to: Noncyclic mastalgia

Noncyclic mastalgia is typically unilateral and localized within 1 quadrant of the breast; however, women may report diffuse pain with radiation to the axilla. The pain is often described as burning, achy, or as soreness.^5,6 There can be considerable overlap in the presentations of cyclic and noncyclic pain and differentiating between the 2 is often not necessary as management is similar.⁸

A thorough review of medications is important as several drugs have been associated with breast pain. These include oral contraceptives, hormone therapy, antidepressants (selective serotonin reuptake inhibitors [SSRIs], venlafaxine, mirtazapine), antipsychotics (haloperidol), and some cardiovascular agents (spironolactone, digoxin).⁵

Inquiring about stress, caffeine intake, smoking status, and bra usage may also yield useful information. Increased stress and caffeine intake have been associated with mastalgia,⁷ and women who are heavy smokers are more likely to have noncyclic hypersensitive breast pain.⁹ In addition, women with large breasts often have noncyclic breast pain, particularly if they don’t wear a sufficiently supportive bra.³

Medical, surgical, family history. Relevant aspects of a woman’s past medical, surgical, and family history include prior breast mass or biopsy, breast surgery, and risk factors associated with breast cancer (menarche age < 12 years, menopause age > 55 years, nulliparity, exposure to ionizing radiation, and family history of breast or ovarian cancer).¹ A thorough history should include questions to evaluate for extra-mammary etiologies of breast pain such as those that are musculoskeletal or dermatologic in nature (TABLE 1^1,5,8,10).

Using an objective measure of pain is not only helpful for evaluating the pain itself, but also for determining the effectiveness of treatment strategies. When using the Cardiff Breast Pain Chart, for example, menstrual cycle and level of pain are recorded on a calendar (see www.breastcancercare.org.uk/sites/default/files/files/breast_pain_chart.pdf).¹¹ If the pain is determined to be cyclic, the concern for malignancy is significantly lower.²

Continue to: Ensure that the physical exam is thorough

Ensure that the physical exam is thorough

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions. Inspect for asymmetry, erythema, rashes, skin dimpling, nipple discharge, and retraction/inversion. Palpate the breasts for any suspicious masses, asymmetry, or tenderness, as well as for axillary and/or supraclavicular lymphadenopathy and chest wall tenderness. This is facilitated by having the patient lie in the lateral decubitus position, allowing the breast to fall away from the chest wall.^5,12,13

Imaging: Preferred method depends on the age of the patient

Women with a palpable mass should be referred for diagnostic imaging (FIGURE 1^1,14). Ultrasonography is the recommended modality for women < 30 years of age (TABLE 2¹⁵). For women between the ages of 30 and 39 years, appropriate initial imaging includes ultrasound, diagnostic mammography, or digital breast tomosynthesis (DBT). For women ≥ 40 years of age, diagnostic mammography or DBT is recommended.¹⁵

Cyclic breast pain. Women with cyclic breast pain do not require further evaluation with imaging. Reassurance and symptomatic treatment is appropriate in most cases, as the risk of malignancy is very low in the absence of other concerning signs or symptoms. A screening mammogram may be appropriate for women > 40 years of age who have not had one in the preceding 12 months.^1-3,10,12,15

Noncyclic breast pain. In contrast, imaging may be appropriate in women who present with noncyclic breast pain depending on the woman’s age and whether the pain is focal (≤ 25% of the breast and axillary tissue) or diffuse (> 25% of the breast and axillary tissue). Although evidence suggests that the risk of malignancy in women with noncyclic breast pain is low, the American College of Radiology advises that imaging may be useful in some patients to provide reassurance and to exclude a treatable cause of breast pain.^3,14 In women with focal pain, ultrasound alone is the preferred modality for women < 30 years of age and ultrasound plus diagnostic mammography is recommended for women ≥ 30 years of age.^3,14

In one small study, the use of ultrasonography in women ages < 30 years with focal breast pain had a sensitivity of 100% and a negative predictive value of 100%.¹⁶ Similarly, another small retrospective study in older women (average age 56 years) with focal breast pain and no palpable mass showed that ultrasound plus diagnostic mammography had a negative predictive value of 100%.⁴ DBT may be used in place of mammography to rule out malignancy in this setting.

Continue to: In general...

In general, routine imaging is not indicated for women with noncyclic diffuse breast pain, although diagnostic mammography or DBT may be considered in women ≥ 40 years of age ¹⁴ (see “Less common diagnoses with breast pain”^4,5,17-21).

Continue to: Treatment...

Nonrandomized studies suggest that reassurance that mastalgia is benign is enough to treat up to 70% of women.^8,22,23 Cyclic breast pain is usually treated symptomatically since the likelihood of breast cancer is extremely low in absence of clinical breast examination abnormalities.² Because treatment for cyclic and noncyclic mastalgia overlaps, available treatments are discussed together on the following pages.

Lifestyle factors associated with breast pain include stress, caffeine consumption, smoking, and having breastfed 3 or more children (P < .05).⁹ Although restriction of caffeine, fat, and salt intake may be attempted to address breast pain, no randomized control trials (RCTs) of these interventions have demonstrated effectiveness in reducing mastalgia.^8,10

Breast imaging is critical in patients with a palpable mass or focal pain but is not necessary in patients with cyclic pain.

Although not supported by RCTs, first-line treatment of mastalgia includes a recommendation that women, particularly those with large, heavy breasts, wear a well-fitted and supportive bra.^8,10

Complementary and alternative medicine treatments for mastalgia

A number of complementary and alternative medicine treatments have demonstrated benefit in treating mastalgia and are often tried before pharmacologic agents (TABLE 3^24-28). Keep in mind, though, that these therapies are not regulated by the US Food and Drug Administration (FDA). So it’s wise to review particular products with your patient before she buys them (or ask her to bring in any bottles of product for you to review).

Flaxseed, omega-3 fatty acids, and soy milk. Flaxseed, a source of phytoestrogens and omega-3 fatty acids, has been shown to reduce cyclic breast pain in 2 small RCTs.^24,25 Breast pain scores were significantly lower for patients ingesting 25 g/d of flaxseed powder compared with placebo.^24,25 Omega-3 fatty acids were also more effective than placebo for relief of cyclic breast pain in 2 small RCTs.^25,26 Another small RCT demonstrated that women who drank soy milk had a nonsignificant improvement in breast pain compared with those who drank cow’s milk.²⁷

Continue to: Chasteberry

Chasteberry. One RCT demonstrated that Vitex agnus-castus, a chasteberry fruit extract, produced significant and clinically meaningful improvement in visual analogue pain scores for mastalgia, with few adverse effects.²⁹ Another RCT assessing breast fullness as part of the premenstrual syndrome showed significant improvement in breast discomfort for women treated with Vitex ­agnus-castus.³⁰

Evening primrose oil (EPO). In at least one small study, EPO was effective in controlling breast pain.²⁸ A more recent meta-analysis of all of the EPO trials including gamolenic acid (the active ingredient of EPO) showed no significant difference in mastalgia compared with placebo.³¹

Pharmacologic Tx options: Start with NSAIDs

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are often recommended as a first-line treatment for mastalgia and are likely effective for some women; however, there is currently insufficient evidence that oral NSAIDs (or acetaminophen) improve pain (TABLE 4^32-37; FIGURE 2^5,13,17). Nevertheless, the potential benefits are thought to outweigh the risk of adverse effects in most patients. A small RCT did demonstrate that topical diclofenac was effective in patients with cyclic and noncyclic mastalgia.³⁸

SSRIs. A meta-analysis of 10 double-blind RCTs of SSRIs used in women with premenstrual symptoms, including 4 studies that specifically included physical symptoms such as breast pain, showed SSRIs to be more effective than placebo at relieving breast pain.³⁵

Progesterones. Several studies have found topical, oral, and injected progesterone ineffective at reducing breast pain.^8,36,39 However, one RCT did show topical vaginal micronized progesterone used in the luteal phase to be effective in reducing breast pain by at least 50%.³⁶

Continue to: Oral contraceptives

Oral contraceptives. For women who use oral contraceptive pills and experience cyclic breast pain, continuous dosing (skipping the pill-free week) or using a lower dose of estrogen may improve symptoms. Postmenopausal women with mastalgia that developed with initiation of hormone therapy may benefit from discontinuing hormone therapy or decreasing the estrogen dose; however, there are no RCTs to offer conclusive evidence of the effectiveness of these interventions.¹⁰

Danazol. Women with severe mastalgia that does not respond to more benign therapies may require hormone therapy. As with all symptom management, it is imperative to engage the patient in a shared decision-making conversation about the risks and benefits of this treatment strategy. Women must be able to balance the potential adverse effects of agents such as danazol and tamoxifen with the need to alleviate pain and improve quality of life.

Oral NSAIDs are often recommended as first-line treatment for mastalgia.

Danazol is the only medication FDA-approved for the treatment of mastalgia. Danazol is an androgen that blocks the release of other gonadotropins to limit hormonal stimulation of breast tissue. One RCT demonstrated that danazol (100 mg bid) reduces breast pain in 60% to 90% of women, although adverse effects often limit utility.⁴⁰ Adverse effects of danazol include weight gain, hot flashes, deepening of the voice, hirsutism, menorrhagia or amenorrhea, muscle cramps, and androgenic effects on a fetus.^8,31,40 Danazol may be best used cyclically during the luteal phase of the menstrual cycle to limit these adverse effects with reduction of the dose to 100 mg/d after relief of symptoms.^31,40

Tamoxifen, a selective estrogen receptor modulator, has been shown to reduce breast pain in 80% to 90% of women, although it is not indicated for mastalgia.⁴⁰ Tamoxifen may cause endometrial thickening, hot flashes, menstrual irregularity, venous thromboembolism, and teratogenicity. The 10 mg/d dose appears to be as effective at improving symptoms as the 20 mg/d dose with fewer adverse effects.^8,31,40

In a head-to-head randomized trial, tamoxifen was superior to danazol for relief of breast pain with fewer adverse effects.³⁴ Experts recommend limiting use of tamoxifen and danazol to 3 to 6 months. Neither of these drugs is considered safe in pregnancy.

Continue to: Bromocriptine

Bromocriptine, a prolactin inhibitor, has been shown to be more effective than placebo in reducing breast pain, although nausea and dizziness contribute to high discontinuation rates. Bromocriptine is less effective than danazol.⁴⁰

Goserelin, which is not available in the United States, is a gonadorelin analog (luteinizing hormone-releasing hormone analog) that produces reversible ovarian suppression. One RCT showed that goserelin injection may be more effective than placebo in reducing breast pain.³⁷ Adverse effects include vaginal dryness, hot flashes, decreased libido, oily skin or hair, decreased breast size, and irritability. It is recommended as treatment only for severe refractory mastalgia and that it be used no longer than 6 months.^31,37

CASE 1

You reassure Ms. S that her history and physical exam are consistent with cyclic breast pain and not malignancy. You review the current US Preventive Services Task Force recommendations for breast cancer screening in women ages 40 to 49 years (Grade C; women who place a higher value on the potential benefit than the potential harms may choose screening).⁴¹ Based on shared decision-making,you offer her a screening mammogram, which returns normal. After confirming that she is using an appropriately-sized supportive bra, you recommend adding 25 g/d of ground flaxseed to her diet.

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions.

After 2 months she reports a 30% improvement in her pain. You then recommend chasteberry extract 4.2 mg/d, which provides additional relief to the point where she can now sleep better and walk for exercise.

CASE 2

You order a diagnostic mammogram of the left breast, which is normal, and an ultrasound that demonstrates a 6-cm deep mass. A biopsy determines that Ms. R has invasive lobular breast cancer—an extremely unlikely outcome of breast pain. She elects to have a double mastectomy and reconstruction and is doing well 4 years later.

CORRESPONDENCE
Sarina Schrager, MD, MS, University of Wisconsin Department of Family Medicine and Community Health, 1100 Delaplaine Ct., Madison, WI, 53715; [email protected].

CASE 1

Robin S is a 40-year-old woman who has never had children or been pregnant. She is in a relationship with a woman so does not use contraception. She has no family history of cancer. She presents with worsening bilateral breast pain that starts 10 days before the onset of her period. The pain has been present for about 4 years, but it has worsened over the last 6 months such that she is unable to wear a bra during these 10 days, finds lying in bed on her side too painful for sleep, and is unable to exercise. She has tried to eliminate caffeine from her diet and takes ibuprofen, but neither of these interventions has controlled her pain. Her breast exam is normal except for diffuse tenderness over both breasts.

CASE 2

Meg R is a 50-year-old healthy woman. She is a G2P2 who breastfed each of her children for 1 year. She does not smoke. She has no family history of breast cancer or other malignancies. She presents with 2 months of deep, left-sided breast pain. She describes the pain as constant, progressive, dull, and achy. She points to a spot in the upper outer quadrant of her left breast and describes the pain as being close to her ribs. She had a screening mammogram 3 weeks earlier that was normal, with findings of dense breasts. She did not tell the technician that she was having pain. Clinical breast examination of both breasts reveals tenderness to deep palpation of the left breast. She has dense breasts but a focal mass is not palpated.

Mastalgia, or breast pain, is one of the most common breast symptoms seen in primary care and a common reason for referrals to breast surgeons. Up to 70% of women will experience breast pain during their lifetime—most in their premenopausal years.^1,2

The most common type of breast pain is cyclic (ie, relating to the menstrual cycle); it accounts for up to 70% of all cases of breast pain in women.^1,3 The other 2 types of breast pain are noncyclic and extramammary. The cause of cyclic breast pain is unclear, but it is likely hormonally mediated and multifactorial. In the vast majority of women with breast pain, no distinct etiology is found, and there is a very low incidence of breast cancer.^2,4

Up to 70% of women will experience breast pain during their lifetime, most in their premenopausal years.

In this review, we describe how to proceed when a woman who is not breastfeeding presents with cyclic or noncyclic breast pain.

Evaluation: Focus on the pain, medications, and history

Evaluation of breast pain should begin with the patient describing the pain, including its quality, location, radiation, and relationship to the menstrual cycle. It’s important to inquire about recent trauma or aggravating activities and to order a pregnancy test for women of childbearing age.¹

Cyclic mastalgia is typically described as diffuse, either unilateral or bilateral, with an aching or heavy quality. The pain is often felt in the upper outer quadrant of the breast with radiation to the axilla. It most commonly occurs during the luteal phase of the menstrual cycle, improves with the onset of menses, and is thought to be related to the increased water content in breast stroma caused by increasing hormone levels during the luteal phase.^5-7

Continue to: Noncyclic mastalgia

Noncyclic mastalgia is typically unilateral and localized within 1 quadrant of the breast; however, women may report diffuse pain with radiation to the axilla. The pain is often described as burning, achy, or as soreness.^5,6 There can be considerable overlap in the presentations of cyclic and noncyclic pain and differentiating between the 2 is often not necessary as management is similar.⁸

A thorough review of medications is important as several drugs have been associated with breast pain. These include oral contraceptives, hormone therapy, antidepressants (selective serotonin reuptake inhibitors [SSRIs], venlafaxine, mirtazapine), antipsychotics (haloperidol), and some cardiovascular agents (spironolactone, digoxin).⁵

Inquiring about stress, caffeine intake, smoking status, and bra usage may also yield useful information. Increased stress and caffeine intake have been associated with mastalgia,⁷ and women who are heavy smokers are more likely to have noncyclic hypersensitive breast pain.⁹ In addition, women with large breasts often have noncyclic breast pain, particularly if they don’t wear a sufficiently supportive bra.³

Medical, surgical, family history. Relevant aspects of a woman’s past medical, surgical, and family history include prior breast mass or biopsy, breast surgery, and risk factors associated with breast cancer (menarche age < 12 years, menopause age > 55 years, nulliparity, exposure to ionizing radiation, and family history of breast or ovarian cancer).¹ A thorough history should include questions to evaluate for extra-mammary etiologies of breast pain such as those that are musculoskeletal or dermatologic in nature (TABLE 1^1,5,8,10).

Using an objective measure of pain is not only helpful for evaluating the pain itself, but also for determining the effectiveness of treatment strategies. When using the Cardiff Breast Pain Chart, for example, menstrual cycle and level of pain are recorded on a calendar (see www.breastcancercare.org.uk/sites/default/files/files/breast_pain_chart.pdf).¹¹ If the pain is determined to be cyclic, the concern for malignancy is significantly lower.²

Continue to: Ensure that the physical exam is thorough

Ensure that the physical exam is thorough

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions. Inspect for asymmetry, erythema, rashes, skin dimpling, nipple discharge, and retraction/inversion. Palpate the breasts for any suspicious masses, asymmetry, or tenderness, as well as for axillary and/or supraclavicular lymphadenopathy and chest wall tenderness. This is facilitated by having the patient lie in the lateral decubitus position, allowing the breast to fall away from the chest wall.^5,12,13

Imaging: Preferred method depends on the age of the patient

Women with a palpable mass should be referred for diagnostic imaging (FIGURE 1^1,14). Ultrasonography is the recommended modality for women < 30 years of age (TABLE 2¹⁵). For women between the ages of 30 and 39 years, appropriate initial imaging includes ultrasound, diagnostic mammography, or digital breast tomosynthesis (DBT). For women ≥ 40 years of age, diagnostic mammography or DBT is recommended.¹⁵

Cyclic breast pain. Women with cyclic breast pain do not require further evaluation with imaging. Reassurance and symptomatic treatment is appropriate in most cases, as the risk of malignancy is very low in the absence of other concerning signs or symptoms. A screening mammogram may be appropriate for women > 40 years of age who have not had one in the preceding 12 months.^1-3,10,12,15

Noncyclic breast pain. In contrast, imaging may be appropriate in women who present with noncyclic breast pain depending on the woman’s age and whether the pain is focal (≤ 25% of the breast and axillary tissue) or diffuse (> 25% of the breast and axillary tissue). Although evidence suggests that the risk of malignancy in women with noncyclic breast pain is low, the American College of Radiology advises that imaging may be useful in some patients to provide reassurance and to exclude a treatable cause of breast pain.^3,14 In women with focal pain, ultrasound alone is the preferred modality for women < 30 years of age and ultrasound plus diagnostic mammography is recommended for women ≥ 30 years of age.^3,14

In one small study, the use of ultrasonography in women ages < 30 years with focal breast pain had a sensitivity of 100% and a negative predictive value of 100%.¹⁶ Similarly, another small retrospective study in older women (average age 56 years) with focal breast pain and no palpable mass showed that ultrasound plus diagnostic mammography had a negative predictive value of 100%.⁴ DBT may be used in place of mammography to rule out malignancy in this setting.

Continue to: In general...

In general, routine imaging is not indicated for women with noncyclic diffuse breast pain, although diagnostic mammography or DBT may be considered in women ≥ 40 years of age ¹⁴ (see “Less common diagnoses with breast pain”^4,5,17-21).

Continue to: Treatment...

Nonrandomized studies suggest that reassurance that mastalgia is benign is enough to treat up to 70% of women.^8,22,23 Cyclic breast pain is usually treated symptomatically since the likelihood of breast cancer is extremely low in absence of clinical breast examination abnormalities.² Because treatment for cyclic and noncyclic mastalgia overlaps, available treatments are discussed together on the following pages.

Lifestyle factors associated with breast pain include stress, caffeine consumption, smoking, and having breastfed 3 or more children (P < .05).⁹ Although restriction of caffeine, fat, and salt intake may be attempted to address breast pain, no randomized control trials (RCTs) of these interventions have demonstrated effectiveness in reducing mastalgia.^8,10

Breast imaging is critical in patients with a palpable mass or focal pain but is not necessary in patients with cyclic pain.

Although not supported by RCTs, first-line treatment of mastalgia includes a recommendation that women, particularly those with large, heavy breasts, wear a well-fitted and supportive bra.^8,10

Complementary and alternative medicine treatments for mastalgia

A number of complementary and alternative medicine treatments have demonstrated benefit in treating mastalgia and are often tried before pharmacologic agents (TABLE 3^24-28). Keep in mind, though, that these therapies are not regulated by the US Food and Drug Administration (FDA). So it’s wise to review particular products with your patient before she buys them (or ask her to bring in any bottles of product for you to review).

Flaxseed, omega-3 fatty acids, and soy milk. Flaxseed, a source of phytoestrogens and omega-3 fatty acids, has been shown to reduce cyclic breast pain in 2 small RCTs.^24,25 Breast pain scores were significantly lower for patients ingesting 25 g/d of flaxseed powder compared with placebo.^24,25 Omega-3 fatty acids were also more effective than placebo for relief of cyclic breast pain in 2 small RCTs.^25,26 Another small RCT demonstrated that women who drank soy milk had a nonsignificant improvement in breast pain compared with those who drank cow’s milk.²⁷

Continue to: Chasteberry

Chasteberry. One RCT demonstrated that Vitex agnus-castus, a chasteberry fruit extract, produced significant and clinically meaningful improvement in visual analogue pain scores for mastalgia, with few adverse effects.²⁹ Another RCT assessing breast fullness as part of the premenstrual syndrome showed significant improvement in breast discomfort for women treated with Vitex ­agnus-castus.³⁰

Evening primrose oil (EPO). In at least one small study, EPO was effective in controlling breast pain.²⁸ A more recent meta-analysis of all of the EPO trials including gamolenic acid (the active ingredient of EPO) showed no significant difference in mastalgia compared with placebo.³¹

Pharmacologic Tx options: Start with NSAIDs

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are often recommended as a first-line treatment for mastalgia and are likely effective for some women; however, there is currently insufficient evidence that oral NSAIDs (or acetaminophen) improve pain (TABLE 4^32-37; FIGURE 2^5,13,17). Nevertheless, the potential benefits are thought to outweigh the risk of adverse effects in most patients. A small RCT did demonstrate that topical diclofenac was effective in patients with cyclic and noncyclic mastalgia.³⁸

SSRIs. A meta-analysis of 10 double-blind RCTs of SSRIs used in women with premenstrual symptoms, including 4 studies that specifically included physical symptoms such as breast pain, showed SSRIs to be more effective than placebo at relieving breast pain.³⁵

Progesterones. Several studies have found topical, oral, and injected progesterone ineffective at reducing breast pain.^8,36,39 However, one RCT did show topical vaginal micronized progesterone used in the luteal phase to be effective in reducing breast pain by at least 50%.³⁶

Continue to: Oral contraceptives

Oral contraceptives. For women who use oral contraceptive pills and experience cyclic breast pain, continuous dosing (skipping the pill-free week) or using a lower dose of estrogen may improve symptoms. Postmenopausal women with mastalgia that developed with initiation of hormone therapy may benefit from discontinuing hormone therapy or decreasing the estrogen dose; however, there are no RCTs to offer conclusive evidence of the effectiveness of these interventions.¹⁰

Danazol. Women with severe mastalgia that does not respond to more benign therapies may require hormone therapy. As with all symptom management, it is imperative to engage the patient in a shared decision-making conversation about the risks and benefits of this treatment strategy. Women must be able to balance the potential adverse effects of agents such as danazol and tamoxifen with the need to alleviate pain and improve quality of life.

Oral NSAIDs are often recommended as first-line treatment for mastalgia.

Danazol is the only medication FDA-approved for the treatment of mastalgia. Danazol is an androgen that blocks the release of other gonadotropins to limit hormonal stimulation of breast tissue. One RCT demonstrated that danazol (100 mg bid) reduces breast pain in 60% to 90% of women, although adverse effects often limit utility.⁴⁰ Adverse effects of danazol include weight gain, hot flashes, deepening of the voice, hirsutism, menorrhagia or amenorrhea, muscle cramps, and androgenic effects on a fetus.^8,31,40 Danazol may be best used cyclically during the luteal phase of the menstrual cycle to limit these adverse effects with reduction of the dose to 100 mg/d after relief of symptoms.^31,40

Tamoxifen, a selective estrogen receptor modulator, has been shown to reduce breast pain in 80% to 90% of women, although it is not indicated for mastalgia.⁴⁰ Tamoxifen may cause endometrial thickening, hot flashes, menstrual irregularity, venous thromboembolism, and teratogenicity. The 10 mg/d dose appears to be as effective at improving symptoms as the 20 mg/d dose with fewer adverse effects.^8,31,40

In a head-to-head randomized trial, tamoxifen was superior to danazol for relief of breast pain with fewer adverse effects.³⁴ Experts recommend limiting use of tamoxifen and danazol to 3 to 6 months. Neither of these drugs is considered safe in pregnancy.

Continue to: Bromocriptine

Bromocriptine, a prolactin inhibitor, has been shown to be more effective than placebo in reducing breast pain, although nausea and dizziness contribute to high discontinuation rates. Bromocriptine is less effective than danazol.⁴⁰

Goserelin, which is not available in the United States, is a gonadorelin analog (luteinizing hormone-releasing hormone analog) that produces reversible ovarian suppression. One RCT showed that goserelin injection may be more effective than placebo in reducing breast pain.³⁷ Adverse effects include vaginal dryness, hot flashes, decreased libido, oily skin or hair, decreased breast size, and irritability. It is recommended as treatment only for severe refractory mastalgia and that it be used no longer than 6 months.^31,37

CASE 1

You reassure Ms. S that her history and physical exam are consistent with cyclic breast pain and not malignancy. You review the current US Preventive Services Task Force recommendations for breast cancer screening in women ages 40 to 49 years (Grade C; women who place a higher value on the potential benefit than the potential harms may choose screening).⁴¹ Based on shared decision-making,you offer her a screening mammogram, which returns normal. After confirming that she is using an appropriately-sized supportive bra, you recommend adding 25 g/d of ground flaxseed to her diet.

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions.

After 2 months she reports a 30% improvement in her pain. You then recommend chasteberry extract 4.2 mg/d, which provides additional relief to the point where she can now sleep better and walk for exercise.

CASE 2

You order a diagnostic mammogram of the left breast, which is normal, and an ultrasound that demonstrates a 6-cm deep mass. A biopsy determines that Ms. R has invasive lobular breast cancer—an extremely unlikely outcome of breast pain. She elects to have a double mastectomy and reconstruction and is doing well 4 years later.

CORRESPONDENCE
Sarina Schrager, MD, MS, University of Wisconsin Department of Family Medicine and Community Health, 1100 Delaplaine Ct., Madison, WI, 53715; [email protected].

CASE 1

Robin S is a 40-year-old woman who has never had children or been pregnant. She is in a relationship with a woman so does not use contraception. She has no family history of cancer. She presents with worsening bilateral breast pain that starts 10 days before the onset of her period. The pain has been present for about 4 years, but it has worsened over the last 6 months such that she is unable to wear a bra during these 10 days, finds lying in bed on her side too painful for sleep, and is unable to exercise. She has tried to eliminate caffeine from her diet and takes ibuprofen, but neither of these interventions has controlled her pain. Her breast exam is normal except for diffuse tenderness over both breasts.

CASE 2

Meg R is a 50-year-old healthy woman. She is a G2P2 who breastfed each of her children for 1 year. She does not smoke. She has no family history of breast cancer or other malignancies. She presents with 2 months of deep, left-sided breast pain. She describes the pain as constant, progressive, dull, and achy. She points to a spot in the upper outer quadrant of her left breast and describes the pain as being close to her ribs. She had a screening mammogram 3 weeks earlier that was normal, with findings of dense breasts. She did not tell the technician that she was having pain. Clinical breast examination of both breasts reveals tenderness to deep palpation of the left breast. She has dense breasts but a focal mass is not palpated.

Mastalgia, or breast pain, is one of the most common breast symptoms seen in primary care and a common reason for referrals to breast surgeons. Up to 70% of women will experience breast pain during their lifetime—most in their premenopausal years.^1,2

The most common type of breast pain is cyclic (ie, relating to the menstrual cycle); it accounts for up to 70% of all cases of breast pain in women.^1,3 The other 2 types of breast pain are noncyclic and extramammary. The cause of cyclic breast pain is unclear, but it is likely hormonally mediated and multifactorial. In the vast majority of women with breast pain, no distinct etiology is found, and there is a very low incidence of breast cancer.^2,4

Up to 70% of women will experience breast pain during their lifetime, most in their premenopausal years.

In this review, we describe how to proceed when a woman who is not breastfeeding presents with cyclic or noncyclic breast pain.

Evaluation: Focus on the pain, medications, and history

Evaluation of breast pain should begin with the patient describing the pain, including its quality, location, radiation, and relationship to the menstrual cycle. It’s important to inquire about recent trauma or aggravating activities and to order a pregnancy test for women of childbearing age.¹

Cyclic mastalgia is typically described as diffuse, either unilateral or bilateral, with an aching or heavy quality. The pain is often felt in the upper outer quadrant of the breast with radiation to the axilla. It most commonly occurs during the luteal phase of the menstrual cycle, improves with the onset of menses, and is thought to be related to the increased water content in breast stroma caused by increasing hormone levels during the luteal phase.^5-7

Continue to: Noncyclic mastalgia

Noncyclic mastalgia is typically unilateral and localized within 1 quadrant of the breast; however, women may report diffuse pain with radiation to the axilla. The pain is often described as burning, achy, or as soreness.^5,6 There can be considerable overlap in the presentations of cyclic and noncyclic pain and differentiating between the 2 is often not necessary as management is similar.⁸

A thorough review of medications is important as several drugs have been associated with breast pain. These include oral contraceptives, hormone therapy, antidepressants (selective serotonin reuptake inhibitors [SSRIs], venlafaxine, mirtazapine), antipsychotics (haloperidol), and some cardiovascular agents (spironolactone, digoxin).⁵

Inquiring about stress, caffeine intake, smoking status, and bra usage may also yield useful information. Increased stress and caffeine intake have been associated with mastalgia,⁷ and women who are heavy smokers are more likely to have noncyclic hypersensitive breast pain.⁹ In addition, women with large breasts often have noncyclic breast pain, particularly if they don’t wear a sufficiently supportive bra.³

Medical, surgical, family history. Relevant aspects of a woman’s past medical, surgical, and family history include prior breast mass or biopsy, breast surgery, and risk factors associated with breast cancer (menarche age < 12 years, menopause age > 55 years, nulliparity, exposure to ionizing radiation, and family history of breast or ovarian cancer).¹ A thorough history should include questions to evaluate for extra-mammary etiologies of breast pain such as those that are musculoskeletal or dermatologic in nature (TABLE 1^1,5,8,10).

Using an objective measure of pain is not only helpful for evaluating the pain itself, but also for determining the effectiveness of treatment strategies. When using the Cardiff Breast Pain Chart, for example, menstrual cycle and level of pain are recorded on a calendar (see www.breastcancercare.org.uk/sites/default/files/files/breast_pain_chart.pdf).¹¹ If the pain is determined to be cyclic, the concern for malignancy is significantly lower.²

Continue to: Ensure that the physical exam is thorough

Ensure that the physical exam is thorough

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions. Inspect for asymmetry, erythema, rashes, skin dimpling, nipple discharge, and retraction/inversion. Palpate the breasts for any suspicious masses, asymmetry, or tenderness, as well as for axillary and/or supraclavicular lymphadenopathy and chest wall tenderness. This is facilitated by having the patient lie in the lateral decubitus position, allowing the breast to fall away from the chest wall.^5,12,13

Imaging: Preferred method depends on the age of the patient

Women with a palpable mass should be referred for diagnostic imaging (FIGURE 1^1,14). Ultrasonography is the recommended modality for women < 30 years of age (TABLE 2¹⁵). For women between the ages of 30 and 39 years, appropriate initial imaging includes ultrasound, diagnostic mammography, or digital breast tomosynthesis (DBT). For women ≥ 40 years of age, diagnostic mammography or DBT is recommended.¹⁵

Cyclic breast pain. Women with cyclic breast pain do not require further evaluation with imaging. Reassurance and symptomatic treatment is appropriate in most cases, as the risk of malignancy is very low in the absence of other concerning signs or symptoms. A screening mammogram may be appropriate for women > 40 years of age who have not had one in the preceding 12 months.^1-3,10,12,15

Noncyclic breast pain. In contrast, imaging may be appropriate in women who present with noncyclic breast pain depending on the woman’s age and whether the pain is focal (≤ 25% of the breast and axillary tissue) or diffuse (> 25% of the breast and axillary tissue). Although evidence suggests that the risk of malignancy in women with noncyclic breast pain is low, the American College of Radiology advises that imaging may be useful in some patients to provide reassurance and to exclude a treatable cause of breast pain.^3,14 In women with focal pain, ultrasound alone is the preferred modality for women < 30 years of age and ultrasound plus diagnostic mammography is recommended for women ≥ 30 years of age.^3,14

In one small study, the use of ultrasonography in women ages < 30 years with focal breast pain had a sensitivity of 100% and a negative predictive value of 100%.¹⁶ Similarly, another small retrospective study in older women (average age 56 years) with focal breast pain and no palpable mass showed that ultrasound plus diagnostic mammography had a negative predictive value of 100%.⁴ DBT may be used in place of mammography to rule out malignancy in this setting.

Continue to: In general...

In general, routine imaging is not indicated for women with noncyclic diffuse breast pain, although diagnostic mammography or DBT may be considered in women ≥ 40 years of age ¹⁴ (see “Less common diagnoses with breast pain”^4,5,17-21).

Continue to: Treatment...

Nonrandomized studies suggest that reassurance that mastalgia is benign is enough to treat up to 70% of women.^8,22,23 Cyclic breast pain is usually treated symptomatically since the likelihood of breast cancer is extremely low in absence of clinical breast examination abnormalities.² Because treatment for cyclic and noncyclic mastalgia overlaps, available treatments are discussed together on the following pages.

Lifestyle factors associated with breast pain include stress, caffeine consumption, smoking, and having breastfed 3 or more children (P < .05).⁹ Although restriction of caffeine, fat, and salt intake may be attempted to address breast pain, no randomized control trials (RCTs) of these interventions have demonstrated effectiveness in reducing mastalgia.^8,10

Breast imaging is critical in patients with a palpable mass or focal pain but is not necessary in patients with cyclic pain.

Although not supported by RCTs, first-line treatment of mastalgia includes a recommendation that women, particularly those with large, heavy breasts, wear a well-fitted and supportive bra.^8,10

Complementary and alternative medicine treatments for mastalgia

A number of complementary and alternative medicine treatments have demonstrated benefit in treating mastalgia and are often tried before pharmacologic agents (TABLE 3^24-28). Keep in mind, though, that these therapies are not regulated by the US Food and Drug Administration (FDA). So it’s wise to review particular products with your patient before she buys them (or ask her to bring in any bottles of product for you to review).

Flaxseed, omega-3 fatty acids, and soy milk. Flaxseed, a source of phytoestrogens and omega-3 fatty acids, has been shown to reduce cyclic breast pain in 2 small RCTs.^24,25 Breast pain scores were significantly lower for patients ingesting 25 g/d of flaxseed powder compared with placebo.^24,25 Omega-3 fatty acids were also more effective than placebo for relief of cyclic breast pain in 2 small RCTs.^25,26 Another small RCT demonstrated that women who drank soy milk had a nonsignificant improvement in breast pain compared with those who drank cow’s milk.²⁷

Continue to: Chasteberry

Chasteberry. One RCT demonstrated that Vitex agnus-castus, a chasteberry fruit extract, produced significant and clinically meaningful improvement in visual analogue pain scores for mastalgia, with few adverse effects.²⁹ Another RCT assessing breast fullness as part of the premenstrual syndrome showed significant improvement in breast discomfort for women treated with Vitex ­agnus-castus.³⁰

Evening primrose oil (EPO). In at least one small study, EPO was effective in controlling breast pain.²⁸ A more recent meta-analysis of all of the EPO trials including gamolenic acid (the active ingredient of EPO) showed no significant difference in mastalgia compared with placebo.³¹

Pharmacologic Tx options: Start with NSAIDs

Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are often recommended as a first-line treatment for mastalgia and are likely effective for some women; however, there is currently insufficient evidence that oral NSAIDs (or acetaminophen) improve pain (TABLE 4^32-37; FIGURE 2^5,13,17). Nevertheless, the potential benefits are thought to outweigh the risk of adverse effects in most patients. A small RCT did demonstrate that topical diclofenac was effective in patients with cyclic and noncyclic mastalgia.³⁸

SSRIs. A meta-analysis of 10 double-blind RCTs of SSRIs used in women with premenstrual symptoms, including 4 studies that specifically included physical symptoms such as breast pain, showed SSRIs to be more effective than placebo at relieving breast pain.³⁵

Progesterones. Several studies have found topical, oral, and injected progesterone ineffective at reducing breast pain.^8,36,39 However, one RCT did show topical vaginal micronized progesterone used in the luteal phase to be effective in reducing breast pain by at least 50%.³⁶

Continue to: Oral contraceptives

Oral contraceptives. For women who use oral contraceptive pills and experience cyclic breast pain, continuous dosing (skipping the pill-free week) or using a lower dose of estrogen may improve symptoms. Postmenopausal women with mastalgia that developed with initiation of hormone therapy may benefit from discontinuing hormone therapy or decreasing the estrogen dose; however, there are no RCTs to offer conclusive evidence of the effectiveness of these interventions.¹⁰

Danazol. Women with severe mastalgia that does not respond to more benign therapies may require hormone therapy. As with all symptom management, it is imperative to engage the patient in a shared decision-making conversation about the risks and benefits of this treatment strategy. Women must be able to balance the potential adverse effects of agents such as danazol and tamoxifen with the need to alleviate pain and improve quality of life.

Oral NSAIDs are often recommended as first-line treatment for mastalgia.

Danazol is the only medication FDA-approved for the treatment of mastalgia. Danazol is an androgen that blocks the release of other gonadotropins to limit hormonal stimulation of breast tissue. One RCT demonstrated that danazol (100 mg bid) reduces breast pain in 60% to 90% of women, although adverse effects often limit utility.⁴⁰ Adverse effects of danazol include weight gain, hot flashes, deepening of the voice, hirsutism, menorrhagia or amenorrhea, muscle cramps, and androgenic effects on a fetus.^8,31,40 Danazol may be best used cyclically during the luteal phase of the menstrual cycle to limit these adverse effects with reduction of the dose to 100 mg/d after relief of symptoms.^31,40

Tamoxifen, a selective estrogen receptor modulator, has been shown to reduce breast pain in 80% to 90% of women, although it is not indicated for mastalgia.⁴⁰ Tamoxifen may cause endometrial thickening, hot flashes, menstrual irregularity, venous thromboembolism, and teratogenicity. The 10 mg/d dose appears to be as effective at improving symptoms as the 20 mg/d dose with fewer adverse effects.^8,31,40

In a head-to-head randomized trial, tamoxifen was superior to danazol for relief of breast pain with fewer adverse effects.³⁴ Experts recommend limiting use of tamoxifen and danazol to 3 to 6 months. Neither of these drugs is considered safe in pregnancy.

Continue to: Bromocriptine

Bromocriptine, a prolactin inhibitor, has been shown to be more effective than placebo in reducing breast pain, although nausea and dizziness contribute to high discontinuation rates. Bromocriptine is less effective than danazol.⁴⁰

Goserelin, which is not available in the United States, is a gonadorelin analog (luteinizing hormone-releasing hormone analog) that produces reversible ovarian suppression. One RCT showed that goserelin injection may be more effective than placebo in reducing breast pain.³⁷ Adverse effects include vaginal dryness, hot flashes, decreased libido, oily skin or hair, decreased breast size, and irritability. It is recommended as treatment only for severe refractory mastalgia and that it be used no longer than 6 months.^31,37

CASE 1

You reassure Ms. S that her history and physical exam are consistent with cyclic breast pain and not malignancy. You review the current US Preventive Services Task Force recommendations for breast cancer screening in women ages 40 to 49 years (Grade C; women who place a higher value on the potential benefit than the potential harms may choose screening).⁴¹ Based on shared decision-making,you offer her a screening mammogram, which returns normal. After confirming that she is using an appropriately-sized supportive bra, you recommend adding 25 g/d of ground flaxseed to her diet.

Women presenting with breast pain should undergo a clinical breast exam in both the upright and supine positions.

After 2 months she reports a 30% improvement in her pain. You then recommend chasteberry extract 4.2 mg/d, which provides additional relief to the point where she can now sleep better and walk for exercise.

CASE 2

You order a diagnostic mammogram of the left breast, which is normal, and an ultrasound that demonstrates a 6-cm deep mass. A biopsy determines that Ms. R has invasive lobular breast cancer—an extremely unlikely outcome of breast pain. She elects to have a double mastectomy and reconstruction and is doing well 4 years later.

CORRESPONDENCE
Sarina Schrager, MD, MS, University of Wisconsin Department of Family Medicine and Community Health, 1100 Delaplaine Ct., Madison, WI, 53715; [email protected].

CASE

Barry S, a 45-year-old man with a new diagnosis of non-Hodgkin’s lymphoma, recently started induction chemotherapy. He has struggled with nausea, profound gustatory changes, and poor appetite; various antiemetics have provided only minimal relief. He tells you that he is hesitant to try “yet another pill” but has heard and read that marijuana (genus Cannabis) is used to alleviate disruptive chemotherapy-induced adverse effects. He asks if this is a treatment you’d recommend for him.

As Mr. S’s physician, how do you respond?

Understandably, some family physicians are hesitant to recommend an unregulated, federally illegal substance characterized by conflicting or absent evidence of safety and effectiveness.¹ Nevertheless, throughout history and in the current court of public opinion, medical Cannabis has overwhelming support,² leading to legalization in most of the United States.

As with many traditionally accepted therapies (whether they are or are not supported by substantial evidence), physicians are expected to provide individualized guidance regarding minimizing risk and maximizing benefit of the therapeutic use of Cannabis. The rapidly growing scientific and commercial fields of medical Cannabis guarantee that information on this topic will constantly be changing—and will often be contradictory. In this article, we review the most common concerns about medical Cannabis and provide up-to-date evidence on its use.

The pharmacology of cannabis

Cannabis sativa was among the earliest plants cultivated by man, with the first evidence of its use in China, approximately 4000 BC, to make twine and rope from its fibers.³ Records of medicinal Cannabis date back to the world’s oldest pharmacopoeia, a written summary of what was known about herbal medicine through the late 16th century.⁴

Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized.

The 2 principal species of Cannabis are sativa and indica. There is no good medical evidence to separate the impacts of either strain; however, a staggering amount of lay information exists about the reported differing effects of each strain.⁵

Chemical constituents. Phytocannabinoids derived from C sativa are the plant’s best-known proteins, constituting a complex lipid-signaling network involved in numerous physiological processes. There are more than 100 known phytocannabinoids, the most well-recognized being Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). Additional sources of cannabinoids include endogenous cannabinoids, or endocannabinoids, and synthetic cannabinoids.

The endocannabinoid system, comprising cannabinoid receptors, endocannabinoids, and their specific enzymes, is a potential therapeutic target for a variety of pathologic processes.^6,7 The 2 most well-studied targets for cannabinoids in the human body are the cannabinoid receptors CB₁ and CB₂, found throughout the body: CB₁, predominantly in the central and peripheral nervous system, and CB₂ in a more limited distribution in the immune and hematopoietic systems. Other pathways activated or antagonized by THC and CBD exist, but are less well-mapped than CB₁ and CB₂.

[polldaddy:10402702]

Continue to: Botanical or synthetic?

Botanical or synthetic? It is important to distinguish between synthetic and plant-based cannabinoids, for you and your patients' benefit. Pharmaceutical (synthetic) THC is just that: THC alone. Whole-plant Cannabis, on the other hand, has hundreds of additional chemicals—most notably, phytocannabinoids and terpenoids. Data on the mechanisms of action and interactions of these additional chemicals are limited.

Although clinical trials have been undertaken with synthetic cannabinoids, there is increasing understanding and interest in the medical community of whole-plant Cannabis as a distinct entity. For example, nabiximols is a novel development in plant-based Cannabis products. Available as an oromucosal spray, a dose provides THC and CBD at 2.7 mg/100 mcL. Nabiximols is not approved by the US Food and Drug Administration (FDA) but is widely used in Canada and Europe.

PHOTO: ANTHONY RODRIGUEZ 2019; PHOTO MANIPULATION: JOHN DENAPOLI

A third class of Cannabis comprises nonregulated synthetic cannabinoids that have no medically recognized benefit. They are solely a drug of abuse; common names include “K2” and “Spice.” These cannabinoids are outside of the scope of our discussion, but patients and providers should be aware of these cannabinoids because they are street-available. Unsuspecting patients might not know the difference between abusive and therapeutic formulations.⁸

Delivery and strength. Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized. All forms come in a range of THC:CBD ratios—from as high as 90% THC content to 0% THC and all CBD-based content. Patients who are naïve to Cannabis might be concerned about formulations with a high THC concentration because of the psychoactive effects of this substance. Given the minimal CNS activity of CBD, a tolerable therapeutic starting point often is a THC:CBD ratio of 1:1, which contains a lower percentage of THC.⁴

Physiologic effects. THC is a partial agonist of CB₁ and CB₂ receptors; CBD functions as an antagonist at both receptors. The primary effects of THC result from activation of CB₁ receptors, which exist in various areas of the cerebrum and cerebellum, as well as in the spinal cord.⁷ THC exerts its psychotropic effects at CB₁ sites in the central nervous system; CBD can antagonize these THC effects at CB₁ receptors. CBD also has anti-inflammatory and other effects that are mediated through peripherally distributed CB₂ receptors.⁹

Continue to: THC has tremendously...

A tolerable therapeutic starting point is a THC:CBD ratio of 1:1.

THC has tremendously complex capacity for activation and inhibition within various neuronal circuits, resulting in effects on mood, appetite, and movement.^1,7 Adverse effects associated with Cannabis are wide-ranging: Most commonly, nausea, drowsiness, fatigue, dry mouth, and dizziness are reported alongside cognitive effects. Rarely, tachycardia, hypotension, hyperemesis, and depression can be seen.

Clinical implications and indications

Clinical indications for legal medical Cannabis vary by state; typically, indications include human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), cachexia, cancer, glaucoma, epilepsy and other seizure disorders, severe and chronic pain, spasticity from neurodegenerative disorders, and irritable bowel syndrome and Crohn’s disease, as well as a wide range of less-universal diagnoses. A patient may have a so-called qualifying diagnosis (ie, having the potential to allow the patient to be certified to purchase and use Cannabis) in one state but not have the same standing in a neighboring state, posing a complex legal issue. Given the significant complexities of performing medical research with plant-based Cannabis in the United States, little research has been done. The result? Policymakers are grappling with questions that only scientific research can answer:

• For which conditions does Cannabis provide medicinal benefit equal to or superior to alternatives?
• What are the appropriate dosages (or CBD:THC ratios), formulations (plant-derived or synthetic), and routes of administration (smoked, ingested, or topical) for various conditions?

Bird’s-eye view of clinical research. A meta-analysis of isolated synthetic and plant-based cannabinoids for medical use was published in 2015.¹⁰ The analysis included more than 6000 patients in 79 trials, most of which assessed whether dronabinol or nabilone (both synthetic isolates) were effective compared to placebo or alternative non-Cannabis-based therapy. The studies examined chemotherapy-induced nausea and vomiting, appetite stimulation in HIV and AIDS, chronic pain, spasticity, depression and anxiety, sleep disorders, and psychosis.

Twenty-eight studies assessed chemotherapy-induced nausea and vomiting. All of these studies indicated a greater benefit from cannabinoids than from alternative antiemetic regimens and placebo; however, that finding did not reach statistical significance across all studies.

There was moderate evidence to suggest the use of Cannabis for neuropathic and nonneuropathic cancer-related pain. However, there is an increased short-term risk of adverse events with synthetic isolates dronabinol (when used for pain) and nabilone (when used for nausea and vomiting).

Continue to: The primary conclusion...

The primary conclusion of the meta-analysis is that further study is required because little evidence exists on the effects and the adverse events of plant-based Cannabis.

HIV infection. Data on Cannabis for the treatment of refractory neuropathy and appetite stimulation in HIV infection is mixed.^10,11 Smoked Cannabis for medically refractory neuropathy was examined in several trials:

• In a randomized crossover trial, researchers found statistically significant subjective improvement in neuropathic pain, with minimal intolerable adverse effects, in the 28 HIV-infected participants who completed the trial.¹¹
• In another study,Cannabis ingested in various forms resulted in appetite stimulation in late-stage HIV infection but did not produce statistically significant weight gain.¹⁰

Pediatric epilepsy. Research on pediatric patients who have epilepsy characterized by refractory seizures has shown that the impact of Cannabis on their disease is promising. Specifically, CBD has shown tremendous potential impact: Patients experienced a statistically significant reduction in the number of seizures.⁹ In 2018, the FDA approved the first plant-based derivative of Cannabis: an oral cannabidiol (marketed as Epidiolex [Greenwich Biosciences, Inc.]) for the treatment of intractable seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, rare and severe forms of epilepsy. Epidiolex is the first FDA-approved drug that contains a purified drug substance derived from marijuana.

CASE

Mr. S’s diagnosis of cancer is broadly included in the list of Cannabis-qualifying illnesses in all 34 states that certify patients for medical Cannabis. He qualifies both because (1) he is a cancer patient and (2) he has not found relief from chemotherapy-induced nausea and vomiting with several targeted therapies, including 5-hydroxytryptamine-receptor antagonists, steroids, and antipsychotics. Evidence supports CB₁ and CB₂ as potential targets for antiemetic treatment.

Research suggests that the use of Cannabis for pediatric patients with refractory seizures is promising.

Given Mr. S’s consequent anorexia, his frustration with taking an increasing number of medications, and possible adverse effects of additional therapy, Cannabis is a reasonable course of action to treat nausea and vomiting. He would be able to use oral tincture or vaporization of oil to further limit his pill burden—likely, with a THC:CBD ratio of 1:1 or similar.

Continue to: Based on recent observational data...

Based on recent observational data from New York Cannabis dispensaries, cancer patients pursing Cannabis to treat chemotherapy-induced symptoms report that (1) either products with a high concentration of THC or products that contain THC and CBD in a 1:1 ratio are most effective and (2) products in 1:1 ratio of THC and CBD are most tolerable.

A legal system at oddsover the status of medical Cannabis

The core legal issue underlying medical Cannabis is a contradiction between federal and state laws.

At the federal level. The federal government regulates the lawful production, possession, and distribution of controlled substances through the Controlled Substances Act (CSA).¹² The CSA is the basis for categorizing certain plants, drugs, and chemicals into 5 schedules, based on the substance’s medical use, potential for abuse, and safety or dependence liability.¹³ Under the CSA, marijuana (along with substances such as heroin and methamphetamine) is categorized as Schedule I¹⁴; ie, the substance

• has high potential for abuse,
• has no accepted therapeutic medical use in the United States, and
• lacks acceptable safety for use under medical supervision.

Despite waxing and waning efforts to protect states from federal prosecution, any use of a Schedule-1 substance violates federal law.¹⁵

Physicians are protected from prosecution or revocation of their prescriptive authority based on their First Amendment right to discuss medical marijuana with patients.

In June 2018, a bipartisan group of federal lawmakers introduced a bill designed to amend the CSA and guarantee the rights of states and territories to self-determine marijuana regulation. The bill established a so-called STATES (Strengthening the Tenth Amendment Through Entrusting States) Act that “amends the Controlled Substances Act (21 U.S.C. § 801 et seq.) so that—as states and tribes comply with a few basic protections—its provisions no longer apply to any person acting in compliance with state or tribal laws relating to the manufacture, production, possession, distribution, dispensation, administration, or delivery of marijuana.”¹⁵

Continue to: The bill was referred to the Senate...

The bill was referred to the Senate and House Judiciary Committees but, ultimately, the STATES Act was blocked from debate in 2018.

On April 4, 2019, the Act was reintroduced in the House (H.R. 2093) and Senate (S. 1028) of the 116th Congress. Although there is bipartisan support for this bill, the timeline for moving it forward is unclear.^16,17

At the state level. Thirty-four states have comprehensive public medical marijuana and Cannabis programs. The National Conference of State Legislatures¹⁸ (www.ncsl.org) designates a program “comprehensive” if it

• includes protection from criminal penalties for using marijuana for a medical purpose,
• allows access to marijuana through home cultivation, dispensaries, or other system,
• permits a variety of strains, including those more potent than what is labeled “low-THC,” and
• allows smoking or vaporization of marijuana products, plant-based material, or extract.

An additional 14 states allow for “low-THC, high-CBD” products for medical reasons, in limited situations, or as a legal defense. Regulation in these states varies widely, however: Some states allow industrialized hemp products only; others do not provide for any in-state production.¹⁸

Last, many states have some form of so-called “affirmative-defense” statutes that allow people charged with marijuana possession to mention use of marijuana for medical purposes as a possible defense.

Continue to: Physician shield

Physician shield. Despite inconsistent and evolving state and federal laws, physicians are protected, based on the Conant v Walters decision, from prosecution or revocation of their prescriptive authority for the professional “recommendation” of the use of medical marijuana.¹⁹ In 2002, the US Ninth Circuit Court of Appeals upheld the permanent injunction, based on a physician’s First Amendment right to discuss medical marijuana with patients.

CASE

Mr. S is amenable to trial of Cannabis to relieve nausea and anorexia. He asks you if he is allowed to use Cannabis at work, were he to return to an office-based desk job—even part-time—during treatment for cancer.

How would you answer Mr. S? Patients are legally protected from workplace penalties and dismissal for using and consuming Cannabis in states with a medical Cannabis law (including the state in which Mr. S resides). However, all employers have some variability in corporate policy, especially if a person works in a federally supported or regulated occupation. It’s always helpful to advise patients who will be using medical Cannabis to be proactive and speak with a human resources or employee health department staff member before beginning a course of medical Cannabis. Additionally, Cannabis with any amount of THC has the ability to alter focus, concentration, and perceptions of time. Thus, if a patient using medical Cannabis with THC asks about driving to work, he should be given the same advice one would offer about driving after consuming alcohol or ingesting opioids.

Common concerns

Ignorance of legal status. Theoretically, the Conant v Walters decision protects physicians from investigation for recommending medical Cannabis even in states where it is illegal. However, you should adhere closely to procedures set out by your state. The National Council of State Legislatures provides up-to-date information on each state’s procedures and programs,¹⁸ and the American Society of Addiction Medicine (www.asam.org) has established standards of professionalism for physicians who discuss medical Cannabis with patients (TABLE).²⁰

Exposure to smoke. Cannabis smoke carries many of the same carcinogens found in tobacco smoke; furthermore, use of Cannabis and tobacco are highly correlated, confounding many population-based studies. The manner of inhalation of Cannabis can result in significantly higher levels of tar and carbon dioxide than with tobacco smoking. Because the effects of Cannabis last longer, however, people who smoke Cannabis may smoke it less often than tobacco smokers smoke tobacco.²¹

Continue to: Large cross-sectional...

Large cross-sectional and longitudinal studies have not found a link between Cannabis smoking and long-term pulmonary consequences, such as chronic obstructive pulmonary disease and lung cancer.^22,23 The technology of Cannabis delivery systems has progressed far more rapidly than the clinical evidence for or against such technology.

Delayed onset of edible products and variation of THC concentration increase risk of overconsumption.

“Vaping” is an informal term for inhalation of aerosolized Cannabis components and water vapor. Vaporizers do not heat Cannabis to the point of combustion; therefore, they provide less exposure to smoke-related toxicants while providing similar time of onset.

Neuropsychiatric adverse effects. Data regarding the relationship between Cannabis use and psychiatric disorders are incompletely understood, in conflict, and related to cannabinoid type. Consider Pennsylvania’s addition of anxiety disorder as a “serious medical condition” covered under the Pennsylvania Medical Marijuana Act.²⁴ Although patients often report the use of medical Cannabis to treat anxiety,²⁵ panic attacks are often associated with Cannabis use.²⁶

While there is a clear association between Cannabis use and psychotic disorder, a causal link has yet to be unequivocally established. However, the rate of psychiatric hospitalization is increased in bipolar disorder and schizophrenia patients who use Cannabis heavily.²⁷

We recommend, therefore, that physicians screen patients for serious mental health concerns before recommending or certifying them to use medical Cannabis.

Continue to: Overconsumption of edibles

Overconsumption of edibles. Cannabis edibles (ie, food products infused with Cannabis extract) are distinct from inhaled Cannabis in regard to onset, duration, and potential for adverse effects. Cannabis edibles might be more popular than inhaled products among older medical Cannabis users.²⁸

Edible Cannabis has a reported onset of 1 to 3 hours (compared to 5-10 minutes with inhaled Cannabis) and a duration of effect of 6 to 8 hours (compared with 2-4 hours for inhaled products).²⁹ These qualities might render Cannabis edibles preferable to inhaled formulations for controlling chronic symptoms and conditions. However, delayed onset of edible products and wide variation in the concentration of THC also increase the risk of overconsumption, which can lead to overdose and self-limited Cannabis-induced psychosis. We recommend providing patient education about the effects of the physiologically active therapeutic compounds tetrahydrocannabinol and cannabidiol, to prevent overconsumption of high-THC products.³⁰

CASE

Mr. S returns to your office after a trial of Cannabis as vaporized oil and reports some relief of nausea and a mild increase in appetite, but no weight gain. He is concerned about overconsumption or overdose, and asks you what the risks of these problems are.

How should you counsel Mr. S? Explain that ingestion of Cannabis has a prolonged onset of action; vaporization has a more rapid onset of action; therefore, he could more easily self-regulate ingestion with the vehicle he has chosen. In states where edible Cannabis products are legal, education is necessary so that patients know how much of the edible to consume and how long they will wait to feel the full impact of the effects of THC.³⁰

Cannabis use disorder in the context of medical marijuana

Cannabis use disorder (CUD) incorporates general diagnostic features of a substance use disorder, including behavioral, cognitive, and physiologic symptoms such as cravings, tolerance, and withdrawal, in the setting of persistent use despite significant substance-related problems.³¹ Features of Cannabis withdrawal syndrome include irritability, anger or aggression, anxiety, depressed mood, restlessness, sleep difficulty, and decreased appetite or weight loss.³¹ Cannabis use disorder can develop in people who use medical Cannabis; however, physiologic symptoms of tolerance and withdrawal can also develop in the setting of appropriate medical use and do not, in isolation, represent CUD.

Continue to: A recent study...

A recent study considered nationwide cross-sectional survey data from the US National Survey of Drug Use and Health to examine the relationship between medical marijuana laws and CUD.³² Study findings did not show an increase in the prevalence of CUD or marijuana use among adults in states with a legalized medical marijuana program. Importantly, when researchers looked at marijuana use among adolescents and young adults, they found no increase in measured outcomes (eg, active [ie, past-month] marijuana use, heavy [> 300 d/yr] use, and a diagnosis of CUD) after medical marijuana laws were passed.³²

A paucity of pediatric data

Cannabis smoke carries many of the same carcinogens found in tobacco smoke.

The adolescent brain might be more vulnerable to the adverse long-term effects of Cannabis; there is potential significant harm associated with Cannabis in children and adolescence. However, accurate data concerning risk and benefit are limited.

The most recent policy statement of the American Academy of Pediatrics (AAP) reflects this paucity of data.³³ The AAP opposes the use of medical Cannabis outside regulation by the FDA, although the organization allows for consideration of compassionate use of medical Cannabis for children who have life-threatening or severely disabling conditions. The AAP does support (1) additional research into pharmaceutical cannabinoids and (2) changing Cannabis from Schedule I to Schedule II to facilitate this process. Since the publication of the policy statement, Pediatrics, the official journal of the AAP, has published a review of medical cannabinoids and found (1) strong evidence for benefit in chemotherapy-induced nausea and vomiting and (2) accumulating evidence of benefit in epilepsy.³⁴

Recognized risk: Not supporting medical Cannabis

At press time, the CDC issued a statement on respiratory illnesses reported after use of e-cigarette products. To learn more, go to www.cdc.gov/media/releases/2019/s0830-statement-e-cigarette.html.

As with all medical decisions, the risks and benefits of certifying patients for medical Cannabis must be balanced against the risks and benefits of not doing so. The risks that accompany failure to certify a patient for medical marijuana fall into 3 categories:

Blocking access to a substance that has potential therapeutic benefit. More data regarding the potential benefits and risks of medical Cannabis will, undoubtedly, dispel some of the uncertainty regarding the decision to certify a patient for medical Cannabis. When you recommend medical Cannabis and certify patients for its use, you do so with the certainty that the Cannabis safety index (ie, risk of overdose or serious adverse effects) is exceedingly low.³⁵

Continue to: Limiting patients to other medications

Limiting patients to other medications that, potentially, carry a risk of more or greater harmful effects. An example is the decision to prescribe an opioid for chronic pain instead of certifying a patient for medical Cannabis. For certain other conditions, including chemotherapy-induced nausea and vomiting, FDA-approved pharmaceuticals might have more reported serious adverse events and interactions than medical Cannabis.³⁶

 Resigning patients to obtain Cannabis from an illegal source.  This speaks to harm reduction and social justice, because obtaining Cannabis from an illegal source carries health and legal risks:

• Increased health risks result from lacing or cutting botanical or synthetic Cannabis products with potentially toxic substances. Cocaine, the rodenticide brodifacoum, methamphetamine, and phencyclidine are all known, or have been reported, to be added to botanical and synthetic Cannabis.³⁷
• Legal repercussions of Cannabis possession are disproportionately racially based, with a significantly higher arrest rate among people of color, even in states where medical Cannabis has been legalized.³⁸

CORRESPONDENCE
Lara Carson Weinstein, MD, MPH, DrPH, Department of Family and Community Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, 1015 Walnut Street, Suite 401, Philadelphia, PA 19107; [email protected].

CASE

Barry S, a 45-year-old man with a new diagnosis of non-Hodgkin’s lymphoma, recently started induction chemotherapy. He has struggled with nausea, profound gustatory changes, and poor appetite; various antiemetics have provided only minimal relief. He tells you that he is hesitant to try “yet another pill” but has heard and read that marijuana (genus Cannabis) is used to alleviate disruptive chemotherapy-induced adverse effects. He asks if this is a treatment you’d recommend for him.

As Mr. S’s physician, how do you respond?

Understandably, some family physicians are hesitant to recommend an unregulated, federally illegal substance characterized by conflicting or absent evidence of safety and effectiveness.¹ Nevertheless, throughout history and in the current court of public opinion, medical Cannabis has overwhelming support,² leading to legalization in most of the United States.

As with many traditionally accepted therapies (whether they are or are not supported by substantial evidence), physicians are expected to provide individualized guidance regarding minimizing risk and maximizing benefit of the therapeutic use of Cannabis. The rapidly growing scientific and commercial fields of medical Cannabis guarantee that information on this topic will constantly be changing—and will often be contradictory. In this article, we review the most common concerns about medical Cannabis and provide up-to-date evidence on its use.

The pharmacology of cannabis

Cannabis sativa was among the earliest plants cultivated by man, with the first evidence of its use in China, approximately 4000 BC, to make twine and rope from its fibers.³ Records of medicinal Cannabis date back to the world’s oldest pharmacopoeia, a written summary of what was known about herbal medicine through the late 16th century.⁴

Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized.

The 2 principal species of Cannabis are sativa and indica. There is no good medical evidence to separate the impacts of either strain; however, a staggering amount of lay information exists about the reported differing effects of each strain.⁵

Chemical constituents. Phytocannabinoids derived from C sativa are the plant’s best-known proteins, constituting a complex lipid-signaling network involved in numerous physiological processes. There are more than 100 known phytocannabinoids, the most well-recognized being Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). Additional sources of cannabinoids include endogenous cannabinoids, or endocannabinoids, and synthetic cannabinoids.

The endocannabinoid system, comprising cannabinoid receptors, endocannabinoids, and their specific enzymes, is a potential therapeutic target for a variety of pathologic processes.^6,7 The 2 most well-studied targets for cannabinoids in the human body are the cannabinoid receptors CB₁ and CB₂, found throughout the body: CB₁, predominantly in the central and peripheral nervous system, and CB₂ in a more limited distribution in the immune and hematopoietic systems. Other pathways activated or antagonized by THC and CBD exist, but are less well-mapped than CB₁ and CB₂.

[polldaddy:10402702]

Continue to: Botanical or synthetic?

Botanical or synthetic? It is important to distinguish between synthetic and plant-based cannabinoids, for you and your patients' benefit. Pharmaceutical (synthetic) THC is just that: THC alone. Whole-plant Cannabis, on the other hand, has hundreds of additional chemicals—most notably, phytocannabinoids and terpenoids. Data on the mechanisms of action and interactions of these additional chemicals are limited.

Although clinical trials have been undertaken with synthetic cannabinoids, there is increasing understanding and interest in the medical community of whole-plant Cannabis as a distinct entity. For example, nabiximols is a novel development in plant-based Cannabis products. Available as an oromucosal spray, a dose provides THC and CBD at 2.7 mg/100 mcL. Nabiximols is not approved by the US Food and Drug Administration (FDA) but is widely used in Canada and Europe.

PHOTO: ANTHONY RODRIGUEZ 2019; PHOTO MANIPULATION: JOHN DENAPOLI

A third class of Cannabis comprises nonregulated synthetic cannabinoids that have no medically recognized benefit. They are solely a drug of abuse; common names include “K2” and “Spice.” These cannabinoids are outside of the scope of our discussion, but patients and providers should be aware of these cannabinoids because they are street-available. Unsuspecting patients might not know the difference between abusive and therapeutic formulations.⁸

Delivery and strength. Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized. All forms come in a range of THC:CBD ratios—from as high as 90% THC content to 0% THC and all CBD-based content. Patients who are naïve to Cannabis might be concerned about formulations with a high THC concentration because of the psychoactive effects of this substance. Given the minimal CNS activity of CBD, a tolerable therapeutic starting point often is a THC:CBD ratio of 1:1, which contains a lower percentage of THC.⁴

Physiologic effects. THC is a partial agonist of CB₁ and CB₂ receptors; CBD functions as an antagonist at both receptors. The primary effects of THC result from activation of CB₁ receptors, which exist in various areas of the cerebrum and cerebellum, as well as in the spinal cord.⁷ THC exerts its psychotropic effects at CB₁ sites in the central nervous system; CBD can antagonize these THC effects at CB₁ receptors. CBD also has anti-inflammatory and other effects that are mediated through peripherally distributed CB₂ receptors.⁹

Continue to: THC has tremendously...

A tolerable therapeutic starting point is a THC:CBD ratio of 1:1.

THC has tremendously complex capacity for activation and inhibition within various neuronal circuits, resulting in effects on mood, appetite, and movement.^1,7 Adverse effects associated with Cannabis are wide-ranging: Most commonly, nausea, drowsiness, fatigue, dry mouth, and dizziness are reported alongside cognitive effects. Rarely, tachycardia, hypotension, hyperemesis, and depression can be seen.

Clinical implications and indications

Clinical indications for legal medical Cannabis vary by state; typically, indications include human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), cachexia, cancer, glaucoma, epilepsy and other seizure disorders, severe and chronic pain, spasticity from neurodegenerative disorders, and irritable bowel syndrome and Crohn’s disease, as well as a wide range of less-universal diagnoses. A patient may have a so-called qualifying diagnosis (ie, having the potential to allow the patient to be certified to purchase and use Cannabis) in one state but not have the same standing in a neighboring state, posing a complex legal issue. Given the significant complexities of performing medical research with plant-based Cannabis in the United States, little research has been done. The result? Policymakers are grappling with questions that only scientific research can answer:

• For which conditions does Cannabis provide medicinal benefit equal to or superior to alternatives?
• What are the appropriate dosages (or CBD:THC ratios), formulations (plant-derived or synthetic), and routes of administration (smoked, ingested, or topical) for various conditions?

Bird’s-eye view of clinical research. A meta-analysis of isolated synthetic and plant-based cannabinoids for medical use was published in 2015.¹⁰ The analysis included more than 6000 patients in 79 trials, most of which assessed whether dronabinol or nabilone (both synthetic isolates) were effective compared to placebo or alternative non-Cannabis-based therapy. The studies examined chemotherapy-induced nausea and vomiting, appetite stimulation in HIV and AIDS, chronic pain, spasticity, depression and anxiety, sleep disorders, and psychosis.

Twenty-eight studies assessed chemotherapy-induced nausea and vomiting. All of these studies indicated a greater benefit from cannabinoids than from alternative antiemetic regimens and placebo; however, that finding did not reach statistical significance across all studies.

There was moderate evidence to suggest the use of Cannabis for neuropathic and nonneuropathic cancer-related pain. However, there is an increased short-term risk of adverse events with synthetic isolates dronabinol (when used for pain) and nabilone (when used for nausea and vomiting).

Continue to: The primary conclusion...

The primary conclusion of the meta-analysis is that further study is required because little evidence exists on the effects and the adverse events of plant-based Cannabis.

HIV infection. Data on Cannabis for the treatment of refractory neuropathy and appetite stimulation in HIV infection is mixed.^10,11 Smoked Cannabis for medically refractory neuropathy was examined in several trials:

• In a randomized crossover trial, researchers found statistically significant subjective improvement in neuropathic pain, with minimal intolerable adverse effects, in the 28 HIV-infected participants who completed the trial.¹¹
• In another study,Cannabis ingested in various forms resulted in appetite stimulation in late-stage HIV infection but did not produce statistically significant weight gain.¹⁰

Pediatric epilepsy. Research on pediatric patients who have epilepsy characterized by refractory seizures has shown that the impact of Cannabis on their disease is promising. Specifically, CBD has shown tremendous potential impact: Patients experienced a statistically significant reduction in the number of seizures.⁹ In 2018, the FDA approved the first plant-based derivative of Cannabis: an oral cannabidiol (marketed as Epidiolex [Greenwich Biosciences, Inc.]) for the treatment of intractable seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, rare and severe forms of epilepsy. Epidiolex is the first FDA-approved drug that contains a purified drug substance derived from marijuana.

CASE

Mr. S’s diagnosis of cancer is broadly included in the list of Cannabis-qualifying illnesses in all 34 states that certify patients for medical Cannabis. He qualifies both because (1) he is a cancer patient and (2) he has not found relief from chemotherapy-induced nausea and vomiting with several targeted therapies, including 5-hydroxytryptamine-receptor antagonists, steroids, and antipsychotics. Evidence supports CB₁ and CB₂ as potential targets for antiemetic treatment.

Research suggests that the use of Cannabis for pediatric patients with refractory seizures is promising.

Given Mr. S’s consequent anorexia, his frustration with taking an increasing number of medications, and possible adverse effects of additional therapy, Cannabis is a reasonable course of action to treat nausea and vomiting. He would be able to use oral tincture or vaporization of oil to further limit his pill burden—likely, with a THC:CBD ratio of 1:1 or similar.

Continue to: Based on recent observational data...

Based on recent observational data from New York Cannabis dispensaries, cancer patients pursing Cannabis to treat chemotherapy-induced symptoms report that (1) either products with a high concentration of THC or products that contain THC and CBD in a 1:1 ratio are most effective and (2) products in 1:1 ratio of THC and CBD are most tolerable.

A legal system at oddsover the status of medical Cannabis

The core legal issue underlying medical Cannabis is a contradiction between federal and state laws.

At the federal level. The federal government regulates the lawful production, possession, and distribution of controlled substances through the Controlled Substances Act (CSA).¹² The CSA is the basis for categorizing certain plants, drugs, and chemicals into 5 schedules, based on the substance’s medical use, potential for abuse, and safety or dependence liability.¹³ Under the CSA, marijuana (along with substances such as heroin and methamphetamine) is categorized as Schedule I¹⁴; ie, the substance

• has high potential for abuse,
• has no accepted therapeutic medical use in the United States, and
• lacks acceptable safety for use under medical supervision.

Despite waxing and waning efforts to protect states from federal prosecution, any use of a Schedule-1 substance violates federal law.¹⁵

Physicians are protected from prosecution or revocation of their prescriptive authority based on their First Amendment right to discuss medical marijuana with patients.

In June 2018, a bipartisan group of federal lawmakers introduced a bill designed to amend the CSA and guarantee the rights of states and territories to self-determine marijuana regulation. The bill established a so-called STATES (Strengthening the Tenth Amendment Through Entrusting States) Act that “amends the Controlled Substances Act (21 U.S.C. § 801 et seq.) so that—as states and tribes comply with a few basic protections—its provisions no longer apply to any person acting in compliance with state or tribal laws relating to the manufacture, production, possession, distribution, dispensation, administration, or delivery of marijuana.”¹⁵

Continue to: The bill was referred to the Senate...

The bill was referred to the Senate and House Judiciary Committees but, ultimately, the STATES Act was blocked from debate in 2018.

On April 4, 2019, the Act was reintroduced in the House (H.R. 2093) and Senate (S. 1028) of the 116th Congress. Although there is bipartisan support for this bill, the timeline for moving it forward is unclear.^16,17

At the state level. Thirty-four states have comprehensive public medical marijuana and Cannabis programs. The National Conference of State Legislatures¹⁸ (www.ncsl.org) designates a program “comprehensive” if it

• includes protection from criminal penalties for using marijuana for a medical purpose,
• allows access to marijuana through home cultivation, dispensaries, or other system,
• permits a variety of strains, including those more potent than what is labeled “low-THC,” and
• allows smoking or vaporization of marijuana products, plant-based material, or extract.

An additional 14 states allow for “low-THC, high-CBD” products for medical reasons, in limited situations, or as a legal defense. Regulation in these states varies widely, however: Some states allow industrialized hemp products only; others do not provide for any in-state production.¹⁸

Last, many states have some form of so-called “affirmative-defense” statutes that allow people charged with marijuana possession to mention use of marijuana for medical purposes as a possible defense.

Continue to: Physician shield

Physician shield. Despite inconsistent and evolving state and federal laws, physicians are protected, based on the Conant v Walters decision, from prosecution or revocation of their prescriptive authority for the professional “recommendation” of the use of medical marijuana.¹⁹ In 2002, the US Ninth Circuit Court of Appeals upheld the permanent injunction, based on a physician’s First Amendment right to discuss medical marijuana with patients.

CASE

Mr. S is amenable to trial of Cannabis to relieve nausea and anorexia. He asks you if he is allowed to use Cannabis at work, were he to return to an office-based desk job—even part-time—during treatment for cancer.

How would you answer Mr. S? Patients are legally protected from workplace penalties and dismissal for using and consuming Cannabis in states with a medical Cannabis law (including the state in which Mr. S resides). However, all employers have some variability in corporate policy, especially if a person works in a federally supported or regulated occupation. It’s always helpful to advise patients who will be using medical Cannabis to be proactive and speak with a human resources or employee health department staff member before beginning a course of medical Cannabis. Additionally, Cannabis with any amount of THC has the ability to alter focus, concentration, and perceptions of time. Thus, if a patient using medical Cannabis with THC asks about driving to work, he should be given the same advice one would offer about driving after consuming alcohol or ingesting opioids.

Common concerns

Ignorance of legal status. Theoretically, the Conant v Walters decision protects physicians from investigation for recommending medical Cannabis even in states where it is illegal. However, you should adhere closely to procedures set out by your state. The National Council of State Legislatures provides up-to-date information on each state’s procedures and programs,¹⁸ and the American Society of Addiction Medicine (www.asam.org) has established standards of professionalism for physicians who discuss medical Cannabis with patients (TABLE).²⁰

Exposure to smoke. Cannabis smoke carries many of the same carcinogens found in tobacco smoke; furthermore, use of Cannabis and tobacco are highly correlated, confounding many population-based studies. The manner of inhalation of Cannabis can result in significantly higher levels of tar and carbon dioxide than with tobacco smoking. Because the effects of Cannabis last longer, however, people who smoke Cannabis may smoke it less often than tobacco smokers smoke tobacco.²¹

Continue to: Large cross-sectional...

Large cross-sectional and longitudinal studies have not found a link between Cannabis smoking and long-term pulmonary consequences, such as chronic obstructive pulmonary disease and lung cancer.^22,23 The technology of Cannabis delivery systems has progressed far more rapidly than the clinical evidence for or against such technology.

Delayed onset of edible products and variation of THC concentration increase risk of overconsumption.

“Vaping” is an informal term for inhalation of aerosolized Cannabis components and water vapor. Vaporizers do not heat Cannabis to the point of combustion; therefore, they provide less exposure to smoke-related toxicants while providing similar time of onset.

Neuropsychiatric adverse effects. Data regarding the relationship between Cannabis use and psychiatric disorders are incompletely understood, in conflict, and related to cannabinoid type. Consider Pennsylvania’s addition of anxiety disorder as a “serious medical condition” covered under the Pennsylvania Medical Marijuana Act.²⁴ Although patients often report the use of medical Cannabis to treat anxiety,²⁵ panic attacks are often associated with Cannabis use.²⁶

While there is a clear association between Cannabis use and psychotic disorder, a causal link has yet to be unequivocally established. However, the rate of psychiatric hospitalization is increased in bipolar disorder and schizophrenia patients who use Cannabis heavily.²⁷

We recommend, therefore, that physicians screen patients for serious mental health concerns before recommending or certifying them to use medical Cannabis.

Continue to: Overconsumption of edibles

Overconsumption of edibles. Cannabis edibles (ie, food products infused with Cannabis extract) are distinct from inhaled Cannabis in regard to onset, duration, and potential for adverse effects. Cannabis edibles might be more popular than inhaled products among older medical Cannabis users.²⁸

Edible Cannabis has a reported onset of 1 to 3 hours (compared to 5-10 minutes with inhaled Cannabis) and a duration of effect of 6 to 8 hours (compared with 2-4 hours for inhaled products).²⁹ These qualities might render Cannabis edibles preferable to inhaled formulations for controlling chronic symptoms and conditions. However, delayed onset of edible products and wide variation in the concentration of THC also increase the risk of overconsumption, which can lead to overdose and self-limited Cannabis-induced psychosis. We recommend providing patient education about the effects of the physiologically active therapeutic compounds tetrahydrocannabinol and cannabidiol, to prevent overconsumption of high-THC products.³⁰

CASE

Mr. S returns to your office after a trial of Cannabis as vaporized oil and reports some relief of nausea and a mild increase in appetite, but no weight gain. He is concerned about overconsumption or overdose, and asks you what the risks of these problems are.

How should you counsel Mr. S? Explain that ingestion of Cannabis has a prolonged onset of action; vaporization has a more rapid onset of action; therefore, he could more easily self-regulate ingestion with the vehicle he has chosen. In states where edible Cannabis products are legal, education is necessary so that patients know how much of the edible to consume and how long they will wait to feel the full impact of the effects of THC.³⁰

Cannabis use disorder in the context of medical marijuana

Cannabis use disorder (CUD) incorporates general diagnostic features of a substance use disorder, including behavioral, cognitive, and physiologic symptoms such as cravings, tolerance, and withdrawal, in the setting of persistent use despite significant substance-related problems.³¹ Features of Cannabis withdrawal syndrome include irritability, anger or aggression, anxiety, depressed mood, restlessness, sleep difficulty, and decreased appetite or weight loss.³¹ Cannabis use disorder can develop in people who use medical Cannabis; however, physiologic symptoms of tolerance and withdrawal can also develop in the setting of appropriate medical use and do not, in isolation, represent CUD.

Continue to: A recent study...

A recent study considered nationwide cross-sectional survey data from the US National Survey of Drug Use and Health to examine the relationship between medical marijuana laws and CUD.³² Study findings did not show an increase in the prevalence of CUD or marijuana use among adults in states with a legalized medical marijuana program. Importantly, when researchers looked at marijuana use among adolescents and young adults, they found no increase in measured outcomes (eg, active [ie, past-month] marijuana use, heavy [> 300 d/yr] use, and a diagnosis of CUD) after medical marijuana laws were passed.³²

A paucity of pediatric data

Cannabis smoke carries many of the same carcinogens found in tobacco smoke.

The adolescent brain might be more vulnerable to the adverse long-term effects of Cannabis; there is potential significant harm associated with Cannabis in children and adolescence. However, accurate data concerning risk and benefit are limited.

The most recent policy statement of the American Academy of Pediatrics (AAP) reflects this paucity of data.³³ The AAP opposes the use of medical Cannabis outside regulation by the FDA, although the organization allows for consideration of compassionate use of medical Cannabis for children who have life-threatening or severely disabling conditions. The AAP does support (1) additional research into pharmaceutical cannabinoids and (2) changing Cannabis from Schedule I to Schedule II to facilitate this process. Since the publication of the policy statement, Pediatrics, the official journal of the AAP, has published a review of medical cannabinoids and found (1) strong evidence for benefit in chemotherapy-induced nausea and vomiting and (2) accumulating evidence of benefit in epilepsy.³⁴

Recognized risk: Not supporting medical Cannabis

At press time, the CDC issued a statement on respiratory illnesses reported after use of e-cigarette products. To learn more, go to www.cdc.gov/media/releases/2019/s0830-statement-e-cigarette.html.

As with all medical decisions, the risks and benefits of certifying patients for medical Cannabis must be balanced against the risks and benefits of not doing so. The risks that accompany failure to certify a patient for medical marijuana fall into 3 categories:

Blocking access to a substance that has potential therapeutic benefit. More data regarding the potential benefits and risks of medical Cannabis will, undoubtedly, dispel some of the uncertainty regarding the decision to certify a patient for medical Cannabis. When you recommend medical Cannabis and certify patients for its use, you do so with the certainty that the Cannabis safety index (ie, risk of overdose or serious adverse effects) is exceedingly low.³⁵

Continue to: Limiting patients to other medications

Limiting patients to other medications that, potentially, carry a risk of more or greater harmful effects. An example is the decision to prescribe an opioid for chronic pain instead of certifying a patient for medical Cannabis. For certain other conditions, including chemotherapy-induced nausea and vomiting, FDA-approved pharmaceuticals might have more reported serious adverse events and interactions than medical Cannabis.³⁶

 Resigning patients to obtain Cannabis from an illegal source.  This speaks to harm reduction and social justice, because obtaining Cannabis from an illegal source carries health and legal risks:

• Increased health risks result from lacing or cutting botanical or synthetic Cannabis products with potentially toxic substances. Cocaine, the rodenticide brodifacoum, methamphetamine, and phencyclidine are all known, or have been reported, to be added to botanical and synthetic Cannabis.³⁷
• Legal repercussions of Cannabis possession are disproportionately racially based, with a significantly higher arrest rate among people of color, even in states where medical Cannabis has been legalized.³⁸

CORRESPONDENCE
Lara Carson Weinstein, MD, MPH, DrPH, Department of Family and Community Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, 1015 Walnut Street, Suite 401, Philadelphia, PA 19107; [email protected].

CASE

Barry S, a 45-year-old man with a new diagnosis of non-Hodgkin’s lymphoma, recently started induction chemotherapy. He has struggled with nausea, profound gustatory changes, and poor appetite; various antiemetics have provided only minimal relief. He tells you that he is hesitant to try “yet another pill” but has heard and read that marijuana (genus Cannabis) is used to alleviate disruptive chemotherapy-induced adverse effects. He asks if this is a treatment you’d recommend for him.

As Mr. S’s physician, how do you respond?

Understandably, some family physicians are hesitant to recommend an unregulated, federally illegal substance characterized by conflicting or absent evidence of safety and effectiveness.¹ Nevertheless, throughout history and in the current court of public opinion, medical Cannabis has overwhelming support,² leading to legalization in most of the United States.

As with many traditionally accepted therapies (whether they are or are not supported by substantial evidence), physicians are expected to provide individualized guidance regarding minimizing risk and maximizing benefit of the therapeutic use of Cannabis. The rapidly growing scientific and commercial fields of medical Cannabis guarantee that information on this topic will constantly be changing—and will often be contradictory. In this article, we review the most common concerns about medical Cannabis and provide up-to-date evidence on its use.

The pharmacology of cannabis

Cannabis sativa was among the earliest plants cultivated by man, with the first evidence of its use in China, approximately 4000 BC, to make twine and rope from its fibers.³ Records of medicinal Cannabis date back to the world’s oldest pharmacopoeia, a written summary of what was known about herbal medicine through the late 16th century.⁴

Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized.

The 2 principal species of Cannabis are sativa and indica. There is no good medical evidence to separate the impacts of either strain; however, a staggering amount of lay information exists about the reported differing effects of each strain.⁵

Chemical constituents. Phytocannabinoids derived from C sativa are the plant’s best-known proteins, constituting a complex lipid-signaling network involved in numerous physiological processes. There are more than 100 known phytocannabinoids, the most well-recognized being Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). Additional sources of cannabinoids include endogenous cannabinoids, or endocannabinoids, and synthetic cannabinoids.

The endocannabinoid system, comprising cannabinoid receptors, endocannabinoids, and their specific enzymes, is a potential therapeutic target for a variety of pathologic processes.^6,7 The 2 most well-studied targets for cannabinoids in the human body are the cannabinoid receptors CB₁ and CB₂, found throughout the body: CB₁, predominantly in the central and peripheral nervous system, and CB₂ in a more limited distribution in the immune and hematopoietic systems. Other pathways activated or antagonized by THC and CBD exist, but are less well-mapped than CB₁ and CB₂.

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Continue to: Botanical or synthetic?

Botanical or synthetic? It is important to distinguish between synthetic and plant-based cannabinoids, for you and your patients' benefit. Pharmaceutical (synthetic) THC is just that: THC alone. Whole-plant Cannabis, on the other hand, has hundreds of additional chemicals—most notably, phytocannabinoids and terpenoids. Data on the mechanisms of action and interactions of these additional chemicals are limited.

Although clinical trials have been undertaken with synthetic cannabinoids, there is increasing understanding and interest in the medical community of whole-plant Cannabis as a distinct entity. For example, nabiximols is a novel development in plant-based Cannabis products. Available as an oromucosal spray, a dose provides THC and CBD at 2.7 mg/100 mcL. Nabiximols is not approved by the US Food and Drug Administration (FDA) but is widely used in Canada and Europe.

PHOTO: ANTHONY RODRIGUEZ 2019; PHOTO MANIPULATION: JOHN DENAPOLI

A third class of Cannabis comprises nonregulated synthetic cannabinoids that have no medically recognized benefit. They are solely a drug of abuse; common names include “K2” and “Spice.” These cannabinoids are outside of the scope of our discussion, but patients and providers should be aware of these cannabinoids because they are street-available. Unsuspecting patients might not know the difference between abusive and therapeutic formulations.⁸

Delivery and strength. Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized. All forms come in a range of THC:CBD ratios—from as high as 90% THC content to 0% THC and all CBD-based content. Patients who are naïve to Cannabis might be concerned about formulations with a high THC concentration because of the psychoactive effects of this substance. Given the minimal CNS activity of CBD, a tolerable therapeutic starting point often is a THC:CBD ratio of 1:1, which contains a lower percentage of THC.⁴

Physiologic effects. THC is a partial agonist of CB₁ and CB₂ receptors; CBD functions as an antagonist at both receptors. The primary effects of THC result from activation of CB₁ receptors, which exist in various areas of the cerebrum and cerebellum, as well as in the spinal cord.⁷ THC exerts its psychotropic effects at CB₁ sites in the central nervous system; CBD can antagonize these THC effects at CB₁ receptors. CBD also has anti-inflammatory and other effects that are mediated through peripherally distributed CB₂ receptors.⁹

Continue to: THC has tremendously...

A tolerable therapeutic starting point is a THC:CBD ratio of 1:1.

THC has tremendously complex capacity for activation and inhibition within various neuronal circuits, resulting in effects on mood, appetite, and movement.^1,7 Adverse effects associated with Cannabis are wide-ranging: Most commonly, nausea, drowsiness, fatigue, dry mouth, and dizziness are reported alongside cognitive effects. Rarely, tachycardia, hypotension, hyperemesis, and depression can be seen.

Clinical implications and indications

Clinical indications for legal medical Cannabis vary by state; typically, indications include human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), cachexia, cancer, glaucoma, epilepsy and other seizure disorders, severe and chronic pain, spasticity from neurodegenerative disorders, and irritable bowel syndrome and Crohn’s disease, as well as a wide range of less-universal diagnoses. A patient may have a so-called qualifying diagnosis (ie, having the potential to allow the patient to be certified to purchase and use Cannabis) in one state but not have the same standing in a neighboring state, posing a complex legal issue. Given the significant complexities of performing medical research with plant-based Cannabis in the United States, little research has been done. The result? Policymakers are grappling with questions that only scientific research can answer:

• For which conditions does Cannabis provide medicinal benefit equal to or superior to alternatives?
• What are the appropriate dosages (or CBD:THC ratios), formulations (plant-derived or synthetic), and routes of administration (smoked, ingested, or topical) for various conditions?

Bird’s-eye view of clinical research. A meta-analysis of isolated synthetic and plant-based cannabinoids for medical use was published in 2015.¹⁰ The analysis included more than 6000 patients in 79 trials, most of which assessed whether dronabinol or nabilone (both synthetic isolates) were effective compared to placebo or alternative non-Cannabis-based therapy. The studies examined chemotherapy-induced nausea and vomiting, appetite stimulation in HIV and AIDS, chronic pain, spasticity, depression and anxiety, sleep disorders, and psychosis.

Twenty-eight studies assessed chemotherapy-induced nausea and vomiting. All of these studies indicated a greater benefit from cannabinoids than from alternative antiemetic regimens and placebo; however, that finding did not reach statistical significance across all studies.

There was moderate evidence to suggest the use of Cannabis for neuropathic and nonneuropathic cancer-related pain. However, there is an increased short-term risk of adverse events with synthetic isolates dronabinol (when used for pain) and nabilone (when used for nausea and vomiting).

Continue to: The primary conclusion...

The primary conclusion of the meta-analysis is that further study is required because little evidence exists on the effects and the adverse events of plant-based Cannabis.

HIV infection. Data on Cannabis for the treatment of refractory neuropathy and appetite stimulation in HIV infection is mixed.^10,11 Smoked Cannabis for medically refractory neuropathy was examined in several trials:

• In a randomized crossover trial, researchers found statistically significant subjective improvement in neuropathic pain, with minimal intolerable adverse effects, in the 28 HIV-infected participants who completed the trial.¹¹
• In another study,Cannabis ingested in various forms resulted in appetite stimulation in late-stage HIV infection but did not produce statistically significant weight gain.¹⁰

Pediatric epilepsy. Research on pediatric patients who have epilepsy characterized by refractory seizures has shown that the impact of Cannabis on their disease is promising. Specifically, CBD has shown tremendous potential impact: Patients experienced a statistically significant reduction in the number of seizures.⁹ In 2018, the FDA approved the first plant-based derivative of Cannabis: an oral cannabidiol (marketed as Epidiolex [Greenwich Biosciences, Inc.]) for the treatment of intractable seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, rare and severe forms of epilepsy. Epidiolex is the first FDA-approved drug that contains a purified drug substance derived from marijuana.

CASE

Mr. S’s diagnosis of cancer is broadly included in the list of Cannabis-qualifying illnesses in all 34 states that certify patients for medical Cannabis. He qualifies both because (1) he is a cancer patient and (2) he has not found relief from chemotherapy-induced nausea and vomiting with several targeted therapies, including 5-hydroxytryptamine-receptor antagonists, steroids, and antipsychotics. Evidence supports CB₁ and CB₂ as potential targets for antiemetic treatment.

Research suggests that the use of Cannabis for pediatric patients with refractory seizures is promising.

Given Mr. S’s consequent anorexia, his frustration with taking an increasing number of medications, and possible adverse effects of additional therapy, Cannabis is a reasonable course of action to treat nausea and vomiting. He would be able to use oral tincture or vaporization of oil to further limit his pill burden—likely, with a THC:CBD ratio of 1:1 or similar.

Continue to: Based on recent observational data...

Based on recent observational data from New York Cannabis dispensaries, cancer patients pursing Cannabis to treat chemotherapy-induced symptoms report that (1) either products with a high concentration of THC or products that contain THC and CBD in a 1:1 ratio are most effective and (2) products in 1:1 ratio of THC and CBD are most tolerable.

A legal system at oddsover the status of medical Cannabis

The core legal issue underlying medical Cannabis is a contradiction between federal and state laws.

At the federal level. The federal government regulates the lawful production, possession, and distribution of controlled substances through the Controlled Substances Act (CSA).¹² The CSA is the basis for categorizing certain plants, drugs, and chemicals into 5 schedules, based on the substance’s medical use, potential for abuse, and safety or dependence liability.¹³ Under the CSA, marijuana (along with substances such as heroin and methamphetamine) is categorized as Schedule I¹⁴; ie, the substance

• has high potential for abuse,
• has no accepted therapeutic medical use in the United States, and
• lacks acceptable safety for use under medical supervision.

Despite waxing and waning efforts to protect states from federal prosecution, any use of a Schedule-1 substance violates federal law.¹⁵

Physicians are protected from prosecution or revocation of their prescriptive authority based on their First Amendment right to discuss medical marijuana with patients.

In June 2018, a bipartisan group of federal lawmakers introduced a bill designed to amend the CSA and guarantee the rights of states and territories to self-determine marijuana regulation. The bill established a so-called STATES (Strengthening the Tenth Amendment Through Entrusting States) Act that “amends the Controlled Substances Act (21 U.S.C. § 801 et seq.) so that—as states and tribes comply with a few basic protections—its provisions no longer apply to any person acting in compliance with state or tribal laws relating to the manufacture, production, possession, distribution, dispensation, administration, or delivery of marijuana.”¹⁵

Continue to: The bill was referred to the Senate...

The bill was referred to the Senate and House Judiciary Committees but, ultimately, the STATES Act was blocked from debate in 2018.

On April 4, 2019, the Act was reintroduced in the House (H.R. 2093) and Senate (S. 1028) of the 116th Congress. Although there is bipartisan support for this bill, the timeline for moving it forward is unclear.^16,17

At the state level. Thirty-four states have comprehensive public medical marijuana and Cannabis programs. The National Conference of State Legislatures¹⁸ (www.ncsl.org) designates a program “comprehensive” if it

• includes protection from criminal penalties for using marijuana for a medical purpose,
• allows access to marijuana through home cultivation, dispensaries, or other system,
• permits a variety of strains, including those more potent than what is labeled “low-THC,” and
• allows smoking or vaporization of marijuana products, plant-based material, or extract.

An additional 14 states allow for “low-THC, high-CBD” products for medical reasons, in limited situations, or as a legal defense. Regulation in these states varies widely, however: Some states allow industrialized hemp products only; others do not provide for any in-state production.¹⁸

Last, many states have some form of so-called “affirmative-defense” statutes that allow people charged with marijuana possession to mention use of marijuana for medical purposes as a possible defense.

Continue to: Physician shield

Physician shield. Despite inconsistent and evolving state and federal laws, physicians are protected, based on the Conant v Walters decision, from prosecution or revocation of their prescriptive authority for the professional “recommendation” of the use of medical marijuana.¹⁹ In 2002, the US Ninth Circuit Court of Appeals upheld the permanent injunction, based on a physician’s First Amendment right to discuss medical marijuana with patients.

CASE

Mr. S is amenable to trial of Cannabis to relieve nausea and anorexia. He asks you if he is allowed to use Cannabis at work, were he to return to an office-based desk job—even part-time—during treatment for cancer.

How would you answer Mr. S? Patients are legally protected from workplace penalties and dismissal for using and consuming Cannabis in states with a medical Cannabis law (including the state in which Mr. S resides). However, all employers have some variability in corporate policy, especially if a person works in a federally supported or regulated occupation. It’s always helpful to advise patients who will be using medical Cannabis to be proactive and speak with a human resources or employee health department staff member before beginning a course of medical Cannabis. Additionally, Cannabis with any amount of THC has the ability to alter focus, concentration, and perceptions of time. Thus, if a patient using medical Cannabis with THC asks about driving to work, he should be given the same advice one would offer about driving after consuming alcohol or ingesting opioids.

Common concerns

Ignorance of legal status. Theoretically, the Conant v Walters decision protects physicians from investigation for recommending medical Cannabis even in states where it is illegal. However, you should adhere closely to procedures set out by your state. The National Council of State Legislatures provides up-to-date information on each state’s procedures and programs,¹⁸ and the American Society of Addiction Medicine (www.asam.org) has established standards of professionalism for physicians who discuss medical Cannabis with patients (TABLE).²⁰

Exposure to smoke. Cannabis smoke carries many of the same carcinogens found in tobacco smoke; furthermore, use of Cannabis and tobacco are highly correlated, confounding many population-based studies. The manner of inhalation of Cannabis can result in significantly higher levels of tar and carbon dioxide than with tobacco smoking. Because the effects of Cannabis last longer, however, people who smoke Cannabis may smoke it less often than tobacco smokers smoke tobacco.²¹

Continue to: Large cross-sectional...

Large cross-sectional and longitudinal studies have not found a link between Cannabis smoking and long-term pulmonary consequences, such as chronic obstructive pulmonary disease and lung cancer.^22,23 The technology of Cannabis delivery systems has progressed far more rapidly than the clinical evidence for or against such technology.

Delayed onset of edible products and variation of THC concentration increase risk of overconsumption.

“Vaping” is an informal term for inhalation of aerosolized Cannabis components and water vapor. Vaporizers do not heat Cannabis to the point of combustion; therefore, they provide less exposure to smoke-related toxicants while providing similar time of onset.

Neuropsychiatric adverse effects. Data regarding the relationship between Cannabis use and psychiatric disorders are incompletely understood, in conflict, and related to cannabinoid type. Consider Pennsylvania’s addition of anxiety disorder as a “serious medical condition” covered under the Pennsylvania Medical Marijuana Act.²⁴ Although patients often report the use of medical Cannabis to treat anxiety,²⁵ panic attacks are often associated with Cannabis use.²⁶

While there is a clear association between Cannabis use and psychotic disorder, a causal link has yet to be unequivocally established. However, the rate of psychiatric hospitalization is increased in bipolar disorder and schizophrenia patients who use Cannabis heavily.²⁷

We recommend, therefore, that physicians screen patients for serious mental health concerns before recommending or certifying them to use medical Cannabis.

Continue to: Overconsumption of edibles

Overconsumption of edibles. Cannabis edibles (ie, food products infused with Cannabis extract) are distinct from inhaled Cannabis in regard to onset, duration, and potential for adverse effects. Cannabis edibles might be more popular than inhaled products among older medical Cannabis users.²⁸

Edible Cannabis has a reported onset of 1 to 3 hours (compared to 5-10 minutes with inhaled Cannabis) and a duration of effect of 6 to 8 hours (compared with 2-4 hours for inhaled products).²⁹ These qualities might render Cannabis edibles preferable to inhaled formulations for controlling chronic symptoms and conditions. However, delayed onset of edible products and wide variation in the concentration of THC also increase the risk of overconsumption, which can lead to overdose and self-limited Cannabis-induced psychosis. We recommend providing patient education about the effects of the physiologically active therapeutic compounds tetrahydrocannabinol and cannabidiol, to prevent overconsumption of high-THC products.³⁰

CASE

Mr. S returns to your office after a trial of Cannabis as vaporized oil and reports some relief of nausea and a mild increase in appetite, but no weight gain. He is concerned about overconsumption or overdose, and asks you what the risks of these problems are.

How should you counsel Mr. S? Explain that ingestion of Cannabis has a prolonged onset of action; vaporization has a more rapid onset of action; therefore, he could more easily self-regulate ingestion with the vehicle he has chosen. In states where edible Cannabis products are legal, education is necessary so that patients know how much of the edible to consume and how long they will wait to feel the full impact of the effects of THC.³⁰

Cannabis use disorder in the context of medical marijuana

Cannabis use disorder (CUD) incorporates general diagnostic features of a substance use disorder, including behavioral, cognitive, and physiologic symptoms such as cravings, tolerance, and withdrawal, in the setting of persistent use despite significant substance-related problems.³¹ Features of Cannabis withdrawal syndrome include irritability, anger or aggression, anxiety, depressed mood, restlessness, sleep difficulty, and decreased appetite or weight loss.³¹ Cannabis use disorder can develop in people who use medical Cannabis; however, physiologic symptoms of tolerance and withdrawal can also develop in the setting of appropriate medical use and do not, in isolation, represent CUD.

Continue to: A recent study...

A recent study considered nationwide cross-sectional survey data from the US National Survey of Drug Use and Health to examine the relationship between medical marijuana laws and CUD.³² Study findings did not show an increase in the prevalence of CUD or marijuana use among adults in states with a legalized medical marijuana program. Importantly, when researchers looked at marijuana use among adolescents and young adults, they found no increase in measured outcomes (eg, active [ie, past-month] marijuana use, heavy [> 300 d/yr] use, and a diagnosis of CUD) after medical marijuana laws were passed.³²

A paucity of pediatric data

Cannabis smoke carries many of the same carcinogens found in tobacco smoke.

The adolescent brain might be more vulnerable to the adverse long-term effects of Cannabis; there is potential significant harm associated with Cannabis in children and adolescence. However, accurate data concerning risk and benefit are limited.

The most recent policy statement of the American Academy of Pediatrics (AAP) reflects this paucity of data.³³ The AAP opposes the use of medical Cannabis outside regulation by the FDA, although the organization allows for consideration of compassionate use of medical Cannabis for children who have life-threatening or severely disabling conditions. The AAP does support (1) additional research into pharmaceutical cannabinoids and (2) changing Cannabis from Schedule I to Schedule II to facilitate this process. Since the publication of the policy statement, Pediatrics, the official journal of the AAP, has published a review of medical cannabinoids and found (1) strong evidence for benefit in chemotherapy-induced nausea and vomiting and (2) accumulating evidence of benefit in epilepsy.³⁴

Recognized risk: Not supporting medical Cannabis

At press time, the CDC issued a statement on respiratory illnesses reported after use of e-cigarette products. To learn more, go to www.cdc.gov/media/releases/2019/s0830-statement-e-cigarette.html.

As with all medical decisions, the risks and benefits of certifying patients for medical Cannabis must be balanced against the risks and benefits of not doing so. The risks that accompany failure to certify a patient for medical marijuana fall into 3 categories:

Blocking access to a substance that has potential therapeutic benefit. More data regarding the potential benefits and risks of medical Cannabis will, undoubtedly, dispel some of the uncertainty regarding the decision to certify a patient for medical Cannabis. When you recommend medical Cannabis and certify patients for its use, you do so with the certainty that the Cannabis safety index (ie, risk of overdose or serious adverse effects) is exceedingly low.³⁵

Continue to: Limiting patients to other medications

Limiting patients to other medications that, potentially, carry a risk of more or greater harmful effects. An example is the decision to prescribe an opioid for chronic pain instead of certifying a patient for medical Cannabis. For certain other conditions, including chemotherapy-induced nausea and vomiting, FDA-approved pharmaceuticals might have more reported serious adverse events and interactions than medical Cannabis.³⁶

 Resigning patients to obtain Cannabis from an illegal source.  This speaks to harm reduction and social justice, because obtaining Cannabis from an illegal source carries health and legal risks:

• Increased health risks result from lacing or cutting botanical or synthetic Cannabis products with potentially toxic substances. Cocaine, the rodenticide brodifacoum, methamphetamine, and phencyclidine are all known, or have been reported, to be added to botanical and synthetic Cannabis.³⁷
• Legal repercussions of Cannabis possession are disproportionately racially based, with a significantly higher arrest rate among people of color, even in states where medical Cannabis has been legalized.³⁸

CORRESPONDENCE
Lara Carson Weinstein, MD, MPH, DrPH, Department of Family and Community Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, 1015 Walnut Street, Suite 401, Philadelphia, PA 19107; [email protected].