Cultural diversity is indeed a barrier we need to clear to provide good health care to all. But the challenge of physician-patient communication goes beyond differences in sex, race, ethnicity, age, and level of literacy. Dialogue between physicians and patients is not always easy. There are barriers everywhere that can obstruct our best plans and impede a successful clinical outcome. And we may not even realize that the patient has hit a barrier until long after the visit, when we discover that medication has been taken “the wrong way” or not at all, that studies were not obtained, or that follow-up visits were not arranged.

Communication barriers include use of medical terms that we assume patients understand, lack of attention to clues of anxiety in our patients or their families that will adversely affect their memory of the visit, not finding out the patient’s actual concerns, and loss of the human connection in our rush to finish charting and to stay on time. But it is this connection that often drives the action plan to a successful conclusion.

What can we do in this era of one patient every 15 minutes? Try to make a genuine connection with every patient. This will enhance engagement and the retention of knowledge. Address the patient’s concerns, not just our own. Write legibly or type in the patient instruction section of the electronic medical record the key messages from the visit—diagnosis, plan, tests yet to be done—and give this to the patient at every visit. It is not insulting to do this, nor is it insulting to explain the details of what may seem like an intuitively obvious procedure or therapy. Ask the patient what his or her major concern is, and be sure to address it.

Often, the biggest barrier is that we physicians forget that each patient comes to us with a unique set of fears, rationalizations, and biases that we need to address (even if initially unspoken), just as we address the challenges of diagnosis and therapy. Patients don’t all think like doctors, but we need to be able to think like patients.

Cultural diversity is indeed a barrier we need to clear to provide good health care to all. But the challenge of physician-patient communication goes beyond differences in sex, race, ethnicity, age, and level of literacy. Dialogue between physicians and patients is not always easy. There are barriers everywhere that can obstruct our best plans and impede a successful clinical outcome. And we may not even realize that the patient has hit a barrier until long after the visit, when we discover that medication has been taken “the wrong way” or not at all, that studies were not obtained, or that follow-up visits were not arranged.

Communication barriers include use of medical terms that we assume patients understand, lack of attention to clues of anxiety in our patients or their families that will adversely affect their memory of the visit, not finding out the patient’s actual concerns, and loss of the human connection in our rush to finish charting and to stay on time. But it is this connection that often drives the action plan to a successful conclusion.

What can we do in this era of one patient every 15 minutes? Try to make a genuine connection with every patient. This will enhance engagement and the retention of knowledge. Address the patient’s concerns, not just our own. Write legibly or type in the patient instruction section of the electronic medical record the key messages from the visit—diagnosis, plan, tests yet to be done—and give this to the patient at every visit. It is not insulting to do this, nor is it insulting to explain the details of what may seem like an intuitively obvious procedure or therapy. Ask the patient what his or her major concern is, and be sure to address it.

Often, the biggest barrier is that we physicians forget that each patient comes to us with a unique set of fears, rationalizations, and biases that we need to address (even if initially unspoken), just as we address the challenges of diagnosis and therapy. Patients don’t all think like doctors, but we need to be able to think like patients.

Cultural diversity is indeed a barrier we need to clear to provide good health care to all. But the challenge of physician-patient communication goes beyond differences in sex, race, ethnicity, age, and level of literacy. Dialogue between physicians and patients is not always easy. There are barriers everywhere that can obstruct our best plans and impede a successful clinical outcome. And we may not even realize that the patient has hit a barrier until long after the visit, when we discover that medication has been taken “the wrong way” or not at all, that studies were not obtained, or that follow-up visits were not arranged.

Communication barriers include use of medical terms that we assume patients understand, lack of attention to clues of anxiety in our patients or their families that will adversely affect their memory of the visit, not finding out the patient’s actual concerns, and loss of the human connection in our rush to finish charting and to stay on time. But it is this connection that often drives the action plan to a successful conclusion.

What can we do in this era of one patient every 15 minutes? Try to make a genuine connection with every patient. This will enhance engagement and the retention of knowledge. Address the patient’s concerns, not just our own. Write legibly or type in the patient instruction section of the electronic medical record the key messages from the visit—diagnosis, plan, tests yet to be done—and give this to the patient at every visit. It is not insulting to do this, nor is it insulting to explain the details of what may seem like an intuitively obvious procedure or therapy. Ask the patient what his or her major concern is, and be sure to address it.

Often, the biggest barrier is that we physicians forget that each patient comes to us with a unique set of fears, rationalizations, and biases that we need to address (even if initially unspoken), just as we address the challenges of diagnosis and therapy. Patients don’t all think like doctors, but we need to be able to think like patients.

An english-speaking middle-aged woman from an ethnic minority group presents to her internist for follow-up of her chronic medical problems, which include diabetes, high blood pressure, asthma, and high cholesterol. Although she sees her physician regularly, her medical conditions are not optimally controlled.

At one of the visits, her physician gives her a list of her medications and, while reviewing it, explains—not for the first time—the importance of taking all of them as prescribed. The patient looks at the paper for a while, and then cautiously tells the physician, “But I can’t read.”

This patient presented to our practice several years ago. The scenario may be familiar to many primary physicians, except for the ending— ie, the patient telling her physician that she cannot read.

Her case raises several questions:

• Why did the physician not realize at the first encounter that she could not read the names of her prescribed medications?
• Why did the patient wait to tell her physician that important fact?
• And to what extent did her inability to read contribute to the poor control of her chronic medical problems?

Patients like this one are the human faces behind the statistics about health disparities—the worse outcomes noted in minority populations. Here, we discuss the issues of cross-cultural communication and health literacy as they relate to health care disparities.

DISPARITY IS NOT ONLY DUE TO LACK OF ACCESS

Health care disparity has been an important topic of discussion in medicine in the past decade.

In a 2003 publication,¹ the Institute of Medicine identified lower quality of health care in minority populations as a serious problem. Further, it disputed the long-held belief that the differences in health care between minority and nonminority populations could be explained by lack of access to medical services in minority groups. Instead, it cited factors at the level of the health care system, the level of the patient, and the “care-process level” (ie, the physician-patient encounter) as contributing in distinct ways to the problem.¹

A CALL FOR CULTURAL COMPETENCE

In a policy paper published in 2010, the American College of Physicians² reviewed the progress made in addressing health care disparities. In addition, noting that an individual’s environment, income, level of education, and other factors all affect health, it called for a concerted effort to improve insurance coverage, health literacy, and the health care delivery system; to address stressors both within and outside the health care system; and to recruit more minority health care workers.

None of these things seems like anything a busy practicing clinician could do much about. However, we can try to improve our cultural competence in our interactions with patients on an individual level.

The report recommends that physicians and other health care professionals be sensitive to cultural diversity among patients. It also says we should recognize our preconceived perceptions of minority patients that may affect their treatment and contribute to disparities in health care in minorities. To those ends, it calls for cultural competence training in medical school to improve cultural awareness and sensitivity.²

The Office of Minority Health broadly defines cultural and linguistic competence in health as “a set of congruent behaviors, attitudes, and policies that come together in a system, agency, or among professionals that enables effective work in cross-cultural situations.”³ Cultural competence training should focus on being aware of one’s personal bias, as well as on education about culture-specific norms or knowledge of possible causes of mistrust in minority groups.

For example, many African Americans may mistrust the medical system, given the awareness of previous inequities such as the notorious Tuskegee syphilis study (in which informed consent was not used and treatment that was needed was withheld). Further, beliefs about health in minority populations may be discordant with the Western medical model.⁴

RECOGNIZING OUR OWN BIASES

Preconceived perceptions on the part of the physician may be shaped by previous experiences with patients from a specific minority group or by personal bias. Unfortunately, even a well-meaning physician who has tried to learn about cultural norms of specific minority groups can be at risk of stereotyping by assuming that all members of that group hold the same beliefs. From the patient’s viewpoint, they can also be molded by previous experiences of health care inequities or unfavorable interactions with physicians.

For example, in the case we described above, perhaps the physician had assumed that the patient was noncompliant and therefore did not look for reasons for the poor control of her medical problems, or maybe the patient did not trust the physician enough to explain the reason for her difficulty with understanding how to take her medications.

Being aware of our own unconscious stereotyping of minority groups is an important step in effectively communicating with patients from different cultural backgrounds or with low health literacy. We also need to reflect about our own health belief system and try to incorporate the patient’s viewpoint into decision-making.

If, on reflection, we recognize that we do harbor biases, we ought to think about ways to better accommodate patients from different backgrounds and literacy levels, including trying to learn more about their culture or mastering techniques to effectively explain treatment plans to low-literacy patients.

ALL ENCOUNTERS WITH PATIENTS ARE ‘CROSS-CULTURAL’

In health care, “cross-cultural communication” does not refer only to interactions between persons from different ethnic backgrounds or with different beliefs about health. Health care has a culture of its own, creating a cross-cultural encounter the moment a person enters your office or clinic in the role of “patient.”

Carillo et al⁵ categorized issues that may pose difficulties in a cross-cultural encounter as those of authority, physical contact, communication styles, gender, sexuality, and family.

Physician-patient communication is a complicated issue. Many patients will not question a physician if their own cultural norms view it as disrespectful—even if they have very specific fears about the diagnosis or treatment plan. They may also defer any important decision to a family member who has the authority to make decisions for the family.

Frequently, miscommunication is unintentional. In a recent study of hospitalized patients,⁶ 77% of the physicians believed that their patients understood their diagnoses, while only 57% of patients could correctly state this information.

WHAT DOES THE PATIENT THINK?

A key issue in cross-cultural communication, and one that is often neglected, is to address a patient’s fears about his or her illness. In the study mentioned above, more than half of the patients who reported having anxieties or fears in the hospital stated that their physicians did not discuss their fears.⁶ But if we fail to do so, patients may be less satisfied with the treatment plan and may not accept our recommendations.

A patient’s understanding of his or her illness may be very different from the biomedical explanation. For example, we once saw an elderly man who was admitted to the hospital with back pain due to metastatic prostate cancer, but who was convinced that his symptoms were caused by a voodoo “hex” placed on him by his ex-wife.

For example, for the man who thought that his ex-wife put a hex on him, asking him “What do you think has caused your problem?” during the initial history-taking would allow him to express his concern about the hex and give the physician an opportunity to learn of this fear and then to offer the biomedical explanation for the problem and for the recommended treatment.

What happens more often in practice is that the specific fear is not addressed at the start of the encounter. Consequently, the patient is less likely to follow through with the treatment plan, as he or she does not feel the prescribed treatment is fixing the real problem. This process of exploring the explanatory model of illness may be viewed on a practical level as a way of managing expectations in the clinical care of culturally diverse populations.

HEALTH LITERACY: MORE THAN THE ABILITY TO READ

The better you know how to read, the healthier you probably are. In fact, a study found that a person’s literacy level correlated more strongly with health than did race or formal education level.⁹ (Apparently, attending school does not necessarily mean that people know how to read, and not attending school doesn’t mean that they don’t.)

Even more important than literacy may be health literacy, defined by Ratzan and Parker as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.”⁸ It includes basic math and critical-thinking skills that allow patients to use medications properly and participate in treatment decisions. Thus, health literacy is much more than the ability to read.

Even people who read and write very well may have trouble when confronted with the complexities of navigating our health care system, such as appointment scheduling, specialty referrals, and follow-up testing and procedures: their health literacy may be lower than their general literacy. We had a patient, a highly trained professional, who was confused by instructions for preparing for colonoscopy on a patient handout. Another similar patient could not understand the dosing of eye drops after cataract surgery because the instructions on the discharge paperwork were unclear.

However, limited health literacy disproportionately affects minority groups and is linked to poorer health care outcomes. Thus, addressing limited health literacy is important in addressing health care disparities. Effective physician-patient communication about treatment plans is fundamental to providing equitable care to patients from minority groups, some of whom may be at high risk for low health literacy.

Below, we will review some of the data on health literacy and offer suggestions for screening and interventions for those whose health literacy is limited.

36% have basic or below-basic reading skills

Every 10 years, the US Department of Education completes its National Assessment of Adult Literacy. Its 2003 survey—the most recent—included 19,000 adults in the community and in prison, interviewed at their place of residence.¹⁰ Each participant completed a set of tasks to measure his or her ability to read, understand, and interpret text and to use and interpret numbers.

Participants were divided into four categories based on the results: proficient (12%), intermediate (53%), basic (22%), and below basic (14%). Additionally, 5% of potential participants could not be tested because they had insufficient skills to participate in the survey.

Low literacy puts patients at risk

Although literacy is not the same as health literacy, functionally, those who have basic or below-basic literacy skills (36% of the US population) are at high risk for encountering problems in the US health care system. For example, they would have difficulty with most patient education handouts and health insurance forms.

Limited health literacy exacts both personal and financial costs. Patients with low health literacy are less likely to understand how to take their medications, what prescription warning labels mean, how to schedule follow-up appointments, and how to fill out health insurance forms.^11–14

Medicare managed-care enrollees are more likely to be hospitalized if they have limited health literacy,¹⁵ and diabetic Medicaid patients who have limited health literacy are less likely to have good glycemic control.¹⁶ One study showed annual health care costs of $10,688 for Medicaid enrollees with limited health literacy compared with $2,891 for all enrollees.¹⁷ The total cost of limited health literacy to the US health care system is estimated to be between $50 and $73 billion per year.¹⁸

Screening for limited health literacy: You can’t tell just by looking

Given the high costs of low health literacy, identifying patients who have it is of paramount importance.

Groups who are more likely to have limited health literacy include the elderly, the poor, the unemployed, high school dropouts, members of minority groups, recent immigrants, and people for whom English is a second language.

However, these demographic factors are not sufficient as a screen for low health literacy—you can't tell just by looking. Red flags for low health literacy include difficulty filling out forms in the office, missed appointments, nonadherence to medication regimens, failure to follow up with scheduled testing, and difficulty reading written materials, often masked with a statement such as “I forgot my glasses and will read this at home.”

A number of screening tests have been developed, including the Rapid Estimate of Adult Literacy in Medicine (REALM)¹⁹ and the Test for Functional Health Literacy in Adults (TOFHLA).²⁰ These tests are long, making them difficult to incorporate into a patient visit in a busy primary care practice, but they are useful for research. A newer screening test asks the patient to review a nutrition label and answer six questions.²¹

The most useful screening test for clinical use may consist of a single question. Questions that have been validated:

• “How often do you need to have someone help you when you read instructions, pamphlets, or other written material from your doctor or pharmacy?” Positive answers are “sometimes,” “often,” or “always.”
• “How confident are you filling out medical forms by yourself?” Positive answers are “somewhat,” “a little bit,” or “not at all.”^22–24

These questions can be included either in the initial screening by a nurse or medical assistant or as part of the social history portion of the interview with the physician.

A “brown bag review” can also be helpful. Patients are asked to bring in their medications (often in a brown bag—hence the name). Asking the patient to identify each medication by name and the indication for it can uncover knowledge gaps that indicate low health literacy.

The point to remember is that patients with low health literacy will probably not tell you that they do not understand. However, they would appreciate being asked in a nonthreatening manner.

 

 

Make your office a shame-free environment

Many experts advocate a “universal precautions approach,” in which interventions to address low health literacy are incorporated into routine office practice for all patients. Practice sites should adopt a culture of a “shame-free environment,” in which support staff encourage patients to ask questions and are trained to offer assistance to those having difficulty reading or filling out forms.

On a broader level, medical offices and hospitals can partner with adult-learning specialists to help patients gain skills to navigate the health care system. All signage should be clear and should use plain language as opposed to medical terms. Medical forms and questionnaires should be designed to collect only essential information and should be written at a sixth-grade reading level or below. Patient instructions and educational materials should also be clear and free of jargon.

The ‘teach-back’ technique

The “teach-back” technique is a simple method to confirm patient understanding at the end of the visit. This involves asking patients in a nonthreatening way to explain or demonstrate what they have been told. Examples:

• “I want to make sure I have explained things correctly. Can you tell me how you plan to take your medication when you go home?”
• “I want to make sure I have done a good job explaining things to you. When you go home and tell your spouse about your visit today, what will you say?”

These questions should be asked in a nonthreatening way. Put the burden of explanation on yourself as the first step, and let the patient know you are willing to explain again more thoroughly any instructions that may have not been clearly understood.

Other measures

Pictures and computer-based education may be useful for some patients who have difficulty reading.

Weiss²⁵ advocates six steps to improve communication with patients in all encounters: slow down; use plain, nonmedical language; show or draw pictures; limit the amount of information provided; use the teach-back technique; and create a shame-free environment, encouraging questions.

Improving health literacy, as it relates to cross-cultural communication of treatment plans, must encompass understanding of health beliefs often based on cultural norms, in order to come to agreement on a mutually acceptable plan of care. Physicians should be aware of preferences for nontraditional or complementary treatments that may reflect specific cultural beliefs.

IF THE PATIENT DOES NOT SPEAK ENGLISH

Verbal communication across language barriers poses another layer of challenge. A trained interpreter should be used whenever possible when treating a patient who speaks a different language than that of the practitioner. When family members are used as interpreters, there are risks that the patient may not fully disclose facts about the history of illness or specific symptoms, and also that family members may place their own “twist” on the story when translating.

The physician should speak directly to the patient in a normal tone of voice. In this setting, also remember that nonverbal communication can be misinterpreted. Gestures should be avoided. Finally, be aware that personal space is viewed differently depending on cultural background, as is eye contact.

It is helpful to have a pre-interview meeting with the interpreter to explain the format of the interview, as well as a post-interview meeting to ensure all parties felt they effectively communicated during the encounter.

TOWARD EQUITABLE CARE

Health care disparities are the result of multiple determinants. In December 2008, a National Institutes of Health summit conference cited not only barriers to access, but also the interaction of biological, behavioral, social, environmental, economic, cultural, and political factors, and noted that the causes and effects of health disparities transcend health care.²⁶

Clearly, an individual physician’s efforts will not be all that is needed to eliminate health disparities. A team-based approach is essential, using skills of nonphysician members of the health care team such as nurses, medical assistants, social workers, and case managers. Continued opportunity for professional training and development in provider-patient communication skills should be offered.

However, the impact of effective cross-cultural communication and managing low health literacy populations on the physician-patient level should not be understated. As practitioners treating patients from diverse backgrounds, improving self-awareness, eliciting the patient’s explanatory model, and assuring understanding of treatment plans for patients with low health literacy or with language barriers, we can do our part in working toward equitable care for all patients.

An english-speaking middle-aged woman from an ethnic minority group presents to her internist for follow-up of her chronic medical problems, which include diabetes, high blood pressure, asthma, and high cholesterol. Although she sees her physician regularly, her medical conditions are not optimally controlled.

At one of the visits, her physician gives her a list of her medications and, while reviewing it, explains—not for the first time—the importance of taking all of them as prescribed. The patient looks at the paper for a while, and then cautiously tells the physician, “But I can’t read.”

This patient presented to our practice several years ago. The scenario may be familiar to many primary physicians, except for the ending— ie, the patient telling her physician that she cannot read.

Her case raises several questions:

• Why did the physician not realize at the first encounter that she could not read the names of her prescribed medications?
• Why did the patient wait to tell her physician that important fact?
• And to what extent did her inability to read contribute to the poor control of her chronic medical problems?

Patients like this one are the human faces behind the statistics about health disparities—the worse outcomes noted in minority populations. Here, we discuss the issues of cross-cultural communication and health literacy as they relate to health care disparities.

DISPARITY IS NOT ONLY DUE TO LACK OF ACCESS

Health care disparity has been an important topic of discussion in medicine in the past decade.

In a 2003 publication,¹ the Institute of Medicine identified lower quality of health care in minority populations as a serious problem. Further, it disputed the long-held belief that the differences in health care between minority and nonminority populations could be explained by lack of access to medical services in minority groups. Instead, it cited factors at the level of the health care system, the level of the patient, and the “care-process level” (ie, the physician-patient encounter) as contributing in distinct ways to the problem.¹

A CALL FOR CULTURAL COMPETENCE

In a policy paper published in 2010, the American College of Physicians² reviewed the progress made in addressing health care disparities. In addition, noting that an individual’s environment, income, level of education, and other factors all affect health, it called for a concerted effort to improve insurance coverage, health literacy, and the health care delivery system; to address stressors both within and outside the health care system; and to recruit more minority health care workers.

None of these things seems like anything a busy practicing clinician could do much about. However, we can try to improve our cultural competence in our interactions with patients on an individual level.

The report recommends that physicians and other health care professionals be sensitive to cultural diversity among patients. It also says we should recognize our preconceived perceptions of minority patients that may affect their treatment and contribute to disparities in health care in minorities. To those ends, it calls for cultural competence training in medical school to improve cultural awareness and sensitivity.²

The Office of Minority Health broadly defines cultural and linguistic competence in health as “a set of congruent behaviors, attitudes, and policies that come together in a system, agency, or among professionals that enables effective work in cross-cultural situations.”³ Cultural competence training should focus on being aware of one’s personal bias, as well as on education about culture-specific norms or knowledge of possible causes of mistrust in minority groups.

For example, many African Americans may mistrust the medical system, given the awareness of previous inequities such as the notorious Tuskegee syphilis study (in which informed consent was not used and treatment that was needed was withheld). Further, beliefs about health in minority populations may be discordant with the Western medical model.⁴

RECOGNIZING OUR OWN BIASES

Preconceived perceptions on the part of the physician may be shaped by previous experiences with patients from a specific minority group or by personal bias. Unfortunately, even a well-meaning physician who has tried to learn about cultural norms of specific minority groups can be at risk of stereotyping by assuming that all members of that group hold the same beliefs. From the patient’s viewpoint, they can also be molded by previous experiences of health care inequities or unfavorable interactions with physicians.

For example, in the case we described above, perhaps the physician had assumed that the patient was noncompliant and therefore did not look for reasons for the poor control of her medical problems, or maybe the patient did not trust the physician enough to explain the reason for her difficulty with understanding how to take her medications.

Being aware of our own unconscious stereotyping of minority groups is an important step in effectively communicating with patients from different cultural backgrounds or with low health literacy. We also need to reflect about our own health belief system and try to incorporate the patient’s viewpoint into decision-making.

If, on reflection, we recognize that we do harbor biases, we ought to think about ways to better accommodate patients from different backgrounds and literacy levels, including trying to learn more about their culture or mastering techniques to effectively explain treatment plans to low-literacy patients.

ALL ENCOUNTERS WITH PATIENTS ARE ‘CROSS-CULTURAL’

In health care, “cross-cultural communication” does not refer only to interactions between persons from different ethnic backgrounds or with different beliefs about health. Health care has a culture of its own, creating a cross-cultural encounter the moment a person enters your office or clinic in the role of “patient.”

Carillo et al⁵ categorized issues that may pose difficulties in a cross-cultural encounter as those of authority, physical contact, communication styles, gender, sexuality, and family.

Physician-patient communication is a complicated issue. Many patients will not question a physician if their own cultural norms view it as disrespectful—even if they have very specific fears about the diagnosis or treatment plan. They may also defer any important decision to a family member who has the authority to make decisions for the family.

Frequently, miscommunication is unintentional. In a recent study of hospitalized patients,⁶ 77% of the physicians believed that their patients understood their diagnoses, while only 57% of patients could correctly state this information.

WHAT DOES THE PATIENT THINK?

A key issue in cross-cultural communication, and one that is often neglected, is to address a patient’s fears about his or her illness. In the study mentioned above, more than half of the patients who reported having anxieties or fears in the hospital stated that their physicians did not discuss their fears.⁶ But if we fail to do so, patients may be less satisfied with the treatment plan and may not accept our recommendations.

A patient’s understanding of his or her illness may be very different from the biomedical explanation. For example, we once saw an elderly man who was admitted to the hospital with back pain due to metastatic prostate cancer, but who was convinced that his symptoms were caused by a voodoo “hex” placed on him by his ex-wife.

For example, for the man who thought that his ex-wife put a hex on him, asking him “What do you think has caused your problem?” during the initial history-taking would allow him to express his concern about the hex and give the physician an opportunity to learn of this fear and then to offer the biomedical explanation for the problem and for the recommended treatment.

What happens more often in practice is that the specific fear is not addressed at the start of the encounter. Consequently, the patient is less likely to follow through with the treatment plan, as he or she does not feel the prescribed treatment is fixing the real problem. This process of exploring the explanatory model of illness may be viewed on a practical level as a way of managing expectations in the clinical care of culturally diverse populations.

HEALTH LITERACY: MORE THAN THE ABILITY TO READ

The better you know how to read, the healthier you probably are. In fact, a study found that a person’s literacy level correlated more strongly with health than did race or formal education level.⁹ (Apparently, attending school does not necessarily mean that people know how to read, and not attending school doesn’t mean that they don’t.)

Even more important than literacy may be health literacy, defined by Ratzan and Parker as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.”⁸ It includes basic math and critical-thinking skills that allow patients to use medications properly and participate in treatment decisions. Thus, health literacy is much more than the ability to read.

Even people who read and write very well may have trouble when confronted with the complexities of navigating our health care system, such as appointment scheduling, specialty referrals, and follow-up testing and procedures: their health literacy may be lower than their general literacy. We had a patient, a highly trained professional, who was confused by instructions for preparing for colonoscopy on a patient handout. Another similar patient could not understand the dosing of eye drops after cataract surgery because the instructions on the discharge paperwork were unclear.

However, limited health literacy disproportionately affects minority groups and is linked to poorer health care outcomes. Thus, addressing limited health literacy is important in addressing health care disparities. Effective physician-patient communication about treatment plans is fundamental to providing equitable care to patients from minority groups, some of whom may be at high risk for low health literacy.

Below, we will review some of the data on health literacy and offer suggestions for screening and interventions for those whose health literacy is limited.

36% have basic or below-basic reading skills

Every 10 years, the US Department of Education completes its National Assessment of Adult Literacy. Its 2003 survey—the most recent—included 19,000 adults in the community and in prison, interviewed at their place of residence.¹⁰ Each participant completed a set of tasks to measure his or her ability to read, understand, and interpret text and to use and interpret numbers.

Participants were divided into four categories based on the results: proficient (12%), intermediate (53%), basic (22%), and below basic (14%). Additionally, 5% of potential participants could not be tested because they had insufficient skills to participate in the survey.

Low literacy puts patients at risk

Although literacy is not the same as health literacy, functionally, those who have basic or below-basic literacy skills (36% of the US population) are at high risk for encountering problems in the US health care system. For example, they would have difficulty with most patient education handouts and health insurance forms.

Limited health literacy exacts both personal and financial costs. Patients with low health literacy are less likely to understand how to take their medications, what prescription warning labels mean, how to schedule follow-up appointments, and how to fill out health insurance forms.^11–14

Medicare managed-care enrollees are more likely to be hospitalized if they have limited health literacy,¹⁵ and diabetic Medicaid patients who have limited health literacy are less likely to have good glycemic control.¹⁶ One study showed annual health care costs of $10,688 for Medicaid enrollees with limited health literacy compared with $2,891 for all enrollees.¹⁷ The total cost of limited health literacy to the US health care system is estimated to be between $50 and $73 billion per year.¹⁸

Screening for limited health literacy: You can’t tell just by looking

Given the high costs of low health literacy, identifying patients who have it is of paramount importance.

Groups who are more likely to have limited health literacy include the elderly, the poor, the unemployed, high school dropouts, members of minority groups, recent immigrants, and people for whom English is a second language.

However, these demographic factors are not sufficient as a screen for low health literacy—you can't tell just by looking. Red flags for low health literacy include difficulty filling out forms in the office, missed appointments, nonadherence to medication regimens, failure to follow up with scheduled testing, and difficulty reading written materials, often masked with a statement such as “I forgot my glasses and will read this at home.”

A number of screening tests have been developed, including the Rapid Estimate of Adult Literacy in Medicine (REALM)¹⁹ and the Test for Functional Health Literacy in Adults (TOFHLA).²⁰ These tests are long, making them difficult to incorporate into a patient visit in a busy primary care practice, but they are useful for research. A newer screening test asks the patient to review a nutrition label and answer six questions.²¹

The most useful screening test for clinical use may consist of a single question. Questions that have been validated:

• “How often do you need to have someone help you when you read instructions, pamphlets, or other written material from your doctor or pharmacy?” Positive answers are “sometimes,” “often,” or “always.”
• “How confident are you filling out medical forms by yourself?” Positive answers are “somewhat,” “a little bit,” or “not at all.”^22–24

These questions can be included either in the initial screening by a nurse or medical assistant or as part of the social history portion of the interview with the physician.

A “brown bag review” can also be helpful. Patients are asked to bring in their medications (often in a brown bag—hence the name). Asking the patient to identify each medication by name and the indication for it can uncover knowledge gaps that indicate low health literacy.

The point to remember is that patients with low health literacy will probably not tell you that they do not understand. However, they would appreciate being asked in a nonthreatening manner.

 

 

Make your office a shame-free environment

Many experts advocate a “universal precautions approach,” in which interventions to address low health literacy are incorporated into routine office practice for all patients. Practice sites should adopt a culture of a “shame-free environment,” in which support staff encourage patients to ask questions and are trained to offer assistance to those having difficulty reading or filling out forms.

On a broader level, medical offices and hospitals can partner with adult-learning specialists to help patients gain skills to navigate the health care system. All signage should be clear and should use plain language as opposed to medical terms. Medical forms and questionnaires should be designed to collect only essential information and should be written at a sixth-grade reading level or below. Patient instructions and educational materials should also be clear and free of jargon.

The ‘teach-back’ technique

The “teach-back” technique is a simple method to confirm patient understanding at the end of the visit. This involves asking patients in a nonthreatening way to explain or demonstrate what they have been told. Examples:

• “I want to make sure I have explained things correctly. Can you tell me how you plan to take your medication when you go home?”
• “I want to make sure I have done a good job explaining things to you. When you go home and tell your spouse about your visit today, what will you say?”

These questions should be asked in a nonthreatening way. Put the burden of explanation on yourself as the first step, and let the patient know you are willing to explain again more thoroughly any instructions that may have not been clearly understood.

Other measures

Pictures and computer-based education may be useful for some patients who have difficulty reading.

Weiss²⁵ advocates six steps to improve communication with patients in all encounters: slow down; use plain, nonmedical language; show or draw pictures; limit the amount of information provided; use the teach-back technique; and create a shame-free environment, encouraging questions.

Improving health literacy, as it relates to cross-cultural communication of treatment plans, must encompass understanding of health beliefs often based on cultural norms, in order to come to agreement on a mutually acceptable plan of care. Physicians should be aware of preferences for nontraditional or complementary treatments that may reflect specific cultural beliefs.

IF THE PATIENT DOES NOT SPEAK ENGLISH

Verbal communication across language barriers poses another layer of challenge. A trained interpreter should be used whenever possible when treating a patient who speaks a different language than that of the practitioner. When family members are used as interpreters, there are risks that the patient may not fully disclose facts about the history of illness or specific symptoms, and also that family members may place their own “twist” on the story when translating.

The physician should speak directly to the patient in a normal tone of voice. In this setting, also remember that nonverbal communication can be misinterpreted. Gestures should be avoided. Finally, be aware that personal space is viewed differently depending on cultural background, as is eye contact.

It is helpful to have a pre-interview meeting with the interpreter to explain the format of the interview, as well as a post-interview meeting to ensure all parties felt they effectively communicated during the encounter.

TOWARD EQUITABLE CARE

Health care disparities are the result of multiple determinants. In December 2008, a National Institutes of Health summit conference cited not only barriers to access, but also the interaction of biological, behavioral, social, environmental, economic, cultural, and political factors, and noted that the causes and effects of health disparities transcend health care.²⁶

Clearly, an individual physician’s efforts will not be all that is needed to eliminate health disparities. A team-based approach is essential, using skills of nonphysician members of the health care team such as nurses, medical assistants, social workers, and case managers. Continued opportunity for professional training and development in provider-patient communication skills should be offered.

However, the impact of effective cross-cultural communication and managing low health literacy populations on the physician-patient level should not be understated. As practitioners treating patients from diverse backgrounds, improving self-awareness, eliciting the patient’s explanatory model, and assuring understanding of treatment plans for patients with low health literacy or with language barriers, we can do our part in working toward equitable care for all patients.

An english-speaking middle-aged woman from an ethnic minority group presents to her internist for follow-up of her chronic medical problems, which include diabetes, high blood pressure, asthma, and high cholesterol. Although she sees her physician regularly, her medical conditions are not optimally controlled.

At one of the visits, her physician gives her a list of her medications and, while reviewing it, explains—not for the first time—the importance of taking all of them as prescribed. The patient looks at the paper for a while, and then cautiously tells the physician, “But I can’t read.”

This patient presented to our practice several years ago. The scenario may be familiar to many primary physicians, except for the ending— ie, the patient telling her physician that she cannot read.

Her case raises several questions:

• Why did the physician not realize at the first encounter that she could not read the names of her prescribed medications?
• Why did the patient wait to tell her physician that important fact?
• And to what extent did her inability to read contribute to the poor control of her chronic medical problems?

Patients like this one are the human faces behind the statistics about health disparities—the worse outcomes noted in minority populations. Here, we discuss the issues of cross-cultural communication and health literacy as they relate to health care disparities.

DISPARITY IS NOT ONLY DUE TO LACK OF ACCESS

Health care disparity has been an important topic of discussion in medicine in the past decade.

In a 2003 publication,¹ the Institute of Medicine identified lower quality of health care in minority populations as a serious problem. Further, it disputed the long-held belief that the differences in health care between minority and nonminority populations could be explained by lack of access to medical services in minority groups. Instead, it cited factors at the level of the health care system, the level of the patient, and the “care-process level” (ie, the physician-patient encounter) as contributing in distinct ways to the problem.¹

A CALL FOR CULTURAL COMPETENCE

In a policy paper published in 2010, the American College of Physicians² reviewed the progress made in addressing health care disparities. In addition, noting that an individual’s environment, income, level of education, and other factors all affect health, it called for a concerted effort to improve insurance coverage, health literacy, and the health care delivery system; to address stressors both within and outside the health care system; and to recruit more minority health care workers.

None of these things seems like anything a busy practicing clinician could do much about. However, we can try to improve our cultural competence in our interactions with patients on an individual level.

The report recommends that physicians and other health care professionals be sensitive to cultural diversity among patients. It also says we should recognize our preconceived perceptions of minority patients that may affect their treatment and contribute to disparities in health care in minorities. To those ends, it calls for cultural competence training in medical school to improve cultural awareness and sensitivity.²

The Office of Minority Health broadly defines cultural and linguistic competence in health as “a set of congruent behaviors, attitudes, and policies that come together in a system, agency, or among professionals that enables effective work in cross-cultural situations.”³ Cultural competence training should focus on being aware of one’s personal bias, as well as on education about culture-specific norms or knowledge of possible causes of mistrust in minority groups.

For example, many African Americans may mistrust the medical system, given the awareness of previous inequities such as the notorious Tuskegee syphilis study (in which informed consent was not used and treatment that was needed was withheld). Further, beliefs about health in minority populations may be discordant with the Western medical model.⁴

RECOGNIZING OUR OWN BIASES

Preconceived perceptions on the part of the physician may be shaped by previous experiences with patients from a specific minority group or by personal bias. Unfortunately, even a well-meaning physician who has tried to learn about cultural norms of specific minority groups can be at risk of stereotyping by assuming that all members of that group hold the same beliefs. From the patient’s viewpoint, they can also be molded by previous experiences of health care inequities or unfavorable interactions with physicians.

For example, in the case we described above, perhaps the physician had assumed that the patient was noncompliant and therefore did not look for reasons for the poor control of her medical problems, or maybe the patient did not trust the physician enough to explain the reason for her difficulty with understanding how to take her medications.

Being aware of our own unconscious stereotyping of minority groups is an important step in effectively communicating with patients from different cultural backgrounds or with low health literacy. We also need to reflect about our own health belief system and try to incorporate the patient’s viewpoint into decision-making.

If, on reflection, we recognize that we do harbor biases, we ought to think about ways to better accommodate patients from different backgrounds and literacy levels, including trying to learn more about their culture or mastering techniques to effectively explain treatment plans to low-literacy patients.

ALL ENCOUNTERS WITH PATIENTS ARE ‘CROSS-CULTURAL’

In health care, “cross-cultural communication” does not refer only to interactions between persons from different ethnic backgrounds or with different beliefs about health. Health care has a culture of its own, creating a cross-cultural encounter the moment a person enters your office or clinic in the role of “patient.”

Carillo et al⁵ categorized issues that may pose difficulties in a cross-cultural encounter as those of authority, physical contact, communication styles, gender, sexuality, and family.

Physician-patient communication is a complicated issue. Many patients will not question a physician if their own cultural norms view it as disrespectful—even if they have very specific fears about the diagnosis or treatment plan. They may also defer any important decision to a family member who has the authority to make decisions for the family.

Frequently, miscommunication is unintentional. In a recent study of hospitalized patients,⁶ 77% of the physicians believed that their patients understood their diagnoses, while only 57% of patients could correctly state this information.

WHAT DOES THE PATIENT THINK?

A key issue in cross-cultural communication, and one that is often neglected, is to address a patient’s fears about his or her illness. In the study mentioned above, more than half of the patients who reported having anxieties or fears in the hospital stated that their physicians did not discuss their fears.⁶ But if we fail to do so, patients may be less satisfied with the treatment plan and may not accept our recommendations.

A patient’s understanding of his or her illness may be very different from the biomedical explanation. For example, we once saw an elderly man who was admitted to the hospital with back pain due to metastatic prostate cancer, but who was convinced that his symptoms were caused by a voodoo “hex” placed on him by his ex-wife.

For example, for the man who thought that his ex-wife put a hex on him, asking him “What do you think has caused your problem?” during the initial history-taking would allow him to express his concern about the hex and give the physician an opportunity to learn of this fear and then to offer the biomedical explanation for the problem and for the recommended treatment.

What happens more often in practice is that the specific fear is not addressed at the start of the encounter. Consequently, the patient is less likely to follow through with the treatment plan, as he or she does not feel the prescribed treatment is fixing the real problem. This process of exploring the explanatory model of illness may be viewed on a practical level as a way of managing expectations in the clinical care of culturally diverse populations.

HEALTH LITERACY: MORE THAN THE ABILITY TO READ

The better you know how to read, the healthier you probably are. In fact, a study found that a person’s literacy level correlated more strongly with health than did race or formal education level.⁹ (Apparently, attending school does not necessarily mean that people know how to read, and not attending school doesn’t mean that they don’t.)

Even more important than literacy may be health literacy, defined by Ratzan and Parker as “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.”⁸ It includes basic math and critical-thinking skills that allow patients to use medications properly and participate in treatment decisions. Thus, health literacy is much more than the ability to read.

Even people who read and write very well may have trouble when confronted with the complexities of navigating our health care system, such as appointment scheduling, specialty referrals, and follow-up testing and procedures: their health literacy may be lower than their general literacy. We had a patient, a highly trained professional, who was confused by instructions for preparing for colonoscopy on a patient handout. Another similar patient could not understand the dosing of eye drops after cataract surgery because the instructions on the discharge paperwork were unclear.

However, limited health literacy disproportionately affects minority groups and is linked to poorer health care outcomes. Thus, addressing limited health literacy is important in addressing health care disparities. Effective physician-patient communication about treatment plans is fundamental to providing equitable care to patients from minority groups, some of whom may be at high risk for low health literacy.

Below, we will review some of the data on health literacy and offer suggestions for screening and interventions for those whose health literacy is limited.

36% have basic or below-basic reading skills

Every 10 years, the US Department of Education completes its National Assessment of Adult Literacy. Its 2003 survey—the most recent—included 19,000 adults in the community and in prison, interviewed at their place of residence.¹⁰ Each participant completed a set of tasks to measure his or her ability to read, understand, and interpret text and to use and interpret numbers.

Participants were divided into four categories based on the results: proficient (12%), intermediate (53%), basic (22%), and below basic (14%). Additionally, 5% of potential participants could not be tested because they had insufficient skills to participate in the survey.

Low literacy puts patients at risk

Although literacy is not the same as health literacy, functionally, those who have basic or below-basic literacy skills (36% of the US population) are at high risk for encountering problems in the US health care system. For example, they would have difficulty with most patient education handouts and health insurance forms.

Limited health literacy exacts both personal and financial costs. Patients with low health literacy are less likely to understand how to take their medications, what prescription warning labels mean, how to schedule follow-up appointments, and how to fill out health insurance forms.^11–14

Medicare managed-care enrollees are more likely to be hospitalized if they have limited health literacy,¹⁵ and diabetic Medicaid patients who have limited health literacy are less likely to have good glycemic control.¹⁶ One study showed annual health care costs of $10,688 for Medicaid enrollees with limited health literacy compared with $2,891 for all enrollees.¹⁷ The total cost of limited health literacy to the US health care system is estimated to be between $50 and $73 billion per year.¹⁸

Screening for limited health literacy: You can’t tell just by looking

Given the high costs of low health literacy, identifying patients who have it is of paramount importance.

Groups who are more likely to have limited health literacy include the elderly, the poor, the unemployed, high school dropouts, members of minority groups, recent immigrants, and people for whom English is a second language.

However, these demographic factors are not sufficient as a screen for low health literacy—you can't tell just by looking. Red flags for low health literacy include difficulty filling out forms in the office, missed appointments, nonadherence to medication regimens, failure to follow up with scheduled testing, and difficulty reading written materials, often masked with a statement such as “I forgot my glasses and will read this at home.”

A number of screening tests have been developed, including the Rapid Estimate of Adult Literacy in Medicine (REALM)¹⁹ and the Test for Functional Health Literacy in Adults (TOFHLA).²⁰ These tests are long, making them difficult to incorporate into a patient visit in a busy primary care practice, but they are useful for research. A newer screening test asks the patient to review a nutrition label and answer six questions.²¹

The most useful screening test for clinical use may consist of a single question. Questions that have been validated:

• “How often do you need to have someone help you when you read instructions, pamphlets, or other written material from your doctor or pharmacy?” Positive answers are “sometimes,” “often,” or “always.”
• “How confident are you filling out medical forms by yourself?” Positive answers are “somewhat,” “a little bit,” or “not at all.”^22–24

These questions can be included either in the initial screening by a nurse or medical assistant or as part of the social history portion of the interview with the physician.

A “brown bag review” can also be helpful. Patients are asked to bring in their medications (often in a brown bag—hence the name). Asking the patient to identify each medication by name and the indication for it can uncover knowledge gaps that indicate low health literacy.

The point to remember is that patients with low health literacy will probably not tell you that they do not understand. However, they would appreciate being asked in a nonthreatening manner.

 

 

Make your office a shame-free environment

Many experts advocate a “universal precautions approach,” in which interventions to address low health literacy are incorporated into routine office practice for all patients. Practice sites should adopt a culture of a “shame-free environment,” in which support staff encourage patients to ask questions and are trained to offer assistance to those having difficulty reading or filling out forms.

On a broader level, medical offices and hospitals can partner with adult-learning specialists to help patients gain skills to navigate the health care system. All signage should be clear and should use plain language as opposed to medical terms. Medical forms and questionnaires should be designed to collect only essential information and should be written at a sixth-grade reading level or below. Patient instructions and educational materials should also be clear and free of jargon.

The ‘teach-back’ technique

The “teach-back” technique is a simple method to confirm patient understanding at the end of the visit. This involves asking patients in a nonthreatening way to explain or demonstrate what they have been told. Examples:

• “I want to make sure I have explained things correctly. Can you tell me how you plan to take your medication when you go home?”
• “I want to make sure I have done a good job explaining things to you. When you go home and tell your spouse about your visit today, what will you say?”

These questions should be asked in a nonthreatening way. Put the burden of explanation on yourself as the first step, and let the patient know you are willing to explain again more thoroughly any instructions that may have not been clearly understood.

Other measures

Pictures and computer-based education may be useful for some patients who have difficulty reading.

Weiss²⁵ advocates six steps to improve communication with patients in all encounters: slow down; use plain, nonmedical language; show or draw pictures; limit the amount of information provided; use the teach-back technique; and create a shame-free environment, encouraging questions.

Improving health literacy, as it relates to cross-cultural communication of treatment plans, must encompass understanding of health beliefs often based on cultural norms, in order to come to agreement on a mutually acceptable plan of care. Physicians should be aware of preferences for nontraditional or complementary treatments that may reflect specific cultural beliefs.

IF THE PATIENT DOES NOT SPEAK ENGLISH

Verbal communication across language barriers poses another layer of challenge. A trained interpreter should be used whenever possible when treating a patient who speaks a different language than that of the practitioner. When family members are used as interpreters, there are risks that the patient may not fully disclose facts about the history of illness or specific symptoms, and also that family members may place their own “twist” on the story when translating.

The physician should speak directly to the patient in a normal tone of voice. In this setting, also remember that nonverbal communication can be misinterpreted. Gestures should be avoided. Finally, be aware that personal space is viewed differently depending on cultural background, as is eye contact.

It is helpful to have a pre-interview meeting with the interpreter to explain the format of the interview, as well as a post-interview meeting to ensure all parties felt they effectively communicated during the encounter.

TOWARD EQUITABLE CARE

Health care disparities are the result of multiple determinants. In December 2008, a National Institutes of Health summit conference cited not only barriers to access, but also the interaction of biological, behavioral, social, environmental, economic, cultural, and political factors, and noted that the causes and effects of health disparities transcend health care.²⁶

Clearly, an individual physician’s efforts will not be all that is needed to eliminate health disparities. A team-based approach is essential, using skills of nonphysician members of the health care team such as nurses, medical assistants, social workers, and case managers. Continued opportunity for professional training and development in provider-patient communication skills should be offered.

However, the impact of effective cross-cultural communication and managing low health literacy populations on the physician-patient level should not be understated. As practitioners treating patients from diverse backgrounds, improving self-awareness, eliciting the patient’s explanatory model, and assuring understanding of treatment plans for patients with low health literacy or with language barriers, we can do our part in working toward equitable care for all patients.

A 29-year-old woman with a history of frequent migraines presented to her primary care provider for a refill of medication. For the past two years she had been taking rizatriptan 10 mg, but with little relief. She stated that she had continued to experience discrete migraines several days per month, often clustered around menses. The severity of the headaches had negatively affected her work attendance, productivity, and social interactions. She wondered if she should be taking a different kind of medication.

The patient had been diagnosed with migraines at age 12, just prior to menarche. She described her headache as a unilateral, sharp throbbing pain associated with increased sensitivity to light and sound as well as nausea. She denied any history of head trauma. She had no allergies, and the only other medications she was taking at the time were an oral contraceptive (ethinyl estradiol/norgestimate 0.035 mg/0.18 mg with an oral triphasic 21/7 treatment cycle) and fluoxetine 20 mg for depression.

The patient worked daytime hours as a sales representative. She considered herself active, exercised regularly, ate a balanced diet, and slept well. She consumed no more than two to four alcoholic drinks per month and denied the use of herbals, dietary supplements, tobacco, or illegal drugs.

The patient stated that her mother had frequent headaches but had never sought a medical explanation or treatment. She was unaware of any other family history of headaches, and there was no family history of cardiovascular disease. Her sister had been diagnosed with a prolactinoma at age 25. At age 26, the patient had undergone a pituitary protocol MRI of the head with and without contrast, with negative results.

On examination, the patient was alert and oriented with normal vital signs. Her pupils were equal and reactive to light, and no papilledema was evident on fundoscopic examination. The cranial nerves were grossly intact and no other neurologic deficits were appreciated. No carotid bruits were present on cardiovascular exam.

Based on the patient’s history and physical exam, she met the International Classification of Headache Disorders (ICHD-II)¹ diagnostic criteria for migraine without aura (1.1). When asked to recall the onset and frequency of attacks she had had in the previous four weeks, she noted that they regularly occurred during her menstrual cycle.

She was subsequently asked to begin a diary to record her headache characteristics, severity, and duration, with days of menstruation noted. The Migraine Disability Assessment (MIDAS) questionnaire² (see Tables 1 and 2²) was performed to measure the migraine attacks’ impact on the patient’s life; her score indicated that the headaches were causing her severe disability.

The patient’s abortive migraine medication was changed from rizatriptan 10 mg to the combination sumatriptan/naproxen sodium 85 mg/500 mg. She was instructed to take the initial dose as soon as she noticed signs of an impending migraine and to repeat the dose in two hours if symptoms persisted. The possibility of starting a preventive medication was discussed, but the patient wanted to evaluate her response to the combination triptan/NSAID before considering migraine prophylaxis.

Three months later, the patient returned for follow-up, including a review of her headache diary. She stated that the frequency and intensity of attacks had not decreased; acute treatment with sumatriptan/naproxen sodium made her headaches more bearable but did not ameliorate symptoms. The patient had recorded a detailed account of each migraine which, based on the ICHD-II criteria,¹ demonstrated a pattern of headache occurrences consistent with menstrually related migraine. She reported a total of 18 headaches in the previous three months, 12 of which had occurred within the five-day perimenstrual period (see Figure 1).

Based on this information and the fact that the patient’s headaches were resistant to previous treatments, it was decided to alter the approach to her migraine management once more. In an effort to limit estrogen fluctuations during her menstrual cycle, her oral contraceptive was changed from ethinyl estradiol/norgestimate to a 12-week placebo-free monophasic regimen of ethinyl estradiol/levonorgestrel 20 mg/90 mcg. For intermittent prophylaxis, she was instructed to take frovatriptan 2.5 mg twice daily, beginning two days prior to the start of menses and continuing through the last day of her cycle. For acute treatment of breakthrough migraines, she was prescribed sumatriptan 20-mg nasal spray to take at the first sign of migraine symptoms and instructed to repeat the dose if the pain persisted or returned.

The patient continued to track her headaches in the diary and was seen in the office after three months of following the revised menstrual migraine management plan. She reported fewer migraines associated with her menstrual cycle and noted that they were less severe and shorter in duration. When she repeated the MIDAS test, her score was reduced from 23 to 10. In the subsequent nine months she has reported a consistent decrease in migraine prevalence and now rarely needs the abortive therapy.

DISCUSSION
Migraine, though commonly encountered in clinical practice, is a complex disorder. For women, migraine headaches have been recognized by the World Health Organization as the 12th leading cause of “life lived with a disabling condition.”³ Pure menstrual migraine and menstrually related migraine will be the focus of discussion here.

Etiology
Menstrually related migraine (comparable to pure menstrual migraine, although the latter is distinguished by occurring only during the perimenstrual period¹) is recognized as a distinct type of migraine associated with perimenstrual hormone fluctuations.⁴ Of women who experience migraine, 42% to 61% can associate their attacks with the perimenstrual period⁵; this is defined as two days before to three days after the start of menstruation.

It has also been determined that women are more likely to have migraine attacks during the late luteal and early follicular phases (when there is a natural drop in estrogen levels) than in other phases (when estrogen levels are higher).⁶ Despite clinical evidence to support this estrogen withdrawal theory, the pathophysiology is not completely understood. It is possible that affected women are more sensitive than other women to the decrease in estrogen levels that occurs with menstruation.⁷

History and Physical Findings of Menstrual Migraines
Almost every woman with perimenstrual migraines reports an absence of aura.⁷ In the evaluation of headache, the same criteria for migraine without aura pertain to the classifications of pure menstrual migraine (PMM) or menstrually related migraine (MRM).¹ Correlation of migraine attacks to the onset of menses is the key finding in the patient history to differentiate menstrual migraine from migraine without aura in women.⁸ Furthermore, perimenstrual migraines are often of longer duration and more difficult to treat than migraines not associated with hormone fluctuations.⁹

In order to distinguish between PMM and MRM, it is important to understand that pure menstrual migraine attacks take place exclusively in the five-day perimenstrual window and at no other times of the cycle. The criteria for MRM allow for attacks at other times of the cycle.¹

In addition to causing physical pain, menstrual migraines can impact work performance, household activities, and personal relationships. The MIDAS questionnaire is a disability assessment tool that can reveal to the practitioner how migraines have affected the patient’s life over the previous three months.¹⁰ This is a useful method to identify patients with disabling migraines, determine their need for treatment, and monitor treatment efficacy.

Diagnosis
Menstrual migraine is a clinical diagnosis made by findings from the patient’s history. The International Headache Society has established specific diagnostic criteria in the ICHD-II for both PMM and MRM.¹ An accurate and detailed migraine history is invaluable for the diagnosis of menstrual migraine. Although a formal questionnaire can serve as a good screening tool, it relies on the patient’s ability to recall specific times and dates with accuracy.¹¹ Recall bias can be misleading in any attempt to confirm a diagnosis. The patient’s conscientious use of a daily headache diary or calendar (see Figure 2, for example) can lead to a precise record of the characteristics and timing of migraines, overcoming these obstacles.

Brain imaging is necessary if the patient’s symptoms suggest a critical etiology that requires immediate diagnosis and management. Red flags include sudden onset of a severe headache, a headache characterized as “the worst headache of the patient’s life,” a change in headache pattern, altered mental status, an abnormal neurologic examination, or fever with neck stiffness.¹²

Treatment Options for Menstrual Migraine
There is no FDA-approved treatment specific for menstrual migraines; however, medications used for management of nonmenstrual migraines are also those most commonly prescribed for women with menstrual migraine headaches.¹³ Because these headaches are frequently more severe and of longer duration than nonmenstrual migraine headaches, a combination of intermittent preventive therapy, hormone manipulation, and acute treatment strategies is often necessary.⁴

Acute therapy is aimed to treat migraine pain quickly and effectively with minimal adverse effects or need for additional medication. Triptans have been the mainstay of menstrual migraine treatment and have been proven effective for both acute attacks and prevention.⁴ Sumatriptan has a rapid onset of action and may be given orally as a 50- or 100-mg tablet, as a 6-mg subcutaneous injection, or as a 20-mg nasal spray.¹⁴

Abortive therapies are most effective when taken at the first sign of an attack. Patients can repeat the dose in two hours if the headache persists or recurs, to a maximum of two doses in 24 hours.¹⁵ Rizatriptan is another triptan used for acute treatment of menstrual migraine headaches. Its initial 10-mg dose can be repeated every two hours, to a maximum of 30 mg per 24 hours. NSAIDs, such as naproxen sodium, have also been recommended in acute migraine attacks. They seem to work synergistically with triptans, inhibiting prostaglandin synthesis and blocking neurogenic inflammation.¹⁵

Clinical study results have demonstrated superior pain relief and decreased migraine recurrence when a triptan and NSAID are used in combination, compared with use of either medication alone.⁴ A single-tablet formulation of sumatriptan 85 mg and naproxen sodium 500 mg may be considered for initial therapy in hard-to-treat patients.¹⁴ 

Preventive therapy should be considered when responsiveness to acute treatment is inadequate.⁴ Nonhormonal intermittent prophylactic treatment is recommended two days prior to the beginning of menses, continuing for five days.¹⁶ Longer-acting triptans, such as frova­triptan 2.5 mg and naratriptan 1.0 mg, dosed twice daily, have been demonstrated as effective in clinical trials when used during the perimenstrual period.^17,18

The advantage of short-term therapy over daily prophylaxis is the potential to avoid adverse effects seen with continuous exposure to the drug.³ However, successful therapy relies on consistency in menstruation, and therefore may not be ideal for women with irregular cycles or those with coexisting nonmenstrual migraines.¹⁶ Estrogen-based therapy is an option for these women and for those who have failed nonhormonal methods.¹⁹

The goal of hormone prophylaxis is to prevent or reduce the physiologic decline in estradiol that occurs in the late luteal phase.⁴ Clinical studies have been conducted using various hormonal strategies to maintain steady estradiol levels, all of which decreased migraine prevalence.¹⁹ Estrogen fluctuations can be minimized by eliminating the placebo week in traditional estrogen/progestin oral contraceptives to achieve an extended-cycle regimen, resembling that of the 12-week ethinyl estradiol/levonorgestrel formulation.¹⁹

Continuous use of combined oral contraceptives is also an option for relief of menstrual migraine. When cyclic or extended-cycle regimens allow for menses, supplemental estrogen (10- to 20-mg ethinyl estradiol) is recommended during the hormone-free week.¹⁴

CONCLUSION
Proper diagnosis of menstrual migraines, using screening tools and the MIDAS questionnaire, can help practitioners provide the most effective migraine management for their patients. The most important step toward a good prognosis is acknowledging menstrual migraine as a unique headache disorder and formulating a precise diagnosis in order to identify individually tailored treatment options. With proper identification and integrated acute and prophylactic treatment, women with menstrual migraines are able to lead a healthier, more satisfying life.

REFERENCES
1. International Headache Society. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24(suppl 1):1-160.

2. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology. 2001;56(6 suppl 1):S20-S28.

3. MacGregor EA. Perimenstrual headaches: unmet needs. Curr Pain Headache Rep. 2008;12(6):468-474.

4. Mannix LK. Menstrual-related pain conditions: dysmenorrhea and migraine. J Womens Health (Larchmt). 2008;17(5):879-891.

5. Martin VT. New theories in the pathogenesis of menstrual migraine. Curr Pain Headache Rep. 2008;12(6):453-462.

6. MacGregor EA. Migraine headache in perimenopausal and menopausal women. Curr Pain Headache Rep. 2009;13(5):399-403.

7. Martin VT, Wernke S, Mandell K, et al. Symptoms of premenstrual syndrome and their association with migraine headache. Headache. 2006; 46(1):125-137.

8. Martin VT, Behbehani M. Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis—part 2. Headache. 2006;46(3):365-386.

9. Granella F, Sances G, Allais G, et al. Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres. Cephalalgia. 2004;24(9):707-716.

10. Hutchinson SL, Silberstein SD. Menstrual migraine: case studies of women with estrogen-related headaches. Headache. 2008;48 suppl 3:S131-S141.

11. Tepper SJ, Zatochill M, Szeto M, et al. Development of a simple menstrual migraine screening tool for obstetric and gynecology clinics: the Menstrual Migraine Assessment Tool. Headache. 2008; 48(10):1419-1425.

12. Marcus DA. Focus on primary care diagnosis and management of headache in women. Obstet Gynecol Surv. 1999;54(6):395-402.

13. Tepper SJ. Tailoring management strategies for the patient with menstrual migraine: focus on prevention and treatment. Headache. 2006;46(suppl 2):S61-S68.

14. Lay CL, Payne R. Recognition and treatment of menstrual migraine. Neurologist. 2007;13(4):197-204.

15. Henry KA, Cohen CI. Perimenstrual headache: treatment options. Curr Pain Headache Rep. 2009;13(1):82-88.

16. Calhoun AH. Estrogen-associated migraine. www.uptodate.com/contents/estrogen-associated-migraine. Accessed May 4, 2011.

17. Silberstein SD, Elkind AH, Schreiber C, et al. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology. 2004;63:261-269.

18. Mannix LK, Savani N, Landy S, et al. Efficacy and tolerability of naratriptan for short-term prevention of menstrually related migraine: data from two randomized, double-blind, placebo-controlled studies. Headache. 2007;47(7):1037-1049.

19. Calhoun AH, Hutchinson S. Hormonal therapies for menstrual migraine. Curr Pain Headache Rep. 2009;13(5):381-385.

A 29-year-old woman with a history of frequent migraines presented to her primary care provider for a refill of medication. For the past two years she had been taking rizatriptan 10 mg, but with little relief. She stated that she had continued to experience discrete migraines several days per month, often clustered around menses. The severity of the headaches had negatively affected her work attendance, productivity, and social interactions. She wondered if she should be taking a different kind of medication.

The patient had been diagnosed with migraines at age 12, just prior to menarche. She described her headache as a unilateral, sharp throbbing pain associated with increased sensitivity to light and sound as well as nausea. She denied any history of head trauma. She had no allergies, and the only other medications she was taking at the time were an oral contraceptive (ethinyl estradiol/norgestimate 0.035 mg/0.18 mg with an oral triphasic 21/7 treatment cycle) and fluoxetine 20 mg for depression.

The patient worked daytime hours as a sales representative. She considered herself active, exercised regularly, ate a balanced diet, and slept well. She consumed no more than two to four alcoholic drinks per month and denied the use of herbals, dietary supplements, tobacco, or illegal drugs.

The patient stated that her mother had frequent headaches but had never sought a medical explanation or treatment. She was unaware of any other family history of headaches, and there was no family history of cardiovascular disease. Her sister had been diagnosed with a prolactinoma at age 25. At age 26, the patient had undergone a pituitary protocol MRI of the head with and without contrast, with negative results.

On examination, the patient was alert and oriented with normal vital signs. Her pupils were equal and reactive to light, and no papilledema was evident on fundoscopic examination. The cranial nerves were grossly intact and no other neurologic deficits were appreciated. No carotid bruits were present on cardiovascular exam.

Based on the patient’s history and physical exam, she met the International Classification of Headache Disorders (ICHD-II)¹ diagnostic criteria for migraine without aura (1.1). When asked to recall the onset and frequency of attacks she had had in the previous four weeks, she noted that they regularly occurred during her menstrual cycle.

She was subsequently asked to begin a diary to record her headache characteristics, severity, and duration, with days of menstruation noted. The Migraine Disability Assessment (MIDAS) questionnaire² (see Tables 1 and 2²) was performed to measure the migraine attacks’ impact on the patient’s life; her score indicated that the headaches were causing her severe disability.

The patient’s abortive migraine medication was changed from rizatriptan 10 mg to the combination sumatriptan/naproxen sodium 85 mg/500 mg. She was instructed to take the initial dose as soon as she noticed signs of an impending migraine and to repeat the dose in two hours if symptoms persisted. The possibility of starting a preventive medication was discussed, but the patient wanted to evaluate her response to the combination triptan/NSAID before considering migraine prophylaxis.

Three months later, the patient returned for follow-up, including a review of her headache diary. She stated that the frequency and intensity of attacks had not decreased; acute treatment with sumatriptan/naproxen sodium made her headaches more bearable but did not ameliorate symptoms. The patient had recorded a detailed account of each migraine which, based on the ICHD-II criteria,¹ demonstrated a pattern of headache occurrences consistent with menstrually related migraine. She reported a total of 18 headaches in the previous three months, 12 of which had occurred within the five-day perimenstrual period (see Figure 1).

Based on this information and the fact that the patient’s headaches were resistant to previous treatments, it was decided to alter the approach to her migraine management once more. In an effort to limit estrogen fluctuations during her menstrual cycle, her oral contraceptive was changed from ethinyl estradiol/norgestimate to a 12-week placebo-free monophasic regimen of ethinyl estradiol/levonorgestrel 20 mg/90 mcg. For intermittent prophylaxis, she was instructed to take frovatriptan 2.5 mg twice daily, beginning two days prior to the start of menses and continuing through the last day of her cycle. For acute treatment of breakthrough migraines, she was prescribed sumatriptan 20-mg nasal spray to take at the first sign of migraine symptoms and instructed to repeat the dose if the pain persisted or returned.

The patient continued to track her headaches in the diary and was seen in the office after three months of following the revised menstrual migraine management plan. She reported fewer migraines associated with her menstrual cycle and noted that they were less severe and shorter in duration. When she repeated the MIDAS test, her score was reduced from 23 to 10. In the subsequent nine months she has reported a consistent decrease in migraine prevalence and now rarely needs the abortive therapy.

DISCUSSION
Migraine, though commonly encountered in clinical practice, is a complex disorder. For women, migraine headaches have been recognized by the World Health Organization as the 12th leading cause of “life lived with a disabling condition.”³ Pure menstrual migraine and menstrually related migraine will be the focus of discussion here.

Etiology
Menstrually related migraine (comparable to pure menstrual migraine, although the latter is distinguished by occurring only during the perimenstrual period¹) is recognized as a distinct type of migraine associated with perimenstrual hormone fluctuations.⁴ Of women who experience migraine, 42% to 61% can associate their attacks with the perimenstrual period⁵; this is defined as two days before to three days after the start of menstruation.

It has also been determined that women are more likely to have migraine attacks during the late luteal and early follicular phases (when there is a natural drop in estrogen levels) than in other phases (when estrogen levels are higher).⁶ Despite clinical evidence to support this estrogen withdrawal theory, the pathophysiology is not completely understood. It is possible that affected women are more sensitive than other women to the decrease in estrogen levels that occurs with menstruation.⁷

History and Physical Findings of Menstrual Migraines
Almost every woman with perimenstrual migraines reports an absence of aura.⁷ In the evaluation of headache, the same criteria for migraine without aura pertain to the classifications of pure menstrual migraine (PMM) or menstrually related migraine (MRM).¹ Correlation of migraine attacks to the onset of menses is the key finding in the patient history to differentiate menstrual migraine from migraine without aura in women.⁸ Furthermore, perimenstrual migraines are often of longer duration and more difficult to treat than migraines not associated with hormone fluctuations.⁹

In order to distinguish between PMM and MRM, it is important to understand that pure menstrual migraine attacks take place exclusively in the five-day perimenstrual window and at no other times of the cycle. The criteria for MRM allow for attacks at other times of the cycle.¹

In addition to causing physical pain, menstrual migraines can impact work performance, household activities, and personal relationships. The MIDAS questionnaire is a disability assessment tool that can reveal to the practitioner how migraines have affected the patient’s life over the previous three months.¹⁰ This is a useful method to identify patients with disabling migraines, determine their need for treatment, and monitor treatment efficacy.

Diagnosis
Menstrual migraine is a clinical diagnosis made by findings from the patient’s history. The International Headache Society has established specific diagnostic criteria in the ICHD-II for both PMM and MRM.¹ An accurate and detailed migraine history is invaluable for the diagnosis of menstrual migraine. Although a formal questionnaire can serve as a good screening tool, it relies on the patient’s ability to recall specific times and dates with accuracy.¹¹ Recall bias can be misleading in any attempt to confirm a diagnosis. The patient’s conscientious use of a daily headache diary or calendar (see Figure 2, for example) can lead to a precise record of the characteristics and timing of migraines, overcoming these obstacles.

Brain imaging is necessary if the patient’s symptoms suggest a critical etiology that requires immediate diagnosis and management. Red flags include sudden onset of a severe headache, a headache characterized as “the worst headache of the patient’s life,” a change in headache pattern, altered mental status, an abnormal neurologic examination, or fever with neck stiffness.¹²

Treatment Options for Menstrual Migraine
There is no FDA-approved treatment specific for menstrual migraines; however, medications used for management of nonmenstrual migraines are also those most commonly prescribed for women with menstrual migraine headaches.¹³ Because these headaches are frequently more severe and of longer duration than nonmenstrual migraine headaches, a combination of intermittent preventive therapy, hormone manipulation, and acute treatment strategies is often necessary.⁴

Acute therapy is aimed to treat migraine pain quickly and effectively with minimal adverse effects or need for additional medication. Triptans have been the mainstay of menstrual migraine treatment and have been proven effective for both acute attacks and prevention.⁴ Sumatriptan has a rapid onset of action and may be given orally as a 50- or 100-mg tablet, as a 6-mg subcutaneous injection, or as a 20-mg nasal spray.¹⁴

Abortive therapies are most effective when taken at the first sign of an attack. Patients can repeat the dose in two hours if the headache persists or recurs, to a maximum of two doses in 24 hours.¹⁵ Rizatriptan is another triptan used for acute treatment of menstrual migraine headaches. Its initial 10-mg dose can be repeated every two hours, to a maximum of 30 mg per 24 hours. NSAIDs, such as naproxen sodium, have also been recommended in acute migraine attacks. They seem to work synergistically with triptans, inhibiting prostaglandin synthesis and blocking neurogenic inflammation.¹⁵

Clinical study results have demonstrated superior pain relief and decreased migraine recurrence when a triptan and NSAID are used in combination, compared with use of either medication alone.⁴ A single-tablet formulation of sumatriptan 85 mg and naproxen sodium 500 mg may be considered for initial therapy in hard-to-treat patients.¹⁴ 

Preventive therapy should be considered when responsiveness to acute treatment is inadequate.⁴ Nonhormonal intermittent prophylactic treatment is recommended two days prior to the beginning of menses, continuing for five days.¹⁶ Longer-acting triptans, such as frova­triptan 2.5 mg and naratriptan 1.0 mg, dosed twice daily, have been demonstrated as effective in clinical trials when used during the perimenstrual period.^17,18

The advantage of short-term therapy over daily prophylaxis is the potential to avoid adverse effects seen with continuous exposure to the drug.³ However, successful therapy relies on consistency in menstruation, and therefore may not be ideal for women with irregular cycles or those with coexisting nonmenstrual migraines.¹⁶ Estrogen-based therapy is an option for these women and for those who have failed nonhormonal methods.¹⁹

The goal of hormone prophylaxis is to prevent or reduce the physiologic decline in estradiol that occurs in the late luteal phase.⁴ Clinical studies have been conducted using various hormonal strategies to maintain steady estradiol levels, all of which decreased migraine prevalence.¹⁹ Estrogen fluctuations can be minimized by eliminating the placebo week in traditional estrogen/progestin oral contraceptives to achieve an extended-cycle regimen, resembling that of the 12-week ethinyl estradiol/levonorgestrel formulation.¹⁹

Continuous use of combined oral contraceptives is also an option for relief of menstrual migraine. When cyclic or extended-cycle regimens allow for menses, supplemental estrogen (10- to 20-mg ethinyl estradiol) is recommended during the hormone-free week.¹⁴

CONCLUSION
Proper diagnosis of menstrual migraines, using screening tools and the MIDAS questionnaire, can help practitioners provide the most effective migraine management for their patients. The most important step toward a good prognosis is acknowledging menstrual migraine as a unique headache disorder and formulating a precise diagnosis in order to identify individually tailored treatment options. With proper identification and integrated acute and prophylactic treatment, women with menstrual migraines are able to lead a healthier, more satisfying life.

REFERENCES
1. International Headache Society. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24(suppl 1):1-160.

2. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology. 2001;56(6 suppl 1):S20-S28.

3. MacGregor EA. Perimenstrual headaches: unmet needs. Curr Pain Headache Rep. 2008;12(6):468-474.

4. Mannix LK. Menstrual-related pain conditions: dysmenorrhea and migraine. J Womens Health (Larchmt). 2008;17(5):879-891.

5. Martin VT. New theories in the pathogenesis of menstrual migraine. Curr Pain Headache Rep. 2008;12(6):453-462.

6. MacGregor EA. Migraine headache in perimenopausal and menopausal women. Curr Pain Headache Rep. 2009;13(5):399-403.

7. Martin VT, Wernke S, Mandell K, et al. Symptoms of premenstrual syndrome and their association with migraine headache. Headache. 2006; 46(1):125-137.

8. Martin VT, Behbehani M. Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis—part 2. Headache. 2006;46(3):365-386.

9. Granella F, Sances G, Allais G, et al. Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres. Cephalalgia. 2004;24(9):707-716.

10. Hutchinson SL, Silberstein SD. Menstrual migraine: case studies of women with estrogen-related headaches. Headache. 2008;48 suppl 3:S131-S141.

11. Tepper SJ, Zatochill M, Szeto M, et al. Development of a simple menstrual migraine screening tool for obstetric and gynecology clinics: the Menstrual Migraine Assessment Tool. Headache. 2008; 48(10):1419-1425.

12. Marcus DA. Focus on primary care diagnosis and management of headache in women. Obstet Gynecol Surv. 1999;54(6):395-402.

13. Tepper SJ. Tailoring management strategies for the patient with menstrual migraine: focus on prevention and treatment. Headache. 2006;46(suppl 2):S61-S68.

14. Lay CL, Payne R. Recognition and treatment of menstrual migraine. Neurologist. 2007;13(4):197-204.

15. Henry KA, Cohen CI. Perimenstrual headache: treatment options. Curr Pain Headache Rep. 2009;13(1):82-88.

16. Calhoun AH. Estrogen-associated migraine. www.uptodate.com/contents/estrogen-associated-migraine. Accessed May 4, 2011.

17. Silberstein SD, Elkind AH, Schreiber C, et al. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology. 2004;63:261-269.

18. Mannix LK, Savani N, Landy S, et al. Efficacy and tolerability of naratriptan for short-term prevention of menstrually related migraine: data from two randomized, double-blind, placebo-controlled studies. Headache. 2007;47(7):1037-1049.

19. Calhoun AH, Hutchinson S. Hormonal therapies for menstrual migraine. Curr Pain Headache Rep. 2009;13(5):381-385.

A 29-year-old woman with a history of frequent migraines presented to her primary care provider for a refill of medication. For the past two years she had been taking rizatriptan 10 mg, but with little relief. She stated that she had continued to experience discrete migraines several days per month, often clustered around menses. The severity of the headaches had negatively affected her work attendance, productivity, and social interactions. She wondered if she should be taking a different kind of medication.

The patient had been diagnosed with migraines at age 12, just prior to menarche. She described her headache as a unilateral, sharp throbbing pain associated with increased sensitivity to light and sound as well as nausea. She denied any history of head trauma. She had no allergies, and the only other medications she was taking at the time were an oral contraceptive (ethinyl estradiol/norgestimate 0.035 mg/0.18 mg with an oral triphasic 21/7 treatment cycle) and fluoxetine 20 mg for depression.

The patient worked daytime hours as a sales representative. She considered herself active, exercised regularly, ate a balanced diet, and slept well. She consumed no more than two to four alcoholic drinks per month and denied the use of herbals, dietary supplements, tobacco, or illegal drugs.

The patient stated that her mother had frequent headaches but had never sought a medical explanation or treatment. She was unaware of any other family history of headaches, and there was no family history of cardiovascular disease. Her sister had been diagnosed with a prolactinoma at age 25. At age 26, the patient had undergone a pituitary protocol MRI of the head with and without contrast, with negative results.

On examination, the patient was alert and oriented with normal vital signs. Her pupils were equal and reactive to light, and no papilledema was evident on fundoscopic examination. The cranial nerves were grossly intact and no other neurologic deficits were appreciated. No carotid bruits were present on cardiovascular exam.

Based on the patient’s history and physical exam, she met the International Classification of Headache Disorders (ICHD-II)¹ diagnostic criteria for migraine without aura (1.1). When asked to recall the onset and frequency of attacks she had had in the previous four weeks, she noted that they regularly occurred during her menstrual cycle.

She was subsequently asked to begin a diary to record her headache characteristics, severity, and duration, with days of menstruation noted. The Migraine Disability Assessment (MIDAS) questionnaire² (see Tables 1 and 2²) was performed to measure the migraine attacks’ impact on the patient’s life; her score indicated that the headaches were causing her severe disability.

The patient’s abortive migraine medication was changed from rizatriptan 10 mg to the combination sumatriptan/naproxen sodium 85 mg/500 mg. She was instructed to take the initial dose as soon as she noticed signs of an impending migraine and to repeat the dose in two hours if symptoms persisted. The possibility of starting a preventive medication was discussed, but the patient wanted to evaluate her response to the combination triptan/NSAID before considering migraine prophylaxis.

Three months later, the patient returned for follow-up, including a review of her headache diary. She stated that the frequency and intensity of attacks had not decreased; acute treatment with sumatriptan/naproxen sodium made her headaches more bearable but did not ameliorate symptoms. The patient had recorded a detailed account of each migraine which, based on the ICHD-II criteria,¹ demonstrated a pattern of headache occurrences consistent with menstrually related migraine. She reported a total of 18 headaches in the previous three months, 12 of which had occurred within the five-day perimenstrual period (see Figure 1).

Based on this information and the fact that the patient’s headaches were resistant to previous treatments, it was decided to alter the approach to her migraine management once more. In an effort to limit estrogen fluctuations during her menstrual cycle, her oral contraceptive was changed from ethinyl estradiol/norgestimate to a 12-week placebo-free monophasic regimen of ethinyl estradiol/levonorgestrel 20 mg/90 mcg. For intermittent prophylaxis, she was instructed to take frovatriptan 2.5 mg twice daily, beginning two days prior to the start of menses and continuing through the last day of her cycle. For acute treatment of breakthrough migraines, she was prescribed sumatriptan 20-mg nasal spray to take at the first sign of migraine symptoms and instructed to repeat the dose if the pain persisted or returned.

The patient continued to track her headaches in the diary and was seen in the office after three months of following the revised menstrual migraine management plan. She reported fewer migraines associated with her menstrual cycle and noted that they were less severe and shorter in duration. When she repeated the MIDAS test, her score was reduced from 23 to 10. In the subsequent nine months she has reported a consistent decrease in migraine prevalence and now rarely needs the abortive therapy.

DISCUSSION
Migraine, though commonly encountered in clinical practice, is a complex disorder. For women, migraine headaches have been recognized by the World Health Organization as the 12th leading cause of “life lived with a disabling condition.”³ Pure menstrual migraine and menstrually related migraine will be the focus of discussion here.

Etiology
Menstrually related migraine (comparable to pure menstrual migraine, although the latter is distinguished by occurring only during the perimenstrual period¹) is recognized as a distinct type of migraine associated with perimenstrual hormone fluctuations.⁴ Of women who experience migraine, 42% to 61% can associate their attacks with the perimenstrual period⁵; this is defined as two days before to three days after the start of menstruation.

It has also been determined that women are more likely to have migraine attacks during the late luteal and early follicular phases (when there is a natural drop in estrogen levels) than in other phases (when estrogen levels are higher).⁶ Despite clinical evidence to support this estrogen withdrawal theory, the pathophysiology is not completely understood. It is possible that affected women are more sensitive than other women to the decrease in estrogen levels that occurs with menstruation.⁷

History and Physical Findings of Menstrual Migraines
Almost every woman with perimenstrual migraines reports an absence of aura.⁷ In the evaluation of headache, the same criteria for migraine without aura pertain to the classifications of pure menstrual migraine (PMM) or menstrually related migraine (MRM).¹ Correlation of migraine attacks to the onset of menses is the key finding in the patient history to differentiate menstrual migraine from migraine without aura in women.⁸ Furthermore, perimenstrual migraines are often of longer duration and more difficult to treat than migraines not associated with hormone fluctuations.⁹

In order to distinguish between PMM and MRM, it is important to understand that pure menstrual migraine attacks take place exclusively in the five-day perimenstrual window and at no other times of the cycle. The criteria for MRM allow for attacks at other times of the cycle.¹

In addition to causing physical pain, menstrual migraines can impact work performance, household activities, and personal relationships. The MIDAS questionnaire is a disability assessment tool that can reveal to the practitioner how migraines have affected the patient’s life over the previous three months.¹⁰ This is a useful method to identify patients with disabling migraines, determine their need for treatment, and monitor treatment efficacy.

Diagnosis
Menstrual migraine is a clinical diagnosis made by findings from the patient’s history. The International Headache Society has established specific diagnostic criteria in the ICHD-II for both PMM and MRM.¹ An accurate and detailed migraine history is invaluable for the diagnosis of menstrual migraine. Although a formal questionnaire can serve as a good screening tool, it relies on the patient’s ability to recall specific times and dates with accuracy.¹¹ Recall bias can be misleading in any attempt to confirm a diagnosis. The patient’s conscientious use of a daily headache diary or calendar (see Figure 2, for example) can lead to a precise record of the characteristics and timing of migraines, overcoming these obstacles.

Brain imaging is necessary if the patient’s symptoms suggest a critical etiology that requires immediate diagnosis and management. Red flags include sudden onset of a severe headache, a headache characterized as “the worst headache of the patient’s life,” a change in headache pattern, altered mental status, an abnormal neurologic examination, or fever with neck stiffness.¹²

Treatment Options for Menstrual Migraine
There is no FDA-approved treatment specific for menstrual migraines; however, medications used for management of nonmenstrual migraines are also those most commonly prescribed for women with menstrual migraine headaches.¹³ Because these headaches are frequently more severe and of longer duration than nonmenstrual migraine headaches, a combination of intermittent preventive therapy, hormone manipulation, and acute treatment strategies is often necessary.⁴

Acute therapy is aimed to treat migraine pain quickly and effectively with minimal adverse effects or need for additional medication. Triptans have been the mainstay of menstrual migraine treatment and have been proven effective for both acute attacks and prevention.⁴ Sumatriptan has a rapid onset of action and may be given orally as a 50- or 100-mg tablet, as a 6-mg subcutaneous injection, or as a 20-mg nasal spray.¹⁴

Abortive therapies are most effective when taken at the first sign of an attack. Patients can repeat the dose in two hours if the headache persists or recurs, to a maximum of two doses in 24 hours.¹⁵ Rizatriptan is another triptan used for acute treatment of menstrual migraine headaches. Its initial 10-mg dose can be repeated every two hours, to a maximum of 30 mg per 24 hours. NSAIDs, such as naproxen sodium, have also been recommended in acute migraine attacks. They seem to work synergistically with triptans, inhibiting prostaglandin synthesis and blocking neurogenic inflammation.¹⁵

Clinical study results have demonstrated superior pain relief and decreased migraine recurrence when a triptan and NSAID are used in combination, compared with use of either medication alone.⁴ A single-tablet formulation of sumatriptan 85 mg and naproxen sodium 500 mg may be considered for initial therapy in hard-to-treat patients.¹⁴ 

Preventive therapy should be considered when responsiveness to acute treatment is inadequate.⁴ Nonhormonal intermittent prophylactic treatment is recommended two days prior to the beginning of menses, continuing for five days.¹⁶ Longer-acting triptans, such as frova­triptan 2.5 mg and naratriptan 1.0 mg, dosed twice daily, have been demonstrated as effective in clinical trials when used during the perimenstrual period.^17,18

The advantage of short-term therapy over daily prophylaxis is the potential to avoid adverse effects seen with continuous exposure to the drug.³ However, successful therapy relies on consistency in menstruation, and therefore may not be ideal for women with irregular cycles or those with coexisting nonmenstrual migraines.¹⁶ Estrogen-based therapy is an option for these women and for those who have failed nonhormonal methods.¹⁹

The goal of hormone prophylaxis is to prevent or reduce the physiologic decline in estradiol that occurs in the late luteal phase.⁴ Clinical studies have been conducted using various hormonal strategies to maintain steady estradiol levels, all of which decreased migraine prevalence.¹⁹ Estrogen fluctuations can be minimized by eliminating the placebo week in traditional estrogen/progestin oral contraceptives to achieve an extended-cycle regimen, resembling that of the 12-week ethinyl estradiol/levonorgestrel formulation.¹⁹

Continuous use of combined oral contraceptives is also an option for relief of menstrual migraine. When cyclic or extended-cycle regimens allow for menses, supplemental estrogen (10- to 20-mg ethinyl estradiol) is recommended during the hormone-free week.¹⁴

CONCLUSION
Proper diagnosis of menstrual migraines, using screening tools and the MIDAS questionnaire, can help practitioners provide the most effective migraine management for their patients. The most important step toward a good prognosis is acknowledging menstrual migraine as a unique headache disorder and formulating a precise diagnosis in order to identify individually tailored treatment options. With proper identification and integrated acute and prophylactic treatment, women with menstrual migraines are able to lead a healthier, more satisfying life.

REFERENCES
1. International Headache Society. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24(suppl 1):1-160.

2. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology. 2001;56(6 suppl 1):S20-S28.

3. MacGregor EA. Perimenstrual headaches: unmet needs. Curr Pain Headache Rep. 2008;12(6):468-474.

4. Mannix LK. Menstrual-related pain conditions: dysmenorrhea and migraine. J Womens Health (Larchmt). 2008;17(5):879-891.

5. Martin VT. New theories in the pathogenesis of menstrual migraine. Curr Pain Headache Rep. 2008;12(6):453-462.

6. MacGregor EA. Migraine headache in perimenopausal and menopausal women. Curr Pain Headache Rep. 2009;13(5):399-403.

7. Martin VT, Wernke S, Mandell K, et al. Symptoms of premenstrual syndrome and their association with migraine headache. Headache. 2006; 46(1):125-137.

8. Martin VT, Behbehani M. Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis—part 2. Headache. 2006;46(3):365-386.

9. Granella F, Sances G, Allais G, et al. Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres. Cephalalgia. 2004;24(9):707-716.

10. Hutchinson SL, Silberstein SD. Menstrual migraine: case studies of women with estrogen-related headaches. Headache. 2008;48 suppl 3:S131-S141.

11. Tepper SJ, Zatochill M, Szeto M, et al. Development of a simple menstrual migraine screening tool for obstetric and gynecology clinics: the Menstrual Migraine Assessment Tool. Headache. 2008; 48(10):1419-1425.

12. Marcus DA. Focus on primary care diagnosis and management of headache in women. Obstet Gynecol Surv. 1999;54(6):395-402.

13. Tepper SJ. Tailoring management strategies for the patient with menstrual migraine: focus on prevention and treatment. Headache. 2006;46(suppl 2):S61-S68.

14. Lay CL, Payne R. Recognition and treatment of menstrual migraine. Neurologist. 2007;13(4):197-204.

15. Henry KA, Cohen CI. Perimenstrual headache: treatment options. Curr Pain Headache Rep. 2009;13(1):82-88.

16. Calhoun AH. Estrogen-associated migraine. www.uptodate.com/contents/estrogen-associated-migraine. Accessed May 4, 2011.

17. Silberstein SD, Elkind AH, Schreiber C, et al. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology. 2004;63:261-269.

18. Mannix LK, Savani N, Landy S, et al. Efficacy and tolerability of naratriptan for short-term prevention of menstrually related migraine: data from two randomized, double-blind, placebo-controlled studies. Headache. 2007;47(7):1037-1049.

19. Calhoun AH, Hutchinson S. Hormonal therapies for menstrual migraine. Curr Pain Headache Rep. 2009;13(5):381-385.

A 21-year-old woman presents with a history of recurrent renal stones. Her serum calcium level is 11.5 mg/dL (normal, 8.6 to 10.5 mg/dL); serum phosphorus, 2.4 mg/dL (2.5 to 4.8 mg/dL); intact parathyroid hormone (PTH), 198 pg/mL (7 to 53 pg/mL); and serum 25-hydroxyvitamin D [25(OH)D], 12.6 ng/mL (30 to 60 ng/mL). After six weeks of therapy with vitamin D (50,000 IU three times/week), the serum calcium level is 11 mg/dL; PTH, 164 pg/mL; and 25(OH)D, 28 ng/mL. With all lab results improved but still abnormal, what other information would be helpful?

With this particular case, the striking history is recurrent renal stones. Analysis of one of the stones to determine if they are calcium oxalate would be beneficial; however, a 24-hour urine calcium measurement would provide useful information about the potential cause of the renal stones. Vitamin D deficiency can cause mild hypercalcemia but can also mask underlying primary hyperparathyroidism—as it did in this case. A Tc-99 sestamibi parathyroid scan will often localize a parathyroid adenoma.

This patient’s 24-hour urine calcium was high, and her parathyroid scan suggested an adenoma in the left lower lobe of the thyroid. An experienced parathyroid surgeon was consulted, and surgical excision of a 1.5-cm parathyroid adenoma followed. The intraoperative PTH went from 183 to 39 pg/mL, and the intraoperative calcium from 11.6 to 9.2 mg/dL. There was no postoperative hypocalcemia.

Q: What is the differential diagnosis for hypercalcemia?

• Parathyroid adenoma or carcinoma

• Hypercalcemia of malignancy (eg, breast, lung, pancreas)

• Multiple myeloma

• Multiple endocrine neoplasia types 1 and 2

• Familial hypocalciuric hypercalcemia

• Excess 1,25 dihydroxy vitamin D [1,25(OH)2D] production: sarcoid or other granulomatous disorders, lymphomas

• Miscellaneous: immobilization, milk-alkali syndrome, and parenteral nutrition

• Drug-related: vitamin D deficiency or intoxication; use of thiazide diuretics or lithium

• Nonparathyroid endocrine causes: hyperthyroidism, pheo­chromocytoma, Addison’s disease, islet cell tumors

Q: What are the clinical manifestations of hypercalcemia?

Mild hypercalcemia is usually asymp­tomatic, especially if serum calcium is 10.5 to 11.5 mg/dL. Polyuria and polydypsia, renal stones, constipation, nausea, and weight loss are nonspecific symptoms. Decreased mental alertness and depression can be seen, especially if calcium is higher than 12 mg/dL. Bone pain, arthralgias, and decreased bone density can occur with longstanding hypercalcemia. ECG changes, including bradycardia, atrioventricular block, and short QT interval, are sometimes noted.

Q: What is the significance of familial hypocalciuric hypercalcemia (FHH)?   

Patients with this genetic disorder, which involves mutated calcium-sensor receptors, often have a mildly elevated PTH but may have a normal PTH in the presence of hypercalcemia. A 24-hour urine calcium level below 100 mg is indicative of FHH.

A calcium/creatinine clearance ratio (calculated as urine calcium/serum calcium divided by urine creatinine/serum creatinine) of < 0.01 is suggestive of FHH, particularly if there is a family history of mild hypercalcemia.

An important point is that parathyroid surgery is ineffective in these patients, and they seldom develop clinical symptoms or stones.

Q: Often, hypercalcemia is identified through routine labs. What diagnostic studies should be obtained with the initial work-up?

Since it is not uncommon to discover mild hypercalcemia on routine labs, it may be prudent to simply recheck serum calcium before launching into an extensive work-up. A comprehensive metabolic panel will give you the calcium, albumin, and serum protein. 

When serum albumin is reduced, a corrected calcium level is calculated by adding 0.8 mg/dL to the total calcium for every decrement of 1 g/dL in serum albumin below the reference value of 4 g/dL. Serum phosphate is often low, except in secondary hyperparathyroidism due to renal failure, in which case phosphate is high. Urine calcium excretion may be high or normal. 

A 25(OH)D level should also be obtained, as vitamin D deficiency is a common cause of hypercalcemia. Adequate vitamin D replacement will often correct the hypercalcemia; however, vitamin D deficiency may be masking underlying primary hyperparathyroidism. 

The PTH level will be high in primary hyperparathyroidism, although it is possible to have a normal intact PTH in patients who have had long-standing mild primary hyperparathyroidism. Secondary hyperparathyroidism due to vitamin D deficiency will also result in an elevated PTH.

A suppressed PTH level in the presence of severe hypercalcemia suggests nonparathyroid-mediated hypercalcemia, often due to malignancy. Hypercalcemia of malignancy is usually symptomatic and severe (≥ 15 mg/dL). 

Q: What other nonroutine studies should be considered in the work-up?

A 24-hour urine for calcium, phosphorus, and creatinine clearance, as well as a DXA bone density test, are important for making treatment decisions. A Tc-99 sestamibi parathyroid scan is important to localize a parathyroid adenoma.

Ultrasound of the neck may help to localize an enlarged parathyroid gland, especially if the scan is negative or equivocal. 

Q: What are the complications of untreated hypercalcemia?

These include renal stones and urinary tract infections; peptic ulcer; altered mental status; pancreatitis; and during pregnancy, neonatal hypocalcemia.

Q: What is the medical treatment for hypercalcemia?

For acute hypercalcemia, use IV fluids at a high rate, such as normal saline 2,000 cc/hr, unless contraindicated.

Bisphosphonates, such as IV zoledronic acid, are potent inhibitors of bone resorption of calcium and can temporarily treat hypercalcemia, especially in cases of malignancy or severe hyperparathyroidism. It is important to know that oral bisphosphonates are not effective in treating hypercalcemia.

Avoid thiazide diuretics, as well as vitamin A, vitamin D, and calcium supplements. Another caveat: In the face of vitamin D deficiency, correct the vitamin D level to 40 to 60 ng/dL. Patients with 1,25(OH)2D-mediated hypercalcemia should be treated with glucocorticoids (prednisone or IV hydrocortisone), as they decrease 1,25(OH)2D.

Cinacalcet is approved for treatment of secondary hyperparathyroidism due to chronic renal failure, parathyroid carcinoma, and severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. The mode of action of cinacalcet is by binding to the parathyroid glands’ extracellular calcium-sensing receptors (CaSRs) to increase their affinity for extracellular calcium and decrease PTH secretion production.

Q: What are the indications for surgical intervention?

Surgery is recommended for patients with kidney stones or bone disease or with notable symptoms; those who have osteoporosis (identified on DXA scan); patients younger than 50; and those with a glomerular filtration rate below 60 mL/min and calcium 1.0 mg/dL or more above the upper limit of normal. Surgical removal of a parathyroid adenoma usually results in a cure.

Q: What causes secondary hyperparathyroidism?

Chronic renal failure is usually the cause. Hyperphosphatemia and decreased 1,25(OH)2D produce a decrease in ionized calcium. The parathyroid glands are thus stimulated and enlarge.

Vitamin D deficiency is another common cause; it is corrected with adequate vitamin D replacement. Once the vitamin D level is corrected, additional calcium supplementation should be given.

Q: What is the prognosis of hypercalcemia?

Primary hyperparathyroidism is usually chronic and progressive unless surgically cured or medically corrected. The prognosis of hypercalcemia is directly related to the degree of renal impairment or the underlying cause, such as malignancy. The presence of pancreatitis increases the mortality rate.

Regular monitoring and follow-up are important, especially if there is a trend of worsening hypercalcemia and etiology has not been identified. Monitor calcium and albumin at least every three months and renal function at least every six months.

Furthermore, check the 24-hour urine calcium and order DXA bone density testing annually.           

SUGGESTED READING
American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons. AACE/AAES position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Prac. 2005;11(1): 49-54.

McPhee SJ, Papadakis MA, eds. 2011 Current Medical Diagnosis and Treatment. McGraw Hill; 2011:1090-1097; 1098-1105; 1575-1579.

Jameson J, ed. Harrison’s Endocrinology. 2nd ed. McGraw Hill; 2010:367-378; 406-410; 411-442.

Brown SA. Hyperparathyroidism. In: Runge MS, Greganti MA, eds. Netter’s Internal Medicine. 2nd ed. Saunders; 2009:316-320.

Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Third International Workshop. J Clin Endocrinol Metab. 2009;94(2):335-339.

A 21-year-old woman presents with a history of recurrent renal stones. Her serum calcium level is 11.5 mg/dL (normal, 8.6 to 10.5 mg/dL); serum phosphorus, 2.4 mg/dL (2.5 to 4.8 mg/dL); intact parathyroid hormone (PTH), 198 pg/mL (7 to 53 pg/mL); and serum 25-hydroxyvitamin D [25(OH)D], 12.6 ng/mL (30 to 60 ng/mL). After six weeks of therapy with vitamin D (50,000 IU three times/week), the serum calcium level is 11 mg/dL; PTH, 164 pg/mL; and 25(OH)D, 28 ng/mL. With all lab results improved but still abnormal, what other information would be helpful?

With this particular case, the striking history is recurrent renal stones. Analysis of one of the stones to determine if they are calcium oxalate would be beneficial; however, a 24-hour urine calcium measurement would provide useful information about the potential cause of the renal stones. Vitamin D deficiency can cause mild hypercalcemia but can also mask underlying primary hyperparathyroidism—as it did in this case. A Tc-99 sestamibi parathyroid scan will often localize a parathyroid adenoma.

This patient’s 24-hour urine calcium was high, and her parathyroid scan suggested an adenoma in the left lower lobe of the thyroid. An experienced parathyroid surgeon was consulted, and surgical excision of a 1.5-cm parathyroid adenoma followed. The intraoperative PTH went from 183 to 39 pg/mL, and the intraoperative calcium from 11.6 to 9.2 mg/dL. There was no postoperative hypocalcemia.

Q: What is the differential diagnosis for hypercalcemia?

• Parathyroid adenoma or carcinoma

• Hypercalcemia of malignancy (eg, breast, lung, pancreas)

• Multiple myeloma

• Multiple endocrine neoplasia types 1 and 2

• Familial hypocalciuric hypercalcemia

• Excess 1,25 dihydroxy vitamin D [1,25(OH)2D] production: sarcoid or other granulomatous disorders, lymphomas

• Miscellaneous: immobilization, milk-alkali syndrome, and parenteral nutrition

• Drug-related: vitamin D deficiency or intoxication; use of thiazide diuretics or lithium

• Nonparathyroid endocrine causes: hyperthyroidism, pheo­chromocytoma, Addison’s disease, islet cell tumors

Q: What are the clinical manifestations of hypercalcemia?

Mild hypercalcemia is usually asymp­tomatic, especially if serum calcium is 10.5 to 11.5 mg/dL. Polyuria and polydypsia, renal stones, constipation, nausea, and weight loss are nonspecific symptoms. Decreased mental alertness and depression can be seen, especially if calcium is higher than 12 mg/dL. Bone pain, arthralgias, and decreased bone density can occur with longstanding hypercalcemia. ECG changes, including bradycardia, atrioventricular block, and short QT interval, are sometimes noted.

Q: What is the significance of familial hypocalciuric hypercalcemia (FHH)?   

Patients with this genetic disorder, which involves mutated calcium-sensor receptors, often have a mildly elevated PTH but may have a normal PTH in the presence of hypercalcemia. A 24-hour urine calcium level below 100 mg is indicative of FHH.

A calcium/creatinine clearance ratio (calculated as urine calcium/serum calcium divided by urine creatinine/serum creatinine) of < 0.01 is suggestive of FHH, particularly if there is a family history of mild hypercalcemia.

An important point is that parathyroid surgery is ineffective in these patients, and they seldom develop clinical symptoms or stones.

Q: Often, hypercalcemia is identified through routine labs. What diagnostic studies should be obtained with the initial work-up?

Since it is not uncommon to discover mild hypercalcemia on routine labs, it may be prudent to simply recheck serum calcium before launching into an extensive work-up. A comprehensive metabolic panel will give you the calcium, albumin, and serum protein. 

When serum albumin is reduced, a corrected calcium level is calculated by adding 0.8 mg/dL to the total calcium for every decrement of 1 g/dL in serum albumin below the reference value of 4 g/dL. Serum phosphate is often low, except in secondary hyperparathyroidism due to renal failure, in which case phosphate is high. Urine calcium excretion may be high or normal. 

A 25(OH)D level should also be obtained, as vitamin D deficiency is a common cause of hypercalcemia. Adequate vitamin D replacement will often correct the hypercalcemia; however, vitamin D deficiency may be masking underlying primary hyperparathyroidism. 

The PTH level will be high in primary hyperparathyroidism, although it is possible to have a normal intact PTH in patients who have had long-standing mild primary hyperparathyroidism. Secondary hyperparathyroidism due to vitamin D deficiency will also result in an elevated PTH.

A suppressed PTH level in the presence of severe hypercalcemia suggests nonparathyroid-mediated hypercalcemia, often due to malignancy. Hypercalcemia of malignancy is usually symptomatic and severe (≥ 15 mg/dL). 

Q: What other nonroutine studies should be considered in the work-up?

A 24-hour urine for calcium, phosphorus, and creatinine clearance, as well as a DXA bone density test, are important for making treatment decisions. A Tc-99 sestamibi parathyroid scan is important to localize a parathyroid adenoma.

Ultrasound of the neck may help to localize an enlarged parathyroid gland, especially if the scan is negative or equivocal. 

Q: What are the complications of untreated hypercalcemia?

These include renal stones and urinary tract infections; peptic ulcer; altered mental status; pancreatitis; and during pregnancy, neonatal hypocalcemia.

Q: What is the medical treatment for hypercalcemia?

For acute hypercalcemia, use IV fluids at a high rate, such as normal saline 2,000 cc/hr, unless contraindicated.

Bisphosphonates, such as IV zoledronic acid, are potent inhibitors of bone resorption of calcium and can temporarily treat hypercalcemia, especially in cases of malignancy or severe hyperparathyroidism. It is important to know that oral bisphosphonates are not effective in treating hypercalcemia.

Avoid thiazide diuretics, as well as vitamin A, vitamin D, and calcium supplements. Another caveat: In the face of vitamin D deficiency, correct the vitamin D level to 40 to 60 ng/dL. Patients with 1,25(OH)2D-mediated hypercalcemia should be treated with glucocorticoids (prednisone or IV hydrocortisone), as they decrease 1,25(OH)2D.

Cinacalcet is approved for treatment of secondary hyperparathyroidism due to chronic renal failure, parathyroid carcinoma, and severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. The mode of action of cinacalcet is by binding to the parathyroid glands’ extracellular calcium-sensing receptors (CaSRs) to increase their affinity for extracellular calcium and decrease PTH secretion production.

Q: What are the indications for surgical intervention?

Surgery is recommended for patients with kidney stones or bone disease or with notable symptoms; those who have osteoporosis (identified on DXA scan); patients younger than 50; and those with a glomerular filtration rate below 60 mL/min and calcium 1.0 mg/dL or more above the upper limit of normal. Surgical removal of a parathyroid adenoma usually results in a cure.

Q: What causes secondary hyperparathyroidism?

Chronic renal failure is usually the cause. Hyperphosphatemia and decreased 1,25(OH)2D produce a decrease in ionized calcium. The parathyroid glands are thus stimulated and enlarge.

Vitamin D deficiency is another common cause; it is corrected with adequate vitamin D replacement. Once the vitamin D level is corrected, additional calcium supplementation should be given.

Q: What is the prognosis of hypercalcemia?

Primary hyperparathyroidism is usually chronic and progressive unless surgically cured or medically corrected. The prognosis of hypercalcemia is directly related to the degree of renal impairment or the underlying cause, such as malignancy. The presence of pancreatitis increases the mortality rate.

Regular monitoring and follow-up are important, especially if there is a trend of worsening hypercalcemia and etiology has not been identified. Monitor calcium and albumin at least every three months and renal function at least every six months.

Furthermore, check the 24-hour urine calcium and order DXA bone density testing annually.           

SUGGESTED READING
American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons. AACE/AAES position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Prac. 2005;11(1): 49-54.

McPhee SJ, Papadakis MA, eds. 2011 Current Medical Diagnosis and Treatment. McGraw Hill; 2011:1090-1097; 1098-1105; 1575-1579.

Jameson J, ed. Harrison’s Endocrinology. 2nd ed. McGraw Hill; 2010:367-378; 406-410; 411-442.

Brown SA. Hyperparathyroidism. In: Runge MS, Greganti MA, eds. Netter’s Internal Medicine. 2nd ed. Saunders; 2009:316-320.

Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Third International Workshop. J Clin Endocrinol Metab. 2009;94(2):335-339.

A 21-year-old woman presents with a history of recurrent renal stones. Her serum calcium level is 11.5 mg/dL (normal, 8.6 to 10.5 mg/dL); serum phosphorus, 2.4 mg/dL (2.5 to 4.8 mg/dL); intact parathyroid hormone (PTH), 198 pg/mL (7 to 53 pg/mL); and serum 25-hydroxyvitamin D [25(OH)D], 12.6 ng/mL (30 to 60 ng/mL). After six weeks of therapy with vitamin D (50,000 IU three times/week), the serum calcium level is 11 mg/dL; PTH, 164 pg/mL; and 25(OH)D, 28 ng/mL. With all lab results improved but still abnormal, what other information would be helpful?

With this particular case, the striking history is recurrent renal stones. Analysis of one of the stones to determine if they are calcium oxalate would be beneficial; however, a 24-hour urine calcium measurement would provide useful information about the potential cause of the renal stones. Vitamin D deficiency can cause mild hypercalcemia but can also mask underlying primary hyperparathyroidism—as it did in this case. A Tc-99 sestamibi parathyroid scan will often localize a parathyroid adenoma.

This patient’s 24-hour urine calcium was high, and her parathyroid scan suggested an adenoma in the left lower lobe of the thyroid. An experienced parathyroid surgeon was consulted, and surgical excision of a 1.5-cm parathyroid adenoma followed. The intraoperative PTH went from 183 to 39 pg/mL, and the intraoperative calcium from 11.6 to 9.2 mg/dL. There was no postoperative hypocalcemia.

Q: What is the differential diagnosis for hypercalcemia?

• Parathyroid adenoma or carcinoma

• Hypercalcemia of malignancy (eg, breast, lung, pancreas)

• Multiple myeloma

• Multiple endocrine neoplasia types 1 and 2

• Familial hypocalciuric hypercalcemia

• Excess 1,25 dihydroxy vitamin D [1,25(OH)2D] production: sarcoid or other granulomatous disorders, lymphomas

• Miscellaneous: immobilization, milk-alkali syndrome, and parenteral nutrition

• Drug-related: vitamin D deficiency or intoxication; use of thiazide diuretics or lithium

• Nonparathyroid endocrine causes: hyperthyroidism, pheo­chromocytoma, Addison’s disease, islet cell tumors

Q: What are the clinical manifestations of hypercalcemia?

Mild hypercalcemia is usually asymp­tomatic, especially if serum calcium is 10.5 to 11.5 mg/dL. Polyuria and polydypsia, renal stones, constipation, nausea, and weight loss are nonspecific symptoms. Decreased mental alertness and depression can be seen, especially if calcium is higher than 12 mg/dL. Bone pain, arthralgias, and decreased bone density can occur with longstanding hypercalcemia. ECG changes, including bradycardia, atrioventricular block, and short QT interval, are sometimes noted.

Q: What is the significance of familial hypocalciuric hypercalcemia (FHH)?   

Patients with this genetic disorder, which involves mutated calcium-sensor receptors, often have a mildly elevated PTH but may have a normal PTH in the presence of hypercalcemia. A 24-hour urine calcium level below 100 mg is indicative of FHH.

A calcium/creatinine clearance ratio (calculated as urine calcium/serum calcium divided by urine creatinine/serum creatinine) of < 0.01 is suggestive of FHH, particularly if there is a family history of mild hypercalcemia.

An important point is that parathyroid surgery is ineffective in these patients, and they seldom develop clinical symptoms or stones.

Q: Often, hypercalcemia is identified through routine labs. What diagnostic studies should be obtained with the initial work-up?

Since it is not uncommon to discover mild hypercalcemia on routine labs, it may be prudent to simply recheck serum calcium before launching into an extensive work-up. A comprehensive metabolic panel will give you the calcium, albumin, and serum protein. 

When serum albumin is reduced, a corrected calcium level is calculated by adding 0.8 mg/dL to the total calcium for every decrement of 1 g/dL in serum albumin below the reference value of 4 g/dL. Serum phosphate is often low, except in secondary hyperparathyroidism due to renal failure, in which case phosphate is high. Urine calcium excretion may be high or normal. 

A 25(OH)D level should also be obtained, as vitamin D deficiency is a common cause of hypercalcemia. Adequate vitamin D replacement will often correct the hypercalcemia; however, vitamin D deficiency may be masking underlying primary hyperparathyroidism. 

The PTH level will be high in primary hyperparathyroidism, although it is possible to have a normal intact PTH in patients who have had long-standing mild primary hyperparathyroidism. Secondary hyperparathyroidism due to vitamin D deficiency will also result in an elevated PTH.

A suppressed PTH level in the presence of severe hypercalcemia suggests nonparathyroid-mediated hypercalcemia, often due to malignancy. Hypercalcemia of malignancy is usually symptomatic and severe (≥ 15 mg/dL). 

Q: What other nonroutine studies should be considered in the work-up?

A 24-hour urine for calcium, phosphorus, and creatinine clearance, as well as a DXA bone density test, are important for making treatment decisions. A Tc-99 sestamibi parathyroid scan is important to localize a parathyroid adenoma.

Ultrasound of the neck may help to localize an enlarged parathyroid gland, especially if the scan is negative or equivocal. 

Q: What are the complications of untreated hypercalcemia?

These include renal stones and urinary tract infections; peptic ulcer; altered mental status; pancreatitis; and during pregnancy, neonatal hypocalcemia.

Q: What is the medical treatment for hypercalcemia?

For acute hypercalcemia, use IV fluids at a high rate, such as normal saline 2,000 cc/hr, unless contraindicated.

Bisphosphonates, such as IV zoledronic acid, are potent inhibitors of bone resorption of calcium and can temporarily treat hypercalcemia, especially in cases of malignancy or severe hyperparathyroidism. It is important to know that oral bisphosphonates are not effective in treating hypercalcemia.

Avoid thiazide diuretics, as well as vitamin A, vitamin D, and calcium supplements. Another caveat: In the face of vitamin D deficiency, correct the vitamin D level to 40 to 60 ng/dL. Patients with 1,25(OH)2D-mediated hypercalcemia should be treated with glucocorticoids (prednisone or IV hydrocortisone), as they decrease 1,25(OH)2D.

Cinacalcet is approved for treatment of secondary hyperparathyroidism due to chronic renal failure, parathyroid carcinoma, and severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. The mode of action of cinacalcet is by binding to the parathyroid glands’ extracellular calcium-sensing receptors (CaSRs) to increase their affinity for extracellular calcium and decrease PTH secretion production.

Q: What are the indications for surgical intervention?

Surgery is recommended for patients with kidney stones or bone disease or with notable symptoms; those who have osteoporosis (identified on DXA scan); patients younger than 50; and those with a glomerular filtration rate below 60 mL/min and calcium 1.0 mg/dL or more above the upper limit of normal. Surgical removal of a parathyroid adenoma usually results in a cure.

Q: What causes secondary hyperparathyroidism?

Chronic renal failure is usually the cause. Hyperphosphatemia and decreased 1,25(OH)2D produce a decrease in ionized calcium. The parathyroid glands are thus stimulated and enlarge.

Vitamin D deficiency is another common cause; it is corrected with adequate vitamin D replacement. Once the vitamin D level is corrected, additional calcium supplementation should be given.

Q: What is the prognosis of hypercalcemia?

Primary hyperparathyroidism is usually chronic and progressive unless surgically cured or medically corrected. The prognosis of hypercalcemia is directly related to the degree of renal impairment or the underlying cause, such as malignancy. The presence of pancreatitis increases the mortality rate.

Regular monitoring and follow-up are important, especially if there is a trend of worsening hypercalcemia and etiology has not been identified. Monitor calcium and albumin at least every three months and renal function at least every six months.

Furthermore, check the 24-hour urine calcium and order DXA bone density testing annually.           

SUGGESTED READING
American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons. AACE/AAES position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Prac. 2005;11(1): 49-54.

McPhee SJ, Papadakis MA, eds. 2011 Current Medical Diagnosis and Treatment. McGraw Hill; 2011:1090-1097; 1098-1105; 1575-1579.

Jameson J, ed. Harrison’s Endocrinology. 2nd ed. McGraw Hill; 2010:367-378; 406-410; 411-442.

Brown SA. Hyperparathyroidism. In: Runge MS, Greganti MA, eds. Netter’s Internal Medicine. 2nd ed. Saunders; 2009:316-320.

Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Third International Workshop. J Clin Endocrinol Metab. 2009;94(2):335-339.

Discuss this article at www.facebook.com/CurrentPsychiatry

Of the 56 million American adults who report living with chronic pain almost 60% also exhibit psychiatric disorders such as depression or anxiety.^1,2 Because patients with chronic pain suffer from a mixture of physical and psychological components, managing such conditions is complicated, and using opioids is tempting. However, treatment needs to address the underlying pathology along with social and psychological factors.

Because substance abuse treatment admissions increased by 400% from 1998 to 2008,³ many physicians look to non-opioids and other treatment modalities to control chronic non-cancer pain. Common pharmacologic therapies used to treat chronic pain include tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), antiepileptic drugs (AEDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and, to a lesser extent, atypical antipsychotics. TCAs, SNRIs, AEDs, NSAIDs, and atypical antipsychotics influence a variety of presumed underlying pathophysiological processes, including inflammatory mediators, activity of N-methyl-d-aspartate (NMDA) receptors, and voltage-gated calcium channels. In addition, they increase activity of descending inhibitory pain pathways. Animal studies suggest dysfunction of these inhibitory mechanisms contributes to the central sensitization and hyperexcitability of pain transmitting pathways.⁴

In this article, we discuss psychotropics and other non-opioid agents for treating pain. However, no single solution is best for all patients with chronic pain and this article is not a “how to” guide to avoid administering opioid medication. Also incorporate a multimodal, non-pharmacologic approach whenever possible.

Tricyclic antidepressants

Although this class acts primarily by increasing serotonin levels, norepinephrine and dopamine also are affected depending on the particular medication. Studies have shown that amitriptyline, nortriptyline, and desipramine function well as analgesics independent of their antidepressant effects.⁵ TCAs may improve pain symptoms at lower therapeutic dosages than those used for treating depression.⁵

Although researchers have not elucidated TCAs’ mechanism of action with regards to analgesia, they are thought to act within the concept of the gating theory of pain control,⁶ which functions by activation and inhibition of pain signal transmission. It is believed TCAs act on nociceptive pathways by blocking serotonin and norepinephrine reuptake. Although researchers previously thought that TCAs’ analgesic mechanism was correlated to serotonin reuptake inhibition, this theory has changed. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine have not demonstrated substantial effectiveness in neuropathic pain when compared with TCAs and SNRIs. Recent studies have shown that TCAs may work by blocking sodium channels, similar to local anesthetics and antiarrhythmic agents.⁷

Psychiatrists prescribe TCAs infrequently because of these drugs’ unfavorable side effect profile compared with SSRIs and SNRIs. However, TCAs often are prescribed for pain management as an adjunct to other medications for neuropathic conditions and at lower dosages than those used for treating depression (Table 1).⁸

Table 1

Tricyclic antidepressants used to treat pain

SNRIs

Evidence supports using duloxetine, a potent SNRI that mediates pain inhibition in the descending pathways, for 4 chronic pain conditions:

• diabetic peripheral neuropathic pain
• fibromyalgia
• mechanical low back pain
• pain associated with osteoarthritis.⁹

Titrate the dosage to 60 mg/d and maintain the patient at this dose for at least 4 weeks. Thereafter, according to patient response, the dosage may be titrated to 120 mg/d (off-label) with appropriate vital sign monitoring and routine lab analysis.

Venlafaxine also can mediate pain response in a similar manner to duloxetine, but is not FDA-approved for treating pain. Use caution when prescribing venlafaxine for patients with a history of hypertension. Milnacipran is a relatively new SNRI that has been shown to be effective in treating fibromyalgia in divided doses of 100 to 200 mg/d (Table 2).^9-11

Table 2

Treating pain with serotonin-norepinephrine reuptake inhibitors

Antiepileptic drugs

Several AEDs are used for pain management (Table 3).^12-16 Gabapentin and pregabalin work by binding to voltage-gated calcium channels and decreasing excitatory neurotransmitter release. Along with TCAs, they are considered a first-line treatment for managing neuropathic pain.¹⁷ Gabapentin is FDA-approved for seizures and postherpetic neuralgia, but evidence supports its use in most types of neuropathic pain. Pregabalin is FDA-approved for treating seizures, diabetic peripheral neuropathy, central neuropathic pain, postherpetic neuralgia, and fibromyalgia.

Topiramate inhibits excitatory neurotransmission by enhancing the effects of gamma-aminobutyric acid, and also by blocking NMDA receptors. Topiramate is FDA-approved for seizures and migraine prophylaxis, and is used off-label for treating neuropathic pain. A 12-week trial of topiramate for diabetic neuropathy found significant analgesia in 50% of patients taking the drug, compared with 34% receiving placebo.¹⁸

Lamotrigine is approved for several types of seizures and maintenance of bipolar I disorder, and is used off-label for neuropathic pain. A recent Cochrane database review concluded that lamotrigine is ineffective for neuropathic pain¹⁴; however, some guidelines recommend using lamotrigine to treat neuropathies that do not respond to treatment with carbamazepine.¹⁹

Carbamazepine is a complex AED that is structurally similar to TCAs. It blocks sodium channels and has various pharmacologic properties, including anticholinergic, muscle relaxant, antidepressant, and sedative effects. Carbamazepine has analgesic effects through blockade of synaptic transmission in the trigeminal nucleus and is FDA-approved for seizures, bipolar disorder, neuropathic pain, and trigeminal neuralgia. In a systematic review of 12 trials of carbamazepine that included 4 placebo-controlled trials for trigeminal neuralgia, 2 studies showed a number needed to treat (NNT) of 1.8.²⁰ For diabetic neuropathy, there was insufficient data to calculate NNT.

Oxcarbazepine, an analog of carbamazepine, also is FDA-approved for seizures and is used off-label for neuropathic pain. In the only double-blind trial with positive results, oxcarbazepine titrated to 1,800 mg/d reduced diabetic neuropathy pain scores on a visual analog scale by 24 points—roughly 25%.¹⁵

Table 3

Antiepileptic drugs for pain treatment

Non-opioid analgesics

NSAIDs have antipyretic, analgesic, and anti-inflammatory effects and are used for fever, headache, mild-to-moderate pain, musculoskeletal pain, menstrual pain, and dental pain. They are particularly useful in treating acute pain, often in combination with opioid analgesics. NSAIDs exert their analgesic action through blockade of prostaglandin production via reversible inhibition of cyclooxygenase-1 and cyclooxygenase-2.

The most common side effects of NSAIDs are the result of gastrointestinal (GI) toxicity and include dyspepsia, heartburn, nausea, anorexia, and epigastric pain.²¹ GI ulceration and bleeding are rare but serious complications. To decrease these risks, tell patients to take NSAIDs with food. Add a GI protective agent, such as an H2 blocker or proton pump inhibitor, for patients at higher risk for GI complications.²²

In addition, inhibition of renal prostaglandins by NSAIDs can cause renal toxicity, fluid retention, and edema, potentially exacerbating existing cardiovascular conditions such as hypertension and heart failure. NSAIDs may increase the risk of serious thrombotic events such as myocardial infarction and stroke. Use NSAIDs at the lowest effective dose for the shortest duration possible and generally avoid prescribing in patients at high risk for cardiovascular disease and pregnant women, especially those in their third trimester.^23,24

NSAIDs may cause pharmacodynamic and pharmacokinetic drug-drug interactions. The risk of GI toxicity and bleeding increases when NSAIDs are administered with drugs that also irritate the gastric mucosa or have antiplatelet/anticoagulant effects.²¹ Plasma concentrations of drugs with a narrow therapeutic index that are renally eliminated, such as methotrexate and lithium, can increase to potentially toxic levels with concurrent NSAID use because NSAIDs decrease renal perfusion.²¹ Also, the therapeutic effects of antihypertensives may be attenuated because NSAIDs cause fluid retention.²⁵

Acetaminophen (APAP) is available in several dosage forms as a single ingredient and in combination with opioids in prescription products. For more information about APAP, see the Box below.

Atypical antipsychotics

Although atypical antipsychotics are not often used to treat pain, studies indicate that fibromyalgia patients may benefit from ziprasidone²⁶ and olanzapine,²⁷ most often as an adjunctive treatment rather than monotherapy. Randomized controlled studies indicate poor tolerability with several atypical antipsychotics. Weight gain, akathisia, and somnolence are side effects of some atypical antipsychotics. Additionally, ziprasidone has been associated with QTc prolongation. For chronic pain patients, atypical antipsychotics are most useful for treating psychiatric comorbidities.

Box

Related Resources

• Leo RJ. Chronic nonmalignant pain: How to ‘turn down’ its physiologic triggers. Current Psychiatry. 2008;7(8):19-36.
• Nikolaus T, Zeyfang A. Pharmacological treatments for persistent non-malignant pain in older persons. Drugs Aging. 2004;21(1):19-41.
• World Health Organization. WHO’s pain ladder. www.who.int/cancer/palliative/painladder/en.

Drug Brand Names

• Acetaminophen • Tylenol
• Amitriptyline • Elavil, others
• Amoxapine • Asendin
• Carbamazepine • Tegretol, Carbatrol, others
• Clomipramine • Anafranil
• Desipramine • Norpramin
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Gabapentin • Neurontin, Gralise
• Imipramine • Tofranil
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Methotrexate • Rheumatrex, Trexall
• Milnacipran • Savella
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Pregabalin • Lyrica
• Topiramate • Topamax, Topiragen
• Venlafaxine • Effexor
• iprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Of the 56 million American adults who report living with chronic pain almost 60% also exhibit psychiatric disorders such as depression or anxiety.^1,2 Because patients with chronic pain suffer from a mixture of physical and psychological components, managing such conditions is complicated, and using opioids is tempting. However, treatment needs to address the underlying pathology along with social and psychological factors.

Because substance abuse treatment admissions increased by 400% from 1998 to 2008,³ many physicians look to non-opioids and other treatment modalities to control chronic non-cancer pain. Common pharmacologic therapies used to treat chronic pain include tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), antiepileptic drugs (AEDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and, to a lesser extent, atypical antipsychotics. TCAs, SNRIs, AEDs, NSAIDs, and atypical antipsychotics influence a variety of presumed underlying pathophysiological processes, including inflammatory mediators, activity of N-methyl-d-aspartate (NMDA) receptors, and voltage-gated calcium channels. In addition, they increase activity of descending inhibitory pain pathways. Animal studies suggest dysfunction of these inhibitory mechanisms contributes to the central sensitization and hyperexcitability of pain transmitting pathways.⁴

In this article, we discuss psychotropics and other non-opioid agents for treating pain. However, no single solution is best for all patients with chronic pain and this article is not a “how to” guide to avoid administering opioid medication. Also incorporate a multimodal, non-pharmacologic approach whenever possible.

Tricyclic antidepressants

Although this class acts primarily by increasing serotonin levels, norepinephrine and dopamine also are affected depending on the particular medication. Studies have shown that amitriptyline, nortriptyline, and desipramine function well as analgesics independent of their antidepressant effects.⁵ TCAs may improve pain symptoms at lower therapeutic dosages than those used for treating depression.⁵

Although researchers have not elucidated TCAs’ mechanism of action with regards to analgesia, they are thought to act within the concept of the gating theory of pain control,⁶ which functions by activation and inhibition of pain signal transmission. It is believed TCAs act on nociceptive pathways by blocking serotonin and norepinephrine reuptake. Although researchers previously thought that TCAs’ analgesic mechanism was correlated to serotonin reuptake inhibition, this theory has changed. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine have not demonstrated substantial effectiveness in neuropathic pain when compared with TCAs and SNRIs. Recent studies have shown that TCAs may work by blocking sodium channels, similar to local anesthetics and antiarrhythmic agents.⁷

Psychiatrists prescribe TCAs infrequently because of these drugs’ unfavorable side effect profile compared with SSRIs and SNRIs. However, TCAs often are prescribed for pain management as an adjunct to other medications for neuropathic conditions and at lower dosages than those used for treating depression (Table 1).⁸

Table 1

Tricyclic antidepressants used to treat pain

SNRIs

Evidence supports using duloxetine, a potent SNRI that mediates pain inhibition in the descending pathways, for 4 chronic pain conditions:

• diabetic peripheral neuropathic pain
• fibromyalgia
• mechanical low back pain
• pain associated with osteoarthritis.⁹

Titrate the dosage to 60 mg/d and maintain the patient at this dose for at least 4 weeks. Thereafter, according to patient response, the dosage may be titrated to 120 mg/d (off-label) with appropriate vital sign monitoring and routine lab analysis.

Venlafaxine also can mediate pain response in a similar manner to duloxetine, but is not FDA-approved for treating pain. Use caution when prescribing venlafaxine for patients with a history of hypertension. Milnacipran is a relatively new SNRI that has been shown to be effective in treating fibromyalgia in divided doses of 100 to 200 mg/d (Table 2).^9-11

Table 2

Treating pain with serotonin-norepinephrine reuptake inhibitors

Antiepileptic drugs

Several AEDs are used for pain management (Table 3).^12-16 Gabapentin and pregabalin work by binding to voltage-gated calcium channels and decreasing excitatory neurotransmitter release. Along with TCAs, they are considered a first-line treatment for managing neuropathic pain.¹⁷ Gabapentin is FDA-approved for seizures and postherpetic neuralgia, but evidence supports its use in most types of neuropathic pain. Pregabalin is FDA-approved for treating seizures, diabetic peripheral neuropathy, central neuropathic pain, postherpetic neuralgia, and fibromyalgia.

Topiramate inhibits excitatory neurotransmission by enhancing the effects of gamma-aminobutyric acid, and also by blocking NMDA receptors. Topiramate is FDA-approved for seizures and migraine prophylaxis, and is used off-label for treating neuropathic pain. A 12-week trial of topiramate for diabetic neuropathy found significant analgesia in 50% of patients taking the drug, compared with 34% receiving placebo.¹⁸

Lamotrigine is approved for several types of seizures and maintenance of bipolar I disorder, and is used off-label for neuropathic pain. A recent Cochrane database review concluded that lamotrigine is ineffective for neuropathic pain¹⁴; however, some guidelines recommend using lamotrigine to treat neuropathies that do not respond to treatment with carbamazepine.¹⁹

Carbamazepine is a complex AED that is structurally similar to TCAs. It blocks sodium channels and has various pharmacologic properties, including anticholinergic, muscle relaxant, antidepressant, and sedative effects. Carbamazepine has analgesic effects through blockade of synaptic transmission in the trigeminal nucleus and is FDA-approved for seizures, bipolar disorder, neuropathic pain, and trigeminal neuralgia. In a systematic review of 12 trials of carbamazepine that included 4 placebo-controlled trials for trigeminal neuralgia, 2 studies showed a number needed to treat (NNT) of 1.8.²⁰ For diabetic neuropathy, there was insufficient data to calculate NNT.

Oxcarbazepine, an analog of carbamazepine, also is FDA-approved for seizures and is used off-label for neuropathic pain. In the only double-blind trial with positive results, oxcarbazepine titrated to 1,800 mg/d reduced diabetic neuropathy pain scores on a visual analog scale by 24 points—roughly 25%.¹⁵

Table 3

Antiepileptic drugs for pain treatment

Non-opioid analgesics

NSAIDs have antipyretic, analgesic, and anti-inflammatory effects and are used for fever, headache, mild-to-moderate pain, musculoskeletal pain, menstrual pain, and dental pain. They are particularly useful in treating acute pain, often in combination with opioid analgesics. NSAIDs exert their analgesic action through blockade of prostaglandin production via reversible inhibition of cyclooxygenase-1 and cyclooxygenase-2.

The most common side effects of NSAIDs are the result of gastrointestinal (GI) toxicity and include dyspepsia, heartburn, nausea, anorexia, and epigastric pain.²¹ GI ulceration and bleeding are rare but serious complications. To decrease these risks, tell patients to take NSAIDs with food. Add a GI protective agent, such as an H2 blocker or proton pump inhibitor, for patients at higher risk for GI complications.²²

In addition, inhibition of renal prostaglandins by NSAIDs can cause renal toxicity, fluid retention, and edema, potentially exacerbating existing cardiovascular conditions such as hypertension and heart failure. NSAIDs may increase the risk of serious thrombotic events such as myocardial infarction and stroke. Use NSAIDs at the lowest effective dose for the shortest duration possible and generally avoid prescribing in patients at high risk for cardiovascular disease and pregnant women, especially those in their third trimester.^23,24

NSAIDs may cause pharmacodynamic and pharmacokinetic drug-drug interactions. The risk of GI toxicity and bleeding increases when NSAIDs are administered with drugs that also irritate the gastric mucosa or have antiplatelet/anticoagulant effects.²¹ Plasma concentrations of drugs with a narrow therapeutic index that are renally eliminated, such as methotrexate and lithium, can increase to potentially toxic levels with concurrent NSAID use because NSAIDs decrease renal perfusion.²¹ Also, the therapeutic effects of antihypertensives may be attenuated because NSAIDs cause fluid retention.²⁵

Acetaminophen (APAP) is available in several dosage forms as a single ingredient and in combination with opioids in prescription products. For more information about APAP, see the Box below.

Atypical antipsychotics

Although atypical antipsychotics are not often used to treat pain, studies indicate that fibromyalgia patients may benefit from ziprasidone²⁶ and olanzapine,²⁷ most often as an adjunctive treatment rather than monotherapy. Randomized controlled studies indicate poor tolerability with several atypical antipsychotics. Weight gain, akathisia, and somnolence are side effects of some atypical antipsychotics. Additionally, ziprasidone has been associated with QTc prolongation. For chronic pain patients, atypical antipsychotics are most useful for treating psychiatric comorbidities.

Box

Related Resources

• Leo RJ. Chronic nonmalignant pain: How to ‘turn down’ its physiologic triggers. Current Psychiatry. 2008;7(8):19-36.
• Nikolaus T, Zeyfang A. Pharmacological treatments for persistent non-malignant pain in older persons. Drugs Aging. 2004;21(1):19-41.
• World Health Organization. WHO’s pain ladder. www.who.int/cancer/palliative/painladder/en.

Drug Brand Names

• Acetaminophen • Tylenol
• Amitriptyline • Elavil, others
• Amoxapine • Asendin
• Carbamazepine • Tegretol, Carbatrol, others
• Clomipramine • Anafranil
• Desipramine • Norpramin
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Gabapentin • Neurontin, Gralise
• Imipramine • Tofranil
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Methotrexate • Rheumatrex, Trexall
• Milnacipran • Savella
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Pregabalin • Lyrica
• Topiramate • Topamax, Topiragen
• Venlafaxine • Effexor
• iprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Of the 56 million American adults who report living with chronic pain almost 60% also exhibit psychiatric disorders such as depression or anxiety.^1,2 Because patients with chronic pain suffer from a mixture of physical and psychological components, managing such conditions is complicated, and using opioids is tempting. However, treatment needs to address the underlying pathology along with social and psychological factors.

Because substance abuse treatment admissions increased by 400% from 1998 to 2008,³ many physicians look to non-opioids and other treatment modalities to control chronic non-cancer pain. Common pharmacologic therapies used to treat chronic pain include tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), antiepileptic drugs (AEDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and, to a lesser extent, atypical antipsychotics. TCAs, SNRIs, AEDs, NSAIDs, and atypical antipsychotics influence a variety of presumed underlying pathophysiological processes, including inflammatory mediators, activity of N-methyl-d-aspartate (NMDA) receptors, and voltage-gated calcium channels. In addition, they increase activity of descending inhibitory pain pathways. Animal studies suggest dysfunction of these inhibitory mechanisms contributes to the central sensitization and hyperexcitability of pain transmitting pathways.⁴

In this article, we discuss psychotropics and other non-opioid agents for treating pain. However, no single solution is best for all patients with chronic pain and this article is not a “how to” guide to avoid administering opioid medication. Also incorporate a multimodal, non-pharmacologic approach whenever possible.

Tricyclic antidepressants

Although this class acts primarily by increasing serotonin levels, norepinephrine and dopamine also are affected depending on the particular medication. Studies have shown that amitriptyline, nortriptyline, and desipramine function well as analgesics independent of their antidepressant effects.⁵ TCAs may improve pain symptoms at lower therapeutic dosages than those used for treating depression.⁵

Although researchers have not elucidated TCAs’ mechanism of action with regards to analgesia, they are thought to act within the concept of the gating theory of pain control,⁶ which functions by activation and inhibition of pain signal transmission. It is believed TCAs act on nociceptive pathways by blocking serotonin and norepinephrine reuptake. Although researchers previously thought that TCAs’ analgesic mechanism was correlated to serotonin reuptake inhibition, this theory has changed. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine have not demonstrated substantial effectiveness in neuropathic pain when compared with TCAs and SNRIs. Recent studies have shown that TCAs may work by blocking sodium channels, similar to local anesthetics and antiarrhythmic agents.⁷

Psychiatrists prescribe TCAs infrequently because of these drugs’ unfavorable side effect profile compared with SSRIs and SNRIs. However, TCAs often are prescribed for pain management as an adjunct to other medications for neuropathic conditions and at lower dosages than those used for treating depression (Table 1).⁸

Table 1

Tricyclic antidepressants used to treat pain

SNRIs

Evidence supports using duloxetine, a potent SNRI that mediates pain inhibition in the descending pathways, for 4 chronic pain conditions:

• diabetic peripheral neuropathic pain
• fibromyalgia
• mechanical low back pain
• pain associated with osteoarthritis.⁹

Titrate the dosage to 60 mg/d and maintain the patient at this dose for at least 4 weeks. Thereafter, according to patient response, the dosage may be titrated to 120 mg/d (off-label) with appropriate vital sign monitoring and routine lab analysis.

Venlafaxine also can mediate pain response in a similar manner to duloxetine, but is not FDA-approved for treating pain. Use caution when prescribing venlafaxine for patients with a history of hypertension. Milnacipran is a relatively new SNRI that has been shown to be effective in treating fibromyalgia in divided doses of 100 to 200 mg/d (Table 2).^9-11

Table 2

Treating pain with serotonin-norepinephrine reuptake inhibitors

Antiepileptic drugs

Several AEDs are used for pain management (Table 3).^12-16 Gabapentin and pregabalin work by binding to voltage-gated calcium channels and decreasing excitatory neurotransmitter release. Along with TCAs, they are considered a first-line treatment for managing neuropathic pain.¹⁷ Gabapentin is FDA-approved for seizures and postherpetic neuralgia, but evidence supports its use in most types of neuropathic pain. Pregabalin is FDA-approved for treating seizures, diabetic peripheral neuropathy, central neuropathic pain, postherpetic neuralgia, and fibromyalgia.

Topiramate inhibits excitatory neurotransmission by enhancing the effects of gamma-aminobutyric acid, and also by blocking NMDA receptors. Topiramate is FDA-approved for seizures and migraine prophylaxis, and is used off-label for treating neuropathic pain. A 12-week trial of topiramate for diabetic neuropathy found significant analgesia in 50% of patients taking the drug, compared with 34% receiving placebo.¹⁸

Lamotrigine is approved for several types of seizures and maintenance of bipolar I disorder, and is used off-label for neuropathic pain. A recent Cochrane database review concluded that lamotrigine is ineffective for neuropathic pain¹⁴; however, some guidelines recommend using lamotrigine to treat neuropathies that do not respond to treatment with carbamazepine.¹⁹

Carbamazepine is a complex AED that is structurally similar to TCAs. It blocks sodium channels and has various pharmacologic properties, including anticholinergic, muscle relaxant, antidepressant, and sedative effects. Carbamazepine has analgesic effects through blockade of synaptic transmission in the trigeminal nucleus and is FDA-approved for seizures, bipolar disorder, neuropathic pain, and trigeminal neuralgia. In a systematic review of 12 trials of carbamazepine that included 4 placebo-controlled trials for trigeminal neuralgia, 2 studies showed a number needed to treat (NNT) of 1.8.²⁰ For diabetic neuropathy, there was insufficient data to calculate NNT.

Oxcarbazepine, an analog of carbamazepine, also is FDA-approved for seizures and is used off-label for neuropathic pain. In the only double-blind trial with positive results, oxcarbazepine titrated to 1,800 mg/d reduced diabetic neuropathy pain scores on a visual analog scale by 24 points—roughly 25%.¹⁵

Table 3

Antiepileptic drugs for pain treatment

Non-opioid analgesics

NSAIDs have antipyretic, analgesic, and anti-inflammatory effects and are used for fever, headache, mild-to-moderate pain, musculoskeletal pain, menstrual pain, and dental pain. They are particularly useful in treating acute pain, often in combination with opioid analgesics. NSAIDs exert their analgesic action through blockade of prostaglandin production via reversible inhibition of cyclooxygenase-1 and cyclooxygenase-2.

The most common side effects of NSAIDs are the result of gastrointestinal (GI) toxicity and include dyspepsia, heartburn, nausea, anorexia, and epigastric pain.²¹ GI ulceration and bleeding are rare but serious complications. To decrease these risks, tell patients to take NSAIDs with food. Add a GI protective agent, such as an H2 blocker or proton pump inhibitor, for patients at higher risk for GI complications.²²

In addition, inhibition of renal prostaglandins by NSAIDs can cause renal toxicity, fluid retention, and edema, potentially exacerbating existing cardiovascular conditions such as hypertension and heart failure. NSAIDs may increase the risk of serious thrombotic events such as myocardial infarction and stroke. Use NSAIDs at the lowest effective dose for the shortest duration possible and generally avoid prescribing in patients at high risk for cardiovascular disease and pregnant women, especially those in their third trimester.^23,24

NSAIDs may cause pharmacodynamic and pharmacokinetic drug-drug interactions. The risk of GI toxicity and bleeding increases when NSAIDs are administered with drugs that also irritate the gastric mucosa or have antiplatelet/anticoagulant effects.²¹ Plasma concentrations of drugs with a narrow therapeutic index that are renally eliminated, such as methotrexate and lithium, can increase to potentially toxic levels with concurrent NSAID use because NSAIDs decrease renal perfusion.²¹ Also, the therapeutic effects of antihypertensives may be attenuated because NSAIDs cause fluid retention.²⁵

Acetaminophen (APAP) is available in several dosage forms as a single ingredient and in combination with opioids in prescription products. For more information about APAP, see the Box below.

Atypical antipsychotics

Although atypical antipsychotics are not often used to treat pain, studies indicate that fibromyalgia patients may benefit from ziprasidone²⁶ and olanzapine,²⁷ most often as an adjunctive treatment rather than monotherapy. Randomized controlled studies indicate poor tolerability with several atypical antipsychotics. Weight gain, akathisia, and somnolence are side effects of some atypical antipsychotics. Additionally, ziprasidone has been associated with QTc prolongation. For chronic pain patients, atypical antipsychotics are most useful for treating psychiatric comorbidities.

Box

Related Resources

• Leo RJ. Chronic nonmalignant pain: How to ‘turn down’ its physiologic triggers. Current Psychiatry. 2008;7(8):19-36.
• Nikolaus T, Zeyfang A. Pharmacological treatments for persistent non-malignant pain in older persons. Drugs Aging. 2004;21(1):19-41.
• World Health Organization. WHO’s pain ladder. www.who.int/cancer/palliative/painladder/en.

Drug Brand Names

• Acetaminophen • Tylenol
• Amitriptyline • Elavil, others
• Amoxapine • Asendin
• Carbamazepine • Tegretol, Carbatrol, others
• Clomipramine • Anafranil
• Desipramine • Norpramin
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Gabapentin • Neurontin, Gralise
• Imipramine • Tofranil
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Methotrexate • Rheumatrex, Trexall
• Milnacipran • Savella
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Pregabalin • Lyrica
• Topiramate • Topamax, Topiragen
• Venlafaxine • Effexor
• iprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.