Despite our success in reducing the number of deaths from influenza in the last half-century, we must remain vigilant, since influenza still can kill.^1,2 Gene mutations and reassortment among different strains of influenza viruses pose a significant public health threat, especially in an increasingly mobile world.^3,4

In this article, we will present an update on influenza to better prepare primary care providers to prevent and treat this ongoing threat.

H3N2v: SWINE FLU DÉJÀ VU?

Outbreaks of swine flu at state and county fairs in 2012 are unprecedented and have raised concerns.

From 1990 to 2010, human infections with swine-origin influenza viruses were sporadic, and the US Centers for Disease Control and Prevention (CDC) confirmed a total of only 27 cases during this period.⁵ However, the number has been increasing since 2011: as of August 31, 2012, a total of 309 cases had been reported.⁶

Adapted from Lindstrom S, et al. Human infections with novel reassortant influenza A(H3N2)V viruses, United States, 2011. Emerg Infect Dis 2012; 18:834–837.

Analysis of viral RNA in clinical respiratory specimens from 12 cases in 2011 revealed a variant strain, called H3N2v, which is a hybrid containing genetic material from swine H3N2 and the 2009 human pandemic virus H1N1pdm09. The M gene in this new variant came from the human virus, while the other seven came from the swine virus when a host was infected with both viruses simultaneously (Figure 1). As a result of this genetic reassortment, this variant virus is genetically and antigenically different from seasonal H3N2.

Epidemiologic data showed that children under 10 years of age are especially susceptible to this new variant because they lack immunity, whereas adolescents and adults may have some immunity from cross-reacting antibodies.⁷ Most infected people had been exposed to swine in agriculture, including county and state fairs. So far, evidence suggests only limited human-to-human transmission.⁸ The clinical diagnosis of H3N2v infection relies on the epidemiologic link to exposure to pigs in the week before the onset of illness, since the symptoms are indistinguishable from those of seasonal influenza A or B infections.

In suspected cases, the clinician should notify the local or state public health department and arrange for a special test to be performed on respiratory specimens: the CDC Flu Real-Time Reverse Transcriptase Polymerase Chain Reaction Dx Panel. The reason is that a negative rapid influenza diagnostic test does not rule out influenza infection, and a positive immunofluorescence assay (direct fluorescent antibody staining) cannot specifically detect H3N2v.⁷

The current seasonal influenza vaccine will not protect against H3N2v. The isolates tested to date were susceptible to the neuraminidase inhibitor drugs oseltamivir (Tamiflu) and zanamivir (Relenza) but resistant to amantadine (Symmetrel) and rimantadine (Flumadine).⁹

Whether H3N2v will become a significant problem during the upcoming flu season largely depends on the extent of human-to-human transmission. We need to closely follow updates on this virus.

H5N1: THE LOOMING THREAT OF A BIRD FLU PANDEMIC

Since 2003, influenza A H5N1, a highly pathogenic avian virus, has broken out in Asia, Africa, and the Middle East, killing more than 100 million birds. It also has crossed the species barrier to infect humans, with an unusually high death rate.¹⁰

As of August 10, 2012, the World Health Organization had reported 608 confirmed cases of this virus infecting humans and 359 associated deaths.¹¹ Most infected patients had a history of close contact with diseased poultry, but limited, nonsustained human-to-human transmission can occur during very close, unprotected contact with a severely ill patient.¹²

Molecular studies of this virus revealed further insights into its pathogenesis. Some of the viruses isolated from humans have had mutations that allow them to bind to human-type receptors.¹³ Amino acid substitutions in the polymerase basic protein 2 (PB2) gene are associated with mammalian adaptation, virulence in mice, and viral replication at temperatures present in the upper respiratory tract.¹⁴ Furthermore, higher plasma levels of macrophage- and neutrophil-attractant chemokines and both inflammatory and anti-inflammatory cytokines (interleukin 6, interleukin 10, and interferon gamma) have been observed in patients with H5N1 infection, especially in fatal cases.¹⁵ A recent study found that H5N1 causes significant perturbations in the host’s protein synthesis machinery as early as 1 hour after infection, suggesting that this virus gains an early advantage in replication by using the host’s proteome.¹⁶ The effects of unrestrained viral infection and inflammatory responses induced by H5N1 infection certainly contributed to the primary pathologic process and to death in human fulminant viral pneumonia. The up-regulation of inflammatory cytokines in these infections contributes to the development of sepsis syndrome, acute respiratory distress syndrome, and an increased risk of death, particularly in pregnant women.

Most experts predict that pandemic influenza is probably inevitable.¹⁷ If avian H5N1 and a human influenza virus swap genes in a host such as swine, the new hybrid virus will contain genetic material from both strains and will have surface antigens that the human immune system does not recognize. This could lead to a devastating avian flu pandemic with a very high death rate.¹⁸

An inactivated whole-virus H5N1 vaccine has been developed by the US government to prevent H5N1 infection.¹⁹ For treatment, the neuraminidase inhibitor oseltamivir is the drug of choice.¹⁰ Oseltamivir resistance remains uncommon. ²⁰ Fortunately, zanamivir is still active against oseltamivir-resistant variants that have N1 neuraminidase mutations.²¹

THE 2009 H1N1 PANDEMIC KILLED MORE PEOPLE THAN WE THOUGHT

The fourth flu pandemic of the last 100 years occurred in 2009. (The other three were in 1918, 1957, and 1968.) It was caused by a novel strain, H1N1 of swine origin.²² This 2009 pandemic strain had six genes from the North American swine flu virus and two genes from the Eurasian swine flu virus. The pandemic affected more children and young people (who completely lacked prior immunity to this virus), while older people, who had cross-reacting antibodies, were less affected.

Worldwide, 18,500 people were reported initially to have died in this pandemic from April 2009 to August 2010.²³ However, a recent modeling study estimated the number of respiratory and cardiovascular deaths associated with this pandemic at 283,500—about 15 times higher.²⁴

AN AUSTRALIAN OUTBREAK OF OSELTAMIVIR-RESISTANT H1N1

Many strains of influenza A virus are resistant to amantadine and rimantadine, owing to amino acid substitutions in the M2 protein.²⁵ In contrast, resistance to the neuraminidase inhibitors oseltamivir and zanamivir has been reported only occasionally.²⁶

Until recently, most oseltamivir-resistant viruses were isolated from immunocompromised hosts treated with oseltamivir.^27–29 All the resistant viral isolates contained an amino acid substitution of histidine (H) to tyrosine (Y) at position 275 of the viral neuraminidase.³⁰ In general, transmission of these oseltamivir-resistant strains has been limited and unsustained, but it can occur in settings of close contact, such as hospitals, school camps, or long train rides.^31–35 Oseltamivir-resistant strains were detected in fewer than 1% of isolates from the community during the 2010–2011 influenza season in the Northern Hemisphere and most countries in the Southern Hemisphere during the 2011 flu season.^36,37

However, an outbreak of oseltamivir-resistant H1N1 occurred in Australia between June and August 2011.³⁸ In that outbreak, the isolates from only 15% of the 191 people infected with this virus, designated H1N1pdm09, carried the H257Y neuraminidase substitution.³⁹ Further, only 1 of the 191 patients had received oseltamivir before. More importantly, genetic analysis suggested that the infection spread from a single source.

This was the first reported sustained community transmission of oseltamivir-resistant H1N1 in a community previously unexposed to this drug. As such, it is a warning sign of the potential for a widespread outbreak of this virus. In the event of such an outbreak, inhaled zanamivir would be the only effective treatment available.

THIS SEASON’S TRIVALENT INACTIVATED VACCINE

The trivalent inactivated influenza vaccine for the 2012–2013 season contains three inactivated viruses⁴⁰:

• Influenza A/California/7/2009(H1N1)-like
• Influenza A/Victoria/361/2011(H3N2)-like
• Influenza B/Wisconsin/1/2010-like (Yamagata lineage).

The influenza A H3N2 and influenza B antigens are different from those in the 2011–2012 vaccine.⁴¹ The H1N1 strain is derived from H1N1pdm09, which had been contained in the 2011–2012 seasonal vaccine. This vaccine will not protect against H3N2v or H5N1.

LATEST RECOMMENDATIONS ON VACCINATION

Since 2010, the Advisory Committee on Immunization Practices (ACIP) has recommended annual flu shots for all people older than 6 months in the United States.⁴²

Vaccination should be done before the onset of influenza activity in the community as soon as vaccine is available for the season. However, one should continue offering vaccination throughout the influenza season as long as influenza viruses are circulating in the community.

Children ages 6 months through 8 years not previously vaccinated against influenza should receive two doses of influenza vaccine at least 4 weeks apart for an optimal immune response. The US-licensed Afluria vaccine (CSL Biotherapies, King of Prussia, PA), a trivalent inactivated vaccine, is not recommended for children under 9 years of age because of concern about febrile seizures.^43,44

There is no contraindication to giving inactivated trivalent influenza vaccine to immunosuppressed people.

The live-attenuated influenza vaccine is indicated only for healthy, nonpregnant people age 2 through 49 years and not for people who care for severely immunosuppressed patients who require a protective environment.

For indications for and details about the different available influenza vaccines, see the ACIP’s current recommendations (www.cdc.gov/mmwr/pdf/wk/mm6132.pdf).⁴⁰

Updated recommendations for people allergic to eggs

All currently available influenza vaccines are made by growing the virus in chicken eggs. Therefore, severe allergic and anaphylactic reactions can occur in people with egg allergy. The ACIP recommends that if people experienced only hives after egg exposure, they should still receive the trivalent inactivated vaccine. Recently, the ACIP reviewed data from the Vaccine Adverse Event Reporting System⁴⁵ and issued the following recommendations for the 2012–2013 influenza season⁴⁰:

• In people who are allergic to eggs, only trivalent inactivated vaccine should be used, not the live-attenuated vaccine, because of lack of data for use of the latter in this group.
• Vaccine should be given by providers who are familiar with the signs of egg allergy.
• Patients with a history of egg allergy who have experienced only hives after exposure to eggs should be observed for a minimum of 30 minutes after vaccination.
• Patients who experience lightheadedness, respiratory distress, angioedema, or recurrent emesis or who require epinephrine or emergency medical attention after egg exposure should be referred before vaccination to a physician who has expertise in managing allergic conditions.
• Tolerance to egg-containing foods does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reactions to eggs or egg-containing foods, plus skin or blood testing for immunoglobulin E antibodies to egg proteins.

A high-dose vaccine is available for people 65 years and older

The rates of hospitalization and death due to seasonal flu in elderly people have increased significantly in the last 20 years despite rising rates of vaccination.^46–48 This is largely due to lower serologic response rates and vaccine efficacy in older adults with weaker immune systems.

Several studies have shown that the development of protective antibody titers depends on the dose of antigen.^49–53 A randomized, controlled clinical trial compared the immunogenicity of a high-dose vaccine and a standard-dose vaccine in older adults and found that the level of antibody response was significantly higher with the high-dose vaccine, and that the rate of adverse reactions was the same.⁵⁴

In December 2009, the US Food and Drug Administration (FDA) licensed a new trivalent inactivated influenza vaccine with high doses of hemagglutinin antigens for adults over the age of 65.⁵⁵ Postlicensure safety surveillance in 2010 revealed no serious safety concerns.⁵⁶

At present, the ACIP expresses no preference for standard-dose or high-dose vaccine for adults 65 years of age and older.⁴⁰ Importantly, if only the standard-dose vaccine is at hand, the opportunity for influenza vaccination should not be missed with the intention of giving high-dose vaccine at a later date.

A NEW QUADRIVALENT LIVE-ATTENUATED INFLUENZA VACCINE FOR THE 2013–2014 SEASON

In February 2012, the FDA approved the first quadrivalent live-attenuated influenza vaccine, which is expected to replace the currently available trivalent live-attenuated influenza vaccine in the 2013–2014 flu season. The quadrivalent vaccine will include both lineages of the circulating influenza B viruses (the Victoria and Yamagata lineages). The reasons for this inclusion is the difficulty in predicting which of these viruses will predominate in any given season, and the limited cross-resistance by immunization against one of the lineages.

A recent analysis⁵⁷ estimated that such a vaccine is likely to further reduce influenza cases, related hospitalizations, and deaths compared with the current trivalent vaccine. Like the current trivalent live-attenuated vaccine, the quadrivalent vaccine is inhaled.

EVOLVING VACCINATION POLICY IN HEALTH CARE WORKERS

Starting in January 2013, the Centers for Medicare and Medicaid Services will require hospitals to report how many of their health care workers are vaccinated. These rates will be publicly reported as a measure of hospital quality. This has fueled the ongoing debate about mandating influenza vaccination for health care workers. Studies have shown that the most important factors in increasing influenza vaccination rates among health care workers are requiring vaccination as a condition for employment and making vaccination available on-site, for more than 1 day, at no cost to the worker.⁵⁸

As an alternative, some institutions have implemented a “shot-or-mask” policy whereby a health care worker who elects not to be vaccinated because of medical or religious reasons would be asked to wear a mask during all faceto-face encounters with patients.

NEW ANTIVIRAL DRUGS ON THE HORIZON

The emergence of oseltamivir-resistant strains in recent years caused a great deal of concern in public health regarding the potential for outbreaks of drug-resistant influenza.^{34,35,59–61}

A recent Asian randomized clinical trial reported the efficacy of a long-acting neuraminidase inhibitor, laninamivir octanoate, in the treatment of seasonal influenza.⁶² This study showed that a single inhalation of this drug is effective in treating seasonal influenza, including that caused by oseltamivir-resistant strains in adults. Laninamivir is currently approved in Japan.

CHALLENGES IN PREVENTING AND TREATING INFLUENZA

Despite the great advances that we have made in preventing and treating influenza in the last half-century, we still face many challenges. Each year in the United States, influenza infection results in an estimated 31 million outpatient visits, 226,000 hospital admissions, and 36,000 deaths.⁴²

Antigenic drift and shift. Influenza viruses circulating among animals and humans vary genetically from season to season and within seasons. As a result of this changing viral antigenicity, the virus can evade the human immune system, causing widespread outbreaks.

One of the unique and most remarkable features of influenza virus is the antigenic variation: antigenic drift and antigenic shift. Antigenic drift is the relatively minor antigenic changes that occur frequently within an influenza subtype, typically resulting from genetic mutation of viral RNA coding for hemagglutinin or neuraminidase. This causes annual regional epidemics. In contrast, antigenic shift is the result of genetic material reassortment: the emerging of new viral RNA from different strains of different species. This often leads to global pandemics.

Therefore, it is challenging to accurately predict the antigenic makeup of influenza viruses for each season and to include new emerging antigens in the vaccine production, as we are facing a moving target. We prepare influenza vaccines each season based on past experience.⁶³

Vaccination rates have hit a plateau of 60% to 70% in adults since the 1990s, in spite of greater vaccine supply and recommendations that all adults, regardless of underlying disease, be vaccinated annually.⁶⁴ Similarly, only 51% of children age 6 months to 17 years were vaccinated in the 2010–2011 season.⁶⁵ And vaccination rates are even lower in low-income populations.^66,67

The emergence of oseltamivir-resistant strains in recent years, not only in people exposed to oseltamivir but also in those who haven’t been exposed to this drug, with sustained transmission, certainly raises the possibility of a more difficult epidemic to control.³⁸

Global travel, global infection. Our last H1N1 pandemic in 2009 was an example of how easily the influenza virus can spread rapidly in today’s highly mobile global society.²²

What we must do

As primary health care providers, we must closely monitor the community outbreak and the emergence of drug-resistant strains and strongly recommend vaccination for all patients older than 6 months, since timely vaccination is the cornerstone of influenza prevention. Although many have questioned the efficacy of influenza vaccination, a recent meta-analysis showed a 59% pooled efficacy of the trivalent inactivated vaccine in adults age 18 to 65 years in preventing virologically confirmed influenza, and 83% pooled efficacy of the live-attenuated influenza vaccine in children age 6 months to 7 years.⁶⁸ Novel approaches for vaccination reminders, such as text messaging⁶⁹ in addition to traditional mail or telephone reminders, can improve vaccination compliance in today’s highly mobile world that is more than ever connected.

With the lessons learned from four pandemics in the last century, updated recommendations for prevention, and adequate vaccine supply, we should be ready to face the challenge of another flu season.

Despite our success in reducing the number of deaths from influenza in the last half-century, we must remain vigilant, since influenza still can kill.^1,2 Gene mutations and reassortment among different strains of influenza viruses pose a significant public health threat, especially in an increasingly mobile world.^3,4

In this article, we will present an update on influenza to better prepare primary care providers to prevent and treat this ongoing threat.

H3N2v: SWINE FLU DÉJÀ VU?

Outbreaks of swine flu at state and county fairs in 2012 are unprecedented and have raised concerns.

From 1990 to 2010, human infections with swine-origin influenza viruses were sporadic, and the US Centers for Disease Control and Prevention (CDC) confirmed a total of only 27 cases during this period.⁵ However, the number has been increasing since 2011: as of August 31, 2012, a total of 309 cases had been reported.⁶

Adapted from Lindstrom S, et al. Human infections with novel reassortant influenza A(H3N2)V viruses, United States, 2011. Emerg Infect Dis 2012; 18:834–837.

Analysis of viral RNA in clinical respiratory specimens from 12 cases in 2011 revealed a variant strain, called H3N2v, which is a hybrid containing genetic material from swine H3N2 and the 2009 human pandemic virus H1N1pdm09. The M gene in this new variant came from the human virus, while the other seven came from the swine virus when a host was infected with both viruses simultaneously (Figure 1). As a result of this genetic reassortment, this variant virus is genetically and antigenically different from seasonal H3N2.

Epidemiologic data showed that children under 10 years of age are especially susceptible to this new variant because they lack immunity, whereas adolescents and adults may have some immunity from cross-reacting antibodies.⁷ Most infected people had been exposed to swine in agriculture, including county and state fairs. So far, evidence suggests only limited human-to-human transmission.⁸ The clinical diagnosis of H3N2v infection relies on the epidemiologic link to exposure to pigs in the week before the onset of illness, since the symptoms are indistinguishable from those of seasonal influenza A or B infections.

In suspected cases, the clinician should notify the local or state public health department and arrange for a special test to be performed on respiratory specimens: the CDC Flu Real-Time Reverse Transcriptase Polymerase Chain Reaction Dx Panel. The reason is that a negative rapid influenza diagnostic test does not rule out influenza infection, and a positive immunofluorescence assay (direct fluorescent antibody staining) cannot specifically detect H3N2v.⁷

The current seasonal influenza vaccine will not protect against H3N2v. The isolates tested to date were susceptible to the neuraminidase inhibitor drugs oseltamivir (Tamiflu) and zanamivir (Relenza) but resistant to amantadine (Symmetrel) and rimantadine (Flumadine).⁹

Whether H3N2v will become a significant problem during the upcoming flu season largely depends on the extent of human-to-human transmission. We need to closely follow updates on this virus.

H5N1: THE LOOMING THREAT OF A BIRD FLU PANDEMIC

Since 2003, influenza A H5N1, a highly pathogenic avian virus, has broken out in Asia, Africa, and the Middle East, killing more than 100 million birds. It also has crossed the species barrier to infect humans, with an unusually high death rate.¹⁰

As of August 10, 2012, the World Health Organization had reported 608 confirmed cases of this virus infecting humans and 359 associated deaths.¹¹ Most infected patients had a history of close contact with diseased poultry, but limited, nonsustained human-to-human transmission can occur during very close, unprotected contact with a severely ill patient.¹²

Molecular studies of this virus revealed further insights into its pathogenesis. Some of the viruses isolated from humans have had mutations that allow them to bind to human-type receptors.¹³ Amino acid substitutions in the polymerase basic protein 2 (PB2) gene are associated with mammalian adaptation, virulence in mice, and viral replication at temperatures present in the upper respiratory tract.¹⁴ Furthermore, higher plasma levels of macrophage- and neutrophil-attractant chemokines and both inflammatory and anti-inflammatory cytokines (interleukin 6, interleukin 10, and interferon gamma) have been observed in patients with H5N1 infection, especially in fatal cases.¹⁵ A recent study found that H5N1 causes significant perturbations in the host’s protein synthesis machinery as early as 1 hour after infection, suggesting that this virus gains an early advantage in replication by using the host’s proteome.¹⁶ The effects of unrestrained viral infection and inflammatory responses induced by H5N1 infection certainly contributed to the primary pathologic process and to death in human fulminant viral pneumonia. The up-regulation of inflammatory cytokines in these infections contributes to the development of sepsis syndrome, acute respiratory distress syndrome, and an increased risk of death, particularly in pregnant women.

Most experts predict that pandemic influenza is probably inevitable.¹⁷ If avian H5N1 and a human influenza virus swap genes in a host such as swine, the new hybrid virus will contain genetic material from both strains and will have surface antigens that the human immune system does not recognize. This could lead to a devastating avian flu pandemic with a very high death rate.¹⁸

An inactivated whole-virus H5N1 vaccine has been developed by the US government to prevent H5N1 infection.¹⁹ For treatment, the neuraminidase inhibitor oseltamivir is the drug of choice.¹⁰ Oseltamivir resistance remains uncommon. ²⁰ Fortunately, zanamivir is still active against oseltamivir-resistant variants that have N1 neuraminidase mutations.²¹

THE 2009 H1N1 PANDEMIC KILLED MORE PEOPLE THAN WE THOUGHT

The fourth flu pandemic of the last 100 years occurred in 2009. (The other three were in 1918, 1957, and 1968.) It was caused by a novel strain, H1N1 of swine origin.²² This 2009 pandemic strain had six genes from the North American swine flu virus and two genes from the Eurasian swine flu virus. The pandemic affected more children and young people (who completely lacked prior immunity to this virus), while older people, who had cross-reacting antibodies, were less affected.

Worldwide, 18,500 people were reported initially to have died in this pandemic from April 2009 to August 2010.²³ However, a recent modeling study estimated the number of respiratory and cardiovascular deaths associated with this pandemic at 283,500—about 15 times higher.²⁴

AN AUSTRALIAN OUTBREAK OF OSELTAMIVIR-RESISTANT H1N1

Many strains of influenza A virus are resistant to amantadine and rimantadine, owing to amino acid substitutions in the M2 protein.²⁵ In contrast, resistance to the neuraminidase inhibitors oseltamivir and zanamivir has been reported only occasionally.²⁶

Until recently, most oseltamivir-resistant viruses were isolated from immunocompromised hosts treated with oseltamivir.^27–29 All the resistant viral isolates contained an amino acid substitution of histidine (H) to tyrosine (Y) at position 275 of the viral neuraminidase.³⁰ In general, transmission of these oseltamivir-resistant strains has been limited and unsustained, but it can occur in settings of close contact, such as hospitals, school camps, or long train rides.^31–35 Oseltamivir-resistant strains were detected in fewer than 1% of isolates from the community during the 2010–2011 influenza season in the Northern Hemisphere and most countries in the Southern Hemisphere during the 2011 flu season.^36,37

However, an outbreak of oseltamivir-resistant H1N1 occurred in Australia between June and August 2011.³⁸ In that outbreak, the isolates from only 15% of the 191 people infected with this virus, designated H1N1pdm09, carried the H257Y neuraminidase substitution.³⁹ Further, only 1 of the 191 patients had received oseltamivir before. More importantly, genetic analysis suggested that the infection spread from a single source.

This was the first reported sustained community transmission of oseltamivir-resistant H1N1 in a community previously unexposed to this drug. As such, it is a warning sign of the potential for a widespread outbreak of this virus. In the event of such an outbreak, inhaled zanamivir would be the only effective treatment available.

THIS SEASON’S TRIVALENT INACTIVATED VACCINE

The trivalent inactivated influenza vaccine for the 2012–2013 season contains three inactivated viruses⁴⁰:

• Influenza A/California/7/2009(H1N1)-like
• Influenza A/Victoria/361/2011(H3N2)-like
• Influenza B/Wisconsin/1/2010-like (Yamagata lineage).

The influenza A H3N2 and influenza B antigens are different from those in the 2011–2012 vaccine.⁴¹ The H1N1 strain is derived from H1N1pdm09, which had been contained in the 2011–2012 seasonal vaccine. This vaccine will not protect against H3N2v or H5N1.

LATEST RECOMMENDATIONS ON VACCINATION

Since 2010, the Advisory Committee on Immunization Practices (ACIP) has recommended annual flu shots for all people older than 6 months in the United States.⁴²

Vaccination should be done before the onset of influenza activity in the community as soon as vaccine is available for the season. However, one should continue offering vaccination throughout the influenza season as long as influenza viruses are circulating in the community.

Children ages 6 months through 8 years not previously vaccinated against influenza should receive two doses of influenza vaccine at least 4 weeks apart for an optimal immune response. The US-licensed Afluria vaccine (CSL Biotherapies, King of Prussia, PA), a trivalent inactivated vaccine, is not recommended for children under 9 years of age because of concern about febrile seizures.^43,44

There is no contraindication to giving inactivated trivalent influenza vaccine to immunosuppressed people.

The live-attenuated influenza vaccine is indicated only for healthy, nonpregnant people age 2 through 49 years and not for people who care for severely immunosuppressed patients who require a protective environment.

For indications for and details about the different available influenza vaccines, see the ACIP’s current recommendations (www.cdc.gov/mmwr/pdf/wk/mm6132.pdf).⁴⁰

Updated recommendations for people allergic to eggs

All currently available influenza vaccines are made by growing the virus in chicken eggs. Therefore, severe allergic and anaphylactic reactions can occur in people with egg allergy. The ACIP recommends that if people experienced only hives after egg exposure, they should still receive the trivalent inactivated vaccine. Recently, the ACIP reviewed data from the Vaccine Adverse Event Reporting System⁴⁵ and issued the following recommendations for the 2012–2013 influenza season⁴⁰:

• In people who are allergic to eggs, only trivalent inactivated vaccine should be used, not the live-attenuated vaccine, because of lack of data for use of the latter in this group.
• Vaccine should be given by providers who are familiar with the signs of egg allergy.
• Patients with a history of egg allergy who have experienced only hives after exposure to eggs should be observed for a minimum of 30 minutes after vaccination.
• Patients who experience lightheadedness, respiratory distress, angioedema, or recurrent emesis or who require epinephrine or emergency medical attention after egg exposure should be referred before vaccination to a physician who has expertise in managing allergic conditions.
• Tolerance to egg-containing foods does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reactions to eggs or egg-containing foods, plus skin or blood testing for immunoglobulin E antibodies to egg proteins.

A high-dose vaccine is available for people 65 years and older

The rates of hospitalization and death due to seasonal flu in elderly people have increased significantly in the last 20 years despite rising rates of vaccination.^46–48 This is largely due to lower serologic response rates and vaccine efficacy in older adults with weaker immune systems.

Several studies have shown that the development of protective antibody titers depends on the dose of antigen.^49–53 A randomized, controlled clinical trial compared the immunogenicity of a high-dose vaccine and a standard-dose vaccine in older adults and found that the level of antibody response was significantly higher with the high-dose vaccine, and that the rate of adverse reactions was the same.⁵⁴

In December 2009, the US Food and Drug Administration (FDA) licensed a new trivalent inactivated influenza vaccine with high doses of hemagglutinin antigens for adults over the age of 65.⁵⁵ Postlicensure safety surveillance in 2010 revealed no serious safety concerns.⁵⁶

At present, the ACIP expresses no preference for standard-dose or high-dose vaccine for adults 65 years of age and older.⁴⁰ Importantly, if only the standard-dose vaccine is at hand, the opportunity for influenza vaccination should not be missed with the intention of giving high-dose vaccine at a later date.

A NEW QUADRIVALENT LIVE-ATTENUATED INFLUENZA VACCINE FOR THE 2013–2014 SEASON

In February 2012, the FDA approved the first quadrivalent live-attenuated influenza vaccine, which is expected to replace the currently available trivalent live-attenuated influenza vaccine in the 2013–2014 flu season. The quadrivalent vaccine will include both lineages of the circulating influenza B viruses (the Victoria and Yamagata lineages). The reasons for this inclusion is the difficulty in predicting which of these viruses will predominate in any given season, and the limited cross-resistance by immunization against one of the lineages.

A recent analysis⁵⁷ estimated that such a vaccine is likely to further reduce influenza cases, related hospitalizations, and deaths compared with the current trivalent vaccine. Like the current trivalent live-attenuated vaccine, the quadrivalent vaccine is inhaled.

EVOLVING VACCINATION POLICY IN HEALTH CARE WORKERS

Starting in January 2013, the Centers for Medicare and Medicaid Services will require hospitals to report how many of their health care workers are vaccinated. These rates will be publicly reported as a measure of hospital quality. This has fueled the ongoing debate about mandating influenza vaccination for health care workers. Studies have shown that the most important factors in increasing influenza vaccination rates among health care workers are requiring vaccination as a condition for employment and making vaccination available on-site, for more than 1 day, at no cost to the worker.⁵⁸

As an alternative, some institutions have implemented a “shot-or-mask” policy whereby a health care worker who elects not to be vaccinated because of medical or religious reasons would be asked to wear a mask during all faceto-face encounters with patients.

NEW ANTIVIRAL DRUGS ON THE HORIZON

The emergence of oseltamivir-resistant strains in recent years caused a great deal of concern in public health regarding the potential for outbreaks of drug-resistant influenza.^{34,35,59–61}

A recent Asian randomized clinical trial reported the efficacy of a long-acting neuraminidase inhibitor, laninamivir octanoate, in the treatment of seasonal influenza.⁶² This study showed that a single inhalation of this drug is effective in treating seasonal influenza, including that caused by oseltamivir-resistant strains in adults. Laninamivir is currently approved in Japan.

CHALLENGES IN PREVENTING AND TREATING INFLUENZA

Despite the great advances that we have made in preventing and treating influenza in the last half-century, we still face many challenges. Each year in the United States, influenza infection results in an estimated 31 million outpatient visits, 226,000 hospital admissions, and 36,000 deaths.⁴²

Antigenic drift and shift. Influenza viruses circulating among animals and humans vary genetically from season to season and within seasons. As a result of this changing viral antigenicity, the virus can evade the human immune system, causing widespread outbreaks.

One of the unique and most remarkable features of influenza virus is the antigenic variation: antigenic drift and antigenic shift. Antigenic drift is the relatively minor antigenic changes that occur frequently within an influenza subtype, typically resulting from genetic mutation of viral RNA coding for hemagglutinin or neuraminidase. This causes annual regional epidemics. In contrast, antigenic shift is the result of genetic material reassortment: the emerging of new viral RNA from different strains of different species. This often leads to global pandemics.

Therefore, it is challenging to accurately predict the antigenic makeup of influenza viruses for each season and to include new emerging antigens in the vaccine production, as we are facing a moving target. We prepare influenza vaccines each season based on past experience.⁶³

Vaccination rates have hit a plateau of 60% to 70% in adults since the 1990s, in spite of greater vaccine supply and recommendations that all adults, regardless of underlying disease, be vaccinated annually.⁶⁴ Similarly, only 51% of children age 6 months to 17 years were vaccinated in the 2010–2011 season.⁶⁵ And vaccination rates are even lower in low-income populations.^66,67

The emergence of oseltamivir-resistant strains in recent years, not only in people exposed to oseltamivir but also in those who haven’t been exposed to this drug, with sustained transmission, certainly raises the possibility of a more difficult epidemic to control.³⁸

Global travel, global infection. Our last H1N1 pandemic in 2009 was an example of how easily the influenza virus can spread rapidly in today’s highly mobile global society.²²

What we must do

As primary health care providers, we must closely monitor the community outbreak and the emergence of drug-resistant strains and strongly recommend vaccination for all patients older than 6 months, since timely vaccination is the cornerstone of influenza prevention. Although many have questioned the efficacy of influenza vaccination, a recent meta-analysis showed a 59% pooled efficacy of the trivalent inactivated vaccine in adults age 18 to 65 years in preventing virologically confirmed influenza, and 83% pooled efficacy of the live-attenuated influenza vaccine in children age 6 months to 7 years.⁶⁸ Novel approaches for vaccination reminders, such as text messaging⁶⁹ in addition to traditional mail or telephone reminders, can improve vaccination compliance in today’s highly mobile world that is more than ever connected.

With the lessons learned from four pandemics in the last century, updated recommendations for prevention, and adequate vaccine supply, we should be ready to face the challenge of another flu season.

Despite our success in reducing the number of deaths from influenza in the last half-century, we must remain vigilant, since influenza still can kill.^1,2 Gene mutations and reassortment among different strains of influenza viruses pose a significant public health threat, especially in an increasingly mobile world.^3,4

In this article, we will present an update on influenza to better prepare primary care providers to prevent and treat this ongoing threat.

H3N2v: SWINE FLU DÉJÀ VU?

Outbreaks of swine flu at state and county fairs in 2012 are unprecedented and have raised concerns.

From 1990 to 2010, human infections with swine-origin influenza viruses were sporadic, and the US Centers for Disease Control and Prevention (CDC) confirmed a total of only 27 cases during this period.⁵ However, the number has been increasing since 2011: as of August 31, 2012, a total of 309 cases had been reported.⁶

Adapted from Lindstrom S, et al. Human infections with novel reassortant influenza A(H3N2)V viruses, United States, 2011. Emerg Infect Dis 2012; 18:834–837.

Analysis of viral RNA in clinical respiratory specimens from 12 cases in 2011 revealed a variant strain, called H3N2v, which is a hybrid containing genetic material from swine H3N2 and the 2009 human pandemic virus H1N1pdm09. The M gene in this new variant came from the human virus, while the other seven came from the swine virus when a host was infected with both viruses simultaneously (Figure 1). As a result of this genetic reassortment, this variant virus is genetically and antigenically different from seasonal H3N2.

Epidemiologic data showed that children under 10 years of age are especially susceptible to this new variant because they lack immunity, whereas adolescents and adults may have some immunity from cross-reacting antibodies.⁷ Most infected people had been exposed to swine in agriculture, including county and state fairs. So far, evidence suggests only limited human-to-human transmission.⁸ The clinical diagnosis of H3N2v infection relies on the epidemiologic link to exposure to pigs in the week before the onset of illness, since the symptoms are indistinguishable from those of seasonal influenza A or B infections.

In suspected cases, the clinician should notify the local or state public health department and arrange for a special test to be performed on respiratory specimens: the CDC Flu Real-Time Reverse Transcriptase Polymerase Chain Reaction Dx Panel. The reason is that a negative rapid influenza diagnostic test does not rule out influenza infection, and a positive immunofluorescence assay (direct fluorescent antibody staining) cannot specifically detect H3N2v.⁷

The current seasonal influenza vaccine will not protect against H3N2v. The isolates tested to date were susceptible to the neuraminidase inhibitor drugs oseltamivir (Tamiflu) and zanamivir (Relenza) but resistant to amantadine (Symmetrel) and rimantadine (Flumadine).⁹

Whether H3N2v will become a significant problem during the upcoming flu season largely depends on the extent of human-to-human transmission. We need to closely follow updates on this virus.

H5N1: THE LOOMING THREAT OF A BIRD FLU PANDEMIC

Since 2003, influenza A H5N1, a highly pathogenic avian virus, has broken out in Asia, Africa, and the Middle East, killing more than 100 million birds. It also has crossed the species barrier to infect humans, with an unusually high death rate.¹⁰

As of August 10, 2012, the World Health Organization had reported 608 confirmed cases of this virus infecting humans and 359 associated deaths.¹¹ Most infected patients had a history of close contact with diseased poultry, but limited, nonsustained human-to-human transmission can occur during very close, unprotected contact with a severely ill patient.¹²

Molecular studies of this virus revealed further insights into its pathogenesis. Some of the viruses isolated from humans have had mutations that allow them to bind to human-type receptors.¹³ Amino acid substitutions in the polymerase basic protein 2 (PB2) gene are associated with mammalian adaptation, virulence in mice, and viral replication at temperatures present in the upper respiratory tract.¹⁴ Furthermore, higher plasma levels of macrophage- and neutrophil-attractant chemokines and both inflammatory and anti-inflammatory cytokines (interleukin 6, interleukin 10, and interferon gamma) have been observed in patients with H5N1 infection, especially in fatal cases.¹⁵ A recent study found that H5N1 causes significant perturbations in the host’s protein synthesis machinery as early as 1 hour after infection, suggesting that this virus gains an early advantage in replication by using the host’s proteome.¹⁶ The effects of unrestrained viral infection and inflammatory responses induced by H5N1 infection certainly contributed to the primary pathologic process and to death in human fulminant viral pneumonia. The up-regulation of inflammatory cytokines in these infections contributes to the development of sepsis syndrome, acute respiratory distress syndrome, and an increased risk of death, particularly in pregnant women.

Most experts predict that pandemic influenza is probably inevitable.¹⁷ If avian H5N1 and a human influenza virus swap genes in a host such as swine, the new hybrid virus will contain genetic material from both strains and will have surface antigens that the human immune system does not recognize. This could lead to a devastating avian flu pandemic with a very high death rate.¹⁸

An inactivated whole-virus H5N1 vaccine has been developed by the US government to prevent H5N1 infection.¹⁹ For treatment, the neuraminidase inhibitor oseltamivir is the drug of choice.¹⁰ Oseltamivir resistance remains uncommon. ²⁰ Fortunately, zanamivir is still active against oseltamivir-resistant variants that have N1 neuraminidase mutations.²¹

THE 2009 H1N1 PANDEMIC KILLED MORE PEOPLE THAN WE THOUGHT

The fourth flu pandemic of the last 100 years occurred in 2009. (The other three were in 1918, 1957, and 1968.) It was caused by a novel strain, H1N1 of swine origin.²² This 2009 pandemic strain had six genes from the North American swine flu virus and two genes from the Eurasian swine flu virus. The pandemic affected more children and young people (who completely lacked prior immunity to this virus), while older people, who had cross-reacting antibodies, were less affected.

Worldwide, 18,500 people were reported initially to have died in this pandemic from April 2009 to August 2010.²³ However, a recent modeling study estimated the number of respiratory and cardiovascular deaths associated with this pandemic at 283,500—about 15 times higher.²⁴

AN AUSTRALIAN OUTBREAK OF OSELTAMIVIR-RESISTANT H1N1

Many strains of influenza A virus are resistant to amantadine and rimantadine, owing to amino acid substitutions in the M2 protein.²⁵ In contrast, resistance to the neuraminidase inhibitors oseltamivir and zanamivir has been reported only occasionally.²⁶

Until recently, most oseltamivir-resistant viruses were isolated from immunocompromised hosts treated with oseltamivir.^27–29 All the resistant viral isolates contained an amino acid substitution of histidine (H) to tyrosine (Y) at position 275 of the viral neuraminidase.³⁰ In general, transmission of these oseltamivir-resistant strains has been limited and unsustained, but it can occur in settings of close contact, such as hospitals, school camps, or long train rides.^31–35 Oseltamivir-resistant strains were detected in fewer than 1% of isolates from the community during the 2010–2011 influenza season in the Northern Hemisphere and most countries in the Southern Hemisphere during the 2011 flu season.^36,37

However, an outbreak of oseltamivir-resistant H1N1 occurred in Australia between June and August 2011.³⁸ In that outbreak, the isolates from only 15% of the 191 people infected with this virus, designated H1N1pdm09, carried the H257Y neuraminidase substitution.³⁹ Further, only 1 of the 191 patients had received oseltamivir before. More importantly, genetic analysis suggested that the infection spread from a single source.

This was the first reported sustained community transmission of oseltamivir-resistant H1N1 in a community previously unexposed to this drug. As such, it is a warning sign of the potential for a widespread outbreak of this virus. In the event of such an outbreak, inhaled zanamivir would be the only effective treatment available.

THIS SEASON’S TRIVALENT INACTIVATED VACCINE

The trivalent inactivated influenza vaccine for the 2012–2013 season contains three inactivated viruses⁴⁰:

• Influenza A/California/7/2009(H1N1)-like
• Influenza A/Victoria/361/2011(H3N2)-like
• Influenza B/Wisconsin/1/2010-like (Yamagata lineage).

The influenza A H3N2 and influenza B antigens are different from those in the 2011–2012 vaccine.⁴¹ The H1N1 strain is derived from H1N1pdm09, which had been contained in the 2011–2012 seasonal vaccine. This vaccine will not protect against H3N2v or H5N1.

LATEST RECOMMENDATIONS ON VACCINATION

Since 2010, the Advisory Committee on Immunization Practices (ACIP) has recommended annual flu shots for all people older than 6 months in the United States.⁴²

Vaccination should be done before the onset of influenza activity in the community as soon as vaccine is available for the season. However, one should continue offering vaccination throughout the influenza season as long as influenza viruses are circulating in the community.

Children ages 6 months through 8 years not previously vaccinated against influenza should receive two doses of influenza vaccine at least 4 weeks apart for an optimal immune response. The US-licensed Afluria vaccine (CSL Biotherapies, King of Prussia, PA), a trivalent inactivated vaccine, is not recommended for children under 9 years of age because of concern about febrile seizures.^43,44

There is no contraindication to giving inactivated trivalent influenza vaccine to immunosuppressed people.

The live-attenuated influenza vaccine is indicated only for healthy, nonpregnant people age 2 through 49 years and not for people who care for severely immunosuppressed patients who require a protective environment.

For indications for and details about the different available influenza vaccines, see the ACIP’s current recommendations (www.cdc.gov/mmwr/pdf/wk/mm6132.pdf).⁴⁰

Updated recommendations for people allergic to eggs

All currently available influenza vaccines are made by growing the virus in chicken eggs. Therefore, severe allergic and anaphylactic reactions can occur in people with egg allergy. The ACIP recommends that if people experienced only hives after egg exposure, they should still receive the trivalent inactivated vaccine. Recently, the ACIP reviewed data from the Vaccine Adverse Event Reporting System⁴⁵ and issued the following recommendations for the 2012–2013 influenza season⁴⁰:

• In people who are allergic to eggs, only trivalent inactivated vaccine should be used, not the live-attenuated vaccine, because of lack of data for use of the latter in this group.
• Vaccine should be given by providers who are familiar with the signs of egg allergy.
• Patients with a history of egg allergy who have experienced only hives after exposure to eggs should be observed for a minimum of 30 minutes after vaccination.
• Patients who experience lightheadedness, respiratory distress, angioedema, or recurrent emesis or who require epinephrine or emergency medical attention after egg exposure should be referred before vaccination to a physician who has expertise in managing allergic conditions.
• Tolerance to egg-containing foods does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reactions to eggs or egg-containing foods, plus skin or blood testing for immunoglobulin E antibodies to egg proteins.

A high-dose vaccine is available for people 65 years and older

The rates of hospitalization and death due to seasonal flu in elderly people have increased significantly in the last 20 years despite rising rates of vaccination.^46–48 This is largely due to lower serologic response rates and vaccine efficacy in older adults with weaker immune systems.

Several studies have shown that the development of protective antibody titers depends on the dose of antigen.^49–53 A randomized, controlled clinical trial compared the immunogenicity of a high-dose vaccine and a standard-dose vaccine in older adults and found that the level of antibody response was significantly higher with the high-dose vaccine, and that the rate of adverse reactions was the same.⁵⁴

In December 2009, the US Food and Drug Administration (FDA) licensed a new trivalent inactivated influenza vaccine with high doses of hemagglutinin antigens for adults over the age of 65.⁵⁵ Postlicensure safety surveillance in 2010 revealed no serious safety concerns.⁵⁶

At present, the ACIP expresses no preference for standard-dose or high-dose vaccine for adults 65 years of age and older.⁴⁰ Importantly, if only the standard-dose vaccine is at hand, the opportunity for influenza vaccination should not be missed with the intention of giving high-dose vaccine at a later date.

A NEW QUADRIVALENT LIVE-ATTENUATED INFLUENZA VACCINE FOR THE 2013–2014 SEASON

In February 2012, the FDA approved the first quadrivalent live-attenuated influenza vaccine, which is expected to replace the currently available trivalent live-attenuated influenza vaccine in the 2013–2014 flu season. The quadrivalent vaccine will include both lineages of the circulating influenza B viruses (the Victoria and Yamagata lineages). The reasons for this inclusion is the difficulty in predicting which of these viruses will predominate in any given season, and the limited cross-resistance by immunization against one of the lineages.

A recent analysis⁵⁷ estimated that such a vaccine is likely to further reduce influenza cases, related hospitalizations, and deaths compared with the current trivalent vaccine. Like the current trivalent live-attenuated vaccine, the quadrivalent vaccine is inhaled.

EVOLVING VACCINATION POLICY IN HEALTH CARE WORKERS

Starting in January 2013, the Centers for Medicare and Medicaid Services will require hospitals to report how many of their health care workers are vaccinated. These rates will be publicly reported as a measure of hospital quality. This has fueled the ongoing debate about mandating influenza vaccination for health care workers. Studies have shown that the most important factors in increasing influenza vaccination rates among health care workers are requiring vaccination as a condition for employment and making vaccination available on-site, for more than 1 day, at no cost to the worker.⁵⁸

As an alternative, some institutions have implemented a “shot-or-mask” policy whereby a health care worker who elects not to be vaccinated because of medical or religious reasons would be asked to wear a mask during all faceto-face encounters with patients.

NEW ANTIVIRAL DRUGS ON THE HORIZON

The emergence of oseltamivir-resistant strains in recent years caused a great deal of concern in public health regarding the potential for outbreaks of drug-resistant influenza.^{34,35,59–61}

A recent Asian randomized clinical trial reported the efficacy of a long-acting neuraminidase inhibitor, laninamivir octanoate, in the treatment of seasonal influenza.⁶² This study showed that a single inhalation of this drug is effective in treating seasonal influenza, including that caused by oseltamivir-resistant strains in adults. Laninamivir is currently approved in Japan.

CHALLENGES IN PREVENTING AND TREATING INFLUENZA

Despite the great advances that we have made in preventing and treating influenza in the last half-century, we still face many challenges. Each year in the United States, influenza infection results in an estimated 31 million outpatient visits, 226,000 hospital admissions, and 36,000 deaths.⁴²

Antigenic drift and shift. Influenza viruses circulating among animals and humans vary genetically from season to season and within seasons. As a result of this changing viral antigenicity, the virus can evade the human immune system, causing widespread outbreaks.

One of the unique and most remarkable features of influenza virus is the antigenic variation: antigenic drift and antigenic shift. Antigenic drift is the relatively minor antigenic changes that occur frequently within an influenza subtype, typically resulting from genetic mutation of viral RNA coding for hemagglutinin or neuraminidase. This causes annual regional epidemics. In contrast, antigenic shift is the result of genetic material reassortment: the emerging of new viral RNA from different strains of different species. This often leads to global pandemics.

Therefore, it is challenging to accurately predict the antigenic makeup of influenza viruses for each season and to include new emerging antigens in the vaccine production, as we are facing a moving target. We prepare influenza vaccines each season based on past experience.⁶³

Vaccination rates have hit a plateau of 60% to 70% in adults since the 1990s, in spite of greater vaccine supply and recommendations that all adults, regardless of underlying disease, be vaccinated annually.⁶⁴ Similarly, only 51% of children age 6 months to 17 years were vaccinated in the 2010–2011 season.⁶⁵ And vaccination rates are even lower in low-income populations.^66,67

The emergence of oseltamivir-resistant strains in recent years, not only in people exposed to oseltamivir but also in those who haven’t been exposed to this drug, with sustained transmission, certainly raises the possibility of a more difficult epidemic to control.³⁸

Global travel, global infection. Our last H1N1 pandemic in 2009 was an example of how easily the influenza virus can spread rapidly in today’s highly mobile global society.²²

What we must do

As primary health care providers, we must closely monitor the community outbreak and the emergence of drug-resistant strains and strongly recommend vaccination for all patients older than 6 months, since timely vaccination is the cornerstone of influenza prevention. Although many have questioned the efficacy of influenza vaccination, a recent meta-analysis showed a 59% pooled efficacy of the trivalent inactivated vaccine in adults age 18 to 65 years in preventing virologically confirmed influenza, and 83% pooled efficacy of the live-attenuated influenza vaccine in children age 6 months to 7 years.⁶⁸ Novel approaches for vaccination reminders, such as text messaging⁶⁹ in addition to traditional mail or telephone reminders, can improve vaccination compliance in today’s highly mobile world that is more than ever connected.

With the lessons learned from four pandemics in the last century, updated recommendations for prevention, and adequate vaccine supply, we should be ready to face the challenge of another flu season.

Hormone therapy may reduce the risk of Alzheimer’s disease for women who take the treatment at a time near menopause, but if hormone therapy is begun after menopause it may not reduce such risk, according to a study in the October 30 Neurology. Researchers followed 1,768 women who were part of a population-based study and found that 176 women developed Alzheimer’s disease between 1995 and 2006. Women who used any type of hormone therapy within five years of menopause had a 30% less risk of Alzheimer’s disease. However, those who began hormone therapy five or more years after menopause did not have a reduced disease risk. In addition, women who began opposed compounds in the three years prior to the baseline assessment had an increased risk of Alzheimer’s disease. The association of hormone therapy use and risk of Alzheimer’s disease may depend on the timing of use and deserves further study, the investigators concluded.

Engaging in physical activity may protect older adults from brain atrophy and white matter lesions, researchers reported in the October 23 Neurology. The study examined self-reported leisure and physical activity at age 70 among a sample of 691 adults. At age 73, participants were assessed for structural brain biomarkers, and the investigators found that a higher level of physical activity was significantly associated with higher fractional anisotropy, less atrophy, lower white matter load, and larger gray and normal-appearing white matter volumes. These associations remained significant after adjustments for age, social class, and health status. The researchers noted that although their results support the role of physical activity as a potential neuroprotective factor, “the direction of causation is unclear from this observational study.”

Poor physical performance is associated with greater odds of dementia in persons age 90 or older, according to a study published in the online October 22 Archives of Neurology. The 629 participants (72.5% women) were from The 90+ Study, a population-based, longitudinal, epidemiologic study of aging and dementia. Participants’ mean age was 94, and all-cause dementia was the main outcome measure. Measures of physical performance included a 4-m walk, five chair stands, standing balance, and grip strength. Researchers found that poor physical performance in all measures was significantly associated with an increased risk of dementia. “Our findings suggest that dementia is a complex neurodegenerative process that may affect physical performance and cognition,” the investigators concluded. “Additional research is necessary to determine the temporal relationship between poor physical activity and cognitive dysfunction.”

Exposure to selective serotonin reuptake inhibitors (SSRI) is associated with an increased risk of intracerebral and intracranial hemorrhage, though the absolute risk of those events is low, according to a study published in the October 30 Neurology. In this meta-analysis, investigators searched for controlled observational studies that compared SSRI users with a control group not receiving SSRIs. The researchers found that intracranial and intracerebral hemorrhage were related to SSRI exposure in unadjusted and adjusted analyses. A subset of five studies showed that SSRI exposure combined with oral anticoagulants was linked with an increased risk of bleeding, compared with use of oral anticoagulants alone. “When all studies were analyzed together, increased risk was seen across cohort studies, case-control studies, and case-crossover studies,” the study authors noted.

The herpes zoster vaccine is effective in preventing herpes zoster in older adults, according to research published in the online October 17 Cochrane Database of Systematic Reviews. The study authors conducted a meta-analysis of eight randomized controlled trials of adults who had a mean age older than 60. The trials had a total of 52,269 participants. Patients who received the vaccine had fewer confirmed cases of herpes zoster than those who received placebo. Analysis of age groups showed that vaccine benefits were greatest for patients ages 60 to 69, as well as for those 70 and older. However, persons ages 60 to 69 experienced more frequent side effects than did persons 70 and older. “In general, zoster vaccine is well tolerated; it produces few systemic adverse events and injection site adverse effects of mild to moderate intensity,” wrote the researchers.

Strokes are increasingly occurring in younger patients, researchers reported in the October 23 Neurology. Between 1993 and 1994 and between 1999 and 2005, strokes were recorded in an estimated population of 1.3 million. The investigators used a mixed-model approach to test for differences in age trends over time, and they found that the mean age at stroke decreased by a significant amount, from 71.2 years in 1993/1994 to 69.2 years in 2005. Furthermore, the proportion of all strokes in persons younger than 55 increased from 12.9% in 1993 to 18.6% in 2005. “This is of great public health significance because strokes in younger patients carry the potential for greater lifetime burden of disability and because some potential contributors identified for this trend are modifiable,” the researchers concluded.

The FDA has approved perampanel (Fycompa), an AMPA receptor agonist, as an adjunctive treatment for partial-onset seizures with or without secondarily generalized seizures in patients ages 12 and older with epilepsy. Perampanel is a novel agent that reduces neuronal hyperexcitation associated with seizures by inhibiting glutamate activity at postsynaptic AMPA receptors, and it is the first antiepileptic agent approved in the US to work in this manner. In three phase III, global, randomized, double-blind, placebo-controlled studies (1,480 patients), researchers concluded that perampanel significantly reduced seizure frequency in patients with partial-onset seizures with or without secondary generalized seizures. Patients experienced adverse events that included dizziness, somnolence, fatigue, irritability, falls, nausea, ataxia, balance disorder, gait disturbance, vertigo, and weight gain.

Persons who survive an ischemic stroke and continue smoking have a greater risk of heart attack, death, or another stroke, compared with those who have never smoked, researchers reported in the online October 25 Stroke. The study included 1,589 patients who experienced a first or recurrent ischemic stroke between 1996 and 1999. The investigators tracked the cohort for 10 years and found that patients who smoked when they had a stroke were 30% more likely to have a poor outcome and that current smokers who survived the first 28 days after a stroke had a 42% higher risk of poor outcome. In addition, former smokers had an 18% higher risk of poor outcomes. The authors also noted that smoking had the greatest effect on younger male patients, particularly those from a disadvantaged background.

For every 400 to 500 persons with an intermediate risk of cardiovascular disease who undergo screening for C-reactive protein or fibrinogen, one additional event in a period of 10 years may be prevented, researchers reported in the October 4 New England Journal of Medicine. In a meta-analysis of 52 prospective studies of persons without a history of cardiovascular disease, the investigators sought to determine whether assessing C-reactive protein or fibrinogen in addition to conventional cardiovascular risk factors leads to better prediction of cardiovascular risk.
Of 100,000 adults ages 40 and older, 15,025 would be classified as intermediate risk using conventional factors, and 13,199 would remain if statin therapy were initiated in accordance with guidelines. “Additional targeted assessment of C-reactive protein or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years,” the researchers stated.

Extradural motor cortex stimulation for patients with Parkinson’s disease is a safe procedure that leads to moderate improvement of motor symptoms and in quality of life, according to a study published in the October Neurosurgery. Researchers assessed the safety and efficacy of one year of unilateral extradural motor cortex stimulation in nine patients with Parkinson’s disease. At baseline, participants were evaluated with the Unified Parkinson’s Disease Rating Scale and the Parkinson’s Disease Quality of Life Questionnaire. Quality of life scores increased at months three, six, and 12, and disease scores decreased from baseline during the year. Furthermore, bilateral motor effects were observed after three to four weeks. No surgical complications, adverse events, or cognitive and behavioral changes were observed, the study authors said.

The use of beta blockers is not associated with a lower risk of composite cardiovascular events in patients with either coronary artery disease (CAD) risk factors only, known prior myocardial infarction, or known CAD without myocardial infarction, according to an investigation published in the October 3 JAMA. In this longitudinal, observational study, 44,708 patients were categorized into three cohorts— 14,043 patients with known prior myocardial infarction, 12,012 patients with known CAD but without myocardial infarction, and 18,653 patients with CAD risk factors only. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. For all outcomes tested, investigators found that event rates were not significantly different in patients with beta-blocker use, compared with those without beta-blocker use, even among those in the prior myocardial infarction cohort.

Hormone therapy may reduce the risk of Alzheimer’s disease for women who take the treatment at a time near menopause, but if hormone therapy is begun after menopause it may not reduce such risk, according to a study in the October 30 Neurology. Researchers followed 1,768 women who were part of a population-based study and found that 176 women developed Alzheimer’s disease between 1995 and 2006. Women who used any type of hormone therapy within five years of menopause had a 30% less risk of Alzheimer’s disease. However, those who began hormone therapy five or more years after menopause did not have a reduced disease risk. In addition, women who began opposed compounds in the three years prior to the baseline assessment had an increased risk of Alzheimer’s disease. The association of hormone therapy use and risk of Alzheimer’s disease may depend on the timing of use and deserves further study, the investigators concluded.

Engaging in physical activity may protect older adults from brain atrophy and white matter lesions, researchers reported in the October 23 Neurology. The study examined self-reported leisure and physical activity at age 70 among a sample of 691 adults. At age 73, participants were assessed for structural brain biomarkers, and the investigators found that a higher level of physical activity was significantly associated with higher fractional anisotropy, less atrophy, lower white matter load, and larger gray and normal-appearing white matter volumes. These associations remained significant after adjustments for age, social class, and health status. The researchers noted that although their results support the role of physical activity as a potential neuroprotective factor, “the direction of causation is unclear from this observational study.”

Poor physical performance is associated with greater odds of dementia in persons age 90 or older, according to a study published in the online October 22 Archives of Neurology. The 629 participants (72.5% women) were from The 90+ Study, a population-based, longitudinal, epidemiologic study of aging and dementia. Participants’ mean age was 94, and all-cause dementia was the main outcome measure. Measures of physical performance included a 4-m walk, five chair stands, standing balance, and grip strength. Researchers found that poor physical performance in all measures was significantly associated with an increased risk of dementia. “Our findings suggest that dementia is a complex neurodegenerative process that may affect physical performance and cognition,” the investigators concluded. “Additional research is necessary to determine the temporal relationship between poor physical activity and cognitive dysfunction.”

Exposure to selective serotonin reuptake inhibitors (SSRI) is associated with an increased risk of intracerebral and intracranial hemorrhage, though the absolute risk of those events is low, according to a study published in the October 30 Neurology. In this meta-analysis, investigators searched for controlled observational studies that compared SSRI users with a control group not receiving SSRIs. The researchers found that intracranial and intracerebral hemorrhage were related to SSRI exposure in unadjusted and adjusted analyses. A subset of five studies showed that SSRI exposure combined with oral anticoagulants was linked with an increased risk of bleeding, compared with use of oral anticoagulants alone. “When all studies were analyzed together, increased risk was seen across cohort studies, case-control studies, and case-crossover studies,” the study authors noted.

The herpes zoster vaccine is effective in preventing herpes zoster in older adults, according to research published in the online October 17 Cochrane Database of Systematic Reviews. The study authors conducted a meta-analysis of eight randomized controlled trials of adults who had a mean age older than 60. The trials had a total of 52,269 participants. Patients who received the vaccine had fewer confirmed cases of herpes zoster than those who received placebo. Analysis of age groups showed that vaccine benefits were greatest for patients ages 60 to 69, as well as for those 70 and older. However, persons ages 60 to 69 experienced more frequent side effects than did persons 70 and older. “In general, zoster vaccine is well tolerated; it produces few systemic adverse events and injection site adverse effects of mild to moderate intensity,” wrote the researchers.

Strokes are increasingly occurring in younger patients, researchers reported in the October 23 Neurology. Between 1993 and 1994 and between 1999 and 2005, strokes were recorded in an estimated population of 1.3 million. The investigators used a mixed-model approach to test for differences in age trends over time, and they found that the mean age at stroke decreased by a significant amount, from 71.2 years in 1993/1994 to 69.2 years in 2005. Furthermore, the proportion of all strokes in persons younger than 55 increased from 12.9% in 1993 to 18.6% in 2005. “This is of great public health significance because strokes in younger patients carry the potential for greater lifetime burden of disability and because some potential contributors identified for this trend are modifiable,” the researchers concluded.

The FDA has approved perampanel (Fycompa), an AMPA receptor agonist, as an adjunctive treatment for partial-onset seizures with or without secondarily generalized seizures in patients ages 12 and older with epilepsy. Perampanel is a novel agent that reduces neuronal hyperexcitation associated with seizures by inhibiting glutamate activity at postsynaptic AMPA receptors, and it is the first antiepileptic agent approved in the US to work in this manner. In three phase III, global, randomized, double-blind, placebo-controlled studies (1,480 patients), researchers concluded that perampanel significantly reduced seizure frequency in patients with partial-onset seizures with or without secondary generalized seizures. Patients experienced adverse events that included dizziness, somnolence, fatigue, irritability, falls, nausea, ataxia, balance disorder, gait disturbance, vertigo, and weight gain.

Persons who survive an ischemic stroke and continue smoking have a greater risk of heart attack, death, or another stroke, compared with those who have never smoked, researchers reported in the online October 25 Stroke. The study included 1,589 patients who experienced a first or recurrent ischemic stroke between 1996 and 1999. The investigators tracked the cohort for 10 years and found that patients who smoked when they had a stroke were 30% more likely to have a poor outcome and that current smokers who survived the first 28 days after a stroke had a 42% higher risk of poor outcome. In addition, former smokers had an 18% higher risk of poor outcomes. The authors also noted that smoking had the greatest effect on younger male patients, particularly those from a disadvantaged background.

For every 400 to 500 persons with an intermediate risk of cardiovascular disease who undergo screening for C-reactive protein or fibrinogen, one additional event in a period of 10 years may be prevented, researchers reported in the October 4 New England Journal of Medicine. In a meta-analysis of 52 prospective studies of persons without a history of cardiovascular disease, the investigators sought to determine whether assessing C-reactive protein or fibrinogen in addition to conventional cardiovascular risk factors leads to better prediction of cardiovascular risk.
Of 100,000 adults ages 40 and older, 15,025 would be classified as intermediate risk using conventional factors, and 13,199 would remain if statin therapy were initiated in accordance with guidelines. “Additional targeted assessment of C-reactive protein or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years,” the researchers stated.

Extradural motor cortex stimulation for patients with Parkinson’s disease is a safe procedure that leads to moderate improvement of motor symptoms and in quality of life, according to a study published in the October Neurosurgery. Researchers assessed the safety and efficacy of one year of unilateral extradural motor cortex stimulation in nine patients with Parkinson’s disease. At baseline, participants were evaluated with the Unified Parkinson’s Disease Rating Scale and the Parkinson’s Disease Quality of Life Questionnaire. Quality of life scores increased at months three, six, and 12, and disease scores decreased from baseline during the year. Furthermore, bilateral motor effects were observed after three to four weeks. No surgical complications, adverse events, or cognitive and behavioral changes were observed, the study authors said.

The use of beta blockers is not associated with a lower risk of composite cardiovascular events in patients with either coronary artery disease (CAD) risk factors only, known prior myocardial infarction, or known CAD without myocardial infarction, according to an investigation published in the October 3 JAMA. In this longitudinal, observational study, 44,708 patients were categorized into three cohorts— 14,043 patients with known prior myocardial infarction, 12,012 patients with known CAD but without myocardial infarction, and 18,653 patients with CAD risk factors only. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. For all outcomes tested, investigators found that event rates were not significantly different in patients with beta-blocker use, compared with those without beta-blocker use, even among those in the prior myocardial infarction cohort.

Hormone therapy may reduce the risk of Alzheimer’s disease for women who take the treatment at a time near menopause, but if hormone therapy is begun after menopause it may not reduce such risk, according to a study in the October 30 Neurology. Researchers followed 1,768 women who were part of a population-based study and found that 176 women developed Alzheimer’s disease between 1995 and 2006. Women who used any type of hormone therapy within five years of menopause had a 30% less risk of Alzheimer’s disease. However, those who began hormone therapy five or more years after menopause did not have a reduced disease risk. In addition, women who began opposed compounds in the three years prior to the baseline assessment had an increased risk of Alzheimer’s disease. The association of hormone therapy use and risk of Alzheimer’s disease may depend on the timing of use and deserves further study, the investigators concluded.

Engaging in physical activity may protect older adults from brain atrophy and white matter lesions, researchers reported in the October 23 Neurology. The study examined self-reported leisure and physical activity at age 70 among a sample of 691 adults. At age 73, participants were assessed for structural brain biomarkers, and the investigators found that a higher level of physical activity was significantly associated with higher fractional anisotropy, less atrophy, lower white matter load, and larger gray and normal-appearing white matter volumes. These associations remained significant after adjustments for age, social class, and health status. The researchers noted that although their results support the role of physical activity as a potential neuroprotective factor, “the direction of causation is unclear from this observational study.”

Poor physical performance is associated with greater odds of dementia in persons age 90 or older, according to a study published in the online October 22 Archives of Neurology. The 629 participants (72.5% women) were from The 90+ Study, a population-based, longitudinal, epidemiologic study of aging and dementia. Participants’ mean age was 94, and all-cause dementia was the main outcome measure. Measures of physical performance included a 4-m walk, five chair stands, standing balance, and grip strength. Researchers found that poor physical performance in all measures was significantly associated with an increased risk of dementia. “Our findings suggest that dementia is a complex neurodegenerative process that may affect physical performance and cognition,” the investigators concluded. “Additional research is necessary to determine the temporal relationship between poor physical activity and cognitive dysfunction.”

Exposure to selective serotonin reuptake inhibitors (SSRI) is associated with an increased risk of intracerebral and intracranial hemorrhage, though the absolute risk of those events is low, according to a study published in the October 30 Neurology. In this meta-analysis, investigators searched for controlled observational studies that compared SSRI users with a control group not receiving SSRIs. The researchers found that intracranial and intracerebral hemorrhage were related to SSRI exposure in unadjusted and adjusted analyses. A subset of five studies showed that SSRI exposure combined with oral anticoagulants was linked with an increased risk of bleeding, compared with use of oral anticoagulants alone. “When all studies were analyzed together, increased risk was seen across cohort studies, case-control studies, and case-crossover studies,” the study authors noted.

The herpes zoster vaccine is effective in preventing herpes zoster in older adults, according to research published in the online October 17 Cochrane Database of Systematic Reviews. The study authors conducted a meta-analysis of eight randomized controlled trials of adults who had a mean age older than 60. The trials had a total of 52,269 participants. Patients who received the vaccine had fewer confirmed cases of herpes zoster than those who received placebo. Analysis of age groups showed that vaccine benefits were greatest for patients ages 60 to 69, as well as for those 70 and older. However, persons ages 60 to 69 experienced more frequent side effects than did persons 70 and older. “In general, zoster vaccine is well tolerated; it produces few systemic adverse events and injection site adverse effects of mild to moderate intensity,” wrote the researchers.

Strokes are increasingly occurring in younger patients, researchers reported in the October 23 Neurology. Between 1993 and 1994 and between 1999 and 2005, strokes were recorded in an estimated population of 1.3 million. The investigators used a mixed-model approach to test for differences in age trends over time, and they found that the mean age at stroke decreased by a significant amount, from 71.2 years in 1993/1994 to 69.2 years in 2005. Furthermore, the proportion of all strokes in persons younger than 55 increased from 12.9% in 1993 to 18.6% in 2005. “This is of great public health significance because strokes in younger patients carry the potential for greater lifetime burden of disability and because some potential contributors identified for this trend are modifiable,” the researchers concluded.

The FDA has approved perampanel (Fycompa), an AMPA receptor agonist, as an adjunctive treatment for partial-onset seizures with or without secondarily generalized seizures in patients ages 12 and older with epilepsy. Perampanel is a novel agent that reduces neuronal hyperexcitation associated with seizures by inhibiting glutamate activity at postsynaptic AMPA receptors, and it is the first antiepileptic agent approved in the US to work in this manner. In three phase III, global, randomized, double-blind, placebo-controlled studies (1,480 patients), researchers concluded that perampanel significantly reduced seizure frequency in patients with partial-onset seizures with or without secondary generalized seizures. Patients experienced adverse events that included dizziness, somnolence, fatigue, irritability, falls, nausea, ataxia, balance disorder, gait disturbance, vertigo, and weight gain.

Persons who survive an ischemic stroke and continue smoking have a greater risk of heart attack, death, or another stroke, compared with those who have never smoked, researchers reported in the online October 25 Stroke. The study included 1,589 patients who experienced a first or recurrent ischemic stroke between 1996 and 1999. The investigators tracked the cohort for 10 years and found that patients who smoked when they had a stroke were 30% more likely to have a poor outcome and that current smokers who survived the first 28 days after a stroke had a 42% higher risk of poor outcome. In addition, former smokers had an 18% higher risk of poor outcomes. The authors also noted that smoking had the greatest effect on younger male patients, particularly those from a disadvantaged background.

For every 400 to 500 persons with an intermediate risk of cardiovascular disease who undergo screening for C-reactive protein or fibrinogen, one additional event in a period of 10 years may be prevented, researchers reported in the October 4 New England Journal of Medicine. In a meta-analysis of 52 prospective studies of persons without a history of cardiovascular disease, the investigators sought to determine whether assessing C-reactive protein or fibrinogen in addition to conventional cardiovascular risk factors leads to better prediction of cardiovascular risk.
Of 100,000 adults ages 40 and older, 15,025 would be classified as intermediate risk using conventional factors, and 13,199 would remain if statin therapy were initiated in accordance with guidelines. “Additional targeted assessment of C-reactive protein or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years,” the researchers stated.

Extradural motor cortex stimulation for patients with Parkinson’s disease is a safe procedure that leads to moderate improvement of motor symptoms and in quality of life, according to a study published in the October Neurosurgery. Researchers assessed the safety and efficacy of one year of unilateral extradural motor cortex stimulation in nine patients with Parkinson’s disease. At baseline, participants were evaluated with the Unified Parkinson’s Disease Rating Scale and the Parkinson’s Disease Quality of Life Questionnaire. Quality of life scores increased at months three, six, and 12, and disease scores decreased from baseline during the year. Furthermore, bilateral motor effects were observed after three to four weeks. No surgical complications, adverse events, or cognitive and behavioral changes were observed, the study authors said.

The use of beta blockers is not associated with a lower risk of composite cardiovascular events in patients with either coronary artery disease (CAD) risk factors only, known prior myocardial infarction, or known CAD without myocardial infarction, according to an investigation published in the October 3 JAMA. In this longitudinal, observational study, 44,708 patients were categorized into three cohorts— 14,043 patients with known prior myocardial infarction, 12,012 patients with known CAD but without myocardial infarction, and 18,653 patients with CAD risk factors only. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. For all outcomes tested, investigators found that event rates were not significantly different in patients with beta-blocker use, compared with those without beta-blocker use, even among those in the prior myocardial infarction cohort.

Maggie, 42, presents to the emergency department with chronic intermittent abdominal pain and bloating with constipation and occasional diarrhea. She denies fever, chills, nausea, vomiting, melana, bright red blood per rectum, or changes in stool caliper, and she says she otherwise feels well. 

Relevant lab and study results include: a comprehensive metabolic panel, complete blood count with differential, beta hCG (human chorionic gonadotropin), urinalysis, and amylase and lipase, all within normal limits; pregnancy test, negative; abdominal x-ray, within normal limits except increased stool in distal colon; and abdominal CT, 2.3-cm right adrenal mass and a Hounsfield measurement of 4 units.

Maggie has a right adrenal incidentaloma (incidentally discovered adenoma that was not in the differential diagnosis). Such findings have become all too often the case, due to the immediate access to and overutilization of high-resolution CT, MRI, and ultrasound. We are now seeing a significantly increased number of incidental adrenal lesions/masses discovered on images not intended to look for adrenal-related diseases (eg, Cushing syndrome, pheochromocytomas, and aldosterone-producing adenomas).

Q: How common are adrenal adenomas, and what must I consider?

Incidental adrenal adenomas are found on 4.4% of abdominal CTs, and in one autopsy series were discovered in 8.7%. Prevalence increases with age, with occurrence of < 1% in patients younger than 30 and about 7% for patients 70 or older.

Evaluation is based on two concerns: First, is the adrenal mass benign or malignant? Second, is the mass secretory or nonsecretory (non-hormone secreting) in nature?

The fortunate news about adrenal incidentalomas is that 80% are benign and nonsecretory, which provides immediate reassuring news to the patient. Examples of benign adrenal masses are: adenoma, lipoma, cyst, ganglioneuroma, hematoma, and infection (eg, tuberculosis, fungal).

The other encouraging statistic is that only 1:4,000 adrenal incidentalomas are malignant. Examples of malignant adrenal masses are: adrenocortical carcinoma, metastatic neoplasm, lymphoma, and malignant pheochromocytoma.

Q: Does adrenal adenoma size matter?

 Yes, the larger the size of the adenoma, the higher the association with malignancy. The guide below (based on CT findings) shows not only malignancy potential as it relates to size, but also the importance of Hounsfield units and when surgical intervention is recommended.

Imaging (CT scan)

< 4 cm: homogeneous mass with smooth borders and < 10 Hounsfield units; suggests benign mass (likelihood of malignancy, about 2%)

4 to 6 cm: follow closely, consider surgery (likelihood of malignancy, about 6%)

> 6 cm: surgery indicated (likelihood of malignancy, about 25%)

Some providers and patients inquire whether it is helpful or necessary to biopsy. It is generally not advisable to biopsy, especially if the findings are favorable for benign nonsecretory masses, since there is a high false-negative rate. An indication for biopsy is if the patient has a history of extra-adrenal malignancy; this will distinguish recurrence or metastatic disease from a benign mass. A final proviso: If biopsy is performed, make sure the adrenal mass is not a pheochromocytoma, as biopsy of a hormone-secreting neoplasm can lead to a hypertensive emergency.

Q: How do I determine whether the mass is hormone-secreting?

Although 80% are nonsecretory, you must still maintain a high index of suspicion so as not to miss a potentially problematic and fully treatable adenoma. A thorough history is essential in screening for hormonal excess arising from adrenal adenomas, since the signs and symptoms can be insidious. The three hormones secreted by adrenal adenomas are cortisol, aldosterone, and catecholamines (seen in Cushing syndrome, aldosterone-producing adenoma [APA], and pheochromocytoma, respectively).

It is important to note that Cushing syndrome has an insidious onset and can be easily missed. Hyperaldosteronism presents with hypertension (requiring several medications) and commonly hypokalemia. And pheochromocytoma can be “written off as” anxiety disorder, panic attack, or even hypoglycemia symptoms (especially if patients are treated for diabetes with agents that cause hypoglycemia). To help in your differential diagnosis of secretory adenomas, know that APA accounts for only 1%, and therefore the majority will secrete cortisol and (far less likely) catecholamines.

Q: What is the appropriate laboratory work-up?

The best simple screening test for hypercortisolemia is a 1-mg overnight dexamethasone suppression test. If this value is increased to ≥ 3 µg/dL, it should be followed up with a more sensitive test (a 24-hour urine for creatinine and free cortisol) to further assess for hypercortisolemia.

Patients thought to have a potential pheochromocytoma should undergo measurement of plasma fractionated metanephrines and normetanephrines or 24-hour urine for total metanephrines and fractionated catecholamines.

Finally, for patients with hypokalemia and hypertension or refractory hypertension requiring multiple (> 3) antihypertensive medications, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) should be obtained. A low PRA and a PAC > 15 ng/dL, along with a PAC/PRA ratio of > 20, is highly suggestive of an APA.

Q: What is the treatment and follow-up?

Here is a quick reference guide regarding surgical treatment and medical follow-up and surveillance:

• Adrenalectomy (pheochromocytoma, APA, Cushing syndrome): for masses 4 to 6 cm, consider surgery, especially if > 10 Hounsfield units; for masses > 6 cm, there is an increased risk for malignancy and surgery is required.

• Follow-up for low-suspicion, nonsecretory masses: abdominal CT 3 to 6 months after the initial scan, then annually for 1 to 2 years; hormonal evaluation and follow-up annually for 5 years, to evaluate for signs and symptoms of hormonal excess.

SUGGESTED READING
American Association of Clinical Endocrinologists/American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas. Endocr Pract. 2009;15(Suppl 1).

Management of the Clinically Inapparent Adrenal Mass (Incidentaloma). NIH State-of-the-Science Conference Statement; February 4-6, 2002.

Slawik M, Reincke M. Adrenal incidentalomas (Chapter 20). EndoText.com. www.endotext.org/adrenal/adrenal20/adrenal20.htm. Accessed October 12, 2012.

Fitzgerald PA, Goldfien A. Adrenal medulla. In: Greenspan F, Gardner D, eds. Basic and Clinical Endocrinology. 7th ed. McGraw-Hill: 2003;453-473.

The Washington Manual Endocrinology Specialty Consult. 2005;57-61, 71-84.

Endocrine Secrets. 4th ed. 2005;197-204, 241-252, 257-265.

Cleveland Clinic Endocrine & Metabolism Board Review. www.clevelandclinicmeded.com/live/courses/ann/endoreview/default.asp. Accessed October 12, 2012.

Maggie, 42, presents to the emergency department with chronic intermittent abdominal pain and bloating with constipation and occasional diarrhea. She denies fever, chills, nausea, vomiting, melana, bright red blood per rectum, or changes in stool caliper, and she says she otherwise feels well. 

Relevant lab and study results include: a comprehensive metabolic panel, complete blood count with differential, beta hCG (human chorionic gonadotropin), urinalysis, and amylase and lipase, all within normal limits; pregnancy test, negative; abdominal x-ray, within normal limits except increased stool in distal colon; and abdominal CT, 2.3-cm right adrenal mass and a Hounsfield measurement of 4 units.

Maggie has a right adrenal incidentaloma (incidentally discovered adenoma that was not in the differential diagnosis). Such findings have become all too often the case, due to the immediate access to and overutilization of high-resolution CT, MRI, and ultrasound. We are now seeing a significantly increased number of incidental adrenal lesions/masses discovered on images not intended to look for adrenal-related diseases (eg, Cushing syndrome, pheochromocytomas, and aldosterone-producing adenomas).

Q: How common are adrenal adenomas, and what must I consider?

Incidental adrenal adenomas are found on 4.4% of abdominal CTs, and in one autopsy series were discovered in 8.7%. Prevalence increases with age, with occurrence of < 1% in patients younger than 30 and about 7% for patients 70 or older.

Evaluation is based on two concerns: First, is the adrenal mass benign or malignant? Second, is the mass secretory or nonsecretory (non-hormone secreting) in nature?

The fortunate news about adrenal incidentalomas is that 80% are benign and nonsecretory, which provides immediate reassuring news to the patient. Examples of benign adrenal masses are: adenoma, lipoma, cyst, ganglioneuroma, hematoma, and infection (eg, tuberculosis, fungal).

The other encouraging statistic is that only 1:4,000 adrenal incidentalomas are malignant. Examples of malignant adrenal masses are: adrenocortical carcinoma, metastatic neoplasm, lymphoma, and malignant pheochromocytoma.

Q: Does adrenal adenoma size matter?

 Yes, the larger the size of the adenoma, the higher the association with malignancy. The guide below (based on CT findings) shows not only malignancy potential as it relates to size, but also the importance of Hounsfield units and when surgical intervention is recommended.

Imaging (CT scan)

< 4 cm: homogeneous mass with smooth borders and < 10 Hounsfield units; suggests benign mass (likelihood of malignancy, about 2%)

4 to 6 cm: follow closely, consider surgery (likelihood of malignancy, about 6%)

> 6 cm: surgery indicated (likelihood of malignancy, about 25%)

Some providers and patients inquire whether it is helpful or necessary to biopsy. It is generally not advisable to biopsy, especially if the findings are favorable for benign nonsecretory masses, since there is a high false-negative rate. An indication for biopsy is if the patient has a history of extra-adrenal malignancy; this will distinguish recurrence or metastatic disease from a benign mass. A final proviso: If biopsy is performed, make sure the adrenal mass is not a pheochromocytoma, as biopsy of a hormone-secreting neoplasm can lead to a hypertensive emergency.

Q: How do I determine whether the mass is hormone-secreting?

Although 80% are nonsecretory, you must still maintain a high index of suspicion so as not to miss a potentially problematic and fully treatable adenoma. A thorough history is essential in screening for hormonal excess arising from adrenal adenomas, since the signs and symptoms can be insidious. The three hormones secreted by adrenal adenomas are cortisol, aldosterone, and catecholamines (seen in Cushing syndrome, aldosterone-producing adenoma [APA], and pheochromocytoma, respectively).

It is important to note that Cushing syndrome has an insidious onset and can be easily missed. Hyperaldosteronism presents with hypertension (requiring several medications) and commonly hypokalemia. And pheochromocytoma can be “written off as” anxiety disorder, panic attack, or even hypoglycemia symptoms (especially if patients are treated for diabetes with agents that cause hypoglycemia). To help in your differential diagnosis of secretory adenomas, know that APA accounts for only 1%, and therefore the majority will secrete cortisol and (far less likely) catecholamines.

Q: What is the appropriate laboratory work-up?

The best simple screening test for hypercortisolemia is a 1-mg overnight dexamethasone suppression test. If this value is increased to ≥ 3 µg/dL, it should be followed up with a more sensitive test (a 24-hour urine for creatinine and free cortisol) to further assess for hypercortisolemia.

Patients thought to have a potential pheochromocytoma should undergo measurement of plasma fractionated metanephrines and normetanephrines or 24-hour urine for total metanephrines and fractionated catecholamines.

Finally, for patients with hypokalemia and hypertension or refractory hypertension requiring multiple (> 3) antihypertensive medications, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) should be obtained. A low PRA and a PAC > 15 ng/dL, along with a PAC/PRA ratio of > 20, is highly suggestive of an APA.

Q: What is the treatment and follow-up?

Here is a quick reference guide regarding surgical treatment and medical follow-up and surveillance:

• Adrenalectomy (pheochromocytoma, APA, Cushing syndrome): for masses 4 to 6 cm, consider surgery, especially if > 10 Hounsfield units; for masses > 6 cm, there is an increased risk for malignancy and surgery is required.

• Follow-up for low-suspicion, nonsecretory masses: abdominal CT 3 to 6 months after the initial scan, then annually for 1 to 2 years; hormonal evaluation and follow-up annually for 5 years, to evaluate for signs and symptoms of hormonal excess.

SUGGESTED READING
American Association of Clinical Endocrinologists/American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas. Endocr Pract. 2009;15(Suppl 1).

Management of the Clinically Inapparent Adrenal Mass (Incidentaloma). NIH State-of-the-Science Conference Statement; February 4-6, 2002.

Slawik M, Reincke M. Adrenal incidentalomas (Chapter 20). EndoText.com. www.endotext.org/adrenal/adrenal20/adrenal20.htm. Accessed October 12, 2012.

Fitzgerald PA, Goldfien A. Adrenal medulla. In: Greenspan F, Gardner D, eds. Basic and Clinical Endocrinology. 7th ed. McGraw-Hill: 2003;453-473.

The Washington Manual Endocrinology Specialty Consult. 2005;57-61, 71-84.

Endocrine Secrets. 4th ed. 2005;197-204, 241-252, 257-265.

Cleveland Clinic Endocrine & Metabolism Board Review. www.clevelandclinicmeded.com/live/courses/ann/endoreview/default.asp. Accessed October 12, 2012.

Maggie, 42, presents to the emergency department with chronic intermittent abdominal pain and bloating with constipation and occasional diarrhea. She denies fever, chills, nausea, vomiting, melana, bright red blood per rectum, or changes in stool caliper, and she says she otherwise feels well. 

Relevant lab and study results include: a comprehensive metabolic panel, complete blood count with differential, beta hCG (human chorionic gonadotropin), urinalysis, and amylase and lipase, all within normal limits; pregnancy test, negative; abdominal x-ray, within normal limits except increased stool in distal colon; and abdominal CT, 2.3-cm right adrenal mass and a Hounsfield measurement of 4 units.

Maggie has a right adrenal incidentaloma (incidentally discovered adenoma that was not in the differential diagnosis). Such findings have become all too often the case, due to the immediate access to and overutilization of high-resolution CT, MRI, and ultrasound. We are now seeing a significantly increased number of incidental adrenal lesions/masses discovered on images not intended to look for adrenal-related diseases (eg, Cushing syndrome, pheochromocytomas, and aldosterone-producing adenomas).

Q: How common are adrenal adenomas, and what must I consider?

Incidental adrenal adenomas are found on 4.4% of abdominal CTs, and in one autopsy series were discovered in 8.7%. Prevalence increases with age, with occurrence of < 1% in patients younger than 30 and about 7% for patients 70 or older.

Evaluation is based on two concerns: First, is the adrenal mass benign or malignant? Second, is the mass secretory or nonsecretory (non-hormone secreting) in nature?

The fortunate news about adrenal incidentalomas is that 80% are benign and nonsecretory, which provides immediate reassuring news to the patient. Examples of benign adrenal masses are: adenoma, lipoma, cyst, ganglioneuroma, hematoma, and infection (eg, tuberculosis, fungal).

The other encouraging statistic is that only 1:4,000 adrenal incidentalomas are malignant. Examples of malignant adrenal masses are: adrenocortical carcinoma, metastatic neoplasm, lymphoma, and malignant pheochromocytoma.

Q: Does adrenal adenoma size matter?

 Yes, the larger the size of the adenoma, the higher the association with malignancy. The guide below (based on CT findings) shows not only malignancy potential as it relates to size, but also the importance of Hounsfield units and when surgical intervention is recommended.

Imaging (CT scan)

< 4 cm: homogeneous mass with smooth borders and < 10 Hounsfield units; suggests benign mass (likelihood of malignancy, about 2%)

4 to 6 cm: follow closely, consider surgery (likelihood of malignancy, about 6%)

> 6 cm: surgery indicated (likelihood of malignancy, about 25%)

Some providers and patients inquire whether it is helpful or necessary to biopsy. It is generally not advisable to biopsy, especially if the findings are favorable for benign nonsecretory masses, since there is a high false-negative rate. An indication for biopsy is if the patient has a history of extra-adrenal malignancy; this will distinguish recurrence or metastatic disease from a benign mass. A final proviso: If biopsy is performed, make sure the adrenal mass is not a pheochromocytoma, as biopsy of a hormone-secreting neoplasm can lead to a hypertensive emergency.

Q: How do I determine whether the mass is hormone-secreting?

Although 80% are nonsecretory, you must still maintain a high index of suspicion so as not to miss a potentially problematic and fully treatable adenoma. A thorough history is essential in screening for hormonal excess arising from adrenal adenomas, since the signs and symptoms can be insidious. The three hormones secreted by adrenal adenomas are cortisol, aldosterone, and catecholamines (seen in Cushing syndrome, aldosterone-producing adenoma [APA], and pheochromocytoma, respectively).

It is important to note that Cushing syndrome has an insidious onset and can be easily missed. Hyperaldosteronism presents with hypertension (requiring several medications) and commonly hypokalemia. And pheochromocytoma can be “written off as” anxiety disorder, panic attack, or even hypoglycemia symptoms (especially if patients are treated for diabetes with agents that cause hypoglycemia). To help in your differential diagnosis of secretory adenomas, know that APA accounts for only 1%, and therefore the majority will secrete cortisol and (far less likely) catecholamines.

Q: What is the appropriate laboratory work-up?

The best simple screening test for hypercortisolemia is a 1-mg overnight dexamethasone suppression test. If this value is increased to ≥ 3 µg/dL, it should be followed up with a more sensitive test (a 24-hour urine for creatinine and free cortisol) to further assess for hypercortisolemia.

Patients thought to have a potential pheochromocytoma should undergo measurement of plasma fractionated metanephrines and normetanephrines or 24-hour urine for total metanephrines and fractionated catecholamines.

Finally, for patients with hypokalemia and hypertension or refractory hypertension requiring multiple (> 3) antihypertensive medications, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) should be obtained. A low PRA and a PAC > 15 ng/dL, along with a PAC/PRA ratio of > 20, is highly suggestive of an APA.

Q: What is the treatment and follow-up?

Here is a quick reference guide regarding surgical treatment and medical follow-up and surveillance:

• Adrenalectomy (pheochromocytoma, APA, Cushing syndrome): for masses 4 to 6 cm, consider surgery, especially if > 10 Hounsfield units; for masses > 6 cm, there is an increased risk for malignancy and surgery is required.

• Follow-up for low-suspicion, nonsecretory masses: abdominal CT 3 to 6 months after the initial scan, then annually for 1 to 2 years; hormonal evaluation and follow-up annually for 5 years, to evaluate for signs and symptoms of hormonal excess.

SUGGESTED READING
American Association of Clinical Endocrinologists/American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas. Endocr Pract. 2009;15(Suppl 1).

Management of the Clinically Inapparent Adrenal Mass (Incidentaloma). NIH State-of-the-Science Conference Statement; February 4-6, 2002.

Slawik M, Reincke M. Adrenal incidentalomas (Chapter 20). EndoText.com. www.endotext.org/adrenal/adrenal20/adrenal20.htm. Accessed October 12, 2012.

Fitzgerald PA, Goldfien A. Adrenal medulla. In: Greenspan F, Gardner D, eds. Basic and Clinical Endocrinology. 7th ed. McGraw-Hill: 2003;453-473.

The Washington Manual Endocrinology Specialty Consult. 2005;57-61, 71-84.

Endocrine Secrets. 4th ed. 2005;197-204, 241-252, 257-265.

Cleveland Clinic Endocrine & Metabolism Board Review. www.clevelandclinicmeded.com/live/courses/ann/endoreview/default.asp. Accessed October 12, 2012.

When an atypical presentation is missed

A 50-YEAR-OLD MORBIDLY OBESE MAN went to his family physician with complaints of back pain radiating to the chest, episodic shortness of breath, and diaphoresis. He had a history of uncontrolled high cholesterol. An electrocardiogram showed a Q wave in an inferior lead, which the physician attributed to an old infarct. The doctor didn’t order cardiac enzymes because his office couldn’t do the test.

The physician discharged the patient with a diagnosis of chest pain and a prescription for acetaminophen and hydrocodone. He was scheduled to see a cardiologist in 10 days, but no further cardiology workup was done.

The man died an hour later.

PLAINTIFF’S CLAIM The doctor was negligent in failing to recognize acute coronary syndrome resulting from obstructive coronary artery disease.

THE DEFENSE The patient was discharged in stable condition; cardiac arrest so soon after discharge increased the likelihood that the patient would have suffered sudden cardiac death even if he’d received emergency treatment.

VERDICT $825,000 Virginia settlement.

COMMENT Common, serious problems can present in atypical ways. A high index of suspicion for coronary artery disease in high-risk patients with thoracic pain and shortness of breath—as well as a rapid, thorough evaluation—should keep you out of court (and your patients alive).

Treatment delayed while infection spins out of control

VOMITING, DIARRHEA, AND PAIN AND SWELLING IN THE RIGHT HAND led to an ambulance trip to the emergency department (ED) for a 31-year-old woman. The ED physician diagnosed cellulitis and sepsis. Later that day, the patient was admitted to the intensive care unit, where the admitting physician noted lethargy and confusion, tachycardia, and blueness of the middle and ring fingers on the woman’s right hand. Her medical record suggested that she might have been bitten by a spider.

The patient spent the next 3 days in the ICU in deteriorating condition. She was then transferred to another hospital for treatment of necrotizing fasciitis. She underwent a number of surgeries, including amputation of her right middle and ring fingers, which resulted in significant scarring and deformity of her right hand and forearm.

PLAINTIFF’S CLAIM The defendants were negligent in failing to diagnose necrotizing fasciitis promptly.

THE DEFENSE The defendants who didn’t settle denied any negligence.

VERDICT $80,000 Indiana settlement with the defendant hospital and 1 physician; Indiana defense verdict for the other defendants.

COMMENT When serious infections don’t resolve in a timely manner, expert consultation is imperative.

Inattention to history dooms patient to repeat it

HEADACHES, FEVER, CHILLS, AND JOINT AND MUSCLE PAIN prompted a 42-year-old man to visit his medical group. He told the nurse practitioner (NP) who examined him that his mother had died of a ruptured cerebral aneurysm. The NP diagnosed a viral syndrome, ordered blood tests, and sent the patient home with prescriptions for antibiotics and pain medication. The patient didn’t undergo a neurologic examination.

About 2 weeks later, while continuing to suffer from headaches, the man collapsed and was found unresponsive. A computed tomography scan of his brain showed a subarachnoid hemorrhage and intercerebral hematoma. Further tests revealed a ruptured complex aneurysm, the cause of the hemorrhage. Despite aggressive treatment, the patient fell into a coma and died 3 months later.

PLAINTIFF’S CLAIM The NP should have realized that the patient was at high risk of an aneurysm.

THE DEFENSE No information about the defense is available.

VERDICT $1.5 million New Jersey settlement.

COMMENT I provided expert opinion in a similar case a couple of years ago. The lesson: Pay attention to the family history!

Persistent breast lumps, but no biopsy

ABOUT 3 YEARS AFTER GIVING BIRTH, a 38-year-old woman, who was still breastfeeding, went to her primary care physician complaining of pain, a dime-sized lump in her breast, and discharge from the nipple. The patient’s 2-year-old breast implants limited examination by the nurse practitioner (NP) who saw her. Galactorrhea was diagnosed and the woman was told to stop breastfeeding, apply ice packs, and come back in 2 weeks.

When the patient returned, her only remaining complaint was the lump, which the primary care physician attributed to mastitis. At a routine check-up 5 months later, the patient continued to complain of breast lumps. No breast exam was done, but the woman was referred to a gynecologist. An appointment for a breast ultrasound was scheduled for later in the month, but the patient said she didn’t receive notification of the date.

Metastatic breast cancer was subsequently diagnosed, and the woman died about 3 years later.

PLAINTIFF’S CLAIM The NP and primary care physician should have recommended a biopsy sooner.

THE DEFENSE The care given was proper; an earlier diagnosis wouldn’t have changed the outcome.

VERDICT $750,000 Massachusetts settlement.

COMMENT Failure to recommend biopsy of breast lumps is a leading cause of malpractice cases against family physicians. All persistent breast lumps require referral for biopsy— regardless of the patient’s age.

A red flag that was ignored for too long

A MAN IN HIS EARLY 30S consulted an orthopedist for mid-back pain. The doctor took radiographs of the man’s lower back and reported that he saw nothing amiss. When the man returned 3 months later complaining of the same kind of pain, the orthopedist examined him, prescribed a muscle relaxant, and sent him for physical therapy. The physician did not take any radiographs.

Four months later, the patient came back with pain in his mid-back and ribs. The orthopedist ordered radiographs of the ribs, which were read as normal.

After 18 months, the patient consulted another orthopedist, who ordered a magnetic resonance imaging scan and diagnosed a spinal plasmacytoma at levels T9 to T11. The tumor had destroyed some vertebrae and was compressing the spinal cord.

The patient underwent surgery to remove the tumor and insert screws from T6 to L2 to stabilize the spine. He wore a brace around his torso for months and had a bone marrow transplant. The patient couldn’t return to work.

PLAINTIFF’S CLAIM The tumor was clearly visible on the radiographs taken at the patient’s third visit to the first orthopedist; thoracic spine radiographs should have been taken at the previous 2 visits.

THE DEFENSE No information about the defense is available.

VERDICT $875,000 New Jersey settlement.

COMMENT Current guidelines recommend a red flags approach to imaging. This patient had a red flag—unremitting pain. When back pain persists unabated, it’s time for a thorough evaluation.

When an atypical presentation is missed

A 50-YEAR-OLD MORBIDLY OBESE MAN went to his family physician with complaints of back pain radiating to the chest, episodic shortness of breath, and diaphoresis. He had a history of uncontrolled high cholesterol. An electrocardiogram showed a Q wave in an inferior lead, which the physician attributed to an old infarct. The doctor didn’t order cardiac enzymes because his office couldn’t do the test.

The physician discharged the patient with a diagnosis of chest pain and a prescription for acetaminophen and hydrocodone. He was scheduled to see a cardiologist in 10 days, but no further cardiology workup was done.

The man died an hour later.

PLAINTIFF’S CLAIM The doctor was negligent in failing to recognize acute coronary syndrome resulting from obstructive coronary artery disease.

THE DEFENSE The patient was discharged in stable condition; cardiac arrest so soon after discharge increased the likelihood that the patient would have suffered sudden cardiac death even if he’d received emergency treatment.

VERDICT $825,000 Virginia settlement.

COMMENT Common, serious problems can present in atypical ways. A high index of suspicion for coronary artery disease in high-risk patients with thoracic pain and shortness of breath—as well as a rapid, thorough evaluation—should keep you out of court (and your patients alive).

Treatment delayed while infection spins out of control

VOMITING, DIARRHEA, AND PAIN AND SWELLING IN THE RIGHT HAND led to an ambulance trip to the emergency department (ED) for a 31-year-old woman. The ED physician diagnosed cellulitis and sepsis. Later that day, the patient was admitted to the intensive care unit, where the admitting physician noted lethargy and confusion, tachycardia, and blueness of the middle and ring fingers on the woman’s right hand. Her medical record suggested that she might have been bitten by a spider.

The patient spent the next 3 days in the ICU in deteriorating condition. She was then transferred to another hospital for treatment of necrotizing fasciitis. She underwent a number of surgeries, including amputation of her right middle and ring fingers, which resulted in significant scarring and deformity of her right hand and forearm.

PLAINTIFF’S CLAIM The defendants were negligent in failing to diagnose necrotizing fasciitis promptly.

THE DEFENSE The defendants who didn’t settle denied any negligence.

VERDICT $80,000 Indiana settlement with the defendant hospital and 1 physician; Indiana defense verdict for the other defendants.

COMMENT When serious infections don’t resolve in a timely manner, expert consultation is imperative.

Inattention to history dooms patient to repeat it

HEADACHES, FEVER, CHILLS, AND JOINT AND MUSCLE PAIN prompted a 42-year-old man to visit his medical group. He told the nurse practitioner (NP) who examined him that his mother had died of a ruptured cerebral aneurysm. The NP diagnosed a viral syndrome, ordered blood tests, and sent the patient home with prescriptions for antibiotics and pain medication. The patient didn’t undergo a neurologic examination.

About 2 weeks later, while continuing to suffer from headaches, the man collapsed and was found unresponsive. A computed tomography scan of his brain showed a subarachnoid hemorrhage and intercerebral hematoma. Further tests revealed a ruptured complex aneurysm, the cause of the hemorrhage. Despite aggressive treatment, the patient fell into a coma and died 3 months later.

PLAINTIFF’S CLAIM The NP should have realized that the patient was at high risk of an aneurysm.

THE DEFENSE No information about the defense is available.

VERDICT $1.5 million New Jersey settlement.

COMMENT I provided expert opinion in a similar case a couple of years ago. The lesson: Pay attention to the family history!

Persistent breast lumps, but no biopsy

ABOUT 3 YEARS AFTER GIVING BIRTH, a 38-year-old woman, who was still breastfeeding, went to her primary care physician complaining of pain, a dime-sized lump in her breast, and discharge from the nipple. The patient’s 2-year-old breast implants limited examination by the nurse practitioner (NP) who saw her. Galactorrhea was diagnosed and the woman was told to stop breastfeeding, apply ice packs, and come back in 2 weeks.

When the patient returned, her only remaining complaint was the lump, which the primary care physician attributed to mastitis. At a routine check-up 5 months later, the patient continued to complain of breast lumps. No breast exam was done, but the woman was referred to a gynecologist. An appointment for a breast ultrasound was scheduled for later in the month, but the patient said she didn’t receive notification of the date.

Metastatic breast cancer was subsequently diagnosed, and the woman died about 3 years later.

PLAINTIFF’S CLAIM The NP and primary care physician should have recommended a biopsy sooner.

THE DEFENSE The care given was proper; an earlier diagnosis wouldn’t have changed the outcome.

VERDICT $750,000 Massachusetts settlement.

COMMENT Failure to recommend biopsy of breast lumps is a leading cause of malpractice cases against family physicians. All persistent breast lumps require referral for biopsy— regardless of the patient’s age.

A red flag that was ignored for too long

A MAN IN HIS EARLY 30S consulted an orthopedist for mid-back pain. The doctor took radiographs of the man’s lower back and reported that he saw nothing amiss. When the man returned 3 months later complaining of the same kind of pain, the orthopedist examined him, prescribed a muscle relaxant, and sent him for physical therapy. The physician did not take any radiographs.

Four months later, the patient came back with pain in his mid-back and ribs. The orthopedist ordered radiographs of the ribs, which were read as normal.

After 18 months, the patient consulted another orthopedist, who ordered a magnetic resonance imaging scan and diagnosed a spinal plasmacytoma at levels T9 to T11. The tumor had destroyed some vertebrae and was compressing the spinal cord.

The patient underwent surgery to remove the tumor and insert screws from T6 to L2 to stabilize the spine. He wore a brace around his torso for months and had a bone marrow transplant. The patient couldn’t return to work.

PLAINTIFF’S CLAIM The tumor was clearly visible on the radiographs taken at the patient’s third visit to the first orthopedist; thoracic spine radiographs should have been taken at the previous 2 visits.

THE DEFENSE No information about the defense is available.

VERDICT $875,000 New Jersey settlement.

COMMENT Current guidelines recommend a red flags approach to imaging. This patient had a red flag—unremitting pain. When back pain persists unabated, it’s time for a thorough evaluation.

When an atypical presentation is missed

A 50-YEAR-OLD MORBIDLY OBESE MAN went to his family physician with complaints of back pain radiating to the chest, episodic shortness of breath, and diaphoresis. He had a history of uncontrolled high cholesterol. An electrocardiogram showed a Q wave in an inferior lead, which the physician attributed to an old infarct. The doctor didn’t order cardiac enzymes because his office couldn’t do the test.

The physician discharged the patient with a diagnosis of chest pain and a prescription for acetaminophen and hydrocodone. He was scheduled to see a cardiologist in 10 days, but no further cardiology workup was done.

The man died an hour later.

PLAINTIFF’S CLAIM The doctor was negligent in failing to recognize acute coronary syndrome resulting from obstructive coronary artery disease.

THE DEFENSE The patient was discharged in stable condition; cardiac arrest so soon after discharge increased the likelihood that the patient would have suffered sudden cardiac death even if he’d received emergency treatment.

VERDICT $825,000 Virginia settlement.

COMMENT Common, serious problems can present in atypical ways. A high index of suspicion for coronary artery disease in high-risk patients with thoracic pain and shortness of breath—as well as a rapid, thorough evaluation—should keep you out of court (and your patients alive).

Treatment delayed while infection spins out of control

VOMITING, DIARRHEA, AND PAIN AND SWELLING IN THE RIGHT HAND led to an ambulance trip to the emergency department (ED) for a 31-year-old woman. The ED physician diagnosed cellulitis and sepsis. Later that day, the patient was admitted to the intensive care unit, where the admitting physician noted lethargy and confusion, tachycardia, and blueness of the middle and ring fingers on the woman’s right hand. Her medical record suggested that she might have been bitten by a spider.

The patient spent the next 3 days in the ICU in deteriorating condition. She was then transferred to another hospital for treatment of necrotizing fasciitis. She underwent a number of surgeries, including amputation of her right middle and ring fingers, which resulted in significant scarring and deformity of her right hand and forearm.

PLAINTIFF’S CLAIM The defendants were negligent in failing to diagnose necrotizing fasciitis promptly.

THE DEFENSE The defendants who didn’t settle denied any negligence.

VERDICT $80,000 Indiana settlement with the defendant hospital and 1 physician; Indiana defense verdict for the other defendants.

COMMENT When serious infections don’t resolve in a timely manner, expert consultation is imperative.

Inattention to history dooms patient to repeat it

HEADACHES, FEVER, CHILLS, AND JOINT AND MUSCLE PAIN prompted a 42-year-old man to visit his medical group. He told the nurse practitioner (NP) who examined him that his mother had died of a ruptured cerebral aneurysm. The NP diagnosed a viral syndrome, ordered blood tests, and sent the patient home with prescriptions for antibiotics and pain medication. The patient didn’t undergo a neurologic examination.

About 2 weeks later, while continuing to suffer from headaches, the man collapsed and was found unresponsive. A computed tomography scan of his brain showed a subarachnoid hemorrhage and intercerebral hematoma. Further tests revealed a ruptured complex aneurysm, the cause of the hemorrhage. Despite aggressive treatment, the patient fell into a coma and died 3 months later.

PLAINTIFF’S CLAIM The NP should have realized that the patient was at high risk of an aneurysm.

THE DEFENSE No information about the defense is available.

VERDICT $1.5 million New Jersey settlement.

COMMENT I provided expert opinion in a similar case a couple of years ago. The lesson: Pay attention to the family history!

Persistent breast lumps, but no biopsy

ABOUT 3 YEARS AFTER GIVING BIRTH, a 38-year-old woman, who was still breastfeeding, went to her primary care physician complaining of pain, a dime-sized lump in her breast, and discharge from the nipple. The patient’s 2-year-old breast implants limited examination by the nurse practitioner (NP) who saw her. Galactorrhea was diagnosed and the woman was told to stop breastfeeding, apply ice packs, and come back in 2 weeks.

When the patient returned, her only remaining complaint was the lump, which the primary care physician attributed to mastitis. At a routine check-up 5 months later, the patient continued to complain of breast lumps. No breast exam was done, but the woman was referred to a gynecologist. An appointment for a breast ultrasound was scheduled for later in the month, but the patient said she didn’t receive notification of the date.

Metastatic breast cancer was subsequently diagnosed, and the woman died about 3 years later.

PLAINTIFF’S CLAIM The NP and primary care physician should have recommended a biopsy sooner.

THE DEFENSE The care given was proper; an earlier diagnosis wouldn’t have changed the outcome.

VERDICT $750,000 Massachusetts settlement.

COMMENT Failure to recommend biopsy of breast lumps is a leading cause of malpractice cases against family physicians. All persistent breast lumps require referral for biopsy— regardless of the patient’s age.

A red flag that was ignored for too long

A MAN IN HIS EARLY 30S consulted an orthopedist for mid-back pain. The doctor took radiographs of the man’s lower back and reported that he saw nothing amiss. When the man returned 3 months later complaining of the same kind of pain, the orthopedist examined him, prescribed a muscle relaxant, and sent him for physical therapy. The physician did not take any radiographs.

Four months later, the patient came back with pain in his mid-back and ribs. The orthopedist ordered radiographs of the ribs, which were read as normal.

After 18 months, the patient consulted another orthopedist, who ordered a magnetic resonance imaging scan and diagnosed a spinal plasmacytoma at levels T9 to T11. The tumor had destroyed some vertebrae and was compressing the spinal cord.

The patient underwent surgery to remove the tumor and insert screws from T6 to L2 to stabilize the spine. He wore a brace around his torso for months and had a bone marrow transplant. The patient couldn’t return to work.

PLAINTIFF’S CLAIM The tumor was clearly visible on the radiographs taken at the patient’s third visit to the first orthopedist; thoracic spine radiographs should have been taken at the previous 2 visits.

THE DEFENSE No information about the defense is available.

VERDICT $875,000 New Jersey settlement.

COMMENT Current guidelines recommend a red flags approach to imaging. This patient had a red flag—unremitting pain. When back pain persists unabated, it’s time for a thorough evaluation.

ILLUSTRATIVE CASE

A 65-year-old patient has been taking lorazepam for insomnia for more than a year. You are concerned about her ongoing use of the benzodiazepine and want to wean her from the medication. What strategies can you use to decrease, or eliminate, her use of the drug?

Benzodiazepines are commonly used medications, with an estimated 12-month prevalence of use of 8.6% in the United States.² While short-term use of these antianxiety medications can be effective, long-term use (defined as regular use for >3 months) is associated with significant risk.

Abuse linked to chronic use
Prescription drug abuse has recently become the nation’s leading cause of accidental death, overtaking motor vehicle accidents.³ And tranquilizers, including benzodiazepines, are the second most abused prescription medication, after pain relievers.⁴ In addition to dependence and withdrawal, chronic use of benzodiazepines is associated with daytime somnolence, blunted reflexes, memory loss, cognitive impairment, and an increased risk of falls and fractures—particularly in older patients.⁵

Reducing long-term use of benzodiazepines in a primary care setting is important but challenging. Until recently, most of the successful strategies reported were resource intensive and required multiple office visits.⁶

STUDY SUMMARY: Brief interventions are often effective

This study was a meta-analysis of randomized controlled trials in which “minimal interventions” were compared with usual care for their effectiveness in reducing or eliminating benzodiazepine use in primary care patients. A minimal intervention was defined as a letter, self-help information, or short consultation with a primary care provider. In each case, the message to the patient included (a) an expression of concern about the patient’s long-term use of the medication, (b) information about the potential adverse effects of the medication, and (c) advice on how to gradually reduce or stop using it.

Three studies met the inclusion criteria for randomization, blinding, and analysis by intention-to-treat.^7-9 All 3 (n=615) had a 6-month follow-up period, a higher proportion of women (>60%), and participants with a mean age >60 years. Few patients were lost to follow-up; withdrawal rates were low and similar in all 3 studies. Each study compared a letter with usual care; 2 of the 3 had a third arm that included both a letter and a short consultation.

Pooled results from the studies showed twice the reduction in benzodiazepine use in the intervention groups compared with the control groups (risk ratio [RR]=2.04; 95% confidence interval [CI], 1.5-2.8; P< .001). The RR for cessation of benzodiazepine use was 2.3 (95% CI, 1.3-4.2; P= .003). The number needed to treat for a reduction or cessation of use was 12. The studies reported benzodiazepine reduction rates of 20% to 35% in the intervention groups vs 6% to 15% in the usual care groups.^7-9 There appeared to be no additional benefit to adding the brief consultation compared with the letter alone.

WHAT’S NEW?: This strategy is easy to implement

While many methods to reduce benzodiazepine use have been studied, most involved levels of skill and resources that are not feasible for widespread use. This study found that a letter, stating the risks of continued use of the medication and providing a weaning schedule and tips for handling withdrawal, can be effective in reducing chronic use in a small but significant part of the population.

CAVEATS: Effects of withdrawal went unaddressed

The study did not adequately address the adverse effects of withdrawal from benzodiazepines, with one of the studies reporting significantly worse qualitative (but not quantitative) withdrawal symptoms at 6 months.⁷ This is of particular concern, as withdrawal symptoms are associated with the potential for relapse and concomitant abuse of other drugs and alcohol. We recommend that primary care physicians screen for substance abuse prior to the intervention and arrange for adequate follow-up.

All 3 studies in the meta-analysis lasted 6 months; no longer-term outcomes were reported. In addition, the study did not yield enough information to identify patients who would be most likely to respond to this brief intervention.

CHALLENGES TO IMPLEMENTATION: Determining which patients to target

Identifying patients who are appropriate candidates for this brief intervention and providing adequate monitoring for adverse effects of withdrawal are the main challenges of this practice changer. Nonetheless, chronic benzodiazepine use is of considerable concern, and we believe that this is a useful, and manageable intervention.

Acknowledgement

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

ILLUSTRATIVE CASE

A 65-year-old patient has been taking lorazepam for insomnia for more than a year. You are concerned about her ongoing use of the benzodiazepine and want to wean her from the medication. What strategies can you use to decrease, or eliminate, her use of the drug?

Benzodiazepines are commonly used medications, with an estimated 12-month prevalence of use of 8.6% in the United States.² While short-term use of these antianxiety medications can be effective, long-term use (defined as regular use for >3 months) is associated with significant risk.

Abuse linked to chronic use
Prescription drug abuse has recently become the nation’s leading cause of accidental death, overtaking motor vehicle accidents.³ And tranquilizers, including benzodiazepines, are the second most abused prescription medication, after pain relievers.⁴ In addition to dependence and withdrawal, chronic use of benzodiazepines is associated with daytime somnolence, blunted reflexes, memory loss, cognitive impairment, and an increased risk of falls and fractures—particularly in older patients.⁵

Reducing long-term use of benzodiazepines in a primary care setting is important but challenging. Until recently, most of the successful strategies reported were resource intensive and required multiple office visits.⁶

STUDY SUMMARY: Brief interventions are often effective

This study was a meta-analysis of randomized controlled trials in which “minimal interventions” were compared with usual care for their effectiveness in reducing or eliminating benzodiazepine use in primary care patients. A minimal intervention was defined as a letter, self-help information, or short consultation with a primary care provider. In each case, the message to the patient included (a) an expression of concern about the patient’s long-term use of the medication, (b) information about the potential adverse effects of the medication, and (c) advice on how to gradually reduce or stop using it.

Three studies met the inclusion criteria for randomization, blinding, and analysis by intention-to-treat.^7-9 All 3 (n=615) had a 6-month follow-up period, a higher proportion of women (>60%), and participants with a mean age >60 years. Few patients were lost to follow-up; withdrawal rates were low and similar in all 3 studies. Each study compared a letter with usual care; 2 of the 3 had a third arm that included both a letter and a short consultation.

Pooled results from the studies showed twice the reduction in benzodiazepine use in the intervention groups compared with the control groups (risk ratio [RR]=2.04; 95% confidence interval [CI], 1.5-2.8; P< .001). The RR for cessation of benzodiazepine use was 2.3 (95% CI, 1.3-4.2; P= .003). The number needed to treat for a reduction or cessation of use was 12. The studies reported benzodiazepine reduction rates of 20% to 35% in the intervention groups vs 6% to 15% in the usual care groups.^7-9 There appeared to be no additional benefit to adding the brief consultation compared with the letter alone.

WHAT’S NEW?: This strategy is easy to implement

While many methods to reduce benzodiazepine use have been studied, most involved levels of skill and resources that are not feasible for widespread use. This study found that a letter, stating the risks of continued use of the medication and providing a weaning schedule and tips for handling withdrawal, can be effective in reducing chronic use in a small but significant part of the population.

CAVEATS: Effects of withdrawal went unaddressed

The study did not adequately address the adverse effects of withdrawal from benzodiazepines, with one of the studies reporting significantly worse qualitative (but not quantitative) withdrawal symptoms at 6 months.⁷ This is of particular concern, as withdrawal symptoms are associated with the potential for relapse and concomitant abuse of other drugs and alcohol. We recommend that primary care physicians screen for substance abuse prior to the intervention and arrange for adequate follow-up.

All 3 studies in the meta-analysis lasted 6 months; no longer-term outcomes were reported. In addition, the study did not yield enough information to identify patients who would be most likely to respond to this brief intervention.

CHALLENGES TO IMPLEMENTATION: Determining which patients to target

Identifying patients who are appropriate candidates for this brief intervention and providing adequate monitoring for adverse effects of withdrawal are the main challenges of this practice changer. Nonetheless, chronic benzodiazepine use is of considerable concern, and we believe that this is a useful, and manageable intervention.

Acknowledgement

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

ILLUSTRATIVE CASE

A 65-year-old patient has been taking lorazepam for insomnia for more than a year. You are concerned about her ongoing use of the benzodiazepine and want to wean her from the medication. What strategies can you use to decrease, or eliminate, her use of the drug?

Benzodiazepines are commonly used medications, with an estimated 12-month prevalence of use of 8.6% in the United States.² While short-term use of these antianxiety medications can be effective, long-term use (defined as regular use for >3 months) is associated with significant risk.

Abuse linked to chronic use
Prescription drug abuse has recently become the nation’s leading cause of accidental death, overtaking motor vehicle accidents.³ And tranquilizers, including benzodiazepines, are the second most abused prescription medication, after pain relievers.⁴ In addition to dependence and withdrawal, chronic use of benzodiazepines is associated with daytime somnolence, blunted reflexes, memory loss, cognitive impairment, and an increased risk of falls and fractures—particularly in older patients.⁵

Reducing long-term use of benzodiazepines in a primary care setting is important but challenging. Until recently, most of the successful strategies reported were resource intensive and required multiple office visits.⁶

STUDY SUMMARY: Brief interventions are often effective

This study was a meta-analysis of randomized controlled trials in which “minimal interventions” were compared with usual care for their effectiveness in reducing or eliminating benzodiazepine use in primary care patients. A minimal intervention was defined as a letter, self-help information, or short consultation with a primary care provider. In each case, the message to the patient included (a) an expression of concern about the patient’s long-term use of the medication, (b) information about the potential adverse effects of the medication, and (c) advice on how to gradually reduce or stop using it.

Three studies met the inclusion criteria for randomization, blinding, and analysis by intention-to-treat.^7-9 All 3 (n=615) had a 6-month follow-up period, a higher proportion of women (>60%), and participants with a mean age >60 years. Few patients were lost to follow-up; withdrawal rates were low and similar in all 3 studies. Each study compared a letter with usual care; 2 of the 3 had a third arm that included both a letter and a short consultation.

Pooled results from the studies showed twice the reduction in benzodiazepine use in the intervention groups compared with the control groups (risk ratio [RR]=2.04; 95% confidence interval [CI], 1.5-2.8; P< .001). The RR for cessation of benzodiazepine use was 2.3 (95% CI, 1.3-4.2; P= .003). The number needed to treat for a reduction or cessation of use was 12. The studies reported benzodiazepine reduction rates of 20% to 35% in the intervention groups vs 6% to 15% in the usual care groups.^7-9 There appeared to be no additional benefit to adding the brief consultation compared with the letter alone.

WHAT’S NEW?: This strategy is easy to implement

While many methods to reduce benzodiazepine use have been studied, most involved levels of skill and resources that are not feasible for widespread use. This study found that a letter, stating the risks of continued use of the medication and providing a weaning schedule and tips for handling withdrawal, can be effective in reducing chronic use in a small but significant part of the population.

CAVEATS: Effects of withdrawal went unaddressed

The study did not adequately address the adverse effects of withdrawal from benzodiazepines, with one of the studies reporting significantly worse qualitative (but not quantitative) withdrawal symptoms at 6 months.⁷ This is of particular concern, as withdrawal symptoms are associated with the potential for relapse and concomitant abuse of other drugs and alcohol. We recommend that primary care physicians screen for substance abuse prior to the intervention and arrange for adequate follow-up.

All 3 studies in the meta-analysis lasted 6 months; no longer-term outcomes were reported. In addition, the study did not yield enough information to identify patients who would be most likely to respond to this brief intervention.

CHALLENGES TO IMPLEMENTATION: Determining which patients to target

Identifying patients who are appropriate candidates for this brief intervention and providing adequate monitoring for adverse effects of withdrawal are the main challenges of this practice changer. Nonetheless, chronic benzodiazepine use is of considerable concern, and we believe that this is a useful, and manageable intervention.

Acknowledgement

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

I am delighted by the commonsense approach Drs. Weiss and Lee have taken in advising us to be wary of prescribing—or continuing—too many medications for our older patients (“Is your patient taking too many pills?”). Frankly, this advice applies to all patients, regardless of their age, and to virtually all family physicians. We all have stories about medication overuse. I’d like to tell you 2 of mine.

When Mrs. S, a 68-year-old patient, came to see me for the first time, I scanned her medication list. It included a nasal steroid for allergic rhinitis, a PPI for reflux, and 2 asthma inhalers—albuterol and an inhaled corticosteroid.

I asked her if she had hay fever. She didn’t think so. Heartburn? She said No. A history of asthma? No. So why was she taking these medications? To treat a chronic cough, the patient said. Was the cough better? No.

In the past 12 months, Mrs. S had seen an allergist, a gastroenterologist, and an otolaryngologist. The result? All 3 specialists added their favorite medication. I scanned the patient’s medication list again and noticed that she was taking amitriptyline 25 mg as a sleep aid. Because of the drug’s anticholinergic adverse effects, I had a hunch, and asked her to go one week without the amitriptyline. She agreed.

You can guess the happy ending. Mrs. S’s cough vanished, along with 4 medications she never needed in the first place. She was a victim of the prescribing cascade.

The other story is even more dramatic.

A friend who’s both an FP and a geriatrician became medical director of a local nursing home. To his chagrin, the average number of prescription drugs per resident when he took over was 9.6. Systematically, he went about reevaluating what residents really required. After a year and a half, the average had fallen to 5.4. The residents were no more depressed or agitated, and were generally more alert.

But here’s the catch: I checked back at the nursing home a couple of years after my friend left, and the average number of meds was back up to 10. It takes constant attention to not overprescribe. In fact, I now spend about as much time stopping meds as starting them.

Our health care system is the land of excess. It is up to family physicians—indeed, to all primary care clinicians—to ensure that we only prescribe or continue prescriptions when it’s the right patient, the right medication, at the right time.

Now it’s your turn. Send me your favorite, or most dramatic, medication overtreatment stories for our Letters column. We’ll continue the dialogue there.

I am delighted by the commonsense approach Drs. Weiss and Lee have taken in advising us to be wary of prescribing—or continuing—too many medications for our older patients (“Is your patient taking too many pills?”). Frankly, this advice applies to all patients, regardless of their age, and to virtually all family physicians. We all have stories about medication overuse. I’d like to tell you 2 of mine.

When Mrs. S, a 68-year-old patient, came to see me for the first time, I scanned her medication list. It included a nasal steroid for allergic rhinitis, a PPI for reflux, and 2 asthma inhalers—albuterol and an inhaled corticosteroid.

I asked her if she had hay fever. She didn’t think so. Heartburn? She said No. A history of asthma? No. So why was she taking these medications? To treat a chronic cough, the patient said. Was the cough better? No.

In the past 12 months, Mrs. S had seen an allergist, a gastroenterologist, and an otolaryngologist. The result? All 3 specialists added their favorite medication. I scanned the patient’s medication list again and noticed that she was taking amitriptyline 25 mg as a sleep aid. Because of the drug’s anticholinergic adverse effects, I had a hunch, and asked her to go one week without the amitriptyline. She agreed.

You can guess the happy ending. Mrs. S’s cough vanished, along with 4 medications she never needed in the first place. She was a victim of the prescribing cascade.

The other story is even more dramatic.

A friend who’s both an FP and a geriatrician became medical director of a local nursing home. To his chagrin, the average number of prescription drugs per resident when he took over was 9.6. Systematically, he went about reevaluating what residents really required. After a year and a half, the average had fallen to 5.4. The residents were no more depressed or agitated, and were generally more alert.

But here’s the catch: I checked back at the nursing home a couple of years after my friend left, and the average number of meds was back up to 10. It takes constant attention to not overprescribe. In fact, I now spend about as much time stopping meds as starting them.

Our health care system is the land of excess. It is up to family physicians—indeed, to all primary care clinicians—to ensure that we only prescribe or continue prescriptions when it’s the right patient, the right medication, at the right time.

Now it’s your turn. Send me your favorite, or most dramatic, medication overtreatment stories for our Letters column. We’ll continue the dialogue there.

I am delighted by the commonsense approach Drs. Weiss and Lee have taken in advising us to be wary of prescribing—or continuing—too many medications for our older patients (“Is your patient taking too many pills?”). Frankly, this advice applies to all patients, regardless of their age, and to virtually all family physicians. We all have stories about medication overuse. I’d like to tell you 2 of mine.

When Mrs. S, a 68-year-old patient, came to see me for the first time, I scanned her medication list. It included a nasal steroid for allergic rhinitis, a PPI for reflux, and 2 asthma inhalers—albuterol and an inhaled corticosteroid.

I asked her if she had hay fever. She didn’t think so. Heartburn? She said No. A history of asthma? No. So why was she taking these medications? To treat a chronic cough, the patient said. Was the cough better? No.

In the past 12 months, Mrs. S had seen an allergist, a gastroenterologist, and an otolaryngologist. The result? All 3 specialists added their favorite medication. I scanned the patient’s medication list again and noticed that she was taking amitriptyline 25 mg as a sleep aid. Because of the drug’s anticholinergic adverse effects, I had a hunch, and asked her to go one week without the amitriptyline. She agreed.

You can guess the happy ending. Mrs. S’s cough vanished, along with 4 medications she never needed in the first place. She was a victim of the prescribing cascade.

The other story is even more dramatic.

A friend who’s both an FP and a geriatrician became medical director of a local nursing home. To his chagrin, the average number of prescription drugs per resident when he took over was 9.6. Systematically, he went about reevaluating what residents really required. After a year and a half, the average had fallen to 5.4. The residents were no more depressed or agitated, and were generally more alert.

But here’s the catch: I checked back at the nursing home a couple of years after my friend left, and the average number of meds was back up to 10. It takes constant attention to not overprescribe. In fact, I now spend about as much time stopping meds as starting them.

Our health care system is the land of excess. It is up to family physicians—indeed, to all primary care clinicians—to ensure that we only prescribe or continue prescriptions when it’s the right patient, the right medication, at the right time.

Now it’s your turn. Send me your favorite, or most dramatic, medication overtreatment stories for our Letters column. We’ll continue the dialogue there.

Beliefs about aging itself can also have dramatic consequences, both positive and negative. In one longitudinal study, those who had positive self-perceptions of aging when they were 50 had better health during 2 decades of follow-up and lived, on average, 7½ years longer than those who had negative self-perceptions at the age of 50.⁴

Although little research has focused specifically on pain-related stereotypes held by older adults, their importance has long been recognized.

Twenty years ago, a review found that the failure to incorporate older patients’ beliefs about pain could have a negative effect on pain management.⁵ And in 2011, an Institute of Medicine report found a critical need for public education to counter the myths, misunderstandings, stereotypes, and stigma that hinder pain management in patients across the lifespan.⁶

We set out to identify widely held stereotypes that older adults and physicians have about pain—and to report on primary studies that support or refute them. We focused on noncancer pain. In the pages that follow, we identify 4 key stereotypes that misrepresent the experience of older adults with regard to pain, and present evidence to debunk them.

Stereotype #1: Pain is a natural part of getting older

Chronic pain is often perceived as an age-related condition. In in-depth interviews, older adults with osteoarthritis reported pain as a normal, even essential, part of life. As one patient put it, “That’s how you know you’re alive … you ache.”⁷

Among primary care patients with osteoarthritis, those older than 70 years were more likely than younger patients to believe that people should expect to live with pain as they get older.⁸ And more than half of older adults who responded to a community-based survey considered arthritis to be a natural part of getting old.⁹

Physicians, too, often view pain as an inevitable part of the aging process, giving patients feedback such as “What do you expect? You’re just getting older.”¹⁰

Are they right?

Is pain inevitable? No
In fact, chronic pain is common in older adults, occurring in more than half of those assessed, according to some studies.¹¹ In addition, some epidemiological studies have found an age-related increase in the prevalence of pain,^12-14 with older age predicting a more likely onset of, and failure to recover from, persistent pain.¹⁵ But numerous studies have failed to find a direct relationship between pain and age.

A National Center for Health Statistics report found that 29% of adults between the ages of 45 and 64 years vs 21% of those 65 or older reported pain lasting >24 hours in the month before the survey.¹⁶ And a meta-analysis comparing age-related differences in pain perception found that the highest prevalence of chronic pain occurred at about age 65; a slight decline with advancing age followed, even beyond the age of 85.¹⁷

Chronic pain disorders are less frequent. In fact, many chronic pain disorders occur less frequently with advancing age. Population-based studies have found a lower prevalence of low back, neck, and face pain among older adults compared with their younger counterparts;¹⁶ evidence has also found lower rates of headache and abdominal pain.¹⁸ Other epidemiological studies suggest that the prevalence of musculoskeletal pain generally declines with advancing age,¹⁹ and a study of patients in their last 2 years of life found pain to be inversely correlated with age.²⁰ These findings refute the stereotype that advancing age inexorably involves pain, and challenge the notion that pain in later life is normal and expected, and unworthy of treatment.

Stereotype #2: Pain worsens
over time

Some patients and physicians expect that as people age, their pain will increase in intensity. In one study of community-dwelling older adults, 87% of those surveyed rated the belief that more aches and pains are an accepted part of aging as definitely or somewhat true.²¹ Indeed, patients of all ages have expressed the belief that older age confers greater susceptibility to, and suffering from, painful conditions like arthritis.²² Many common causes of pain in older adults, especially osteoarthritis, are seen as resulting from degenerative changes, which worsen over time.²³

Does pain intensify? Not necessarily
Some studies have linked older age to a worse prognosis for patients with musculoskeletal pain, but a greater number have found that aging has no effect on it.²⁴

Pain does not always progress. In a large cohort of patients with peripheral joint osteoarthritis, radiographic joint space narrowing worsened over 3 years, but this did not correlate consistently with worsening pain.²⁵ When the same cohort was assessed after 8 years, there was significant variability in pain, with no clear progression.²⁶

In another study involving older patients with restrictive back pain, the pain was frequently short-lived and episodic and did not increase with age.²⁷ And in a population sample in Norway, the mean number of pain sites decreased slightly over 14 years in those older than 60 years, while increasing in those aged 44 to 60.²⁸ Another study of patients with knee osteoarthritis identified factors that were protective against a decline in pain-related function: These included good mental health, self-efficacy, social support, and greater activity—but not younger age.²⁹ The enormous heterogeneity in both the experience and the course of pain suggests that age-related pain progression is neither universal nor expected—and contradicts a purely biological paradigm in which pain inevitably worsens over time.

Stereotype #3: Stoicism leads to pain tolerance

Some patients believe that the inability to deal with pain is a sign of being soft or weak, and that a “tough it out” approach makes pain easier to tolerate.⁷ In one survey, older adults were more likely than their younger counterparts to express such stoicism, frequently agreeing with statements like, “I maintain my pride and keep a stiff upper lip when in pain,” “I go on as if nothing had happened …,” and “Pain is something that should be ignored.” ³⁰

Unfortunately, some physicians reinforce such attitudes, telling older patients, in effect, that they’d better “get used to it.”¹⁰ And family and friends may make it worse. Patients taking opioids reported that it wasn’t unusual for those close to them to view their use of these analgesics as a sign of weakness.³¹

Does stoicism help? Probably not
Older adults seem less likely than younger adults to label a sensation as painful, suggesting a more stoic approach in general.³⁰ While some research has found that nociception—the perception of pain in response to painful stimuli—decreases with advancing age,³² other studies have found the opposite.³³ And population-based studies focusing on the consequences of pain indicate that it continues to have powerful negative effects, especially depression and insomnia, in older patients.

The degree of pain experienced is more strongly associated with depression in older patients compared with younger adults,³⁴ and greater pain reduces the likelihood that depression will improve with treatment.³⁵ Pain also continues to interfere with sleep. In one national sample, 25% of those with arthritis said they suffered from insomnia, roughly twice the prevalence of insomnia found in those without arthritis.³⁶ In another study, individuals with arthritis were 3 times more likely to have sleep problems compared with individuals without arthritis³⁷—an association independent of age. Being stoic about pain, it appears, does not diminish its consequences over time or help patients better tolerate it.

Stereotype #4: Prescription analgesics are highly addictive

Patients often think that prescription analgesics, especially opioids, are highly addictive or harmful—and older adults may refuse to take them for fear of becoming addicted.⁷ The stereotype is often shared by family and friends, as well as clinicians.

In one study, one-third of physicians said they hesitated to prescribe opioid medications to older adults because of the risk of addiction (a concern that no clinician with training in geriatrics shared).³⁸ What’s more, 16% of the physicians estimated that about one in 4 older patients receiving chronic opioid therapy becomes addicted. The actual risk is far lower. (More on that below.) News reports of an epidemic of prescription opioid addictions and fatalities,³⁹ including the assertion that opioids are replacing heroin as the primary drug of choice on the street,⁴⁰ may reinforce such stereotypes.

How great is the risk of addiction? For older adults, it’s very low
While rates of aberrant opioid use vary widely depending on the context, one consistent theme is that older age is associated with decreased risk.⁴¹ In one retrospective cohort study of older patients who had recently been started on an opioid medication for the treatment of chronic pain, only 3% showed evidence of behaviors associated with abuse or misuse.⁴²

What’s more, long-term opioid use among older patients with painful conditions is relatively uncommon, and prescription patterns suggest that most older adults discontinue opioids after one or 2 prescriptions.^42-44 Decades of research have found that, although opioid medications can cause physiological dependence, addiction is rare in patients treated with them.^45,46 (To learn more, see “Diagnosing and treating opioid dependence,” J Fam Pract. 2012;61: 588-597.)

Debunking myths: Implications for practice

Our findings—that pain is not a natural part of aging and often improves or remains stable over time, stoicism does not lead to acclimation, and pain medications are not highly addictive in older adults—make it clear that the stereotypes we identified are misconceptions of pain in later life. Debunking these stereotypes has several implications for clinical practice. We recommend the following:

Identify and counter these stereotypes. Avoid reinforcing stereotypes; counter them by summarizing these evidence-based findings for older patients. We believe patients would be receptive.

In one study, more than 80% of patients with osteoarthritis said they wanted prognostic information about the course of the disease, but only about one-third had received it.⁴⁷ Presenting the research findings would challenge patients’ stereotypes and help them reframe their expectations.

Elicit patients’ perspectives. Ask patients about age- and pain-related stereotypes and their expectations and perspectives of what constitutes successful treatment. Research shows that patients often wish to discuss lifestyle changes and nonmedical approaches to pain, for example, but that clinicians typically focus on medications instead.⁴⁸

Emphasize the positive. Frame discussions of pain and aging in a positive light, offering encouragement rather than supporting stoicism or resignation. Attention to protective factors, including good mental health, self-efficacy, social support, and greater activity, may enable older patients to adapt better to any pain they experience.

CORRESPONDENCE 
Stephen Thielke, MD, MSPH, MA, University of Washington, Psychiatry and Behavioral Sciences, Box 356560, Seattle, WA 98195; [email protected]

Beliefs about aging itself can also have dramatic consequences, both positive and negative. In one longitudinal study, those who had positive self-perceptions of aging when they were 50 had better health during 2 decades of follow-up and lived, on average, 7½ years longer than those who had negative self-perceptions at the age of 50.⁴

Although little research has focused specifically on pain-related stereotypes held by older adults, their importance has long been recognized.

Twenty years ago, a review found that the failure to incorporate older patients’ beliefs about pain could have a negative effect on pain management.⁵ And in 2011, an Institute of Medicine report found a critical need for public education to counter the myths, misunderstandings, stereotypes, and stigma that hinder pain management in patients across the lifespan.⁶

We set out to identify widely held stereotypes that older adults and physicians have about pain—and to report on primary studies that support or refute them. We focused on noncancer pain. In the pages that follow, we identify 4 key stereotypes that misrepresent the experience of older adults with regard to pain, and present evidence to debunk them.

Stereotype #1: Pain is a natural part of getting older

Chronic pain is often perceived as an age-related condition. In in-depth interviews, older adults with osteoarthritis reported pain as a normal, even essential, part of life. As one patient put it, “That’s how you know you’re alive … you ache.”⁷

Among primary care patients with osteoarthritis, those older than 70 years were more likely than younger patients to believe that people should expect to live with pain as they get older.⁸ And more than half of older adults who responded to a community-based survey considered arthritis to be a natural part of getting old.⁹

Physicians, too, often view pain as an inevitable part of the aging process, giving patients feedback such as “What do you expect? You’re just getting older.”¹⁰

Are they right?

Is pain inevitable? No
In fact, chronic pain is common in older adults, occurring in more than half of those assessed, according to some studies.¹¹ In addition, some epidemiological studies have found an age-related increase in the prevalence of pain,^12-14 with older age predicting a more likely onset of, and failure to recover from, persistent pain.¹⁵ But numerous studies have failed to find a direct relationship between pain and age.

A National Center for Health Statistics report found that 29% of adults between the ages of 45 and 64 years vs 21% of those 65 or older reported pain lasting >24 hours in the month before the survey.¹⁶ And a meta-analysis comparing age-related differences in pain perception found that the highest prevalence of chronic pain occurred at about age 65; a slight decline with advancing age followed, even beyond the age of 85.¹⁷

Chronic pain disorders are less frequent. In fact, many chronic pain disorders occur less frequently with advancing age. Population-based studies have found a lower prevalence of low back, neck, and face pain among older adults compared with their younger counterparts;¹⁶ evidence has also found lower rates of headache and abdominal pain.¹⁸ Other epidemiological studies suggest that the prevalence of musculoskeletal pain generally declines with advancing age,¹⁹ and a study of patients in their last 2 years of life found pain to be inversely correlated with age.²⁰ These findings refute the stereotype that advancing age inexorably involves pain, and challenge the notion that pain in later life is normal and expected, and unworthy of treatment.

Stereotype #2: Pain worsens
over time

Some patients and physicians expect that as people age, their pain will increase in intensity. In one study of community-dwelling older adults, 87% of those surveyed rated the belief that more aches and pains are an accepted part of aging as definitely or somewhat true.²¹ Indeed, patients of all ages have expressed the belief that older age confers greater susceptibility to, and suffering from, painful conditions like arthritis.²² Many common causes of pain in older adults, especially osteoarthritis, are seen as resulting from degenerative changes, which worsen over time.²³

Does pain intensify? Not necessarily
Some studies have linked older age to a worse prognosis for patients with musculoskeletal pain, but a greater number have found that aging has no effect on it.²⁴

Pain does not always progress. In a large cohort of patients with peripheral joint osteoarthritis, radiographic joint space narrowing worsened over 3 years, but this did not correlate consistently with worsening pain.²⁵ When the same cohort was assessed after 8 years, there was significant variability in pain, with no clear progression.²⁶

In another study involving older patients with restrictive back pain, the pain was frequently short-lived and episodic and did not increase with age.²⁷ And in a population sample in Norway, the mean number of pain sites decreased slightly over 14 years in those older than 60 years, while increasing in those aged 44 to 60.²⁸ Another study of patients with knee osteoarthritis identified factors that were protective against a decline in pain-related function: These included good mental health, self-efficacy, social support, and greater activity—but not younger age.²⁹ The enormous heterogeneity in both the experience and the course of pain suggests that age-related pain progression is neither universal nor expected—and contradicts a purely biological paradigm in which pain inevitably worsens over time.

Stereotype #3: Stoicism leads to pain tolerance

Some patients believe that the inability to deal with pain is a sign of being soft or weak, and that a “tough it out” approach makes pain easier to tolerate.⁷ In one survey, older adults were more likely than their younger counterparts to express such stoicism, frequently agreeing with statements like, “I maintain my pride and keep a stiff upper lip when in pain,” “I go on as if nothing had happened …,” and “Pain is something that should be ignored.” ³⁰

Unfortunately, some physicians reinforce such attitudes, telling older patients, in effect, that they’d better “get used to it.”¹⁰ And family and friends may make it worse. Patients taking opioids reported that it wasn’t unusual for those close to them to view their use of these analgesics as a sign of weakness.³¹

Does stoicism help? Probably not
Older adults seem less likely than younger adults to label a sensation as painful, suggesting a more stoic approach in general.³⁰ While some research has found that nociception—the perception of pain in response to painful stimuli—decreases with advancing age,³² other studies have found the opposite.³³ And population-based studies focusing on the consequences of pain indicate that it continues to have powerful negative effects, especially depression and insomnia, in older patients.

The degree of pain experienced is more strongly associated with depression in older patients compared with younger adults,³⁴ and greater pain reduces the likelihood that depression will improve with treatment.³⁵ Pain also continues to interfere with sleep. In one national sample, 25% of those with arthritis said they suffered from insomnia, roughly twice the prevalence of insomnia found in those without arthritis.³⁶ In another study, individuals with arthritis were 3 times more likely to have sleep problems compared with individuals without arthritis³⁷—an association independent of age. Being stoic about pain, it appears, does not diminish its consequences over time or help patients better tolerate it.

Stereotype #4: Prescription analgesics are highly addictive

Patients often think that prescription analgesics, especially opioids, are highly addictive or harmful—and older adults may refuse to take them for fear of becoming addicted.⁷ The stereotype is often shared by family and friends, as well as clinicians.

In one study, one-third of physicians said they hesitated to prescribe opioid medications to older adults because of the risk of addiction (a concern that no clinician with training in geriatrics shared).³⁸ What’s more, 16% of the physicians estimated that about one in 4 older patients receiving chronic opioid therapy becomes addicted. The actual risk is far lower. (More on that below.) News reports of an epidemic of prescription opioid addictions and fatalities,³⁹ including the assertion that opioids are replacing heroin as the primary drug of choice on the street,⁴⁰ may reinforce such stereotypes.

How great is the risk of addiction? For older adults, it’s very low
While rates of aberrant opioid use vary widely depending on the context, one consistent theme is that older age is associated with decreased risk.⁴¹ In one retrospective cohort study of older patients who had recently been started on an opioid medication for the treatment of chronic pain, only 3% showed evidence of behaviors associated with abuse or misuse.⁴²

What’s more, long-term opioid use among older patients with painful conditions is relatively uncommon, and prescription patterns suggest that most older adults discontinue opioids after one or 2 prescriptions.^42-44 Decades of research have found that, although opioid medications can cause physiological dependence, addiction is rare in patients treated with them.^45,46 (To learn more, see “Diagnosing and treating opioid dependence,” J Fam Pract. 2012;61: 588-597.)

Debunking myths: Implications for practice

Our findings—that pain is not a natural part of aging and often improves or remains stable over time, stoicism does not lead to acclimation, and pain medications are not highly addictive in older adults—make it clear that the stereotypes we identified are misconceptions of pain in later life. Debunking these stereotypes has several implications for clinical practice. We recommend the following:

Identify and counter these stereotypes. Avoid reinforcing stereotypes; counter them by summarizing these evidence-based findings for older patients. We believe patients would be receptive.

In one study, more than 80% of patients with osteoarthritis said they wanted prognostic information about the course of the disease, but only about one-third had received it.⁴⁷ Presenting the research findings would challenge patients’ stereotypes and help them reframe their expectations.

Elicit patients’ perspectives. Ask patients about age- and pain-related stereotypes and their expectations and perspectives of what constitutes successful treatment. Research shows that patients often wish to discuss lifestyle changes and nonmedical approaches to pain, for example, but that clinicians typically focus on medications instead.⁴⁸

Emphasize the positive. Frame discussions of pain and aging in a positive light, offering encouragement rather than supporting stoicism or resignation. Attention to protective factors, including good mental health, self-efficacy, social support, and greater activity, may enable older patients to adapt better to any pain they experience.

CORRESPONDENCE 
Stephen Thielke, MD, MSPH, MA, University of Washington, Psychiatry and Behavioral Sciences, Box 356560, Seattle, WA 98195; [email protected]

Beliefs about aging itself can also have dramatic consequences, both positive and negative. In one longitudinal study, those who had positive self-perceptions of aging when they were 50 had better health during 2 decades of follow-up and lived, on average, 7½ years longer than those who had negative self-perceptions at the age of 50.⁴

Although little research has focused specifically on pain-related stereotypes held by older adults, their importance has long been recognized.

Twenty years ago, a review found that the failure to incorporate older patients’ beliefs about pain could have a negative effect on pain management.⁵ And in 2011, an Institute of Medicine report found a critical need for public education to counter the myths, misunderstandings, stereotypes, and stigma that hinder pain management in patients across the lifespan.⁶

We set out to identify widely held stereotypes that older adults and physicians have about pain—and to report on primary studies that support or refute them. We focused on noncancer pain. In the pages that follow, we identify 4 key stereotypes that misrepresent the experience of older adults with regard to pain, and present evidence to debunk them.

Stereotype #1: Pain is a natural part of getting older

Chronic pain is often perceived as an age-related condition. In in-depth interviews, older adults with osteoarthritis reported pain as a normal, even essential, part of life. As one patient put it, “That’s how you know you’re alive … you ache.”⁷

Among primary care patients with osteoarthritis, those older than 70 years were more likely than younger patients to believe that people should expect to live with pain as they get older.⁸ And more than half of older adults who responded to a community-based survey considered arthritis to be a natural part of getting old.⁹

Physicians, too, often view pain as an inevitable part of the aging process, giving patients feedback such as “What do you expect? You’re just getting older.”¹⁰

Are they right?

Is pain inevitable? No
In fact, chronic pain is common in older adults, occurring in more than half of those assessed, according to some studies.¹¹ In addition, some epidemiological studies have found an age-related increase in the prevalence of pain,^12-14 with older age predicting a more likely onset of, and failure to recover from, persistent pain.¹⁵ But numerous studies have failed to find a direct relationship between pain and age.

A National Center for Health Statistics report found that 29% of adults between the ages of 45 and 64 years vs 21% of those 65 or older reported pain lasting >24 hours in the month before the survey.¹⁶ And a meta-analysis comparing age-related differences in pain perception found that the highest prevalence of chronic pain occurred at about age 65; a slight decline with advancing age followed, even beyond the age of 85.¹⁷

Chronic pain disorders are less frequent. In fact, many chronic pain disorders occur less frequently with advancing age. Population-based studies have found a lower prevalence of low back, neck, and face pain among older adults compared with their younger counterparts;¹⁶ evidence has also found lower rates of headache and abdominal pain.¹⁸ Other epidemiological studies suggest that the prevalence of musculoskeletal pain generally declines with advancing age,¹⁹ and a study of patients in their last 2 years of life found pain to be inversely correlated with age.²⁰ These findings refute the stereotype that advancing age inexorably involves pain, and challenge the notion that pain in later life is normal and expected, and unworthy of treatment.

Stereotype #2: Pain worsens
over time

Some patients and physicians expect that as people age, their pain will increase in intensity. In one study of community-dwelling older adults, 87% of those surveyed rated the belief that more aches and pains are an accepted part of aging as definitely or somewhat true.²¹ Indeed, patients of all ages have expressed the belief that older age confers greater susceptibility to, and suffering from, painful conditions like arthritis.²² Many common causes of pain in older adults, especially osteoarthritis, are seen as resulting from degenerative changes, which worsen over time.²³

Does pain intensify? Not necessarily
Some studies have linked older age to a worse prognosis for patients with musculoskeletal pain, but a greater number have found that aging has no effect on it.²⁴

Pain does not always progress. In a large cohort of patients with peripheral joint osteoarthritis, radiographic joint space narrowing worsened over 3 years, but this did not correlate consistently with worsening pain.²⁵ When the same cohort was assessed after 8 years, there was significant variability in pain, with no clear progression.²⁶

In another study involving older patients with restrictive back pain, the pain was frequently short-lived and episodic and did not increase with age.²⁷ And in a population sample in Norway, the mean number of pain sites decreased slightly over 14 years in those older than 60 years, while increasing in those aged 44 to 60.²⁸ Another study of patients with knee osteoarthritis identified factors that were protective against a decline in pain-related function: These included good mental health, self-efficacy, social support, and greater activity—but not younger age.²⁹ The enormous heterogeneity in both the experience and the course of pain suggests that age-related pain progression is neither universal nor expected—and contradicts a purely biological paradigm in which pain inevitably worsens over time.

Stereotype #3: Stoicism leads to pain tolerance

Some patients believe that the inability to deal with pain is a sign of being soft or weak, and that a “tough it out” approach makes pain easier to tolerate.⁷ In one survey, older adults were more likely than their younger counterparts to express such stoicism, frequently agreeing with statements like, “I maintain my pride and keep a stiff upper lip when in pain,” “I go on as if nothing had happened …,” and “Pain is something that should be ignored.” ³⁰

Unfortunately, some physicians reinforce such attitudes, telling older patients, in effect, that they’d better “get used to it.”¹⁰ And family and friends may make it worse. Patients taking opioids reported that it wasn’t unusual for those close to them to view their use of these analgesics as a sign of weakness.³¹

Does stoicism help? Probably not
Older adults seem less likely than younger adults to label a sensation as painful, suggesting a more stoic approach in general.³⁰ While some research has found that nociception—the perception of pain in response to painful stimuli—decreases with advancing age,³² other studies have found the opposite.³³ And population-based studies focusing on the consequences of pain indicate that it continues to have powerful negative effects, especially depression and insomnia, in older patients.

The degree of pain experienced is more strongly associated with depression in older patients compared with younger adults,³⁴ and greater pain reduces the likelihood that depression will improve with treatment.³⁵ Pain also continues to interfere with sleep. In one national sample, 25% of those with arthritis said they suffered from insomnia, roughly twice the prevalence of insomnia found in those without arthritis.³⁶ In another study, individuals with arthritis were 3 times more likely to have sleep problems compared with individuals without arthritis³⁷—an association independent of age. Being stoic about pain, it appears, does not diminish its consequences over time or help patients better tolerate it.

Stereotype #4: Prescription analgesics are highly addictive

Patients often think that prescription analgesics, especially opioids, are highly addictive or harmful—and older adults may refuse to take them for fear of becoming addicted.⁷ The stereotype is often shared by family and friends, as well as clinicians.

In one study, one-third of physicians said they hesitated to prescribe opioid medications to older adults because of the risk of addiction (a concern that no clinician with training in geriatrics shared).³⁸ What’s more, 16% of the physicians estimated that about one in 4 older patients receiving chronic opioid therapy becomes addicted. The actual risk is far lower. (More on that below.) News reports of an epidemic of prescription opioid addictions and fatalities,³⁹ including the assertion that opioids are replacing heroin as the primary drug of choice on the street,⁴⁰ may reinforce such stereotypes.

How great is the risk of addiction? For older adults, it’s very low
While rates of aberrant opioid use vary widely depending on the context, one consistent theme is that older age is associated with decreased risk.⁴¹ In one retrospective cohort study of older patients who had recently been started on an opioid medication for the treatment of chronic pain, only 3% showed evidence of behaviors associated with abuse or misuse.⁴²

What’s more, long-term opioid use among older patients with painful conditions is relatively uncommon, and prescription patterns suggest that most older adults discontinue opioids after one or 2 prescriptions.^42-44 Decades of research have found that, although opioid medications can cause physiological dependence, addiction is rare in patients treated with them.^45,46 (To learn more, see “Diagnosing and treating opioid dependence,” J Fam Pract. 2012;61: 588-597.)

Debunking myths: Implications for practice

Our findings—that pain is not a natural part of aging and often improves or remains stable over time, stoicism does not lead to acclimation, and pain medications are not highly addictive in older adults—make it clear that the stereotypes we identified are misconceptions of pain in later life. Debunking these stereotypes has several implications for clinical practice. We recommend the following:

Identify and counter these stereotypes. Avoid reinforcing stereotypes; counter them by summarizing these evidence-based findings for older patients. We believe patients would be receptive.

In one study, more than 80% of patients with osteoarthritis said they wanted prognostic information about the course of the disease, but only about one-third had received it.⁴⁷ Presenting the research findings would challenge patients’ stereotypes and help them reframe their expectations.

Elicit patients’ perspectives. Ask patients about age- and pain-related stereotypes and their expectations and perspectives of what constitutes successful treatment. Research shows that patients often wish to discuss lifestyle changes and nonmedical approaches to pain, for example, but that clinicians typically focus on medications instead.⁴⁸

Emphasize the positive. Frame discussions of pain and aging in a positive light, offering encouragement rather than supporting stoicism or resignation. Attention to protective factors, including good mental health, self-efficacy, social support, and greater activity, may enable older patients to adapt better to any pain they experience.

CORRESPONDENCE 
Stephen Thielke, MD, MSPH, MA, University of Washington, Psychiatry and Behavioral Sciences, Box 356560, Seattle, WA 98195; [email protected]