Drug Therapy

Dermatologists are prescribing fewer antibiotics for acne and rosacea, but prescribing after dermatologic surgery has increased in the past decade.

In a study published online Jan. 16 in JAMA Dermatology, researchers report the results of a cross-sectional analysis of antibiotic prescribing by 11,986 dermatologists between 2008 and 2016, using commercial claims data.

The analysis showed that, over this period of time, the overall rate of antibiotic prescribing by dermatologists decreased by 36.6%, from 3.36 courses per 100 dermatologist visits to 2.13 courses. In particular, antibiotic prescribing for acne decreased by 28.1%, from 11.76 courses per 100 visits to 8.45 courses, and for rosacea it decreased by 18.1%, from 10.89 courses per 100 visits to 8.92 courses.

John S. Barbieri, MD, of the department of dermatology, University of Pennsylvania, and his coauthors described the overall decline in antibiotic prescribing as “encouraging,” considering that in 2013 dermatologists were identified as the “most frequent prescribers of oral antibiotics per clinician.” The decline resulted in an estimated 480,000 fewer antibiotic courses a year, they noted.

“Much of the decrease in extended courses of antibiotic therapy is associated with visits for acne and rosacea,” they wrote. “Although recent guidelines suggest limiting the duration of therapy in this patient population, course duration has remained stable over time, suggesting that this decrease may be due to fewer patients being treated with antibiotics rather than patients being treated for a shorter duration.”

However, the rate of oral antibiotic prescriptions associated with surgical visits increased by 69.6%, from 3.92 courses per 100 visits to 6.65. This increase was concerning, given the risk of surgical-site infections was low, the authors pointed out. “In addition, a 2008 advisory statement on antibiotic prophylaxis recommends single-dose perioperative antibiotics for patients at increased risk of surgical-site infection,” they added.

The study also noted a 35.3% increase in antibiotic prescribing for cysts and a 3.2% increase for hidradenitis suppurativa.

Over the entire study period, nearly 1 million courses of oral antibiotics were prescribed. Doxycycline hyclate accounted for around one quarter of prescriptions, as did minocycline, while 19.9% of prescriptions were for cephalexin.

“Given the low rate of infectious complications, even for Mohs surgery, and the lack of evidence to support the use of prolonged rather than single-dose perioperative regimens, the postoperative courses of antibiotics identified in this study may increase risks to patients without substantial benefits,” they added.

The study was partly supported by the National Institute of Arthritis and Musculoskeletal Skin Diseases. No conflicts of interest were declared.

SOURCE: Barbieri J et al. JAMA Dermatology. 2019 Jan 16. doi: 10.1001/jamadermatol.2018.4944.

Dermatologists are prescribing fewer antibiotics for acne and rosacea, but prescribing after dermatologic surgery has increased in the past decade.

In a study published online Jan. 16 in JAMA Dermatology, researchers report the results of a cross-sectional analysis of antibiotic prescribing by 11,986 dermatologists between 2008 and 2016, using commercial claims data.

The analysis showed that, over this period of time, the overall rate of antibiotic prescribing by dermatologists decreased by 36.6%, from 3.36 courses per 100 dermatologist visits to 2.13 courses. In particular, antibiotic prescribing for acne decreased by 28.1%, from 11.76 courses per 100 visits to 8.45 courses, and for rosacea it decreased by 18.1%, from 10.89 courses per 100 visits to 8.92 courses.

John S. Barbieri, MD, of the department of dermatology, University of Pennsylvania, and his coauthors described the overall decline in antibiotic prescribing as “encouraging,” considering that in 2013 dermatologists were identified as the “most frequent prescribers of oral antibiotics per clinician.” The decline resulted in an estimated 480,000 fewer antibiotic courses a year, they noted.

“Much of the decrease in extended courses of antibiotic therapy is associated with visits for acne and rosacea,” they wrote. “Although recent guidelines suggest limiting the duration of therapy in this patient population, course duration has remained stable over time, suggesting that this decrease may be due to fewer patients being treated with antibiotics rather than patients being treated for a shorter duration.”

However, the rate of oral antibiotic prescriptions associated with surgical visits increased by 69.6%, from 3.92 courses per 100 visits to 6.65. This increase was concerning, given the risk of surgical-site infections was low, the authors pointed out. “In addition, a 2008 advisory statement on antibiotic prophylaxis recommends single-dose perioperative antibiotics for patients at increased risk of surgical-site infection,” they added.

The study also noted a 35.3% increase in antibiotic prescribing for cysts and a 3.2% increase for hidradenitis suppurativa.

Over the entire study period, nearly 1 million courses of oral antibiotics were prescribed. Doxycycline hyclate accounted for around one quarter of prescriptions, as did minocycline, while 19.9% of prescriptions were for cephalexin.

“Given the low rate of infectious complications, even for Mohs surgery, and the lack of evidence to support the use of prolonged rather than single-dose perioperative regimens, the postoperative courses of antibiotics identified in this study may increase risks to patients without substantial benefits,” they added.

The study was partly supported by the National Institute of Arthritis and Musculoskeletal Skin Diseases. No conflicts of interest were declared.

SOURCE: Barbieri J et al. JAMA Dermatology. 2019 Jan 16. doi: 10.1001/jamadermatol.2018.4944.

Dermatologists are prescribing fewer antibiotics for acne and rosacea, but prescribing after dermatologic surgery has increased in the past decade.

In a study published online Jan. 16 in JAMA Dermatology, researchers report the results of a cross-sectional analysis of antibiotic prescribing by 11,986 dermatologists between 2008 and 2016, using commercial claims data.

The analysis showed that, over this period of time, the overall rate of antibiotic prescribing by dermatologists decreased by 36.6%, from 3.36 courses per 100 dermatologist visits to 2.13 courses. In particular, antibiotic prescribing for acne decreased by 28.1%, from 11.76 courses per 100 visits to 8.45 courses, and for rosacea it decreased by 18.1%, from 10.89 courses per 100 visits to 8.92 courses.

John S. Barbieri, MD, of the department of dermatology, University of Pennsylvania, and his coauthors described the overall decline in antibiotic prescribing as “encouraging,” considering that in 2013 dermatologists were identified as the “most frequent prescribers of oral antibiotics per clinician.” The decline resulted in an estimated 480,000 fewer antibiotic courses a year, they noted.

“Much of the decrease in extended courses of antibiotic therapy is associated with visits for acne and rosacea,” they wrote. “Although recent guidelines suggest limiting the duration of therapy in this patient population, course duration has remained stable over time, suggesting that this decrease may be due to fewer patients being treated with antibiotics rather than patients being treated for a shorter duration.”

However, the rate of oral antibiotic prescriptions associated with surgical visits increased by 69.6%, from 3.92 courses per 100 visits to 6.65. This increase was concerning, given the risk of surgical-site infections was low, the authors pointed out. “In addition, a 2008 advisory statement on antibiotic prophylaxis recommends single-dose perioperative antibiotics for patients at increased risk of surgical-site infection,” they added.

The study also noted a 35.3% increase in antibiotic prescribing for cysts and a 3.2% increase for hidradenitis suppurativa.

Over the entire study period, nearly 1 million courses of oral antibiotics were prescribed. Doxycycline hyclate accounted for around one quarter of prescriptions, as did minocycline, while 19.9% of prescriptions were for cephalexin.

“Given the low rate of infectious complications, even for Mohs surgery, and the lack of evidence to support the use of prolonged rather than single-dose perioperative regimens, the postoperative courses of antibiotics identified in this study may increase risks to patients without substantial benefits,” they added.

The study was partly supported by the National Institute of Arthritis and Musculoskeletal Skin Diseases. No conflicts of interest were declared.

SOURCE: Barbieri J et al. JAMA Dermatology. 2019 Jan 16. doi: 10.1001/jamadermatol.2018.4944.

The next presidential primary contests are more than a year away. But presumed candidates are already trying to stake a claim to one of health care’s hot-button concerns: surging prescription drug prices.

Kenishirotie/Thinkstock

“This is a 2020 thing,” said Peter B. Bach, MD, who directs the Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center in New York and tracks drug-pricing policy.

Spurred on by midterm election results that showed health care to be a deciding issue, lawmakers – some of whom have already launched presidential-run exploratory committees – are pushing a bevy of new proposals and approaches.

Few if any of those ideas will likely make it to the president’s desk. Nevertheless, Senate Democrats eyeing higher office and seeking street cred in the debate are devising more innovative and aggressive strategies to take on Big Pharma.

“Democrats feel as if they’re really able to experiment,” said Rachel Sachs, an associate law professor at Washington University, St. Louis, who tracks drug-pricing laws.

Some Republicans are also proposing drug-pricing reform, although experts say their approaches are generally less dramatic.

Here are some of the ideas either introduced in legislation or that senators’ offices confirmed they are considering:

• Make a public option for generic drugs. The government could manufacture generics (directly or through a private contractor) if there is a shortage or aren’t enough competitors to keep prices down. This comes from a bill put forth by Sen. Elizabeth Warren (D-Mass.) and Rep. Jan Schakowsky (D-Ill.).
• Let Medicare negotiate drug prices. This idea has many backers – what differs is the method of enforcement. Sen. Sherrod Brown (D-Ohio) has suggested that if the company and the government can’t reach an agreement, the government could take away the company’s patent rights. A proposal from Sen. Bernie Sanders (I-Vt.) and Rep. Elijah Cummings (D-Md.) would address stalled negotiations by letting Medicare pay the lowest amount among: Medicaid’s best price, the highest price a single federal purchaser pays or the median price paid for a specific drug in Canada, France, Germany, Japan, and the United Kingdom.
• Pay what they do abroad. Legislation from Mr. Sanders and Rep. Ro Khanna (D-Calif.) would require companies to price their drugs no higher than the median of what’s charged in Canada, France, Germany, Japan, and the United Kingdom. If manufacturers fail to comply, other companies could get the rights to make those drugs, too.
• Penalize price gouging. This would target manufacturers who raise drug prices more than 30% in 5 years. Punishments could include requiring the company to reimburse those who paid the elevated price, forcing the drug maker to lower its price, or charging a penalty up to three times what a company received from boosting the price. Backers include senators Richard Blumenthal (D-Conn.), Kamala Harris (D-Calif.), Jeff Merkley (D-Ore.), and Amy Klobuchar (D-Minn.).
• Import drugs. A Sanders-Cummings bill would let patients, wholesalers, and pharmacies import drugs from abroad – starting with Canada, and leaving the door open for some other countries. Sen. Chuck Grassley (R-Iowa) and Ms. Klobuchar have a separate bill that is specific to patients getting medicine from Canada alone.
• Abolish “pay for delay.” From Mr. Grassley and Ms. Klobuchar, this legislation would tackle deals in which a branded drugmaker pays off a generic one to keep a competing product from coming to market.

This flurry of proposed lawmaking could add momentum to one of the few policy areas in which conventional Washington wisdom suggests House Democrats, Senate Republicans, and the White House may be able to find common ground.

“Everything is up in the air and anything is possible,” said Walid Gellad, MD, codirector of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. “There are things that can happen that maybe weren’t going to happen before.”

And there’s political pressure. Polls consistently suggest voters have a strong appetite for action. As a candidate, President Trump vowed to make drug prices a top priority. In recent months, the administration has taken steps in this direction, like testing changes to Medicare that might reduce out-of-pocket drug costs. But Congress has been relatively quiet, especially when it comes to challenging the pharmaceutical industry, which remains one of Capitol Hill’s most potent lobbying forces.

One aspect of prescription drug pricing that could see bipartisan action is insulin prices, which have skyrocketed, stoking widespread outcry, and could be a target for bipartisan work. Ms. Warren’s legislation singles out the drug as one the government could produce, and Mr. Cummings has already called in major insulin manufacturers for a drug-pricing hearing later this month. In addition, Rep. Diana DeGette (D-Colo.), the new chair of the House Energy and Commerce Oversight and Investigations Subcommittee, has listed prescription drug pricing as a high priority for her panel. As cochair of the Congressional Diabetes Caucus, Ms. DeGette worked with Rep. Tom Reed (R-N.Y.) to produce a report on the high cost of insulin.

To be sure, some of the concepts, such as drug importation and bolstering development of generic drugs, have been around a long time. But some of the legislation at hand suggests a new kind of thinking.

House Speaker Nancy Pelosi (D-Calif.) has labeled drug pricing a top priority, and the pharmaceutical industry has been bracing for a fight with the new Democratic majority.

Meanwhile, in the GOP-controlled Senate, two powerful lawmakers – Sen. Lamar Alexander (R-Tenn.) and Mr. Grassley – have indicated they want to use their influence to tackle the issue. Mr. Alexander, who chairs the Health, Education, Labor and Pensions Committee, has said cutting health care costs, including drug prices, will be high on his panel’s to-do list this Congress. Mr. Grassley runs the Finance Committee, which oversees pricing issues for Medicare and Medicaid.

“The solution to high drug prices is not just having the government spending more money. ... You need to look at prices,” Dr. Gellad said. “These proposals deal with price. They all directly affect price.”

Given the drug industry’s full-throated opposition to virtually any pricing legislation, Ms. Sachs said, “it is not at all surprising to me to see the Democrats start exploring some of these more radical proposals.”

Still, though, Senate staffers almost uniformly argued that the drug-pricing issue requires more than one single piece of legislation.

For instance, the price-gouging penalty spearheaded by Mr. Blumenthal doesn’t stop drugs from having high initial list prices. Letting Medicare negotiate doesn’t mean people covered by other plans will necessarily see the same savings. Empowering the government to produce competing drugs doesn’t promise to keep prices down long term and doesn’t guarantee that patients will see those savings.

“We need to use every tool available to bring down drug prices and improve competition,” said an aide in Ms. Warren’s office.

KHN’s coverage of prescription drug development, costs and pricing is supported in part by the Laura and John Arnold Foundation. Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

The next presidential primary contests are more than a year away. But presumed candidates are already trying to stake a claim to one of health care’s hot-button concerns: surging prescription drug prices.

Kenishirotie/Thinkstock

“This is a 2020 thing,” said Peter B. Bach, MD, who directs the Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center in New York and tracks drug-pricing policy.

Spurred on by midterm election results that showed health care to be a deciding issue, lawmakers – some of whom have already launched presidential-run exploratory committees – are pushing a bevy of new proposals and approaches.

Few if any of those ideas will likely make it to the president’s desk. Nevertheless, Senate Democrats eyeing higher office and seeking street cred in the debate are devising more innovative and aggressive strategies to take on Big Pharma.

“Democrats feel as if they’re really able to experiment,” said Rachel Sachs, an associate law professor at Washington University, St. Louis, who tracks drug-pricing laws.

Some Republicans are also proposing drug-pricing reform, although experts say their approaches are generally less dramatic.

Here are some of the ideas either introduced in legislation or that senators’ offices confirmed they are considering:

• Make a public option for generic drugs. The government could manufacture generics (directly or through a private contractor) if there is a shortage or aren’t enough competitors to keep prices down. This comes from a bill put forth by Sen. Elizabeth Warren (D-Mass.) and Rep. Jan Schakowsky (D-Ill.).
• Let Medicare negotiate drug prices. This idea has many backers – what differs is the method of enforcement. Sen. Sherrod Brown (D-Ohio) has suggested that if the company and the government can’t reach an agreement, the government could take away the company’s patent rights. A proposal from Sen. Bernie Sanders (I-Vt.) and Rep. Elijah Cummings (D-Md.) would address stalled negotiations by letting Medicare pay the lowest amount among: Medicaid’s best price, the highest price a single federal purchaser pays or the median price paid for a specific drug in Canada, France, Germany, Japan, and the United Kingdom.
• Pay what they do abroad. Legislation from Mr. Sanders and Rep. Ro Khanna (D-Calif.) would require companies to price their drugs no higher than the median of what’s charged in Canada, France, Germany, Japan, and the United Kingdom. If manufacturers fail to comply, other companies could get the rights to make those drugs, too.
• Penalize price gouging. This would target manufacturers who raise drug prices more than 30% in 5 years. Punishments could include requiring the company to reimburse those who paid the elevated price, forcing the drug maker to lower its price, or charging a penalty up to three times what a company received from boosting the price. Backers include senators Richard Blumenthal (D-Conn.), Kamala Harris (D-Calif.), Jeff Merkley (D-Ore.), and Amy Klobuchar (D-Minn.).
• Import drugs. A Sanders-Cummings bill would let patients, wholesalers, and pharmacies import drugs from abroad – starting with Canada, and leaving the door open for some other countries. Sen. Chuck Grassley (R-Iowa) and Ms. Klobuchar have a separate bill that is specific to patients getting medicine from Canada alone.
• Abolish “pay for delay.” From Mr. Grassley and Ms. Klobuchar, this legislation would tackle deals in which a branded drugmaker pays off a generic one to keep a competing product from coming to market.

This flurry of proposed lawmaking could add momentum to one of the few policy areas in which conventional Washington wisdom suggests House Democrats, Senate Republicans, and the White House may be able to find common ground.

“Everything is up in the air and anything is possible,” said Walid Gellad, MD, codirector of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. “There are things that can happen that maybe weren’t going to happen before.”

And there’s political pressure. Polls consistently suggest voters have a strong appetite for action. As a candidate, President Trump vowed to make drug prices a top priority. In recent months, the administration has taken steps in this direction, like testing changes to Medicare that might reduce out-of-pocket drug costs. But Congress has been relatively quiet, especially when it comes to challenging the pharmaceutical industry, which remains one of Capitol Hill’s most potent lobbying forces.

One aspect of prescription drug pricing that could see bipartisan action is insulin prices, which have skyrocketed, stoking widespread outcry, and could be a target for bipartisan work. Ms. Warren’s legislation singles out the drug as one the government could produce, and Mr. Cummings has already called in major insulin manufacturers for a drug-pricing hearing later this month. In addition, Rep. Diana DeGette (D-Colo.), the new chair of the House Energy and Commerce Oversight and Investigations Subcommittee, has listed prescription drug pricing as a high priority for her panel. As cochair of the Congressional Diabetes Caucus, Ms. DeGette worked with Rep. Tom Reed (R-N.Y.) to produce a report on the high cost of insulin.

To be sure, some of the concepts, such as drug importation and bolstering development of generic drugs, have been around a long time. But some of the legislation at hand suggests a new kind of thinking.

House Speaker Nancy Pelosi (D-Calif.) has labeled drug pricing a top priority, and the pharmaceutical industry has been bracing for a fight with the new Democratic majority.

Meanwhile, in the GOP-controlled Senate, two powerful lawmakers – Sen. Lamar Alexander (R-Tenn.) and Mr. Grassley – have indicated they want to use their influence to tackle the issue. Mr. Alexander, who chairs the Health, Education, Labor and Pensions Committee, has said cutting health care costs, including drug prices, will be high on his panel’s to-do list this Congress. Mr. Grassley runs the Finance Committee, which oversees pricing issues for Medicare and Medicaid.

“The solution to high drug prices is not just having the government spending more money. ... You need to look at prices,” Dr. Gellad said. “These proposals deal with price. They all directly affect price.”

Given the drug industry’s full-throated opposition to virtually any pricing legislation, Ms. Sachs said, “it is not at all surprising to me to see the Democrats start exploring some of these more radical proposals.”

Still, though, Senate staffers almost uniformly argued that the drug-pricing issue requires more than one single piece of legislation.

For instance, the price-gouging penalty spearheaded by Mr. Blumenthal doesn’t stop drugs from having high initial list prices. Letting Medicare negotiate doesn’t mean people covered by other plans will necessarily see the same savings. Empowering the government to produce competing drugs doesn’t promise to keep prices down long term and doesn’t guarantee that patients will see those savings.

“We need to use every tool available to bring down drug prices and improve competition,” said an aide in Ms. Warren’s office.

KHN’s coverage of prescription drug development, costs and pricing is supported in part by the Laura and John Arnold Foundation. Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

The next presidential primary contests are more than a year away. But presumed candidates are already trying to stake a claim to one of health care’s hot-button concerns: surging prescription drug prices.

Kenishirotie/Thinkstock

“This is a 2020 thing,” said Peter B. Bach, MD, who directs the Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center in New York and tracks drug-pricing policy.

Spurred on by midterm election results that showed health care to be a deciding issue, lawmakers – some of whom have already launched presidential-run exploratory committees – are pushing a bevy of new proposals and approaches.

Few if any of those ideas will likely make it to the president’s desk. Nevertheless, Senate Democrats eyeing higher office and seeking street cred in the debate are devising more innovative and aggressive strategies to take on Big Pharma.

“Democrats feel as if they’re really able to experiment,” said Rachel Sachs, an associate law professor at Washington University, St. Louis, who tracks drug-pricing laws.

Some Republicans are also proposing drug-pricing reform, although experts say their approaches are generally less dramatic.

Here are some of the ideas either introduced in legislation or that senators’ offices confirmed they are considering:

• Make a public option for generic drugs. The government could manufacture generics (directly or through a private contractor) if there is a shortage or aren’t enough competitors to keep prices down. This comes from a bill put forth by Sen. Elizabeth Warren (D-Mass.) and Rep. Jan Schakowsky (D-Ill.).
• Let Medicare negotiate drug prices. This idea has many backers – what differs is the method of enforcement. Sen. Sherrod Brown (D-Ohio) has suggested that if the company and the government can’t reach an agreement, the government could take away the company’s patent rights. A proposal from Sen. Bernie Sanders (I-Vt.) and Rep. Elijah Cummings (D-Md.) would address stalled negotiations by letting Medicare pay the lowest amount among: Medicaid’s best price, the highest price a single federal purchaser pays or the median price paid for a specific drug in Canada, France, Germany, Japan, and the United Kingdom.
• Pay what they do abroad. Legislation from Mr. Sanders and Rep. Ro Khanna (D-Calif.) would require companies to price their drugs no higher than the median of what’s charged in Canada, France, Germany, Japan, and the United Kingdom. If manufacturers fail to comply, other companies could get the rights to make those drugs, too.
• Penalize price gouging. This would target manufacturers who raise drug prices more than 30% in 5 years. Punishments could include requiring the company to reimburse those who paid the elevated price, forcing the drug maker to lower its price, or charging a penalty up to three times what a company received from boosting the price. Backers include senators Richard Blumenthal (D-Conn.), Kamala Harris (D-Calif.), Jeff Merkley (D-Ore.), and Amy Klobuchar (D-Minn.).
• Import drugs. A Sanders-Cummings bill would let patients, wholesalers, and pharmacies import drugs from abroad – starting with Canada, and leaving the door open for some other countries. Sen. Chuck Grassley (R-Iowa) and Ms. Klobuchar have a separate bill that is specific to patients getting medicine from Canada alone.
• Abolish “pay for delay.” From Mr. Grassley and Ms. Klobuchar, this legislation would tackle deals in which a branded drugmaker pays off a generic one to keep a competing product from coming to market.

This flurry of proposed lawmaking could add momentum to one of the few policy areas in which conventional Washington wisdom suggests House Democrats, Senate Republicans, and the White House may be able to find common ground.

“Everything is up in the air and anything is possible,” said Walid Gellad, MD, codirector of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh. “There are things that can happen that maybe weren’t going to happen before.”

And there’s political pressure. Polls consistently suggest voters have a strong appetite for action. As a candidate, President Trump vowed to make drug prices a top priority. In recent months, the administration has taken steps in this direction, like testing changes to Medicare that might reduce out-of-pocket drug costs. But Congress has been relatively quiet, especially when it comes to challenging the pharmaceutical industry, which remains one of Capitol Hill’s most potent lobbying forces.

One aspect of prescription drug pricing that could see bipartisan action is insulin prices, which have skyrocketed, stoking widespread outcry, and could be a target for bipartisan work. Ms. Warren’s legislation singles out the drug as one the government could produce, and Mr. Cummings has already called in major insulin manufacturers for a drug-pricing hearing later this month. In addition, Rep. Diana DeGette (D-Colo.), the new chair of the House Energy and Commerce Oversight and Investigations Subcommittee, has listed prescription drug pricing as a high priority for her panel. As cochair of the Congressional Diabetes Caucus, Ms. DeGette worked with Rep. Tom Reed (R-N.Y.) to produce a report on the high cost of insulin.

To be sure, some of the concepts, such as drug importation and bolstering development of generic drugs, have been around a long time. But some of the legislation at hand suggests a new kind of thinking.

House Speaker Nancy Pelosi (D-Calif.) has labeled drug pricing a top priority, and the pharmaceutical industry has been bracing for a fight with the new Democratic majority.

Meanwhile, in the GOP-controlled Senate, two powerful lawmakers – Sen. Lamar Alexander (R-Tenn.) and Mr. Grassley – have indicated they want to use their influence to tackle the issue. Mr. Alexander, who chairs the Health, Education, Labor and Pensions Committee, has said cutting health care costs, including drug prices, will be high on his panel’s to-do list this Congress. Mr. Grassley runs the Finance Committee, which oversees pricing issues for Medicare and Medicaid.

“The solution to high drug prices is not just having the government spending more money. ... You need to look at prices,” Dr. Gellad said. “These proposals deal with price. They all directly affect price.”

Given the drug industry’s full-throated opposition to virtually any pricing legislation, Ms. Sachs said, “it is not at all surprising to me to see the Democrats start exploring some of these more radical proposals.”

Still, though, Senate staffers almost uniformly argued that the drug-pricing issue requires more than one single piece of legislation.

For instance, the price-gouging penalty spearheaded by Mr. Blumenthal doesn’t stop drugs from having high initial list prices. Letting Medicare negotiate doesn’t mean people covered by other plans will necessarily see the same savings. Empowering the government to produce competing drugs doesn’t promise to keep prices down long term and doesn’t guarantee that patients will see those savings.

“We need to use every tool available to bring down drug prices and improve competition,” said an aide in Ms. Warren’s office.

KHN’s coverage of prescription drug development, costs and pricing is supported in part by the Laura and John Arnold Foundation. Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Prescribed opioids were associated with an increase in community-acquired pneumonia in patients with and without HIV infection, according to results of a large database study.

People living with HIV (PLWH) appeared to have a greater community-acquired pneumonia (CAP) risk at lower opioid doses and particularly with immunosuppressive opioids compared with uninfected patients, although the difference was not significant, E. Jennifer Edelman, MD, of Yale University, New Haven, Conn., and her colleagues wrote in JAMA Internal Medicine.

The researchers performed a nested case-control study comprising 25,392 participants (98.9% men; mean age, 55 years) in the Veterans Aging Cohort Study from Jan. 1, 2000, through Dec. 31, 2012.

Dr. Edelman and her colleagues compared the characteristics of 4,246 CAP cases with those of 21,146 uninfected controls in the sample. They also compared cases and controls by HIV status. They ran bivariate and multivariate analysis to estimate odds ratios for CAP risk associated with opioid exposure. In addition, the researchers ran models stratified by HIV status and formally checked for an interaction between prescribed opioid characteristics and HIV status.

In unadjusted logistic regression, prescribed opioids were associated with increased odds of CAP, with the greatest risk observed with currently prescribed opioids, compared with past prescribed opioids or no opioids.

Prescribed opioids remained associated with CAP in the adjusted models for past unknown or nonimmunosuppressive (adjusted OR, 1.24; 95% confidence interval, 1.09-1.40) and past immunosuppressive opioid use (aOR, 1.42; 95% CI, 1.21-1.67).

For currently prescribed opioids, nonimmunosuppressive or unknown, the aOR was 1.23 (95% CI, 1.03-1.48). For currently prescribed immunosuppressive opioids, the aOR was 3.18 (95% CI, 2.44-4.14).

The researchers also found evidence of a dose-response effect such that currently prescribed high-dose opioids were associated with the greatest CAP risk, followed by medium- and then by low-dose opioids, whether immunosuppressive or not.

With regard to the effect of HIV status in stratified, adjusted analyses, CAP risk tended to be greater among PLWH with current prescribed opioids, especially immunosuppressive opioids, compared with uninfected patients. However, the overall interaction term for opioid × HIV status was not significant (P = .36).

Although the researchers stated that a limitation of their study was an inability to prove causality or rule out respiratory depression (vs. immunosuppression) as the cause of the increased CAP risk, “the observed effects of opioid immunosuppressive properties and CAP risk lend support to our hypothesis that opioids have clinically relevant immunosuppressive properties.”

Dr. Edelman and her colleagues cited several limitations. For example, they were not able to determine whether patients took their prescribed medications appropriately and assess whether the patients took nonmedically prescribed opioids. Also, because men made up such a large portion of the study population, it is unclear whether the results are generalizable to women.

Nevertheless, the study “adds to growing evidence of potential medical harms associated with prescribed opioids,” they wrote.

“Health care professionals should be aware of this additional CAP risk when they prescribe opioids, and future studies should investigate the effects of opioids prescribed for longer durations and on other immune-related outcomes,” wrote Dr. Edelman and her colleagues. “Understanding whether mitigating the risk of prescribed opioids for CAP is possible by using a lower dose and nonimmunosuppressive opioids awaits further study.”

However, without such data, when prescribed opioids are warranted, physicians should attempt to modify other factors known to affect CAP risk, including smoking and lack of vaccination, Dr. Edelman and her colleagues concluded.

Several U.S. government agencies and Yale University provided funding for the study. The authors reported that they had no conflicts.

[email protected]

SOURCE: Edelman EJ et al. JAMA Intern Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6101.

Prescribed opioids were associated with an increase in community-acquired pneumonia in patients with and without HIV infection, according to results of a large database study.

People living with HIV (PLWH) appeared to have a greater community-acquired pneumonia (CAP) risk at lower opioid doses and particularly with immunosuppressive opioids compared with uninfected patients, although the difference was not significant, E. Jennifer Edelman, MD, of Yale University, New Haven, Conn., and her colleagues wrote in JAMA Internal Medicine.

The researchers performed a nested case-control study comprising 25,392 participants (98.9% men; mean age, 55 years) in the Veterans Aging Cohort Study from Jan. 1, 2000, through Dec. 31, 2012.

Dr. Edelman and her colleagues compared the characteristics of 4,246 CAP cases with those of 21,146 uninfected controls in the sample. They also compared cases and controls by HIV status. They ran bivariate and multivariate analysis to estimate odds ratios for CAP risk associated with opioid exposure. In addition, the researchers ran models stratified by HIV status and formally checked for an interaction between prescribed opioid characteristics and HIV status.

In unadjusted logistic regression, prescribed opioids were associated with increased odds of CAP, with the greatest risk observed with currently prescribed opioids, compared with past prescribed opioids or no opioids.

Prescribed opioids remained associated with CAP in the adjusted models for past unknown or nonimmunosuppressive (adjusted OR, 1.24; 95% confidence interval, 1.09-1.40) and past immunosuppressive opioid use (aOR, 1.42; 95% CI, 1.21-1.67).

For currently prescribed opioids, nonimmunosuppressive or unknown, the aOR was 1.23 (95% CI, 1.03-1.48). For currently prescribed immunosuppressive opioids, the aOR was 3.18 (95% CI, 2.44-4.14).

The researchers also found evidence of a dose-response effect such that currently prescribed high-dose opioids were associated with the greatest CAP risk, followed by medium- and then by low-dose opioids, whether immunosuppressive or not.

With regard to the effect of HIV status in stratified, adjusted analyses, CAP risk tended to be greater among PLWH with current prescribed opioids, especially immunosuppressive opioids, compared with uninfected patients. However, the overall interaction term for opioid × HIV status was not significant (P = .36).

Although the researchers stated that a limitation of their study was an inability to prove causality or rule out respiratory depression (vs. immunosuppression) as the cause of the increased CAP risk, “the observed effects of opioid immunosuppressive properties and CAP risk lend support to our hypothesis that opioids have clinically relevant immunosuppressive properties.”

Dr. Edelman and her colleagues cited several limitations. For example, they were not able to determine whether patients took their prescribed medications appropriately and assess whether the patients took nonmedically prescribed opioids. Also, because men made up such a large portion of the study population, it is unclear whether the results are generalizable to women.

Nevertheless, the study “adds to growing evidence of potential medical harms associated with prescribed opioids,” they wrote.

“Health care professionals should be aware of this additional CAP risk when they prescribe opioids, and future studies should investigate the effects of opioids prescribed for longer durations and on other immune-related outcomes,” wrote Dr. Edelman and her colleagues. “Understanding whether mitigating the risk of prescribed opioids for CAP is possible by using a lower dose and nonimmunosuppressive opioids awaits further study.”

However, without such data, when prescribed opioids are warranted, physicians should attempt to modify other factors known to affect CAP risk, including smoking and lack of vaccination, Dr. Edelman and her colleagues concluded.

Several U.S. government agencies and Yale University provided funding for the study. The authors reported that they had no conflicts.

[email protected]

SOURCE: Edelman EJ et al. JAMA Intern Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6101.

Prescribed opioids were associated with an increase in community-acquired pneumonia in patients with and without HIV infection, according to results of a large database study.

People living with HIV (PLWH) appeared to have a greater community-acquired pneumonia (CAP) risk at lower opioid doses and particularly with immunosuppressive opioids compared with uninfected patients, although the difference was not significant, E. Jennifer Edelman, MD, of Yale University, New Haven, Conn., and her colleagues wrote in JAMA Internal Medicine.

The researchers performed a nested case-control study comprising 25,392 participants (98.9% men; mean age, 55 years) in the Veterans Aging Cohort Study from Jan. 1, 2000, through Dec. 31, 2012.

Dr. Edelman and her colleagues compared the characteristics of 4,246 CAP cases with those of 21,146 uninfected controls in the sample. They also compared cases and controls by HIV status. They ran bivariate and multivariate analysis to estimate odds ratios for CAP risk associated with opioid exposure. In addition, the researchers ran models stratified by HIV status and formally checked for an interaction between prescribed opioid characteristics and HIV status.

In unadjusted logistic regression, prescribed opioids were associated with increased odds of CAP, with the greatest risk observed with currently prescribed opioids, compared with past prescribed opioids or no opioids.

Prescribed opioids remained associated with CAP in the adjusted models for past unknown or nonimmunosuppressive (adjusted OR, 1.24; 95% confidence interval, 1.09-1.40) and past immunosuppressive opioid use (aOR, 1.42; 95% CI, 1.21-1.67).

For currently prescribed opioids, nonimmunosuppressive or unknown, the aOR was 1.23 (95% CI, 1.03-1.48). For currently prescribed immunosuppressive opioids, the aOR was 3.18 (95% CI, 2.44-4.14).

The researchers also found evidence of a dose-response effect such that currently prescribed high-dose opioids were associated with the greatest CAP risk, followed by medium- and then by low-dose opioids, whether immunosuppressive or not.

With regard to the effect of HIV status in stratified, adjusted analyses, CAP risk tended to be greater among PLWH with current prescribed opioids, especially immunosuppressive opioids, compared with uninfected patients. However, the overall interaction term for opioid × HIV status was not significant (P = .36).

Although the researchers stated that a limitation of their study was an inability to prove causality or rule out respiratory depression (vs. immunosuppression) as the cause of the increased CAP risk, “the observed effects of opioid immunosuppressive properties and CAP risk lend support to our hypothesis that opioids have clinically relevant immunosuppressive properties.”

Dr. Edelman and her colleagues cited several limitations. For example, they were not able to determine whether patients took their prescribed medications appropriately and assess whether the patients took nonmedically prescribed opioids. Also, because men made up such a large portion of the study population, it is unclear whether the results are generalizable to women.

Nevertheless, the study “adds to growing evidence of potential medical harms associated with prescribed opioids,” they wrote.

“Health care professionals should be aware of this additional CAP risk when they prescribe opioids, and future studies should investigate the effects of opioids prescribed for longer durations and on other immune-related outcomes,” wrote Dr. Edelman and her colleagues. “Understanding whether mitigating the risk of prescribed opioids for CAP is possible by using a lower dose and nonimmunosuppressive opioids awaits further study.”

However, without such data, when prescribed opioids are warranted, physicians should attempt to modify other factors known to affect CAP risk, including smoking and lack of vaccination, Dr. Edelman and her colleagues concluded.

Several U.S. government agencies and Yale University provided funding for the study. The authors reported that they had no conflicts.

[email protected]

SOURCE: Edelman EJ et al. JAMA Intern Med. 2019 Jan 7. doi: 10.1001/jamainternmed.2018.6101.

The Food and Drug Administration has smoothed the way to OTC naloxone by releasing “drug facts label” templates for manufacturers to use when submitting their products for consideration.

Drug facts labels (DFLs) are required for all OTC drugs, and it’s usually up to manufacturers to develop and test their own to ensure that consumers understand how to use their products.

“Some stakeholders have identified the requirement ... as a barrier to development of OTC naloxone products,” so the agency developed two DFLs on its own – one for nasal spray naloxone, the other for auto-injectors – and completed the necessary label comprehension testing, according to an announcement from FDA Commissioner Scott Gottlieb, MD.

There’s not much else manufactures have to do, except deal with the details of their own products. They “can now focus their efforts on ... how well consumers understand the product-specific information that hasn’t been already tested in the model” DFLs, according to the announcement.

As deaths from opioid abuse continue to climb, the FDA is committed to increasing access to naloxone, which currently requires a prescription. The new DFLs “should jump-start the development of OTC naloxone products ... I personally urge companies to take notice of this pathway that the FDA has opened for them and come to the Agency with applications as soon as possible,” Dr. Gottlieb said.

Comprehension was assessed in more than 700 people, including heroin and prescription opioid users, their friends and families, and adolescents. “Overall, the study demonstrated that” the DFLs are “well-understood by consumers” and acceptable “for use by manufacturers in support of their ... development programs,” according to the announcement.

In a press statement, the American Medical Association applauded the agency’s move “to provide labeling that would allow for over-the-counter availability of naloxone, a move that will save people from opioid-related overdose ... The action should spur efforts by naloxone manufacturers to submit applications for their products to receive over-the-counter status.”

[email protected]

The Food and Drug Administration has smoothed the way to OTC naloxone by releasing “drug facts label” templates for manufacturers to use when submitting their products for consideration.

Drug facts labels (DFLs) are required for all OTC drugs, and it’s usually up to manufacturers to develop and test their own to ensure that consumers understand how to use their products.

“Some stakeholders have identified the requirement ... as a barrier to development of OTC naloxone products,” so the agency developed two DFLs on its own – one for nasal spray naloxone, the other for auto-injectors – and completed the necessary label comprehension testing, according to an announcement from FDA Commissioner Scott Gottlieb, MD.

There’s not much else manufactures have to do, except deal with the details of their own products. They “can now focus their efforts on ... how well consumers understand the product-specific information that hasn’t been already tested in the model” DFLs, according to the announcement.

As deaths from opioid abuse continue to climb, the FDA is committed to increasing access to naloxone, which currently requires a prescription. The new DFLs “should jump-start the development of OTC naloxone products ... I personally urge companies to take notice of this pathway that the FDA has opened for them and come to the Agency with applications as soon as possible,” Dr. Gottlieb said.

Comprehension was assessed in more than 700 people, including heroin and prescription opioid users, their friends and families, and adolescents. “Overall, the study demonstrated that” the DFLs are “well-understood by consumers” and acceptable “for use by manufacturers in support of their ... development programs,” according to the announcement.

In a press statement, the American Medical Association applauded the agency’s move “to provide labeling that would allow for over-the-counter availability of naloxone, a move that will save people from opioid-related overdose ... The action should spur efforts by naloxone manufacturers to submit applications for their products to receive over-the-counter status.”

[email protected]

The Food and Drug Administration has smoothed the way to OTC naloxone by releasing “drug facts label” templates for manufacturers to use when submitting their products for consideration.

Drug facts labels (DFLs) are required for all OTC drugs, and it’s usually up to manufacturers to develop and test their own to ensure that consumers understand how to use their products.

“Some stakeholders have identified the requirement ... as a barrier to development of OTC naloxone products,” so the agency developed two DFLs on its own – one for nasal spray naloxone, the other for auto-injectors – and completed the necessary label comprehension testing, according to an announcement from FDA Commissioner Scott Gottlieb, MD.

There’s not much else manufactures have to do, except deal with the details of their own products. They “can now focus their efforts on ... how well consumers understand the product-specific information that hasn’t been already tested in the model” DFLs, according to the announcement.

As deaths from opioid abuse continue to climb, the FDA is committed to increasing access to naloxone, which currently requires a prescription. The new DFLs “should jump-start the development of OTC naloxone products ... I personally urge companies to take notice of this pathway that the FDA has opened for them and come to the Agency with applications as soon as possible,” Dr. Gottlieb said.

Comprehension was assessed in more than 700 people, including heroin and prescription opioid users, their friends and families, and adolescents. “Overall, the study demonstrated that” the DFLs are “well-understood by consumers” and acceptable “for use by manufacturers in support of their ... development programs,” according to the announcement.

In a press statement, the American Medical Association applauded the agency’s move “to provide labeling that would allow for over-the-counter availability of naloxone, a move that will save people from opioid-related overdose ... The action should spur efforts by naloxone manufacturers to submit applications for their products to receive over-the-counter status.”

[email protected]

More than 23% of all antibiotic prescriptions filled in 2016 were medically unnecessary, and another 36% were questionable, according to an analysis of prescribing data for 19.2 million children and nonelderly adults.

Based on the diagnosis codes for 15.5 million prescriptions filled that year, at least 3.6 million (23.2%) were “inappropriate” – prescribed for conditions for which an antibiotic is almost never recommended, such as acute upper respiratory conditions – and 5.5 million (35.5%) were “potentially inappropriate” – conditions such as acute sinusitis or otitis media, for which an antibiotic is only sometimes recommended, Kao-Ping Chua, MD, PhD, of the University of Michigan, Ann Arbor, and his associates reported in the BMJ.

Only 12.8% of filled prescriptions for the 39 oral antibiotics assessed were classified as “appropriate” under the investigators’ scheme, which assigned an antibiotic appropriateness level to all 91,738 diagnostic codes in the 2016 ICD-10-CM. Finally, 28.5% of antibiotic fills were not associated with a recent diagnosis code, suggesting that they involved phone consultations that did not result in claims or visits that were paid out of pocket and did not make it into the Truven MarketScan Commercial Claims and Encounters database used in the study, the investigators said.

The three highest levels of inappropriate fills were 70.7% in office-based settings, 6.2% in urgent care centers, and 4.7% in emergency departments.

“The unacceptable scale of inappropriate antibiotic prescribing in the United States ... underscores the need to learn more about prescriptions that aren’t justified by a diagnosis – or are written after no diagnosis at all,” coinvestigator Jeffrey Linder, MD, of Northwestern University, Chicago, said in a written statement.

Prescriptions for children, who represented almost a quarter of all antibiotic fills, were less likely to be inappropriate than those for adults aged 18-64 years. Proportions for children were 17.1% inappropriate, 48.7% potentially inappropriate, and 17.0% appropriate, compared with 25.2%, 31.4%, and 11.4%, respectively, for adults, Dr. Chua and his associates said.

“This study shows how data and analytics can help us identify and understand important challenges facing the American health care system,” said Gopal Khanna, director of the Agency for Healthcare Research and Quality, which funded the study. “We now need to use these data to spur change in the prescribing of these very common medications.”

[email protected]

SOURCE: Chua K-P et al. BMJ. 2019;364:k5092. doi: 10.1136/bmj.k5092.

More than 23% of all antibiotic prescriptions filled in 2016 were medically unnecessary, and another 36% were questionable, according to an analysis of prescribing data for 19.2 million children and nonelderly adults.

Based on the diagnosis codes for 15.5 million prescriptions filled that year, at least 3.6 million (23.2%) were “inappropriate” – prescribed for conditions for which an antibiotic is almost never recommended, such as acute upper respiratory conditions – and 5.5 million (35.5%) were “potentially inappropriate” – conditions such as acute sinusitis or otitis media, for which an antibiotic is only sometimes recommended, Kao-Ping Chua, MD, PhD, of the University of Michigan, Ann Arbor, and his associates reported in the BMJ.

Only 12.8% of filled prescriptions for the 39 oral antibiotics assessed were classified as “appropriate” under the investigators’ scheme, which assigned an antibiotic appropriateness level to all 91,738 diagnostic codes in the 2016 ICD-10-CM. Finally, 28.5% of antibiotic fills were not associated with a recent diagnosis code, suggesting that they involved phone consultations that did not result in claims or visits that were paid out of pocket and did not make it into the Truven MarketScan Commercial Claims and Encounters database used in the study, the investigators said.

The three highest levels of inappropriate fills were 70.7% in office-based settings, 6.2% in urgent care centers, and 4.7% in emergency departments.

“The unacceptable scale of inappropriate antibiotic prescribing in the United States ... underscores the need to learn more about prescriptions that aren’t justified by a diagnosis – or are written after no diagnosis at all,” coinvestigator Jeffrey Linder, MD, of Northwestern University, Chicago, said in a written statement.

Prescriptions for children, who represented almost a quarter of all antibiotic fills, were less likely to be inappropriate than those for adults aged 18-64 years. Proportions for children were 17.1% inappropriate, 48.7% potentially inappropriate, and 17.0% appropriate, compared with 25.2%, 31.4%, and 11.4%, respectively, for adults, Dr. Chua and his associates said.

“This study shows how data and analytics can help us identify and understand important challenges facing the American health care system,” said Gopal Khanna, director of the Agency for Healthcare Research and Quality, which funded the study. “We now need to use these data to spur change in the prescribing of these very common medications.”

[email protected]

SOURCE: Chua K-P et al. BMJ. 2019;364:k5092. doi: 10.1136/bmj.k5092.

More than 23% of all antibiotic prescriptions filled in 2016 were medically unnecessary, and another 36% were questionable, according to an analysis of prescribing data for 19.2 million children and nonelderly adults.

Based on the diagnosis codes for 15.5 million prescriptions filled that year, at least 3.6 million (23.2%) were “inappropriate” – prescribed for conditions for which an antibiotic is almost never recommended, such as acute upper respiratory conditions – and 5.5 million (35.5%) were “potentially inappropriate” – conditions such as acute sinusitis or otitis media, for which an antibiotic is only sometimes recommended, Kao-Ping Chua, MD, PhD, of the University of Michigan, Ann Arbor, and his associates reported in the BMJ.

Only 12.8% of filled prescriptions for the 39 oral antibiotics assessed were classified as “appropriate” under the investigators’ scheme, which assigned an antibiotic appropriateness level to all 91,738 diagnostic codes in the 2016 ICD-10-CM. Finally, 28.5% of antibiotic fills were not associated with a recent diagnosis code, suggesting that they involved phone consultations that did not result in claims or visits that were paid out of pocket and did not make it into the Truven MarketScan Commercial Claims and Encounters database used in the study, the investigators said.

The three highest levels of inappropriate fills were 70.7% in office-based settings, 6.2% in urgent care centers, and 4.7% in emergency departments.

“The unacceptable scale of inappropriate antibiotic prescribing in the United States ... underscores the need to learn more about prescriptions that aren’t justified by a diagnosis – or are written after no diagnosis at all,” coinvestigator Jeffrey Linder, MD, of Northwestern University, Chicago, said in a written statement.

Prescriptions for children, who represented almost a quarter of all antibiotic fills, were less likely to be inappropriate than those for adults aged 18-64 years. Proportions for children were 17.1% inappropriate, 48.7% potentially inappropriate, and 17.0% appropriate, compared with 25.2%, 31.4%, and 11.4%, respectively, for adults, Dr. Chua and his associates said.

“This study shows how data and analytics can help us identify and understand important challenges facing the American health care system,” said Gopal Khanna, director of the Agency for Healthcare Research and Quality, which funded the study. “We now need to use these data to spur change in the prescribing of these very common medications.”

[email protected]

SOURCE: Chua K-P et al. BMJ. 2019;364:k5092. doi: 10.1136/bmj.k5092.

In 2016, news reports warned the public of an opioid epidemic gripping the nation.

Karen Mower/iStockphoto

But Madeline Vaughn, then a lead clinical intake coordinator at the Houston-based addiction treatment organization Council on Recovery, sensed something different was going on with the patients she checked in from the street.

Their behavior, marked by twitchy suspicion, a poor memory, and the feeling that someone was following them, signaled that the people coming through the center’s doors were increasingly hooked on a different drug: methamphetamine.

“When you’re in the boots on the ground,” Ms. Vaughn said, “what you see may surprise you, because it’s not in the headlines.”

In the time since, it’s become increasingly clear that, even as the opioid epidemic continues, the toll of methamphetamine use, also known as meth or crystal meth, is on the rise, too.

The rate of overdose deaths involving the stimulant more than tripled from 2011 to 2016, the Centers for Disease Control and Prevention reported.

But unlike the opioid epidemic – for which medications exist to help combat addiction – medical providers have few such tools to help methamphetamine users survive and recover. A drug such as naloxone, which can reverse an opioid overdose, does not exist for meth. And there are no drugs approved by the Food and Drug Administration that can treat a meth addiction.

“We’re realizing that we don’t have everything we might wish we had to address these different kinds of drugs,” said Margaret Jarvis, MD, a psychiatrist and distinguished fellow for the American Society of Addiction Medicine.

Meth revs up the human body, causing euphoria, elevated blood pressure, and energy that enables users to go for days without sleeping or eating. In some cases, long-term use alters the user’s brain and causes psychotic symptoms that can take up to one year after the person has stopped using it to dissipate.

Overdosing can trigger heart attacks, strokes, and seizures, which can make pinpointing the drug’s involvement difficult.

Meth users also tend to abuse other substances, which complicates first responders’ efforts to treat a patient in the event of an overdose, said David Persse, MD, EMS physician director for Houston. With multiple drugs in a patient’s system, overdose symptoms may not neatly fit under the description for one substance.

“If we had five or six miracle drugs,” Dr. Persse said, to use immediately on the scene of the overdose, “it’s still gonna be difficult to know which one that patient needs.”

Research is underway to develop a medication that helps those with methamphetamine addiction overcome their condition. The National Institute on Drug Abuse Clinical Trials Network is testing a combination of naltrexone, a medication typically used to treat opioid and alcohol use disorders, and an antidepressant called bupropion.

And a team from the Universities of Kentucky and Arkansas created a molecule called lobeline that shows promise in blocking meth’s effects in the brain.

For now, though, existing treatments, such as the Matrix Model, a drug counseling technique, and contingency management, which offers patients incentives to stay away from drugs, are key options for what appears to be a meth resurgence, said Dr. Jarvis.

Illegal drugs never disappear from the street, she said. Their popularity waxes and wanes with demand. And as the demand for methamphetamine use increases, the gaps in treatment become more apparent.

Dr. Persse said he hasn’t seen a rise in the number of calls related to methamphetamine overdoses in his area. However, the death toll in Texas from meth now exceeds that of heroin.

Provisional death counts for 2017 showed methamphetamine claimed 813 lives in the Lone Star State. By comparison, 591 people died because of heroin.

The Drug Enforcement Administration reported that the price of meth is the lowest the agency has seen in years. It is increasingly available in the eastern region of the United States. Primary suppliers are Mexican drug cartels. And the meth on the streets is now more than 90% pure.

“The new methods [of making methamphetamine] have really altered the potency,” said Jane Maxwell, PhD, research professor at the University of Texas at Austin’s social work school. “So the meth we’re looking at today is much more potent than it was 10 years ago.”

For Ms. Vaughn, who works as an outpatient therapist and treatment coordinator, these variables are a regular part of her daily challenge. So until the research arms her with something new, her go-to strategy is to use the available tools to tackle her patients’ methamphetamine addiction in layers.

She starts with writing assignments, then coping skills until they are capable of unpacking their trauma. Addiction is rarely the sole demon patients wrestle with, Ms. Vaughn said.

“Substance use is often a symptom for what’s really going on with someone,” she said.

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

In 2016, news reports warned the public of an opioid epidemic gripping the nation.

Karen Mower/iStockphoto

But Madeline Vaughn, then a lead clinical intake coordinator at the Houston-based addiction treatment organization Council on Recovery, sensed something different was going on with the patients she checked in from the street.

Their behavior, marked by twitchy suspicion, a poor memory, and the feeling that someone was following them, signaled that the people coming through the center’s doors were increasingly hooked on a different drug: methamphetamine.

“When you’re in the boots on the ground,” Ms. Vaughn said, “what you see may surprise you, because it’s not in the headlines.”

In the time since, it’s become increasingly clear that, even as the opioid epidemic continues, the toll of methamphetamine use, also known as meth or crystal meth, is on the rise, too.

The rate of overdose deaths involving the stimulant more than tripled from 2011 to 2016, the Centers for Disease Control and Prevention reported.

But unlike the opioid epidemic – for which medications exist to help combat addiction – medical providers have few such tools to help methamphetamine users survive and recover. A drug such as naloxone, which can reverse an opioid overdose, does not exist for meth. And there are no drugs approved by the Food and Drug Administration that can treat a meth addiction.

“We’re realizing that we don’t have everything we might wish we had to address these different kinds of drugs,” said Margaret Jarvis, MD, a psychiatrist and distinguished fellow for the American Society of Addiction Medicine.

Meth revs up the human body, causing euphoria, elevated blood pressure, and energy that enables users to go for days without sleeping or eating. In some cases, long-term use alters the user’s brain and causes psychotic symptoms that can take up to one year after the person has stopped using it to dissipate.

Overdosing can trigger heart attacks, strokes, and seizures, which can make pinpointing the drug’s involvement difficult.

Meth users also tend to abuse other substances, which complicates first responders’ efforts to treat a patient in the event of an overdose, said David Persse, MD, EMS physician director for Houston. With multiple drugs in a patient’s system, overdose symptoms may not neatly fit under the description for one substance.

“If we had five or six miracle drugs,” Dr. Persse said, to use immediately on the scene of the overdose, “it’s still gonna be difficult to know which one that patient needs.”

Research is underway to develop a medication that helps those with methamphetamine addiction overcome their condition. The National Institute on Drug Abuse Clinical Trials Network is testing a combination of naltrexone, a medication typically used to treat opioid and alcohol use disorders, and an antidepressant called bupropion.

And a team from the Universities of Kentucky and Arkansas created a molecule called lobeline that shows promise in blocking meth’s effects in the brain.

For now, though, existing treatments, such as the Matrix Model, a drug counseling technique, and contingency management, which offers patients incentives to stay away from drugs, are key options for what appears to be a meth resurgence, said Dr. Jarvis.

Illegal drugs never disappear from the street, she said. Their popularity waxes and wanes with demand. And as the demand for methamphetamine use increases, the gaps in treatment become more apparent.

Dr. Persse said he hasn’t seen a rise in the number of calls related to methamphetamine overdoses in his area. However, the death toll in Texas from meth now exceeds that of heroin.

Provisional death counts for 2017 showed methamphetamine claimed 813 lives in the Lone Star State. By comparison, 591 people died because of heroin.

The Drug Enforcement Administration reported that the price of meth is the lowest the agency has seen in years. It is increasingly available in the eastern region of the United States. Primary suppliers are Mexican drug cartels. And the meth on the streets is now more than 90% pure.

“The new methods [of making methamphetamine] have really altered the potency,” said Jane Maxwell, PhD, research professor at the University of Texas at Austin’s social work school. “So the meth we’re looking at today is much more potent than it was 10 years ago.”

For Ms. Vaughn, who works as an outpatient therapist and treatment coordinator, these variables are a regular part of her daily challenge. So until the research arms her with something new, her go-to strategy is to use the available tools to tackle her patients’ methamphetamine addiction in layers.

She starts with writing assignments, then coping skills until they are capable of unpacking their trauma. Addiction is rarely the sole demon patients wrestle with, Ms. Vaughn said.

“Substance use is often a symptom for what’s really going on with someone,” she said.

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

In 2016, news reports warned the public of an opioid epidemic gripping the nation.

Karen Mower/iStockphoto

But Madeline Vaughn, then a lead clinical intake coordinator at the Houston-based addiction treatment organization Council on Recovery, sensed something different was going on with the patients she checked in from the street.

Their behavior, marked by twitchy suspicion, a poor memory, and the feeling that someone was following them, signaled that the people coming through the center’s doors were increasingly hooked on a different drug: methamphetamine.

“When you’re in the boots on the ground,” Ms. Vaughn said, “what you see may surprise you, because it’s not in the headlines.”

In the time since, it’s become increasingly clear that, even as the opioid epidemic continues, the toll of methamphetamine use, also known as meth or crystal meth, is on the rise, too.

The rate of overdose deaths involving the stimulant more than tripled from 2011 to 2016, the Centers for Disease Control and Prevention reported.

But unlike the opioid epidemic – for which medications exist to help combat addiction – medical providers have few such tools to help methamphetamine users survive and recover. A drug such as naloxone, which can reverse an opioid overdose, does not exist for meth. And there are no drugs approved by the Food and Drug Administration that can treat a meth addiction.

“We’re realizing that we don’t have everything we might wish we had to address these different kinds of drugs,” said Margaret Jarvis, MD, a psychiatrist and distinguished fellow for the American Society of Addiction Medicine.

Meth revs up the human body, causing euphoria, elevated blood pressure, and energy that enables users to go for days without sleeping or eating. In some cases, long-term use alters the user’s brain and causes psychotic symptoms that can take up to one year after the person has stopped using it to dissipate.

Overdosing can trigger heart attacks, strokes, and seizures, which can make pinpointing the drug’s involvement difficult.

Meth users also tend to abuse other substances, which complicates first responders’ efforts to treat a patient in the event of an overdose, said David Persse, MD, EMS physician director for Houston. With multiple drugs in a patient’s system, overdose symptoms may not neatly fit under the description for one substance.

“If we had five or six miracle drugs,” Dr. Persse said, to use immediately on the scene of the overdose, “it’s still gonna be difficult to know which one that patient needs.”

Research is underway to develop a medication that helps those with methamphetamine addiction overcome their condition. The National Institute on Drug Abuse Clinical Trials Network is testing a combination of naltrexone, a medication typically used to treat opioid and alcohol use disorders, and an antidepressant called bupropion.

And a team from the Universities of Kentucky and Arkansas created a molecule called lobeline that shows promise in blocking meth’s effects in the brain.

For now, though, existing treatments, such as the Matrix Model, a drug counseling technique, and contingency management, which offers patients incentives to stay away from drugs, are key options for what appears to be a meth resurgence, said Dr. Jarvis.

Illegal drugs never disappear from the street, she said. Their popularity waxes and wanes with demand. And as the demand for methamphetamine use increases, the gaps in treatment become more apparent.

Dr. Persse said he hasn’t seen a rise in the number of calls related to methamphetamine overdoses in his area. However, the death toll in Texas from meth now exceeds that of heroin.

Provisional death counts for 2017 showed methamphetamine claimed 813 lives in the Lone Star State. By comparison, 591 people died because of heroin.

The Drug Enforcement Administration reported that the price of meth is the lowest the agency has seen in years. It is increasingly available in the eastern region of the United States. Primary suppliers are Mexican drug cartels. And the meth on the streets is now more than 90% pure.

“The new methods [of making methamphetamine] have really altered the potency,” said Jane Maxwell, PhD, research professor at the University of Texas at Austin’s social work school. “So the meth we’re looking at today is much more potent than it was 10 years ago.”

For Ms. Vaughn, who works as an outpatient therapist and treatment coordinator, these variables are a regular part of her daily challenge. So until the research arms her with something new, her go-to strategy is to use the available tools to tackle her patients’ methamphetamine addiction in layers.

She starts with writing assignments, then coping skills until they are capable of unpacking their trauma. Addiction is rarely the sole demon patients wrestle with, Ms. Vaughn said.

“Substance use is often a symptom for what’s really going on with someone,” she said.

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Anaphylaxis is potentially fatal but can be prevented if the trigger is identified and avoided, and death can be avoided if episodes are treated promptly.

A consensus definition of anaphylaxis has been difficult to achieve, with slight variations among international guidelines. The World Allergy Organization classifies anaphylaxis as immunologic, nonimmunologic, or idiopathic.¹ The National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network highlight clinical symptoms and criteria.² The International Consensus on Food Allergy describes reactions as being immunoglobulin E (IgE)-mediated, cell-mediated, or a combination of the 2 mechanisms.³

Despite the subtle differences in these definitions, all 3 international organizations have a common recommendation for anaphylaxis: once it is diagnosed, epinephrine is the treatment of choice.

EPINEPHRINE IS THE TREATMENT OF CHOICE FOR ANAPHYLAXIS

Anaphylaxis commonly results from exposure to foods, medications, and Hymenoptera venom.⁴ Avoiding triggers is key in preventing anaphylaxis but is not always possible.

Although epinephrine is the cornerstone of the emergency treatment of anaphylaxis, many patients instead receive antihistamines and corticosteroids as initial therapy. Some take these medications on their own, and some receive them in emergency departments and outpatient clinics.⁵

Diphenhydramine, a histamine 1 receptor antagonist, is often used as a first-line medication. But diphenhydramine has a slow onset of action, taking 80 minutes after an oral dose to suppress a histamine-induced cutaneous flare by 50%, and taking 52 minutes with intramuscular administration.⁶ Corticosteroids also have a slow onset of action. These drugs cannot prevent death in anaphylaxis, a condition in which the median time to respiratory or cardiac arrest is 30 minutes after ingestion of food, 15 minutes after envenomation, and 5 minutes after iatrogenic reactions.⁷

Combination therapy with diphenhydra­mine and a histamine 2 receptor antagonist (eg, cimetidine, famotidine) is also commonly used,⁸ but this combination offers no advantage in terms of onset of action, and a Cochrane review could find no definitive evidence for or against the use of histamine 2 receptor antagonists.⁹

Because of their slow onset of action, all of these should be second-line therapies, given after epinephrine. Epinephrine is the first line of treatment because it has a maximal pharmacokinetic effect (time to maximal peak serum level) within 10 minutes of intramuscular injection into the thigh.^10,11

In addition, epinephrine acts on numerous receptors to antagonize the multiple pathologic effects of the mediators released during an anaphylactic episode. In contrast, antihistamines block only 1 mediator, while mediators other than histamine can be responsible for severe events and deaths.^12,13

It is crucial that epinephrine be given immediately, as delay has been associated with fatalities.¹⁴ In addition, guidelines recommend repeating epinephrine dosing after 5 to 15 minutes if the response to the first dose is suboptimal.^1,2 From 16% to 36% of patients may need a second dose.^15–18 Therefore, many physicians recommend that patients at risk of anaphylaxis keep not 1 but 2 epinephrine autoinjectors on hand at all times, and so say the US guidelines for the management of anaphylaxis.¹⁹

WHO SHOULD CARRY AN EPINEPHRINE AUTOINJECTOR?

All published guidelines recommend epinephrine as the drug of choice for anaphylaxis. And an epinephrine autoinjector is indicated for anyone who has experienced an anaphylactic event or is at risk of one, and these patients should carry it with them at all times. Such individuals include those with food allergy or Hymenoptera hypersensitivity.

Food allergy

The foods that most often cause anaphylaxis are peanuts, tree nuts, fish, shellfish, milk, and eggs, but any food can cause a reaction.

The prevalence of food allergy has increased over time, and treatments are limited. Some food desensitization protocols look promising but are still in the research stages. The best treatment at this time is to avoid the offending food, but there are accidental exposures.

Hymenoptera hypersensitivity

Patients who have had anaphylaxis after being stung by insects such as bees, wasps, yellow-faced hornets, white-faced hornets, yellow jackets, and fire ants should be evaluated by an allergist. Skin testing and serum IgE testing helps properly diagnose Hymenoptera hypersensitivity.

Once the diagnosis is confirmed, venom immunotherapy should be considered. Some patients choose only to carry an epinephrine autoinjector and to avoid these insects as much as possible. However, most patients also choose to receive venom immunotherapy, because 80% to 90% of those who receive this treatment for 3 to 5 years do not have a systemic reaction if they are stung again.²⁰

Regardless of whether they choose to undergo immunotherapy, sensitive patients should always carry an epinephrine autoinjector. This is also the case after treatment ends, since the therapy is not 100% effective.

In other patients who may be at increased risk, the mandate for an epinephrine autoinjector is less clear, and the decision to carry one is determined on an individual basis. Such individuals are those receiving allergen immunotherapy, with large local reactions to insect stings, with oral allergy syndrome, with mastocytosis, and with drug allergy. In these cases, the benefit vs the burden of carrying an autoinjector should be discussed with the patient.

Patients on allergen immunotherapy

National guidelines recommend that all patients who receive allergen immunotherapy be monitored in the clinic under a physician’s supervision for 30 minutes after the injection. Fortunately, life-threatening reactions occurring after 30 minutes are rare. But delayed systemic reactions can occur and may account for up to 50% of such events.²¹

Therefore, many physicians consider it prudent for patients on immunotherapy to carry an epinephrine autoinjector, but there is no consensus. A survey²² found that 13.5% of allergists did not prescribe the autoinjector for patients on immunotherapy, while 33.3% prescribed it for all their patients on immunotherapy, and the rest prescribed based on risk.

Since there are no national guidelines on epinephrine autoinjectors for patients on immunotherapy, the decision should be based on the patient’s risks and comorbidities and informed by discussion between the individual patient and his or her allergist.

Patients with large local reactions to insect stings

From 5% to 10% of patients who have large local reactions to insect stings are at risk of systemic reactions.²⁰

Patients with oral allergy syndrome

Oral allergy syndrome, also known as pollen-food allergy, causes itching and mild swelling of the mouth, lips, and throat after eating fresh fruits and vegetables. The prevalence ranges from 2% to 10% of patients with allergies.²³

A survey of allergists found that 20% of patients with oral allergy syndrome had experienced systemic symptoms.²⁴ The survey also showed that the decision to prescribe an epinephrine autoinjector to these patients was highly variable. Only about 30% of allergists recommend epinephrine autoinjectors to patients with oral allergy syndrome, while most believe that the decision should be based on the individual’s symptoms and risk.

More research is needed in the area of food allergy. Because data are limited, there are no national guidelines on whether these patients should carry an epinephrine autoinjector. We agree with the Joint Task Force on Practice Parameters¹⁴ recommendation that the decision be made on an individual basis following discussion between the patient and physician. 

Patients with mastocytosis

Patients with mastocytosis and a history of anaphylaxis are at increased risk for systemic reactions to Hymenoptera venom.

Patients with medication allergy

Once medication allergy has been diagnosed, avoidance is usually effective, obviating the need for an epinephrine autoinjector, although the physician has the option of prescribing one.

CAUTIONS, NOT CONTRAINDICATIONS

Physicians may be reluctant to prescribe an epinephrine autoinjector because of the risk of an adverse reaction in patients with hypertension, coronary artery disease, or arrhythmias, and in elderly patients taking multiple drugs, especially drugs that can interact with epinephrine. Nevertheless, there is no absolute contraindication to the use of epinephrine in anaphylaxis.

In patients with atherosclerosis and cardiovascular disease

Epinephrine increases vasoconstriction, heart rate, and cardiac force of contraction. These effects are beneficial during anaphylaxis, but in rare cases patients have experienced myocardial infarction and acute coronary syndrome after receiving intravenous epinephrine.²⁵ These incidents have naturally prompted reluctance to prescribe it in susceptible patients with coronary disease during anaphylaxis.

Yet epinephrine may not be solely to blame for these adverse responses. Mast cells are abundant in the heart, and their release of mediators can also result in adverse cardiac manifestations, including myocardial infarction.²⁶

Conversely, some drugs used to treat cardiovascular disease can worsen anaphylaxis.

Beta-blockers can cause bronchospasm and decrease cardiac contractility. They can also blunt the pharmacologic effects of epinephrine. There is concern that epinephrine may produce dangerous elevations of blood pressure in patients taking beta-blockers by unopposed alpha-adrenergic stimulation and reflex vagotonic effects.²⁷ And there is evidence that beta-blockers may increase the risk and severity of reactions. One study reported that patients taking beta-blockers are more than 8 times more likely to be hospitalized due to anaphylactoid reaction with bronchospasm.²⁸

Beta-blockers and, to a lesser extent, angiotensin-converting enzyme inhibitors have been shown to increase the risk of anaphylaxis in the emergency department.^29,30 However, some investigators have not found beta-blockers to be a risk factor. A study evaluating anaphylactoid reactions from contrast media found no statistically significant higher risk in patients taking beta-blockers.³¹ Similarly, a study of 3,178 patients on beta-blockers receiving venom immunotherapy or allergen immunotherapy found no increase in the frequency of systemic reactions.³² Nevertheless, overall, more studies support the hypothesis that beta-blockers may be an additional risk factor in anaphylaxis.³³

Thus, clinicians treating patients with cardiovascular disease and anaphylaxis face a dilemma. Although there is concern in this population, epinephrine should not be withheld in patients with cardiovascular disease who are experiencing an anaphylactic event.³³ If epinephrine is not administered, the patient could die.

Elderly patients on multiple medications

Older patients are also at risk of anaphylaxis. But clinicians are reluctant to treat older patients with epinephrine because of concerns about adverse effects.

Epinephrine dispensing rates vary substantially in different age groups: 1.44% for patients under age 17, 0.9% for those ages 17 to 64, and 0.32% for those age 65 or older.³⁴ A Canadian study of 492 patients with anaphylaxis in the emergency department showed that those over age 50 received epinephrine less often than younger patients (36.1% vs 60.5%).³⁵ Cardiovascular complications were more frequent in the older group, occurring in 4 (9.1%) of the 44 older patients who received epinephrine compared with 1 (0.4%) of the 225 younger patients who received it. On the other hand, the rate of adverse effects from subcutaneous epinephrine was no different in older asthma patients compared with younger patients.³⁶

Many older patients take multiple medications, raising concern about adverse effects. Commonly prescribed medications in the elderly can affect the actions of epinephrine. Monoamine oxidase inhibitors retard the catabolism of epinephrine. Tricyclic antidepressants may decrease the reuptake of catecholamines by neurons and thus interfere with the degradation of epinephrine. Digoxin has a narrow therapeutic window and can potentially increase the risk of arrhythmias when given with epinephrine.

Although the clinician must be cautious in treating older patients who have comorbidities, these are not sufficient to withhold prescribing an epinephrine autoinjector to elderly patients at risk of anaphylaxis.

Epinephrine autoinjectors come preloaded for prompt delivery of the drug. They are intended primarily for use by patients themselves in unsupervised settings in suspected anaphylaxis. Simplicity of use and safety must be considered in such a setting so that patients can use the device correctly and are not incorrectly dosed.

Several models are commercially available, with different ergonomic designs and sizes. EpiPen, the first one marketed in the United States, was introduced in 1987. One device (Auvi-Q) contains an audio chip that gives step-by-step instructions at the time of use. It is hoped that this device will reduce errors in usage during this stressful time for patients and caregivers.

In the United States, epinephrine autoinjectors contain either 0.15 or 0.30 mg of the drug, but some clinicians believe this may not be enough. The UK Resuscitation Council recommends 0.50 mg for patients over age 12,³⁷ and an epinephrine autoinjector with that dose is available in Europe.

Subcutaneous vs intramuscular delivery

The package insert for some epinephrine autoinjectors says the injector can be used to treat anaphylaxis by both subcutaneous and intramuscular administration. However, the routes are not equivalent.

The goal in anaphylaxis is to quickly achieve high tissue and plasma epinephrine concentrations, and studies have found that injection into the vastus lateralis muscle, but not the deltoid muscle, results in faster time to peak plasma concentration: 8 minutes for injection in the vastus lateralis muscle and 34 minutes for subcutaneous delivery.^10,11 In addition, injection in the vastus lateralis muscle results in a higher peak plasma concentration than the subcutaneous or deltoid route. Based on these data, intramuscular injection into the vastus lateralis muscle in the thigh appears to be the preferred route of administration of epinephrine.

Obese patients may need a longer needle

Research on the original autoinjector was conducted by the US military, which wanted a rapidly effective and easy-to-use antidote for battlefield exposure to poison gas. The resulting device had 2 separate spring-loaded syringes, 1 containing pralidoxime chloride and the other atropine sulfate. To enable its use through the thick fabric of a chemical warfare suit, the needles were 2.2 cm long.

The first commercial autoinjector to contain epinephrine was made by Survival Technology (Bethesda, MD) in the mid-1970s. The manufacturer considered a 2.2-cm needle to be too long, and the first commercially available epinephrine autoinjector, EpiPen, had a 1.43-cm needle for adult use.

Since then, needle lengths have ranged from 1.17 to 2.5 cm to accommodate different skin-to-muscle depths, with shorter needles for children and longer needles for obese adults.³⁸

However, the prevalence of obesity is high and continues to rise.³⁹ Obesity raises concern that the needles in epinephrine autoinjectors may be too short for the preferred intramuscular delivery, resulting in subcutaneous deposition.

A study that used computed tomography of the thigh found that 1 (2%) of 50 men and 21 (42%) of 50 women studied had a subcutaneous tissue depth greater than 1.43 cm, the needle length in EpiPen. These were not anaphylaxis patients, but the findings suggest that many patients—especially women—may be getting subcutaneous instead of intramuscular delivery with this device.⁴⁰

Another study that used ultrasonography showed that the 1.43-cm EpiPen needle was too short for 36 (31%) of 116 adults.⁴¹ Women were 6.4 times more likely than men to encounter this problem. Other risk factors include higher body mass index, short height, and thicker thighs.

Emerade, an injector with a 2.5-cm needle, is available in some European countries. A longer needle may be helpful in some cases. but we do not yet have enough data to determine the optimal needle length.

Conversely, some children may need shorter needles and may in fact be at risk of having the needle penetrate bone.⁴² The US Food and Drug Administration recently approved a shorter needle for an epinephrine autoinjector (Auvi-Q) to be used in children weighing 7.5 kg to 15 kg.

BARRIERS TO USING EPINEPHRINE AUTOINJECTORS

Many patients do not use their epinephrine autoinjector in times of anaphylaxis or do not have one with them. Common reasons cited by respondents in a survey⁴³ of 1,385 patients included the following:

They took an oral antihistamine instead (38%).

They never received a prescription for an epinephrine autoinjector (28%).

They thought their symptoms were mild and would resolve with time (13%).

They were afraid (6%). There are reports of accidental injection, typically into fingers, hands, and thumbs. Fortunately, most accidental injections do not require a hand surgeon evaluation or surgery.⁴⁴ Conservative therapy and monitoring of the injection site are sufficient in most cases.

They could not afford an epinephrine autoinjector (1%).⁴³ Mylan Pharmaceuticals infamously increased the price of its EpiPen to more than $600 for a package of 2 pens. Generic devices are available in the United States but are still too expensive for some patients and are cumbersome to carry.

However, even expensive epinephrine autoinjectors may be cost-effective. Epidemiologic studies have found that patients who did not use an epinephrine autoinjector incurred a higher burden of cost due to emergency department visits and inpatient hospitalizations.⁴⁵

As a do-it-yourself option, some resourceful patients are obtaining autoinjectors intended for insulin injection, replacing the needle, and filling the injector with epinephrine, at a cost of about $30. (The manufacturer does not endorse this off-label use of their device—www.owenmumford.com/us/patients/if-you-need-to-inject.) Least costly of all is to prescribe multidose vials of epinephrine and regular syringes and teach patients and their caregivers how to draw up the proper dose and give themselves an injection—in essence going back to what was done before 1987.

It was past its expiration date (2%).⁴³ Failure to refill the prescription is common. A California Kaiser Permanente study⁴⁶ showed that only 46% of patients refilled their epinephrine autoinjector prescription at least once, and the refill rate decreased over time: 43% at 1 to 2 year follow-up, 35% at 3 to 4 years, and 30% at 5 years or longer. Based on these data, it is imperative to educate patients regarding the importance of replacing the epinephrine autoinjector when the old one expires.

NEED FOR PATIENT EDUCATION

Even though prompt treatment with epinephrine decreases fatalities, it continues to be underused in the community. In addition, it is often prescribed without adequate training in its use and appropriate emphasis on the need to keep the device on hand at all times and to replace it in a timely manner if it is used or has expired. Physicians need to educate patients on how to avoid triggers and how to recognize symptoms of anaphylaxis whenever they prescribe an epinephrine autoinjector.

Anaphylaxis is potentially fatal but can be prevented if the trigger is identified and avoided, and death can be avoided if episodes are treated promptly.

A consensus definition of anaphylaxis has been difficult to achieve, with slight variations among international guidelines. The World Allergy Organization classifies anaphylaxis as immunologic, nonimmunologic, or idiopathic.¹ The National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network highlight clinical symptoms and criteria.² The International Consensus on Food Allergy describes reactions as being immunoglobulin E (IgE)-mediated, cell-mediated, or a combination of the 2 mechanisms.³

Despite the subtle differences in these definitions, all 3 international organizations have a common recommendation for anaphylaxis: once it is diagnosed, epinephrine is the treatment of choice.

EPINEPHRINE IS THE TREATMENT OF CHOICE FOR ANAPHYLAXIS

Anaphylaxis commonly results from exposure to foods, medications, and Hymenoptera venom.⁴ Avoiding triggers is key in preventing anaphylaxis but is not always possible.

Although epinephrine is the cornerstone of the emergency treatment of anaphylaxis, many patients instead receive antihistamines and corticosteroids as initial therapy. Some take these medications on their own, and some receive them in emergency departments and outpatient clinics.⁵

Diphenhydramine, a histamine 1 receptor antagonist, is often used as a first-line medication. But diphenhydramine has a slow onset of action, taking 80 minutes after an oral dose to suppress a histamine-induced cutaneous flare by 50%, and taking 52 minutes with intramuscular administration.⁶ Corticosteroids also have a slow onset of action. These drugs cannot prevent death in anaphylaxis, a condition in which the median time to respiratory or cardiac arrest is 30 minutes after ingestion of food, 15 minutes after envenomation, and 5 minutes after iatrogenic reactions.⁷

Combination therapy with diphenhydra­mine and a histamine 2 receptor antagonist (eg, cimetidine, famotidine) is also commonly used,⁸ but this combination offers no advantage in terms of onset of action, and a Cochrane review could find no definitive evidence for or against the use of histamine 2 receptor antagonists.⁹

Because of their slow onset of action, all of these should be second-line therapies, given after epinephrine. Epinephrine is the first line of treatment because it has a maximal pharmacokinetic effect (time to maximal peak serum level) within 10 minutes of intramuscular injection into the thigh.^10,11

In addition, epinephrine acts on numerous receptors to antagonize the multiple pathologic effects of the mediators released during an anaphylactic episode. In contrast, antihistamines block only 1 mediator, while mediators other than histamine can be responsible for severe events and deaths.^12,13

It is crucial that epinephrine be given immediately, as delay has been associated with fatalities.¹⁴ In addition, guidelines recommend repeating epinephrine dosing after 5 to 15 minutes if the response to the first dose is suboptimal.^1,2 From 16% to 36% of patients may need a second dose.^15–18 Therefore, many physicians recommend that patients at risk of anaphylaxis keep not 1 but 2 epinephrine autoinjectors on hand at all times, and so say the US guidelines for the management of anaphylaxis.¹⁹

WHO SHOULD CARRY AN EPINEPHRINE AUTOINJECTOR?

All published guidelines recommend epinephrine as the drug of choice for anaphylaxis. And an epinephrine autoinjector is indicated for anyone who has experienced an anaphylactic event or is at risk of one, and these patients should carry it with them at all times. Such individuals include those with food allergy or Hymenoptera hypersensitivity.

Food allergy

The foods that most often cause anaphylaxis are peanuts, tree nuts, fish, shellfish, milk, and eggs, but any food can cause a reaction.

The prevalence of food allergy has increased over time, and treatments are limited. Some food desensitization protocols look promising but are still in the research stages. The best treatment at this time is to avoid the offending food, but there are accidental exposures.

Hymenoptera hypersensitivity

Patients who have had anaphylaxis after being stung by insects such as bees, wasps, yellow-faced hornets, white-faced hornets, yellow jackets, and fire ants should be evaluated by an allergist. Skin testing and serum IgE testing helps properly diagnose Hymenoptera hypersensitivity.

Once the diagnosis is confirmed, venom immunotherapy should be considered. Some patients choose only to carry an epinephrine autoinjector and to avoid these insects as much as possible. However, most patients also choose to receive venom immunotherapy, because 80% to 90% of those who receive this treatment for 3 to 5 years do not have a systemic reaction if they are stung again.²⁰

Regardless of whether they choose to undergo immunotherapy, sensitive patients should always carry an epinephrine autoinjector. This is also the case after treatment ends, since the therapy is not 100% effective.

In other patients who may be at increased risk, the mandate for an epinephrine autoinjector is less clear, and the decision to carry one is determined on an individual basis. Such individuals are those receiving allergen immunotherapy, with large local reactions to insect stings, with oral allergy syndrome, with mastocytosis, and with drug allergy. In these cases, the benefit vs the burden of carrying an autoinjector should be discussed with the patient.

Patients on allergen immunotherapy

National guidelines recommend that all patients who receive allergen immunotherapy be monitored in the clinic under a physician’s supervision for 30 minutes after the injection. Fortunately, life-threatening reactions occurring after 30 minutes are rare. But delayed systemic reactions can occur and may account for up to 50% of such events.²¹

Therefore, many physicians consider it prudent for patients on immunotherapy to carry an epinephrine autoinjector, but there is no consensus. A survey²² found that 13.5% of allergists did not prescribe the autoinjector for patients on immunotherapy, while 33.3% prescribed it for all their patients on immunotherapy, and the rest prescribed based on risk.

Since there are no national guidelines on epinephrine autoinjectors for patients on immunotherapy, the decision should be based on the patient’s risks and comorbidities and informed by discussion between the individual patient and his or her allergist.

Patients with large local reactions to insect stings

From 5% to 10% of patients who have large local reactions to insect stings are at risk of systemic reactions.²⁰

Patients with oral allergy syndrome

Oral allergy syndrome, also known as pollen-food allergy, causes itching and mild swelling of the mouth, lips, and throat after eating fresh fruits and vegetables. The prevalence ranges from 2% to 10% of patients with allergies.²³

A survey of allergists found that 20% of patients with oral allergy syndrome had experienced systemic symptoms.²⁴ The survey also showed that the decision to prescribe an epinephrine autoinjector to these patients was highly variable. Only about 30% of allergists recommend epinephrine autoinjectors to patients with oral allergy syndrome, while most believe that the decision should be based on the individual’s symptoms and risk.

More research is needed in the area of food allergy. Because data are limited, there are no national guidelines on whether these patients should carry an epinephrine autoinjector. We agree with the Joint Task Force on Practice Parameters¹⁴ recommendation that the decision be made on an individual basis following discussion between the patient and physician. 

Patients with mastocytosis

Patients with mastocytosis and a history of anaphylaxis are at increased risk for systemic reactions to Hymenoptera venom.

Patients with medication allergy

Once medication allergy has been diagnosed, avoidance is usually effective, obviating the need for an epinephrine autoinjector, although the physician has the option of prescribing one.

CAUTIONS, NOT CONTRAINDICATIONS

Physicians may be reluctant to prescribe an epinephrine autoinjector because of the risk of an adverse reaction in patients with hypertension, coronary artery disease, or arrhythmias, and in elderly patients taking multiple drugs, especially drugs that can interact with epinephrine. Nevertheless, there is no absolute contraindication to the use of epinephrine in anaphylaxis.

In patients with atherosclerosis and cardiovascular disease

Epinephrine increases vasoconstriction, heart rate, and cardiac force of contraction. These effects are beneficial during anaphylaxis, but in rare cases patients have experienced myocardial infarction and acute coronary syndrome after receiving intravenous epinephrine.²⁵ These incidents have naturally prompted reluctance to prescribe it in susceptible patients with coronary disease during anaphylaxis.

Yet epinephrine may not be solely to blame for these adverse responses. Mast cells are abundant in the heart, and their release of mediators can also result in adverse cardiac manifestations, including myocardial infarction.²⁶

Conversely, some drugs used to treat cardiovascular disease can worsen anaphylaxis.

Beta-blockers can cause bronchospasm and decrease cardiac contractility. They can also blunt the pharmacologic effects of epinephrine. There is concern that epinephrine may produce dangerous elevations of blood pressure in patients taking beta-blockers by unopposed alpha-adrenergic stimulation and reflex vagotonic effects.²⁷ And there is evidence that beta-blockers may increase the risk and severity of reactions. One study reported that patients taking beta-blockers are more than 8 times more likely to be hospitalized due to anaphylactoid reaction with bronchospasm.²⁸

Beta-blockers and, to a lesser extent, angiotensin-converting enzyme inhibitors have been shown to increase the risk of anaphylaxis in the emergency department.^29,30 However, some investigators have not found beta-blockers to be a risk factor. A study evaluating anaphylactoid reactions from contrast media found no statistically significant higher risk in patients taking beta-blockers.³¹ Similarly, a study of 3,178 patients on beta-blockers receiving venom immunotherapy or allergen immunotherapy found no increase in the frequency of systemic reactions.³² Nevertheless, overall, more studies support the hypothesis that beta-blockers may be an additional risk factor in anaphylaxis.³³

Thus, clinicians treating patients with cardiovascular disease and anaphylaxis face a dilemma. Although there is concern in this population, epinephrine should not be withheld in patients with cardiovascular disease who are experiencing an anaphylactic event.³³ If epinephrine is not administered, the patient could die.

Elderly patients on multiple medications

Older patients are also at risk of anaphylaxis. But clinicians are reluctant to treat older patients with epinephrine because of concerns about adverse effects.

Epinephrine dispensing rates vary substantially in different age groups: 1.44% for patients under age 17, 0.9% for those ages 17 to 64, and 0.32% for those age 65 or older.³⁴ A Canadian study of 492 patients with anaphylaxis in the emergency department showed that those over age 50 received epinephrine less often than younger patients (36.1% vs 60.5%).³⁵ Cardiovascular complications were more frequent in the older group, occurring in 4 (9.1%) of the 44 older patients who received epinephrine compared with 1 (0.4%) of the 225 younger patients who received it. On the other hand, the rate of adverse effects from subcutaneous epinephrine was no different in older asthma patients compared with younger patients.³⁶

Many older patients take multiple medications, raising concern about adverse effects. Commonly prescribed medications in the elderly can affect the actions of epinephrine. Monoamine oxidase inhibitors retard the catabolism of epinephrine. Tricyclic antidepressants may decrease the reuptake of catecholamines by neurons and thus interfere with the degradation of epinephrine. Digoxin has a narrow therapeutic window and can potentially increase the risk of arrhythmias when given with epinephrine.

Although the clinician must be cautious in treating older patients who have comorbidities, these are not sufficient to withhold prescribing an epinephrine autoinjector to elderly patients at risk of anaphylaxis.

Epinephrine autoinjectors come preloaded for prompt delivery of the drug. They are intended primarily for use by patients themselves in unsupervised settings in suspected anaphylaxis. Simplicity of use and safety must be considered in such a setting so that patients can use the device correctly and are not incorrectly dosed.

Several models are commercially available, with different ergonomic designs and sizes. EpiPen, the first one marketed in the United States, was introduced in 1987. One device (Auvi-Q) contains an audio chip that gives step-by-step instructions at the time of use. It is hoped that this device will reduce errors in usage during this stressful time for patients and caregivers.

In the United States, epinephrine autoinjectors contain either 0.15 or 0.30 mg of the drug, but some clinicians believe this may not be enough. The UK Resuscitation Council recommends 0.50 mg for patients over age 12,³⁷ and an epinephrine autoinjector with that dose is available in Europe.

Subcutaneous vs intramuscular delivery

The package insert for some epinephrine autoinjectors says the injector can be used to treat anaphylaxis by both subcutaneous and intramuscular administration. However, the routes are not equivalent.

The goal in anaphylaxis is to quickly achieve high tissue and plasma epinephrine concentrations, and studies have found that injection into the vastus lateralis muscle, but not the deltoid muscle, results in faster time to peak plasma concentration: 8 minutes for injection in the vastus lateralis muscle and 34 minutes for subcutaneous delivery.^10,11 In addition, injection in the vastus lateralis muscle results in a higher peak plasma concentration than the subcutaneous or deltoid route. Based on these data, intramuscular injection into the vastus lateralis muscle in the thigh appears to be the preferred route of administration of epinephrine.

Obese patients may need a longer needle

Research on the original autoinjector was conducted by the US military, which wanted a rapidly effective and easy-to-use antidote for battlefield exposure to poison gas. The resulting device had 2 separate spring-loaded syringes, 1 containing pralidoxime chloride and the other atropine sulfate. To enable its use through the thick fabric of a chemical warfare suit, the needles were 2.2 cm long.

The first commercial autoinjector to contain epinephrine was made by Survival Technology (Bethesda, MD) in the mid-1970s. The manufacturer considered a 2.2-cm needle to be too long, and the first commercially available epinephrine autoinjector, EpiPen, had a 1.43-cm needle for adult use.

Since then, needle lengths have ranged from 1.17 to 2.5 cm to accommodate different skin-to-muscle depths, with shorter needles for children and longer needles for obese adults.³⁸

However, the prevalence of obesity is high and continues to rise.³⁹ Obesity raises concern that the needles in epinephrine autoinjectors may be too short for the preferred intramuscular delivery, resulting in subcutaneous deposition.

A study that used computed tomography of the thigh found that 1 (2%) of 50 men and 21 (42%) of 50 women studied had a subcutaneous tissue depth greater than 1.43 cm, the needle length in EpiPen. These were not anaphylaxis patients, but the findings suggest that many patients—especially women—may be getting subcutaneous instead of intramuscular delivery with this device.⁴⁰

Another study that used ultrasonography showed that the 1.43-cm EpiPen needle was too short for 36 (31%) of 116 adults.⁴¹ Women were 6.4 times more likely than men to encounter this problem. Other risk factors include higher body mass index, short height, and thicker thighs.

Emerade, an injector with a 2.5-cm needle, is available in some European countries. A longer needle may be helpful in some cases. but we do not yet have enough data to determine the optimal needle length.

Conversely, some children may need shorter needles and may in fact be at risk of having the needle penetrate bone.⁴² The US Food and Drug Administration recently approved a shorter needle for an epinephrine autoinjector (Auvi-Q) to be used in children weighing 7.5 kg to 15 kg.

BARRIERS TO USING EPINEPHRINE AUTOINJECTORS

Many patients do not use their epinephrine autoinjector in times of anaphylaxis or do not have one with them. Common reasons cited by respondents in a survey⁴³ of 1,385 patients included the following:

They took an oral antihistamine instead (38%).

They never received a prescription for an epinephrine autoinjector (28%).

They thought their symptoms were mild and would resolve with time (13%).

They were afraid (6%). There are reports of accidental injection, typically into fingers, hands, and thumbs. Fortunately, most accidental injections do not require a hand surgeon evaluation or surgery.⁴⁴ Conservative therapy and monitoring of the injection site are sufficient in most cases.

They could not afford an epinephrine autoinjector (1%).⁴³ Mylan Pharmaceuticals infamously increased the price of its EpiPen to more than $600 for a package of 2 pens. Generic devices are available in the United States but are still too expensive for some patients and are cumbersome to carry.

However, even expensive epinephrine autoinjectors may be cost-effective. Epidemiologic studies have found that patients who did not use an epinephrine autoinjector incurred a higher burden of cost due to emergency department visits and inpatient hospitalizations.⁴⁵

As a do-it-yourself option, some resourceful patients are obtaining autoinjectors intended for insulin injection, replacing the needle, and filling the injector with epinephrine, at a cost of about $30. (The manufacturer does not endorse this off-label use of their device—www.owenmumford.com/us/patients/if-you-need-to-inject.) Least costly of all is to prescribe multidose vials of epinephrine and regular syringes and teach patients and their caregivers how to draw up the proper dose and give themselves an injection—in essence going back to what was done before 1987.

It was past its expiration date (2%).⁴³ Failure to refill the prescription is common. A California Kaiser Permanente study⁴⁶ showed that only 46% of patients refilled their epinephrine autoinjector prescription at least once, and the refill rate decreased over time: 43% at 1 to 2 year follow-up, 35% at 3 to 4 years, and 30% at 5 years or longer. Based on these data, it is imperative to educate patients regarding the importance of replacing the epinephrine autoinjector when the old one expires.

NEED FOR PATIENT EDUCATION

Even though prompt treatment with epinephrine decreases fatalities, it continues to be underused in the community. In addition, it is often prescribed without adequate training in its use and appropriate emphasis on the need to keep the device on hand at all times and to replace it in a timely manner if it is used or has expired. Physicians need to educate patients on how to avoid triggers and how to recognize symptoms of anaphylaxis whenever they prescribe an epinephrine autoinjector.

Anaphylaxis is potentially fatal but can be prevented if the trigger is identified and avoided, and death can be avoided if episodes are treated promptly.

A consensus definition of anaphylaxis has been difficult to achieve, with slight variations among international guidelines. The World Allergy Organization classifies anaphylaxis as immunologic, nonimmunologic, or idiopathic.¹ The National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network highlight clinical symptoms and criteria.² The International Consensus on Food Allergy describes reactions as being immunoglobulin E (IgE)-mediated, cell-mediated, or a combination of the 2 mechanisms.³

Despite the subtle differences in these definitions, all 3 international organizations have a common recommendation for anaphylaxis: once it is diagnosed, epinephrine is the treatment of choice.

EPINEPHRINE IS THE TREATMENT OF CHOICE FOR ANAPHYLAXIS

Anaphylaxis commonly results from exposure to foods, medications, and Hymenoptera venom.⁴ Avoiding triggers is key in preventing anaphylaxis but is not always possible.

Although epinephrine is the cornerstone of the emergency treatment of anaphylaxis, many patients instead receive antihistamines and corticosteroids as initial therapy. Some take these medications on their own, and some receive them in emergency departments and outpatient clinics.⁵

Diphenhydramine, a histamine 1 receptor antagonist, is often used as a first-line medication. But diphenhydramine has a slow onset of action, taking 80 minutes after an oral dose to suppress a histamine-induced cutaneous flare by 50%, and taking 52 minutes with intramuscular administration.⁶ Corticosteroids also have a slow onset of action. These drugs cannot prevent death in anaphylaxis, a condition in which the median time to respiratory or cardiac arrest is 30 minutes after ingestion of food, 15 minutes after envenomation, and 5 minutes after iatrogenic reactions.⁷

Combination therapy with diphenhydra­mine and a histamine 2 receptor antagonist (eg, cimetidine, famotidine) is also commonly used,⁸ but this combination offers no advantage in terms of onset of action, and a Cochrane review could find no definitive evidence for or against the use of histamine 2 receptor antagonists.⁹

Because of their slow onset of action, all of these should be second-line therapies, given after epinephrine. Epinephrine is the first line of treatment because it has a maximal pharmacokinetic effect (time to maximal peak serum level) within 10 minutes of intramuscular injection into the thigh.^10,11

In addition, epinephrine acts on numerous receptors to antagonize the multiple pathologic effects of the mediators released during an anaphylactic episode. In contrast, antihistamines block only 1 mediator, while mediators other than histamine can be responsible for severe events and deaths.^12,13

It is crucial that epinephrine be given immediately, as delay has been associated with fatalities.¹⁴ In addition, guidelines recommend repeating epinephrine dosing after 5 to 15 minutes if the response to the first dose is suboptimal.^1,2 From 16% to 36% of patients may need a second dose.^15–18 Therefore, many physicians recommend that patients at risk of anaphylaxis keep not 1 but 2 epinephrine autoinjectors on hand at all times, and so say the US guidelines for the management of anaphylaxis.¹⁹

WHO SHOULD CARRY AN EPINEPHRINE AUTOINJECTOR?

All published guidelines recommend epinephrine as the drug of choice for anaphylaxis. And an epinephrine autoinjector is indicated for anyone who has experienced an anaphylactic event or is at risk of one, and these patients should carry it with them at all times. Such individuals include those with food allergy or Hymenoptera hypersensitivity.

Food allergy

The foods that most often cause anaphylaxis are peanuts, tree nuts, fish, shellfish, milk, and eggs, but any food can cause a reaction.

The prevalence of food allergy has increased over time, and treatments are limited. Some food desensitization protocols look promising but are still in the research stages. The best treatment at this time is to avoid the offending food, but there are accidental exposures.

Hymenoptera hypersensitivity

Patients who have had anaphylaxis after being stung by insects such as bees, wasps, yellow-faced hornets, white-faced hornets, yellow jackets, and fire ants should be evaluated by an allergist. Skin testing and serum IgE testing helps properly diagnose Hymenoptera hypersensitivity.

Once the diagnosis is confirmed, venom immunotherapy should be considered. Some patients choose only to carry an epinephrine autoinjector and to avoid these insects as much as possible. However, most patients also choose to receive venom immunotherapy, because 80% to 90% of those who receive this treatment for 3 to 5 years do not have a systemic reaction if they are stung again.²⁰

Regardless of whether they choose to undergo immunotherapy, sensitive patients should always carry an epinephrine autoinjector. This is also the case after treatment ends, since the therapy is not 100% effective.

In other patients who may be at increased risk, the mandate for an epinephrine autoinjector is less clear, and the decision to carry one is determined on an individual basis. Such individuals are those receiving allergen immunotherapy, with large local reactions to insect stings, with oral allergy syndrome, with mastocytosis, and with drug allergy. In these cases, the benefit vs the burden of carrying an autoinjector should be discussed with the patient.

Patients on allergen immunotherapy

National guidelines recommend that all patients who receive allergen immunotherapy be monitored in the clinic under a physician’s supervision for 30 minutes after the injection. Fortunately, life-threatening reactions occurring after 30 minutes are rare. But delayed systemic reactions can occur and may account for up to 50% of such events.²¹

Therefore, many physicians consider it prudent for patients on immunotherapy to carry an epinephrine autoinjector, but there is no consensus. A survey²² found that 13.5% of allergists did not prescribe the autoinjector for patients on immunotherapy, while 33.3% prescribed it for all their patients on immunotherapy, and the rest prescribed based on risk.

Since there are no national guidelines on epinephrine autoinjectors for patients on immunotherapy, the decision should be based on the patient’s risks and comorbidities and informed by discussion between the individual patient and his or her allergist.

Patients with large local reactions to insect stings

From 5% to 10% of patients who have large local reactions to insect stings are at risk of systemic reactions.²⁰

Patients with oral allergy syndrome

Oral allergy syndrome, also known as pollen-food allergy, causes itching and mild swelling of the mouth, lips, and throat after eating fresh fruits and vegetables. The prevalence ranges from 2% to 10% of patients with allergies.²³

A survey of allergists found that 20% of patients with oral allergy syndrome had experienced systemic symptoms.²⁴ The survey also showed that the decision to prescribe an epinephrine autoinjector to these patients was highly variable. Only about 30% of allergists recommend epinephrine autoinjectors to patients with oral allergy syndrome, while most believe that the decision should be based on the individual’s symptoms and risk.

More research is needed in the area of food allergy. Because data are limited, there are no national guidelines on whether these patients should carry an epinephrine autoinjector. We agree with the Joint Task Force on Practice Parameters¹⁴ recommendation that the decision be made on an individual basis following discussion between the patient and physician. 

Patients with mastocytosis

Patients with mastocytosis and a history of anaphylaxis are at increased risk for systemic reactions to Hymenoptera venom.

Patients with medication allergy

Once medication allergy has been diagnosed, avoidance is usually effective, obviating the need for an epinephrine autoinjector, although the physician has the option of prescribing one.

CAUTIONS, NOT CONTRAINDICATIONS

Physicians may be reluctant to prescribe an epinephrine autoinjector because of the risk of an adverse reaction in patients with hypertension, coronary artery disease, or arrhythmias, and in elderly patients taking multiple drugs, especially drugs that can interact with epinephrine. Nevertheless, there is no absolute contraindication to the use of epinephrine in anaphylaxis.

In patients with atherosclerosis and cardiovascular disease

Epinephrine increases vasoconstriction, heart rate, and cardiac force of contraction. These effects are beneficial during anaphylaxis, but in rare cases patients have experienced myocardial infarction and acute coronary syndrome after receiving intravenous epinephrine.²⁵ These incidents have naturally prompted reluctance to prescribe it in susceptible patients with coronary disease during anaphylaxis.

Yet epinephrine may not be solely to blame for these adverse responses. Mast cells are abundant in the heart, and their release of mediators can also result in adverse cardiac manifestations, including myocardial infarction.²⁶

Conversely, some drugs used to treat cardiovascular disease can worsen anaphylaxis.

Beta-blockers can cause bronchospasm and decrease cardiac contractility. They can also blunt the pharmacologic effects of epinephrine. There is concern that epinephrine may produce dangerous elevations of blood pressure in patients taking beta-blockers by unopposed alpha-adrenergic stimulation and reflex vagotonic effects.²⁷ And there is evidence that beta-blockers may increase the risk and severity of reactions. One study reported that patients taking beta-blockers are more than 8 times more likely to be hospitalized due to anaphylactoid reaction with bronchospasm.²⁸

Beta-blockers and, to a lesser extent, angiotensin-converting enzyme inhibitors have been shown to increase the risk of anaphylaxis in the emergency department.^29,30 However, some investigators have not found beta-blockers to be a risk factor. A study evaluating anaphylactoid reactions from contrast media found no statistically significant higher risk in patients taking beta-blockers.³¹ Similarly, a study of 3,178 patients on beta-blockers receiving venom immunotherapy or allergen immunotherapy found no increase in the frequency of systemic reactions.³² Nevertheless, overall, more studies support the hypothesis that beta-blockers may be an additional risk factor in anaphylaxis.³³

Thus, clinicians treating patients with cardiovascular disease and anaphylaxis face a dilemma. Although there is concern in this population, epinephrine should not be withheld in patients with cardiovascular disease who are experiencing an anaphylactic event.³³ If epinephrine is not administered, the patient could die.

Elderly patients on multiple medications

Older patients are also at risk of anaphylaxis. But clinicians are reluctant to treat older patients with epinephrine because of concerns about adverse effects.

Epinephrine dispensing rates vary substantially in different age groups: 1.44% for patients under age 17, 0.9% for those ages 17 to 64, and 0.32% for those age 65 or older.³⁴ A Canadian study of 492 patients with anaphylaxis in the emergency department showed that those over age 50 received epinephrine less often than younger patients (36.1% vs 60.5%).³⁵ Cardiovascular complications were more frequent in the older group, occurring in 4 (9.1%) of the 44 older patients who received epinephrine compared with 1 (0.4%) of the 225 younger patients who received it. On the other hand, the rate of adverse effects from subcutaneous epinephrine was no different in older asthma patients compared with younger patients.³⁶

Many older patients take multiple medications, raising concern about adverse effects. Commonly prescribed medications in the elderly can affect the actions of epinephrine. Monoamine oxidase inhibitors retard the catabolism of epinephrine. Tricyclic antidepressants may decrease the reuptake of catecholamines by neurons and thus interfere with the degradation of epinephrine. Digoxin has a narrow therapeutic window and can potentially increase the risk of arrhythmias when given with epinephrine.

Although the clinician must be cautious in treating older patients who have comorbidities, these are not sufficient to withhold prescribing an epinephrine autoinjector to elderly patients at risk of anaphylaxis.

Epinephrine autoinjectors come preloaded for prompt delivery of the drug. They are intended primarily for use by patients themselves in unsupervised settings in suspected anaphylaxis. Simplicity of use and safety must be considered in such a setting so that patients can use the device correctly and are not incorrectly dosed.

Several models are commercially available, with different ergonomic designs and sizes. EpiPen, the first one marketed in the United States, was introduced in 1987. One device (Auvi-Q) contains an audio chip that gives step-by-step instructions at the time of use. It is hoped that this device will reduce errors in usage during this stressful time for patients and caregivers.

In the United States, epinephrine autoinjectors contain either 0.15 or 0.30 mg of the drug, but some clinicians believe this may not be enough. The UK Resuscitation Council recommends 0.50 mg for patients over age 12,³⁷ and an epinephrine autoinjector with that dose is available in Europe.

Subcutaneous vs intramuscular delivery

The package insert for some epinephrine autoinjectors says the injector can be used to treat anaphylaxis by both subcutaneous and intramuscular administration. However, the routes are not equivalent.

The goal in anaphylaxis is to quickly achieve high tissue and plasma epinephrine concentrations, and studies have found that injection into the vastus lateralis muscle, but not the deltoid muscle, results in faster time to peak plasma concentration: 8 minutes for injection in the vastus lateralis muscle and 34 minutes for subcutaneous delivery.^10,11 In addition, injection in the vastus lateralis muscle results in a higher peak plasma concentration than the subcutaneous or deltoid route. Based on these data, intramuscular injection into the vastus lateralis muscle in the thigh appears to be the preferred route of administration of epinephrine.

Obese patients may need a longer needle

Research on the original autoinjector was conducted by the US military, which wanted a rapidly effective and easy-to-use antidote for battlefield exposure to poison gas. The resulting device had 2 separate spring-loaded syringes, 1 containing pralidoxime chloride and the other atropine sulfate. To enable its use through the thick fabric of a chemical warfare suit, the needles were 2.2 cm long.

The first commercial autoinjector to contain epinephrine was made by Survival Technology (Bethesda, MD) in the mid-1970s. The manufacturer considered a 2.2-cm needle to be too long, and the first commercially available epinephrine autoinjector, EpiPen, had a 1.43-cm needle for adult use.

Since then, needle lengths have ranged from 1.17 to 2.5 cm to accommodate different skin-to-muscle depths, with shorter needles for children and longer needles for obese adults.³⁸

However, the prevalence of obesity is high and continues to rise.³⁹ Obesity raises concern that the needles in epinephrine autoinjectors may be too short for the preferred intramuscular delivery, resulting in subcutaneous deposition.

A study that used computed tomography of the thigh found that 1 (2%) of 50 men and 21 (42%) of 50 women studied had a subcutaneous tissue depth greater than 1.43 cm, the needle length in EpiPen. These were not anaphylaxis patients, but the findings suggest that many patients—especially women—may be getting subcutaneous instead of intramuscular delivery with this device.⁴⁰

Another study that used ultrasonography showed that the 1.43-cm EpiPen needle was too short for 36 (31%) of 116 adults.⁴¹ Women were 6.4 times more likely than men to encounter this problem. Other risk factors include higher body mass index, short height, and thicker thighs.

Emerade, an injector with a 2.5-cm needle, is available in some European countries. A longer needle may be helpful in some cases. but we do not yet have enough data to determine the optimal needle length.

Conversely, some children may need shorter needles and may in fact be at risk of having the needle penetrate bone.⁴² The US Food and Drug Administration recently approved a shorter needle for an epinephrine autoinjector (Auvi-Q) to be used in children weighing 7.5 kg to 15 kg.

BARRIERS TO USING EPINEPHRINE AUTOINJECTORS

Many patients do not use their epinephrine autoinjector in times of anaphylaxis or do not have one with them. Common reasons cited by respondents in a survey⁴³ of 1,385 patients included the following:

They took an oral antihistamine instead (38%).

They never received a prescription for an epinephrine autoinjector (28%).

They thought their symptoms were mild and would resolve with time (13%).

They were afraid (6%). There are reports of accidental injection, typically into fingers, hands, and thumbs. Fortunately, most accidental injections do not require a hand surgeon evaluation or surgery.⁴⁴ Conservative therapy and monitoring of the injection site are sufficient in most cases.

They could not afford an epinephrine autoinjector (1%).⁴³ Mylan Pharmaceuticals infamously increased the price of its EpiPen to more than $600 for a package of 2 pens. Generic devices are available in the United States but are still too expensive for some patients and are cumbersome to carry.

However, even expensive epinephrine autoinjectors may be cost-effective. Epidemiologic studies have found that patients who did not use an epinephrine autoinjector incurred a higher burden of cost due to emergency department visits and inpatient hospitalizations.⁴⁵

As a do-it-yourself option, some resourceful patients are obtaining autoinjectors intended for insulin injection, replacing the needle, and filling the injector with epinephrine, at a cost of about $30. (The manufacturer does not endorse this off-label use of their device—www.owenmumford.com/us/patients/if-you-need-to-inject.) Least costly of all is to prescribe multidose vials of epinephrine and regular syringes and teach patients and their caregivers how to draw up the proper dose and give themselves an injection—in essence going back to what was done before 1987.

It was past its expiration date (2%).⁴³ Failure to refill the prescription is common. A California Kaiser Permanente study⁴⁶ showed that only 46% of patients refilled their epinephrine autoinjector prescription at least once, and the refill rate decreased over time: 43% at 1 to 2 year follow-up, 35% at 3 to 4 years, and 30% at 5 years or longer. Based on these data, it is imperative to educate patients regarding the importance of replacing the epinephrine autoinjector when the old one expires.

NEED FOR PATIENT EDUCATION

Even though prompt treatment with epinephrine decreases fatalities, it continues to be underused in the community. In addition, it is often prescribed without adequate training in its use and appropriate emphasis on the need to keep the device on hand at all times and to replace it in a timely manner if it is used or has expired. Physicians need to educate patients on how to avoid triggers and how to recognize symptoms of anaphylaxis whenever they prescribe an epinephrine autoinjector.

Stopping dual antiplatelet therapy (DAPT) (eg, clopidogrel plus aspirin) after 3 months is reasonable in patients with stable ischemic heart disease who have a second-generation drug-eluting stent and a high bleeding risk, with stable ischemic disease defined as at least 1 year free of acute coronary syndromes. However, these patients should continue lifelong aspirin monotherapy. Current guidelines suggest that in stable ischemic disease, the risk-benefit ratio may favor an even shorter duration of DAPT than the 6 months currently recommended.¹

STABLE ISCHEMIC HEART DISEASE VS ACUTE CORONARY SYNDROME

Percutaneous coronary intervention for stable ischemic heart disease is indicated primarily in patients with angina that persists despite optimal antianginal therapy.

The prognostic implications of DAPT are different in stable ischemic disease than in acute coronary syndromes. The substrate treated by percutaneous intervention in stable ischemic disease is primarily fibrofatty plaque, as opposed to thrombus in acute coronary syndromes.

Percutaneous intervention significantly improves the prognosis in acute coronary syndromes, whereas its impact on overall survival in stable ischemic heart disease is not well documented. Given these differences, our discussion about DAPT in stable ischemic disease cannot be extrapolated to acute coronary syndromes.

BENEFITS OF DAPT

DAPT is mandatory early after drug-eluting stent placement, when the stent continuously releases medication, inhibiting tissue growth within the lumen of the stent.

Endothelialization of the stent normally occurs during the first 7 to 30 days after placement. During this period, the nonendothelialized stent poses a risk of thrombosis, a life-threatening, catastrophic condition with a mortality rate between 9% and 45%.¹

THERAPY BEYOND 12 MONTHS

Although guidelines have traditionally recommended 12 months of DAPT, the optimal duration is still debated.

A duration beyond 12 months in patients with a history of myocardial infarction was shown to be reasonable in 2 large trials,^2,3 while a 2016 review by Bittl et al⁴ suggested that therapy beyond 12 months in patients with a newer-generation drug-eluting stent could increase the incidence of major bleeding. A detailed discussion of DAPT longer than 12 months is beyond the scope of this article.

EVIDENCE FOR SHORTER DURATION

The results of 5 major trials support shorter duration of DAPT in stable ischemic disease.

The OPTIMIZE⁵ and RESET⁶ trials found that 3 months of DAPT was not inferior to 12 months in terms of ischemic and safety end points.

The ISAR-SAFE,⁷ EXCELLENT,⁸ and SECURITY⁹ trials also reported that 6 months of DAPT was not inferior to 12 months for the primary composite end point of death, stent thrombosis, myocardial infarction, stroke, or major bleeding.

However, these trials may have been underpowered to detect a difference in rates of stent thrombosis with shorter-duration DAPT.

CURRENT GUIDELINES

For patients at high bleeding risk, the current guidelines of the American College of Cardiology and American Heart Association, updated in 2016, suggest that it may be reasonable to discontinue DAPT 3 months after drug-eluting stent placement in patients with stable ischemic heart disease, and at 6 months in patients with acute coronary syndrome (class IIb recommendation, level of evidence C).¹ These recommendations are based on results of randomized controlled trials showing no difference in the rate of stent thrombosis and composite ischemic events with a shorter duration than with 12 months of therapy.^5–10

The evidence for DAPT in stable ischemic disease is based on clopidogrel, with only limited data on ticagrelor.¹ To our knowledge, no study to date has evaluated DAPT in this setting for less than 3 months, and further study is needed to address shorter-duration approaches with current-generation drug-eluting stents Since 2017, all coronary stents implanted in the United States have been second-generation stents.

The decision to stop DAPT in a patient at high risk of bleeding requires a careful assessment of the risks and benefits. Risk factors for bleeding include advanced age, history of major bleeding, anticoagulation, chronic kidney disease (serum creatinine level ≥ 2 mg/dL), platelet count 100 × 10⁹/L or lower, and history of stroke.¹¹

• Age 75 or older: −2 points
• Ages 65 to 74: −1
• Age under 65: 0
• Diabetes mellitus: 1
• Myocardial infarction at presentation: 1
• History of percutaneous coronary intervention or myocardial infarction: 1
• Stent diameter less than 3 mm: 1
• Paclitaxel drug-eluting stent: 1
• Current smoker: 2
• Percutaneous coronary intervention with saphenous vein graft: 2
• Congestive heart failure or left ventricular ejection fraction less than 30%: 2.

A score of 2 or greater favors continuing DAPT, as it indicates higher ischemic risk. A score less than 2 favors discontinuing DAPT, as it indicates higher bleeding risk.^1,2

IF BLEEDING RISK IS HIGH

Preventing and controlling bleeding associated with DAPT is important. The gastrointestinal tract is the most common site of bleeding.

Aspirin inhibits prostaglandin synthesis, leading to disruption of the protective mucous membrane. Therefore, a proton pump inhibitor should be started along with DAPT in patients at high risk of gastrointestinal bleeding.

If a patient’s bleeding risk significantly outweighs the risk of stent thrombosis, or if active hemorrhage makes a patient hemodynamically unstable, antiplatelet therapy must be stopped.¹

FACING SURGERY

For patients with a drug-eluting stent who are on DAPT and are to undergo elective noncardiac surgery, 3 considerations must be kept in mind:

• The risk of stent thrombosis if DAPT needs to be interrupted
• The consequences of delaying the surgical procedure
• The risk and consequences of periprocedural and intraprocedural bleeding if DAPT is continued.

Because clinical evidence for bridging therapy with intravenous antiplatelet or anticoagulant agents is limited, it is difficult to make recommendations about stopping DAPT. However, once bleeding risk is stabilized, DAPT should be restarted as soon as possible.¹

CURRENT RESEARCH

Several trials are under way to further evaluate ways to minimize bleeding risk and shorten the duration of DAPT.

A prospective multicenter trial is evaluating 3-month DAPT in patients at high bleeding risk who undergo placement of an everolimus-eluting stent.¹¹ This study is expected to be completed in August 2019.

Another strategy for patients at high bleeding risk is use of a polymer-free drug-coated coronary stent. In a 2015 trial comparing a biolimus A9-coated stent vs a bare-metal stent, patients received DAPT for 1 month after stent placement. The drug-coated stent was found to be superior in terms of the primary safety end point (cardiac death, myocardial infarction, or stent thrombosis).¹² This stent is not yet approved by the US Food and Drug Administration at the time of this writing.

Further study is needed to evaluate DAPT durations of less than 3 months and to establish the proper timing for safely discontinuing DAPT in difficult clinical scenarios.

WHEN STOPPING MAY BE REASONABLE

According to current guidelines, in patients at high bleeding risk with a second-generation or newer drug-eluting stent for stable ischemic heart disease, discontinuing DAPT 3 months after stent placement may be reasonable.¹ The decision to stop DAPT in these patients requires a careful assessment of the risks and benefits and may be aided by a tool such as the DAPT risk score. However, these recommendations cannot be extrapolated to patients with an acute coronary syndrome within the past year, as they are at higher risk.

TAKE-HOME MESSAGES

• A cardiologist should be consulted before discontinuing DAPT in patients with a drug-eluting stent, especially if the stent was recently placed.
• The duration of therapy depends on the indication for stent placement (stable ischemic heart disease vs acute coronary syndrome) and on stent location.
• Based on the 2016 American College of Cardiology/American Heart Association guidelines,¹ in patients at high bleeding risk with a second-generation drug-eluting stent, discontinuing DAPT is safe after 3 months in patients with stable ischemic heart disease, and after 6 months in patients with an acute coronary syndrome.
• When prescribing DAPT, available evidence favors clopidogrel in patients with stable ischemic heart disease who have a second-generation drug-eluting stent and are at high bleeding risk.
• In these patients, the risk-benefit ratio based on the DAPT score may be useful when considering stopping clopidogrel.       

Stopping dual antiplatelet therapy (DAPT) (eg, clopidogrel plus aspirin) after 3 months is reasonable in patients with stable ischemic heart disease who have a second-generation drug-eluting stent and a high bleeding risk, with stable ischemic disease defined as at least 1 year free of acute coronary syndromes. However, these patients should continue lifelong aspirin monotherapy. Current guidelines suggest that in stable ischemic disease, the risk-benefit ratio may favor an even shorter duration of DAPT than the 6 months currently recommended.¹

STABLE ISCHEMIC HEART DISEASE VS ACUTE CORONARY SYNDROME

Percutaneous coronary intervention for stable ischemic heart disease is indicated primarily in patients with angina that persists despite optimal antianginal therapy.

The prognostic implications of DAPT are different in stable ischemic disease than in acute coronary syndromes. The substrate treated by percutaneous intervention in stable ischemic disease is primarily fibrofatty plaque, as opposed to thrombus in acute coronary syndromes.

Percutaneous intervention significantly improves the prognosis in acute coronary syndromes, whereas its impact on overall survival in stable ischemic heart disease is not well documented. Given these differences, our discussion about DAPT in stable ischemic disease cannot be extrapolated to acute coronary syndromes.

BENEFITS OF DAPT

DAPT is mandatory early after drug-eluting stent placement, when the stent continuously releases medication, inhibiting tissue growth within the lumen of the stent.

Endothelialization of the stent normally occurs during the first 7 to 30 days after placement. During this period, the nonendothelialized stent poses a risk of thrombosis, a life-threatening, catastrophic condition with a mortality rate between 9% and 45%.¹

THERAPY BEYOND 12 MONTHS

Although guidelines have traditionally recommended 12 months of DAPT, the optimal duration is still debated.

A duration beyond 12 months in patients with a history of myocardial infarction was shown to be reasonable in 2 large trials,^2,3 while a 2016 review by Bittl et al⁴ suggested that therapy beyond 12 months in patients with a newer-generation drug-eluting stent could increase the incidence of major bleeding. A detailed discussion of DAPT longer than 12 months is beyond the scope of this article.

EVIDENCE FOR SHORTER DURATION

The results of 5 major trials support shorter duration of DAPT in stable ischemic disease.

The OPTIMIZE⁵ and RESET⁶ trials found that 3 months of DAPT was not inferior to 12 months in terms of ischemic and safety end points.

The ISAR-SAFE,⁷ EXCELLENT,⁸ and SECURITY⁹ trials also reported that 6 months of DAPT was not inferior to 12 months for the primary composite end point of death, stent thrombosis, myocardial infarction, stroke, or major bleeding.

However, these trials may have been underpowered to detect a difference in rates of stent thrombosis with shorter-duration DAPT.

CURRENT GUIDELINES

For patients at high bleeding risk, the current guidelines of the American College of Cardiology and American Heart Association, updated in 2016, suggest that it may be reasonable to discontinue DAPT 3 months after drug-eluting stent placement in patients with stable ischemic heart disease, and at 6 months in patients with acute coronary syndrome (class IIb recommendation, level of evidence C).¹ These recommendations are based on results of randomized controlled trials showing no difference in the rate of stent thrombosis and composite ischemic events with a shorter duration than with 12 months of therapy.^5–10

The evidence for DAPT in stable ischemic disease is based on clopidogrel, with only limited data on ticagrelor.¹ To our knowledge, no study to date has evaluated DAPT in this setting for less than 3 months, and further study is needed to address shorter-duration approaches with current-generation drug-eluting stents Since 2017, all coronary stents implanted in the United States have been second-generation stents.

The decision to stop DAPT in a patient at high risk of bleeding requires a careful assessment of the risks and benefits. Risk factors for bleeding include advanced age, history of major bleeding, anticoagulation, chronic kidney disease (serum creatinine level ≥ 2 mg/dL), platelet count 100 × 10⁹/L or lower, and history of stroke.¹¹

• Age 75 or older: −2 points
• Ages 65 to 74: −1
• Age under 65: 0
• Diabetes mellitus: 1
• Myocardial infarction at presentation: 1
• History of percutaneous coronary intervention or myocardial infarction: 1
• Stent diameter less than 3 mm: 1
• Paclitaxel drug-eluting stent: 1
• Current smoker: 2
• Percutaneous coronary intervention with saphenous vein graft: 2
• Congestive heart failure or left ventricular ejection fraction less than 30%: 2.

A score of 2 or greater favors continuing DAPT, as it indicates higher ischemic risk. A score less than 2 favors discontinuing DAPT, as it indicates higher bleeding risk.^1,2

IF BLEEDING RISK IS HIGH

Preventing and controlling bleeding associated with DAPT is important. The gastrointestinal tract is the most common site of bleeding.

Aspirin inhibits prostaglandin synthesis, leading to disruption of the protective mucous membrane. Therefore, a proton pump inhibitor should be started along with DAPT in patients at high risk of gastrointestinal bleeding.

If a patient’s bleeding risk significantly outweighs the risk of stent thrombosis, or if active hemorrhage makes a patient hemodynamically unstable, antiplatelet therapy must be stopped.¹

FACING SURGERY

For patients with a drug-eluting stent who are on DAPT and are to undergo elective noncardiac surgery, 3 considerations must be kept in mind:

• The risk of stent thrombosis if DAPT needs to be interrupted
• The consequences of delaying the surgical procedure
• The risk and consequences of periprocedural and intraprocedural bleeding if DAPT is continued.

Because clinical evidence for bridging therapy with intravenous antiplatelet or anticoagulant agents is limited, it is difficult to make recommendations about stopping DAPT. However, once bleeding risk is stabilized, DAPT should be restarted as soon as possible.¹

CURRENT RESEARCH

Several trials are under way to further evaluate ways to minimize bleeding risk and shorten the duration of DAPT.

A prospective multicenter trial is evaluating 3-month DAPT in patients at high bleeding risk who undergo placement of an everolimus-eluting stent.¹¹ This study is expected to be completed in August 2019.

Another strategy for patients at high bleeding risk is use of a polymer-free drug-coated coronary stent. In a 2015 trial comparing a biolimus A9-coated stent vs a bare-metal stent, patients received DAPT for 1 month after stent placement. The drug-coated stent was found to be superior in terms of the primary safety end point (cardiac death, myocardial infarction, or stent thrombosis).¹² This stent is not yet approved by the US Food and Drug Administration at the time of this writing.

Further study is needed to evaluate DAPT durations of less than 3 months and to establish the proper timing for safely discontinuing DAPT in difficult clinical scenarios.

WHEN STOPPING MAY BE REASONABLE

According to current guidelines, in patients at high bleeding risk with a second-generation or newer drug-eluting stent for stable ischemic heart disease, discontinuing DAPT 3 months after stent placement may be reasonable.¹ The decision to stop DAPT in these patients requires a careful assessment of the risks and benefits and may be aided by a tool such as the DAPT risk score. However, these recommendations cannot be extrapolated to patients with an acute coronary syndrome within the past year, as they are at higher risk.

TAKE-HOME MESSAGES

• A cardiologist should be consulted before discontinuing DAPT in patients with a drug-eluting stent, especially if the stent was recently placed.
• The duration of therapy depends on the indication for stent placement (stable ischemic heart disease vs acute coronary syndrome) and on stent location.
• Based on the 2016 American College of Cardiology/American Heart Association guidelines,¹ in patients at high bleeding risk with a second-generation drug-eluting stent, discontinuing DAPT is safe after 3 months in patients with stable ischemic heart disease, and after 6 months in patients with an acute coronary syndrome.
• When prescribing DAPT, available evidence favors clopidogrel in patients with stable ischemic heart disease who have a second-generation drug-eluting stent and are at high bleeding risk.
• In these patients, the risk-benefit ratio based on the DAPT score may be useful when considering stopping clopidogrel.       

Stopping dual antiplatelet therapy (DAPT) (eg, clopidogrel plus aspirin) after 3 months is reasonable in patients with stable ischemic heart disease who have a second-generation drug-eluting stent and a high bleeding risk, with stable ischemic disease defined as at least 1 year free of acute coronary syndromes. However, these patients should continue lifelong aspirin monotherapy. Current guidelines suggest that in stable ischemic disease, the risk-benefit ratio may favor an even shorter duration of DAPT than the 6 months currently recommended.¹

STABLE ISCHEMIC HEART DISEASE VS ACUTE CORONARY SYNDROME

Percutaneous coronary intervention for stable ischemic heart disease is indicated primarily in patients with angina that persists despite optimal antianginal therapy.

The prognostic implications of DAPT are different in stable ischemic disease than in acute coronary syndromes. The substrate treated by percutaneous intervention in stable ischemic disease is primarily fibrofatty plaque, as opposed to thrombus in acute coronary syndromes.

Percutaneous intervention significantly improves the prognosis in acute coronary syndromes, whereas its impact on overall survival in stable ischemic heart disease is not well documented. Given these differences, our discussion about DAPT in stable ischemic disease cannot be extrapolated to acute coronary syndromes.

BENEFITS OF DAPT

DAPT is mandatory early after drug-eluting stent placement, when the stent continuously releases medication, inhibiting tissue growth within the lumen of the stent.

Endothelialization of the stent normally occurs during the first 7 to 30 days after placement. During this period, the nonendothelialized stent poses a risk of thrombosis, a life-threatening, catastrophic condition with a mortality rate between 9% and 45%.¹

THERAPY BEYOND 12 MONTHS

Although guidelines have traditionally recommended 12 months of DAPT, the optimal duration is still debated.

A duration beyond 12 months in patients with a history of myocardial infarction was shown to be reasonable in 2 large trials,^2,3 while a 2016 review by Bittl et al⁴ suggested that therapy beyond 12 months in patients with a newer-generation drug-eluting stent could increase the incidence of major bleeding. A detailed discussion of DAPT longer than 12 months is beyond the scope of this article.

EVIDENCE FOR SHORTER DURATION

The results of 5 major trials support shorter duration of DAPT in stable ischemic disease.

The OPTIMIZE⁵ and RESET⁶ trials found that 3 months of DAPT was not inferior to 12 months in terms of ischemic and safety end points.

The ISAR-SAFE,⁷ EXCELLENT,⁸ and SECURITY⁹ trials also reported that 6 months of DAPT was not inferior to 12 months for the primary composite end point of death, stent thrombosis, myocardial infarction, stroke, or major bleeding.

However, these trials may have been underpowered to detect a difference in rates of stent thrombosis with shorter-duration DAPT.

CURRENT GUIDELINES

For patients at high bleeding risk, the current guidelines of the American College of Cardiology and American Heart Association, updated in 2016, suggest that it may be reasonable to discontinue DAPT 3 months after drug-eluting stent placement in patients with stable ischemic heart disease, and at 6 months in patients with acute coronary syndrome (class IIb recommendation, level of evidence C).¹ These recommendations are based on results of randomized controlled trials showing no difference in the rate of stent thrombosis and composite ischemic events with a shorter duration than with 12 months of therapy.^5–10

The evidence for DAPT in stable ischemic disease is based on clopidogrel, with only limited data on ticagrelor.¹ To our knowledge, no study to date has evaluated DAPT in this setting for less than 3 months, and further study is needed to address shorter-duration approaches with current-generation drug-eluting stents Since 2017, all coronary stents implanted in the United States have been second-generation stents.

The decision to stop DAPT in a patient at high risk of bleeding requires a careful assessment of the risks and benefits. Risk factors for bleeding include advanced age, history of major bleeding, anticoagulation, chronic kidney disease (serum creatinine level ≥ 2 mg/dL), platelet count 100 × 10⁹/L or lower, and history of stroke.¹¹

• Age 75 or older: −2 points
• Ages 65 to 74: −1
• Age under 65: 0
• Diabetes mellitus: 1
• Myocardial infarction at presentation: 1
• History of percutaneous coronary intervention or myocardial infarction: 1
• Stent diameter less than 3 mm: 1
• Paclitaxel drug-eluting stent: 1
• Current smoker: 2
• Percutaneous coronary intervention with saphenous vein graft: 2
• Congestive heart failure or left ventricular ejection fraction less than 30%: 2.

A score of 2 or greater favors continuing DAPT, as it indicates higher ischemic risk. A score less than 2 favors discontinuing DAPT, as it indicates higher bleeding risk.^1,2

IF BLEEDING RISK IS HIGH

Preventing and controlling bleeding associated with DAPT is important. The gastrointestinal tract is the most common site of bleeding.

Aspirin inhibits prostaglandin synthesis, leading to disruption of the protective mucous membrane. Therefore, a proton pump inhibitor should be started along with DAPT in patients at high risk of gastrointestinal bleeding.

If a patient’s bleeding risk significantly outweighs the risk of stent thrombosis, or if active hemorrhage makes a patient hemodynamically unstable, antiplatelet therapy must be stopped.¹

FACING SURGERY

For patients with a drug-eluting stent who are on DAPT and are to undergo elective noncardiac surgery, 3 considerations must be kept in mind:

• The risk of stent thrombosis if DAPT needs to be interrupted
• The consequences of delaying the surgical procedure
• The risk and consequences of periprocedural and intraprocedural bleeding if DAPT is continued.

Because clinical evidence for bridging therapy with intravenous antiplatelet or anticoagulant agents is limited, it is difficult to make recommendations about stopping DAPT. However, once bleeding risk is stabilized, DAPT should be restarted as soon as possible.¹

CURRENT RESEARCH

Several trials are under way to further evaluate ways to minimize bleeding risk and shorten the duration of DAPT.

A prospective multicenter trial is evaluating 3-month DAPT in patients at high bleeding risk who undergo placement of an everolimus-eluting stent.¹¹ This study is expected to be completed in August 2019.

Another strategy for patients at high bleeding risk is use of a polymer-free drug-coated coronary stent. In a 2015 trial comparing a biolimus A9-coated stent vs a bare-metal stent, patients received DAPT for 1 month after stent placement. The drug-coated stent was found to be superior in terms of the primary safety end point (cardiac death, myocardial infarction, or stent thrombosis).¹² This stent is not yet approved by the US Food and Drug Administration at the time of this writing.

Further study is needed to evaluate DAPT durations of less than 3 months and to establish the proper timing for safely discontinuing DAPT in difficult clinical scenarios.

WHEN STOPPING MAY BE REASONABLE

According to current guidelines, in patients at high bleeding risk with a second-generation or newer drug-eluting stent for stable ischemic heart disease, discontinuing DAPT 3 months after stent placement may be reasonable.¹ The decision to stop DAPT in these patients requires a careful assessment of the risks and benefits and may be aided by a tool such as the DAPT risk score. However, these recommendations cannot be extrapolated to patients with an acute coronary syndrome within the past year, as they are at higher risk.

TAKE-HOME MESSAGES

• A cardiologist should be consulted before discontinuing DAPT in patients with a drug-eluting stent, especially if the stent was recently placed.
• The duration of therapy depends on the indication for stent placement (stable ischemic heart disease vs acute coronary syndrome) and on stent location.
• Based on the 2016 American College of Cardiology/American Heart Association guidelines,¹ in patients at high bleeding risk with a second-generation drug-eluting stent, discontinuing DAPT is safe after 3 months in patients with stable ischemic heart disease, and after 6 months in patients with an acute coronary syndrome.
• When prescribing DAPT, available evidence favors clopidogrel in patients with stable ischemic heart disease who have a second-generation drug-eluting stent and are at high bleeding risk.
• In these patients, the risk-benefit ratio based on the DAPT score may be useful when considering stopping clopidogrel.       

Most patients should receive it, with exceptions as noted below. Metformin is the cornerstone of diabetes therapy and should be considered in all patients with type 2 diabetes. Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE)^1,2 recommend it as first-line treatment for type 2 diabetes. It lowers blood glucose levels by inhibiting hepatic glucose production, and it does not tend to cause hypoglycemia.

However, metformin is underused. A 2012 study showed that only 50% to 70% of patients with type 2 diabetes treated with a sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or glucagon-like peptide-1 analogue also received metformin.³ This occurred despite guidelines recommending continuing metformin when starting other diabetes drugs.⁴

EVIDENCE METFORMIN IS EFFECTIVE

The United Kingdom Prospective Diabetes Study (UKPDS)⁵ found that metformin significantly reduced the incidence of:

• Any diabetes-related end point (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53–0.87)
• Myocardial infarction (HR 0.61, 95% CI 0.41–0.89)
• Diabetes-related death (HR 0.58, 95% CI 0.37–0.91)
• All-cause mortality (HR 0.64; 95% CI 0.45–0.91).

The Hyperinsulinemia: Outcomes of Its Metabolic Effects (HOME) trial,⁶ a multicenter trial conducted in the Netherlands, evaluated the effect of adding  metformin (vs placebo) to existing insulin regimens. Metformin recipients had a significantly lower rate of macrovascular mortality (HR 0.61, 95% CI 0.40–0.94, P = .02), but not of the primary end point, an aggregate of microvascular and macrovascular morbidity and mortality.

The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus With Coronary Artery Disease trial,⁷ a multicenter trial conducted in China, compared the effects of metformin vs glipizide on cardiovascular outcomes. At about 3 years of treatment, the metformin group had a significantly lower rate of the composite primary end point of recurrent cardiovascular events (HR 0.54, 95% CI 0.30–0.90). This end point included nonfatal myocardial infarction, nonfatal stroke, arterial revascularization by percutaneous transluminal coronary angioplasty or by coronary artery bypass graft, death from a cardiovascular cause, and death from any cause.

These studies prompted the ADA to emphasize that metformin can reduce the risk of cardiovascular events or death. Metformin also has been shown to be weight-neutral or to induce slight weight loss. Furthermore, it is inexpensive.

WHAT ABOUT THE RENAL EFFECTS?

Because metformin is renally cleared, it has caused some concern about nephrotoxicity, especially lactic acidosis, in patients with impaired renal function. But the most recent guidelines have relaxed the criteria for metformin use in this patient population.

Revised labeling

Metformin’s labeling,⁸ revised in 2016, states the following:

• If the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73 m², metformin is contraindicated
• If the eGFR is between 30 and 45 mL/min/1.73 m², metformin is not recommended
• If the eGFR is below 45 mL/min/1.73 m² in a patient taking metformin, the risks and benefits of continuing treatment should be assessed, the dosage may need to be adjusted, and renal function should be monitored more frequently.⁸

These labeling revisions were based on a systematic review by Inzucchi et al⁹ that found metformin is not associated with increased rates of lactic acidosis in patients with mild to moderate kidney disease. Subsequently, an observational study published in 2018 by Lazarus et al¹⁰ showed that metformin increases the risk of acidosis only at eGFR levels below 30 mL/min/1.73 m². Also, a Cochrane review published in 2003 did not find a single case of lactic acidosis in 347 trials with 70,490 patient-years of metformin treatment.¹¹

Previous guidelines used serum creatinine levels, with metformin contraindicated at levels of 1.5 mg/dL or above for men and 1.4 mg/dL for women, or with abnormal creatinine clearance. The ADA and the AACE now use the eGFR^1,2 instead of the serum creatinine level to measure kidney function because it better accounts for factors such as the patient’s age, sex, race, and weight.

Despite the evidence, the common patient perception is that metformin is nephrotoxic, and it is important for practitioners to dispel this myth during clinic visits.

What about metformin use with contrast agents?

Labeling has a precautionary note stating that metformin should be held at the time of, or prior to, any imaging procedure involving iodinated contrast agents in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. The eGFR should be reevaluated 48 hours after the imaging procedure.⁸

Additionally, if the iodinated contrast agent causes acute kidney injury, metformin could accumulate, with resultant lactate accumulation.

The American College of Radiology (ACR) has proposed less stringent guidelines for metformin during radiocontrast imaging studies. This change is based on evidence that lactic acidosis is rare­—about 10 cases per 100,000 patient-years—and that there are no reports of lactic acidosis after intravenously administered iodinated contrast in properly selected patients.^12,13

The ACR divides patients taking metformin into 2 categories:

• No evidence of acute kidney injury and eGFR greater than 30 mL/min/1.73 m²
• Either acute kidney injury or chronic kidney disease with eGFR below 30 mL/min/1.73 m² or undergoing arterial catheter studies with a high chance of embolization to the renal arteries.¹⁴

For the first group, they recommend against discontinuing metformin before or after giving iodinated contrast or checking kidney function after the procedure.

For the second group, they recommend holding metformin before and 48 hours after the procedure. It should not be restarted until renal function is confirmed to be normal.

The ADA recommends¹ continuing metformin after initiating insulin. However, in clinical practice, it is often not done.

Clinical trials have shown that combining metformin with insulin significantly improves glycemic control, prevents weight gain, and decreases insulin requirements.^15,16 One trial¹⁶ also looked at cardiovascular end points during a 4-year follow-up period;  combining metformin with insulin decreased the macrovascular disease-related event rate compared with insulin alone.

In the HOME trial,⁶ which added metformin to the existing insulin regimen, both groups gained weight, but the metformin group had gained about 3 kg less than the placebo group at the end of the 4.3-year trial. Metformin did not increase the risk of hypoglycemia, but it also did not reduce the risk of microvascular disease.

Concomitant metformin reduces costs

These days, practitioners can choose from a large selection of diabetes drugs. These include insulins with better pharmacokinetic profiles, as well as newer classes of noninsulin agents such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues.

Metformin is less expensive than these newer drugs, and using it concomitantly with other diabetes drugs can decrease their dosage requirements, which in turn decreases their monthly costs.

GASTROINTESTINAL EFFECTS

Metformin’s gastrointestinal adverse effects such as diarrhea, flatulence, nausea, and vomiting are a barrier to its use. The actual incidence rate of diarrhea varies widely in randomized trials and observational studies, and gastrointestinal effects are worse in metformin-naive patients, as well as those who have chronic gastritis or Helicobacter pylori infection.¹⁷

We have found that starting metformin at a low dose and up-titrating it over several weeks increases tolerability. We often start patients at 500 mg/day and increase the dosage by 1 500-mg tablet every 1 to 2 weeks. Also, we have noticed that intolerance is more likely in patients who eat a high-carbohydrate diet, but there is no high-level evidence to back this up because patients in clinical trials all undergo nutrition counseling and are therefore more likely to adhere to the low-carbohydrate diet.

Also, the extended-release formulation is more tolerable than the immediate-release formulation and has similar glycemic efficacy. It may be an option as first-line therapy or for patients who have significant adverse effects from immediate-release metformin.¹⁸ For patients on the immediate-release formulation, taking it with meals helps lessen some gastrointestinal effects, and this should be emphasized at every visit.

Finally, we limit the metformin dose to 2,000 mg/day, rather than the 2,550 mg/day allowed on labeling. Garber et al¹⁹ found that the lower dosage still provides the maximum clinical efficacy.

OTHER CAUTIONS

Metformin should be avoided in patients with acute or unstable heart failure because of the increased risk of lactic acidosis.

It also should be avoided in patients with hepatic impairment, according to the labeling. But this remains controversial in practice. Zhang et al²⁰ showed that continuing metformin in patients with diabetes and cirrhosis decreases the mortality risk by 57% compared with those taken off metformin.

Diet and lifestyle measures need to be emphasized at each visit. Wing et al²¹ showed that calorie restriction regardless of weight loss is beneficial for glycemic control and insulin sensitivity in obese patients with diabetes.

TAKE-HOME POINTS

Metformin improves glycemic control without tending to cause weight gain or hypoglycemia. It may also have cardiovascular benefits. Metformin is an inexpensive agent that should be continued, if tolerated, in those who need additional agents for glycemic control. It should be considered in all adult patients with type 2 diabetes.   

Most patients should receive it, with exceptions as noted below. Metformin is the cornerstone of diabetes therapy and should be considered in all patients with type 2 diabetes. Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE)^1,2 recommend it as first-line treatment for type 2 diabetes. It lowers blood glucose levels by inhibiting hepatic glucose production, and it does not tend to cause hypoglycemia.

However, metformin is underused. A 2012 study showed that only 50% to 70% of patients with type 2 diabetes treated with a sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or glucagon-like peptide-1 analogue also received metformin.³ This occurred despite guidelines recommending continuing metformin when starting other diabetes drugs.⁴

EVIDENCE METFORMIN IS EFFECTIVE

The United Kingdom Prospective Diabetes Study (UKPDS)⁵ found that metformin significantly reduced the incidence of:

• Any diabetes-related end point (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53–0.87)
• Myocardial infarction (HR 0.61, 95% CI 0.41–0.89)
• Diabetes-related death (HR 0.58, 95% CI 0.37–0.91)
• All-cause mortality (HR 0.64; 95% CI 0.45–0.91).

The Hyperinsulinemia: Outcomes of Its Metabolic Effects (HOME) trial,⁶ a multicenter trial conducted in the Netherlands, evaluated the effect of adding  metformin (vs placebo) to existing insulin regimens. Metformin recipients had a significantly lower rate of macrovascular mortality (HR 0.61, 95% CI 0.40–0.94, P = .02), but not of the primary end point, an aggregate of microvascular and macrovascular morbidity and mortality.

The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus With Coronary Artery Disease trial,⁷ a multicenter trial conducted in China, compared the effects of metformin vs glipizide on cardiovascular outcomes. At about 3 years of treatment, the metformin group had a significantly lower rate of the composite primary end point of recurrent cardiovascular events (HR 0.54, 95% CI 0.30–0.90). This end point included nonfatal myocardial infarction, nonfatal stroke, arterial revascularization by percutaneous transluminal coronary angioplasty or by coronary artery bypass graft, death from a cardiovascular cause, and death from any cause.

These studies prompted the ADA to emphasize that metformin can reduce the risk of cardiovascular events or death. Metformin also has been shown to be weight-neutral or to induce slight weight loss. Furthermore, it is inexpensive.

WHAT ABOUT THE RENAL EFFECTS?

Because metformin is renally cleared, it has caused some concern about nephrotoxicity, especially lactic acidosis, in patients with impaired renal function. But the most recent guidelines have relaxed the criteria for metformin use in this patient population.

Revised labeling

Metformin’s labeling,⁸ revised in 2016, states the following:

• If the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73 m², metformin is contraindicated
• If the eGFR is between 30 and 45 mL/min/1.73 m², metformin is not recommended
• If the eGFR is below 45 mL/min/1.73 m² in a patient taking metformin, the risks and benefits of continuing treatment should be assessed, the dosage may need to be adjusted, and renal function should be monitored more frequently.⁸

These labeling revisions were based on a systematic review by Inzucchi et al⁹ that found metformin is not associated with increased rates of lactic acidosis in patients with mild to moderate kidney disease. Subsequently, an observational study published in 2018 by Lazarus et al¹⁰ showed that metformin increases the risk of acidosis only at eGFR levels below 30 mL/min/1.73 m². Also, a Cochrane review published in 2003 did not find a single case of lactic acidosis in 347 trials with 70,490 patient-years of metformin treatment.¹¹

Previous guidelines used serum creatinine levels, with metformin contraindicated at levels of 1.5 mg/dL or above for men and 1.4 mg/dL for women, or with abnormal creatinine clearance. The ADA and the AACE now use the eGFR^1,2 instead of the serum creatinine level to measure kidney function because it better accounts for factors such as the patient’s age, sex, race, and weight.

Despite the evidence, the common patient perception is that metformin is nephrotoxic, and it is important for practitioners to dispel this myth during clinic visits.

What about metformin use with contrast agents?

Labeling has a precautionary note stating that metformin should be held at the time of, or prior to, any imaging procedure involving iodinated contrast agents in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. The eGFR should be reevaluated 48 hours after the imaging procedure.⁸

Additionally, if the iodinated contrast agent causes acute kidney injury, metformin could accumulate, with resultant lactate accumulation.

The American College of Radiology (ACR) has proposed less stringent guidelines for metformin during radiocontrast imaging studies. This change is based on evidence that lactic acidosis is rare­—about 10 cases per 100,000 patient-years—and that there are no reports of lactic acidosis after intravenously administered iodinated contrast in properly selected patients.^12,13

The ACR divides patients taking metformin into 2 categories:

• No evidence of acute kidney injury and eGFR greater than 30 mL/min/1.73 m²
• Either acute kidney injury or chronic kidney disease with eGFR below 30 mL/min/1.73 m² or undergoing arterial catheter studies with a high chance of embolization to the renal arteries.¹⁴

For the first group, they recommend against discontinuing metformin before or after giving iodinated contrast or checking kidney function after the procedure.

For the second group, they recommend holding metformin before and 48 hours after the procedure. It should not be restarted until renal function is confirmed to be normal.

The ADA recommends¹ continuing metformin after initiating insulin. However, in clinical practice, it is often not done.

Clinical trials have shown that combining metformin with insulin significantly improves glycemic control, prevents weight gain, and decreases insulin requirements.^15,16 One trial¹⁶ also looked at cardiovascular end points during a 4-year follow-up period;  combining metformin with insulin decreased the macrovascular disease-related event rate compared with insulin alone.

In the HOME trial,⁶ which added metformin to the existing insulin regimen, both groups gained weight, but the metformin group had gained about 3 kg less than the placebo group at the end of the 4.3-year trial. Metformin did not increase the risk of hypoglycemia, but it also did not reduce the risk of microvascular disease.

Concomitant metformin reduces costs

These days, practitioners can choose from a large selection of diabetes drugs. These include insulins with better pharmacokinetic profiles, as well as newer classes of noninsulin agents such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues.

Metformin is less expensive than these newer drugs, and using it concomitantly with other diabetes drugs can decrease their dosage requirements, which in turn decreases their monthly costs.

GASTROINTESTINAL EFFECTS

Metformin’s gastrointestinal adverse effects such as diarrhea, flatulence, nausea, and vomiting are a barrier to its use. The actual incidence rate of diarrhea varies widely in randomized trials and observational studies, and gastrointestinal effects are worse in metformin-naive patients, as well as those who have chronic gastritis or Helicobacter pylori infection.¹⁷

We have found that starting metformin at a low dose and up-titrating it over several weeks increases tolerability. We often start patients at 500 mg/day and increase the dosage by 1 500-mg tablet every 1 to 2 weeks. Also, we have noticed that intolerance is more likely in patients who eat a high-carbohydrate diet, but there is no high-level evidence to back this up because patients in clinical trials all undergo nutrition counseling and are therefore more likely to adhere to the low-carbohydrate diet.

Also, the extended-release formulation is more tolerable than the immediate-release formulation and has similar glycemic efficacy. It may be an option as first-line therapy or for patients who have significant adverse effects from immediate-release metformin.¹⁸ For patients on the immediate-release formulation, taking it with meals helps lessen some gastrointestinal effects, and this should be emphasized at every visit.

Finally, we limit the metformin dose to 2,000 mg/day, rather than the 2,550 mg/day allowed on labeling. Garber et al¹⁹ found that the lower dosage still provides the maximum clinical efficacy.

OTHER CAUTIONS

Metformin should be avoided in patients with acute or unstable heart failure because of the increased risk of lactic acidosis.

It also should be avoided in patients with hepatic impairment, according to the labeling. But this remains controversial in practice. Zhang et al²⁰ showed that continuing metformin in patients with diabetes and cirrhosis decreases the mortality risk by 57% compared with those taken off metformin.

Diet and lifestyle measures need to be emphasized at each visit. Wing et al²¹ showed that calorie restriction regardless of weight loss is beneficial for glycemic control and insulin sensitivity in obese patients with diabetes.

TAKE-HOME POINTS

Metformin improves glycemic control without tending to cause weight gain or hypoglycemia. It may also have cardiovascular benefits. Metformin is an inexpensive agent that should be continued, if tolerated, in those who need additional agents for glycemic control. It should be considered in all adult patients with type 2 diabetes.   

Most patients should receive it, with exceptions as noted below. Metformin is the cornerstone of diabetes therapy and should be considered in all patients with type 2 diabetes. Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE)^1,2 recommend it as first-line treatment for type 2 diabetes. It lowers blood glucose levels by inhibiting hepatic glucose production, and it does not tend to cause hypoglycemia.

However, metformin is underused. A 2012 study showed that only 50% to 70% of patients with type 2 diabetes treated with a sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or glucagon-like peptide-1 analogue also received metformin.³ This occurred despite guidelines recommending continuing metformin when starting other diabetes drugs.⁴

EVIDENCE METFORMIN IS EFFECTIVE

The United Kingdom Prospective Diabetes Study (UKPDS)⁵ found that metformin significantly reduced the incidence of:

• Any diabetes-related end point (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53–0.87)
• Myocardial infarction (HR 0.61, 95% CI 0.41–0.89)
• Diabetes-related death (HR 0.58, 95% CI 0.37–0.91)
• All-cause mortality (HR 0.64; 95% CI 0.45–0.91).

The Hyperinsulinemia: Outcomes of Its Metabolic Effects (HOME) trial,⁶ a multicenter trial conducted in the Netherlands, evaluated the effect of adding  metformin (vs placebo) to existing insulin regimens. Metformin recipients had a significantly lower rate of macrovascular mortality (HR 0.61, 95% CI 0.40–0.94, P = .02), but not of the primary end point, an aggregate of microvascular and macrovascular morbidity and mortality.

The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus With Coronary Artery Disease trial,⁷ a multicenter trial conducted in China, compared the effects of metformin vs glipizide on cardiovascular outcomes. At about 3 years of treatment, the metformin group had a significantly lower rate of the composite primary end point of recurrent cardiovascular events (HR 0.54, 95% CI 0.30–0.90). This end point included nonfatal myocardial infarction, nonfatal stroke, arterial revascularization by percutaneous transluminal coronary angioplasty or by coronary artery bypass graft, death from a cardiovascular cause, and death from any cause.

These studies prompted the ADA to emphasize that metformin can reduce the risk of cardiovascular events or death. Metformin also has been shown to be weight-neutral or to induce slight weight loss. Furthermore, it is inexpensive.

WHAT ABOUT THE RENAL EFFECTS?

Because metformin is renally cleared, it has caused some concern about nephrotoxicity, especially lactic acidosis, in patients with impaired renal function. But the most recent guidelines have relaxed the criteria for metformin use in this patient population.

Revised labeling

Metformin’s labeling,⁸ revised in 2016, states the following:

• If the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73 m², metformin is contraindicated
• If the eGFR is between 30 and 45 mL/min/1.73 m², metformin is not recommended
• If the eGFR is below 45 mL/min/1.73 m² in a patient taking metformin, the risks and benefits of continuing treatment should be assessed, the dosage may need to be adjusted, and renal function should be monitored more frequently.⁸

These labeling revisions were based on a systematic review by Inzucchi et al⁹ that found metformin is not associated with increased rates of lactic acidosis in patients with mild to moderate kidney disease. Subsequently, an observational study published in 2018 by Lazarus et al¹⁰ showed that metformin increases the risk of acidosis only at eGFR levels below 30 mL/min/1.73 m². Also, a Cochrane review published in 2003 did not find a single case of lactic acidosis in 347 trials with 70,490 patient-years of metformin treatment.¹¹

Previous guidelines used serum creatinine levels, with metformin contraindicated at levels of 1.5 mg/dL or above for men and 1.4 mg/dL for women, or with abnormal creatinine clearance. The ADA and the AACE now use the eGFR^1,2 instead of the serum creatinine level to measure kidney function because it better accounts for factors such as the patient’s age, sex, race, and weight.

Despite the evidence, the common patient perception is that metformin is nephrotoxic, and it is important for practitioners to dispel this myth during clinic visits.

What about metformin use with contrast agents?

Labeling has a precautionary note stating that metformin should be held at the time of, or prior to, any imaging procedure involving iodinated contrast agents in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. The eGFR should be reevaluated 48 hours after the imaging procedure.⁸

Additionally, if the iodinated contrast agent causes acute kidney injury, metformin could accumulate, with resultant lactate accumulation.

The American College of Radiology (ACR) has proposed less stringent guidelines for metformin during radiocontrast imaging studies. This change is based on evidence that lactic acidosis is rare­—about 10 cases per 100,000 patient-years—and that there are no reports of lactic acidosis after intravenously administered iodinated contrast in properly selected patients.^12,13

The ACR divides patients taking metformin into 2 categories:

• No evidence of acute kidney injury and eGFR greater than 30 mL/min/1.73 m²
• Either acute kidney injury or chronic kidney disease with eGFR below 30 mL/min/1.73 m² or undergoing arterial catheter studies with a high chance of embolization to the renal arteries.¹⁴

For the first group, they recommend against discontinuing metformin before or after giving iodinated contrast or checking kidney function after the procedure.

For the second group, they recommend holding metformin before and 48 hours after the procedure. It should not be restarted until renal function is confirmed to be normal.

The ADA recommends¹ continuing metformin after initiating insulin. However, in clinical practice, it is often not done.

Clinical trials have shown that combining metformin with insulin significantly improves glycemic control, prevents weight gain, and decreases insulin requirements.^15,16 One trial¹⁶ also looked at cardiovascular end points during a 4-year follow-up period;  combining metformin with insulin decreased the macrovascular disease-related event rate compared with insulin alone.

In the HOME trial,⁶ which added metformin to the existing insulin regimen, both groups gained weight, but the metformin group had gained about 3 kg less than the placebo group at the end of the 4.3-year trial. Metformin did not increase the risk of hypoglycemia, but it also did not reduce the risk of microvascular disease.

Concomitant metformin reduces costs

These days, practitioners can choose from a large selection of diabetes drugs. These include insulins with better pharmacokinetic profiles, as well as newer classes of noninsulin agents such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues.

Metformin is less expensive than these newer drugs, and using it concomitantly with other diabetes drugs can decrease their dosage requirements, which in turn decreases their monthly costs.

GASTROINTESTINAL EFFECTS

Metformin’s gastrointestinal adverse effects such as diarrhea, flatulence, nausea, and vomiting are a barrier to its use. The actual incidence rate of diarrhea varies widely in randomized trials and observational studies, and gastrointestinal effects are worse in metformin-naive patients, as well as those who have chronic gastritis or Helicobacter pylori infection.¹⁷

We have found that starting metformin at a low dose and up-titrating it over several weeks increases tolerability. We often start patients at 500 mg/day and increase the dosage by 1 500-mg tablet every 1 to 2 weeks. Also, we have noticed that intolerance is more likely in patients who eat a high-carbohydrate diet, but there is no high-level evidence to back this up because patients in clinical trials all undergo nutrition counseling and are therefore more likely to adhere to the low-carbohydrate diet.

Also, the extended-release formulation is more tolerable than the immediate-release formulation and has similar glycemic efficacy. It may be an option as first-line therapy or for patients who have significant adverse effects from immediate-release metformin.¹⁸ For patients on the immediate-release formulation, taking it with meals helps lessen some gastrointestinal effects, and this should be emphasized at every visit.

Finally, we limit the metformin dose to 2,000 mg/day, rather than the 2,550 mg/day allowed on labeling. Garber et al¹⁹ found that the lower dosage still provides the maximum clinical efficacy.

OTHER CAUTIONS

Metformin should be avoided in patients with acute or unstable heart failure because of the increased risk of lactic acidosis.

It also should be avoided in patients with hepatic impairment, according to the labeling. But this remains controversial in practice. Zhang et al²⁰ showed that continuing metformin in patients with diabetes and cirrhosis decreases the mortality risk by 57% compared with those taken off metformin.

Diet and lifestyle measures need to be emphasized at each visit. Wing et al²¹ showed that calorie restriction regardless of weight loss is beneficial for glycemic control and insulin sensitivity in obese patients with diabetes.

TAKE-HOME POINTS

Metformin improves glycemic control without tending to cause weight gain or hypoglycemia. It may also have cardiovascular benefits. Metformin is an inexpensive agent that should be continued, if tolerated, in those who need additional agents for glycemic control. It should be considered in all adult patients with type 2 diabetes.   

While some classes of medications used to treat psychi­atric disorders, such as stimulants and benzodiazepines, are well-recognized as controlled substances and drugs of abuse, clinicians may be less familiar with the potential misuse/abuse of other psychiatric medications. This article reviews the evidence related to the misuse/abuse of anticholinergics, antidepressants, antipsychotics, and gabapentinoids.

The terms “misuse,” “abuse,” and “addiction” are used variably in the literature without standardized definitions. For this review, “misuse/abuse (M/A)” will be used to collectively describe self-administration that is recreational or otherwise inconsistent with legal or medical guidelines, unless a specific distinction is made. Whether or not the medications reviewed are truly “addictive” will be briefly discussed for each drug class, but the focus will be on clinically relevant aspects of M/A, including:

• excessive self-administration
• self-administration by non-oral routes
• co-administration with other drugs of abuse
• malingering of psychiatric symptoms to obtain prescriptions
• diversion for sale to third parties
• toxicity from overdose.

Anticholinergic medications

The first case describing the deliberate M/A of an anticholinergic medication for its euphoric effects was published in 1960.Further reportsfollowed in Europe before the M/A potential of prescription anticholinergic medications among psychiatric patients with an overdose syndrome characterized by atropinism and toxic psychosis was more widely recognized in the United States in the 1970s. Most reported cases of M/A to date have occurred among patients with psychiatric illness because anticholinergic medications, including trihexyphenidyl, benztropine, biperiden, procyclidine, and orphenadrine, were commonly prescribed for the management of first-generation and high dopamine D2-affinity antipsychotic-induced extrapyramidal symptoms (EPS). For example, one study of 234 consecutively hospitalized patients with schizophrenia noted an anticholinergic M/A incidence of 6.5%.¹

However, anticholinergic M/A is not limited to individuals with psychotic disorders. A UK study of 154 admissions to an inpatient unit specializing in behavioral disturbances found a 12-month trihexyphenidyl M/A incidence of 17%; the most common diagnosis among abusers was antisocial personality disorder.² Anticholinergic M/A has also been reported among patients with a primary diagnosis of substance use disorders (SUDs)³ as well as more indiscriminately in prison settings,⁴ with some inmates exchanging trihexyphenidyl as currency and using it recreationally by crushing it into powder and smoking it with tobacco.⁵ Others have noted that abusers sometimes take anticholinergics with alcohol in order to “potentiate” the effects of each substance.^6,7 Pullen et al⁸ described individuals with and without psychiatric illness who stole anticholinergic medications, purchased them from other patients, or bought them “on the street.” Malingering EPS in order to obtain anticholinergic medications has also been well documented.⁹ Clearly, anticholinergic M/A can occur in psychiatric and non-psychiatric populations, both within and outside of clinical settings. Although anticholinergic M/A appears to be less frequent in the United States now that second-generation antipsychotics (SGAs) are more frequently prescribed, M/A remains common in some settings outside of the United States.⁷

Among the various anticholinergic medications prescribed for EPS, trihexyphenidyl has been reported to have the greatest M/A potential, which has been attributed to its potency,¹⁰ its stimulating effects (whereas benztropine is more sedating),¹¹ and its former popularity among prescribers.⁸ Marken et al¹¹ published a review of 110 reports of M/A occurring in patients receiving anticholinergic medications as part of psychiatric treatment in which 69% of cases involved taking trihexyphenidyl 15 to 60 mg at a time (recommended dosing is 6 to 10 mg/d in divided doses).Most of these patients were prescribed anticholinergic medications for diagnostically appropriate reasons—only 7% were described as “true abusers” with no medical indication. Anticholinergic M/A was typically driven by a desire for euphoric and psychedelic/hallucinogenic effects, although in some cases, anticholinergic M/A was attributed to self-medication of EPS and depressive symptoms. These findings illustrate the blurred distinction between recreational use and perceived subjective benefit, and match those of a subsequent study of 50 psychiatric patients who reported anticholinergic M/A not only to “get high,” but to “decrease depression,” “increase energy,” and decrease antipsychotic adverse effects.¹² Once again, trihexyphenidyl was the most frequently misused anticholinergic in this sample.

Table 1^{2,3,7,8,10-15} outlines the subjective effects sought and experienced by anticholinergic abusers as well as potential toxic effects; there is the potential for overlap. Several authors have also described physiologic dependence with long-term trihexyphenidyl use, including tolerance and a withdrawal/abstinence syndrome.^7,16 In addition, there have been several reports of coma¹³ and death in the setting of intended suicide by overdose of anticholinergic medications.^14,15

Although anticholinergic M/A in the United States now appears to be less common, clinicians should remain aware of the M/A potential of anticholinergic medications prescribed for EPS. Management of M/A involves:

• detection
• reducing anticholinergic exposure by managing EPS with alternative strategies, such as switching or reducing the dose of the antipsychotic medication
• gradual tapering of anticholinergic medications to minimize withdrawal.¹¹

Continue to: Antidepressants

Haddad¹⁷ published a review of 21 English-language case reports from 1966 to 1998 describing antidepressant use in which individuals met DSM-IV criteria for substance dependence to the medication. An additional 14 cases of antidepressant M/A were excluded based on insufficient details to support a diagnosis of dependence. The 21 reported cases involved:

• tranylcypromine (a monoamine oxidase inhibitor [MAOI])
• amitriptyline (a tricyclic antidepressant [TCA])
• fluoxetine (a selective serotonin reuptake inhibitor [SSRI])
• amineptine (a TCA previously available in France but removed from the market in 1999 in part due to its abuse potential)
• nomifensine (a norepinephrine/dopamine reuptake inhibitor previously available in the United Kingdom but removed in 1986 due to hemolytic anemia).

In 95% of cases, the antidepressants were prescribed for treatment of an affective disorder but were abused for stimulant effects or the perceived ability to lift mood, cause euphoria or a “high,” or to improve functioning. Two-thirds of cases involved patients with preexisting substance misuse. Placing the case reports in the context of the millions of patients prescribed antidepressants during this period, Haddad concluded the “incidence of [antidepressant] addiction [is] so low as to be clinically irrelevant.”¹⁷

Despite this conclusion, Haddad singled out amineptine and tranylcypromine as antidepressants with some evidence of true addictive potential.^17,18 A more recent case series described 14 patients who met DSM-IV criteria for substance abuse of tertiary amine TCAs (which have strong anticholinergic activity) and concluded that “misuse of [TCAs] is more common than generally appreciated.”¹⁹ In keeping with that claim, a study of 54 outpatients taking unspecified antidepressants found that up to 15% met DSM-III-R criteria for substance dependence (for the antidepressant) in the past year, although that rate was much lower than the rate of benzodiazepine dependence (47%) in a comparative sample.²⁰ Finally, a comprehensive review by Evans and Sullivan²¹ found anecdotal reports published before 2014 that detailed misuse, abuse, and dependence with MAOIs, TCAs, fluoxetine, venlafaxine, bupropion, tianeptine, and amineptine. Taken together, existing evidence indicates that select individuals—typically those with other SUD comorbidity—sometimes misuse antidepressants in a way that suggests addiction.

Still, while it is well known that abrupt cessation of antidepressants can result in a discontinuation syndrome characterized by flu-like symptoms, nausea, and dizziness,²² physiologic withdrawal effects must be distinguished from historical definitions of substance “abuse” and the broader concept of psychological “addiction” or drug dependence^18,23 now incorporated into the DSM-5 definition of SUDs.²⁴ Indeed, although withdrawal symptoms were reported by more than half of those who took antidepressants and responded to a recent online survey,²⁵ evidence to support the existence of significant antidepressant tolerance, craving, or compulsive use is lacking.^17,18 Antidepressants as a class do not appear to be significantly rewarding or reinforcing and, on the contrary, discontinuation by patients is common in clinical practice.²⁶ The popular claim that some individuals taking antidepressants “can’t quit”²⁷ must also be disentangled from loss of therapeutic effects upon cessation.

Bupropion. A more convincing argument for antidepressant addiction can be made for bupropion, a weak norepinephrine and dopamine reuptake inhibitor with an otherwise unclear mechanism of action.²⁸ In 2002, the first report of recreational bupropion M/A described a 13-year-old girl who took 2,400 mg orally (recommended maximum dose is 450 mg/d in divided doses) after being told it would give her “a better high than amphetamine.”²⁹ This was followed in the same year by the first report of recreational M/A of bupropion via nasal insufflation (snorting), resulting in a seizure,³⁰ and in 2013 by the first published case of M/A by IV self-administration.³¹

Continue to: The M/A potential of bupropion...

The M/A potential of bupropion, most commonly via intranasal administration, is now broadly recognized based on several case reports describing desired effects that include a euphoric high and a stimulating “buzz” similar to that of cocaine or methamphetamine but less intense.^29-36 Among recreational users, bupropion tablets are referred to as “welbys,” “wellies,” “dubs,” or “barnies.”³⁷ Media coverage of a 2013 outbreak of bupropion M/A in Toronto detailed administration by snorting, smoking, and injection, and described bupropion as “poor man’s cocaine.”³⁸ Between 2003 and 2016, 2,232 cases of bupropion misuse/abuse/dependence adverse drug reactions were reported to the European Monitoring Agency.³⁷ A review of intentional bupropion M/A reported to US Poison Control Centers between 2000 to 2013 found 975 such cases, with the yearly number tripling between 2000 and 2012.³⁹ In this sample, nearly half (45%) of the users were age 13 to 19, and 76% of cases involved oral ingestion. In addition to bupropion M/A among younger people, individuals who misuse bupropion often include those with existing SUDs but limited access to illicit stimulants and those trying to evade detection by urine toxicology screening.³³ For example, widespread use and diversion has been well documented within correctional settings, and as a result, many facilities have removed bupropion from their formularies.^{21,28,33,34,40}

Beyond desired effects, the most common adverse events associated with bupropion M/A are listed in Table 2,^{28,30,32-34,36,39} along with their incidence based on cases brought to the attention of US Poison Control Centers.³⁹ With relatively little evidence of a significant bupropion withdrawal syndrome,³⁷ the argument in favor of modeling bupropion as a truly addictive drug is limited to anecdotal reports of cravings and compulsive self-administration³⁵ and pro-dopaminergic activity (reuptake inhibition) that might provide a mechanism for potential rewarding and reinforcing effects.⁴⁰ While early preclinical studies of bupropion failed to provide evidence of amphetamine-like abuse potential,^41,42 non-oral administration in amounts well beyond therapeutic dosing could account for euphoric effects and a greater risk of psychological dependence and addiction.^21,28,40

Bupropion also has an FDA indication as an aid to smoking cessation treatment, and the medication demonstrated early promise in the pharmacologic treatment of psycho­stimulant use disorders, with reported improvements in cravings and other SUD outcomes.^43-45 However, subsequent randomized controlled trials (RCTs) failed to demonstrate a clear therapeutic role for bupropion in the treatment of cocaine^46,47 and methamphetamine use disorders (although some secondary analyses suggest possible therapeutic effects among non-daily stimulant users who are able to maintain good adherence with bupropion).^48-51 Given these overall discouraging results, the additive seizure risk of bupropion use with concomitant psychostimulant use, and the potential for M/A and diversion of bupropion (particularly among those with existing SUDs), the use of bupropion for the off-label treatment of stimulant use disorders is not advised.

Antipsychotics

As dopamine antagonists, antipsychotics are typically considered to have low potential for rewarding or reinforcing effects. Indeed, misuse of antipsychotics was a rarity in the first-generation era, with only a few published reports of haloperidol M/A within a small cluster of naïve young people who developed acute EPS,⁵² and a report of diversion in a prison with the “sadistic” intent of inflicting dystonic reactions on others.⁵³ A more recent report described 2additional cases of M/A involving haloperidol and trifluoperazine.⁵⁴ Some authors have described occasional drug-seeking behavior for low-potency D2 blockers such as chlorpromazine, presumably based on their M/A as anticholinergic medications.⁵⁵

The potential for antipsychotic M/A has gained wider recognition since the advent of the SGAs. Three cases of prescription olanzapine M/A have been published to date. One involved a man who malingered manic symptoms to obtain olanzapine, taking ≥40 mg at a time (beyond his prescribed dose of 20 mg twice daily) to get a “buzz,” and combining it with alcohol and benzodiazepines for additive effects or to “come down” from cocaine.⁵⁶ This patient noted that olanzapine was “a popular drug at parties” and was bought, sold, or traded among users, and occasionally administered intravenously. Two other cases described women who self-administered olanzapine, 40 to 50 mg/d, for euphoric and anxiolytic effects.^57,58 James et al⁵⁹ detailed a sample of 28 adults who reported “non-medical use” of olanzapine for anxiolytic effects, as a sleep aid, or to “escape from worries.”

Continue to: Quetiapine

Quetiapine. In contrast to some reports of olanzapine M/A in which the line between M/A and “self-medication” was blurred, quetiapine has become a more convincing example of clear recreational antipsychotic M/A. Since the first report of oral and intranasal quetiapine M/A in the Los Angeles County Jail published in 2004,⁵⁵ subsequent cases have detailed other novel methods of recreational self-administration^60-68 (Table 3^55,60-68), and additional reports have been published in non-English language journals.^69,70 Collectively, these case reports have detailed that quetiapine is:

• misused for primary subjective effects as well as to mitigate the unpleasant effects of other drugs^60,67
• referred to as “quell,”“Q,” “Susie-Q,” “squirrel,” and “baby heroin”^55,71,72
• often obtained by malingering psychiatric symptoms^55,61,63,65
• diverted/sold with “street value” both within and outside of psychiatric facilities and correctional settings.^{55,60-62,67,68,73}

These anecdotal accounts of quetiapine M/A have since been corroborated on a larger scale based on several retrospective studies. Although early reports of quetiapine M/A occurring in correctional settings have resulted in formulary removal,^71,74 quetiapine M/A is by no means limited to forensic populations and is especially common among those with comorbid SUDs. A survey of 74 patients enrolled in a Canadian methadone program reported that nearly 60% had misused quetiapine at some point.⁷⁵ Among an Australian sample of 868 individuals with active IV drug abuse, 31% reported having misused quetiapine.⁷⁶ Finally, within a small sample of patients with SUDs admitted to a detoxification unit in New York City, 17% reported M/A of SGAs.⁷⁷ In this study, SGAs were often taken in conjunction with other drugs of abuse in order to “recover” from or “enhance” the effects of other drugs or to “experiment.” Quetiapine was by far the most frequently abused SGA, reported in 96% of the sample; the most frequently reported SGA/drug combinations were quetiapine/alcohol/opioids, quetiapine/cocaine, and quetiapine/opioids.

Looking more broadly at poison center data, reports to the US National Poison Data System (NPDS) from 2005 to 2011 included 3,116 cases of quetiapine abuse (37.5%, defined as intentional recreational use in order to obtain a “high”) or misuse (62.5%, defined as improper use or dosing for non-recreational purposes).⁷⁸ A more recent analysis of NPDS reports from 2003 to 2013 found 2,118 cases of quetiapine abuse, representing 61% of all cases of reported SGA abuse.⁷⁹ An analysis of the European Medicines Agency Adverse Drug Database yielded 18,112 reports of quetia­pine misuse, abuse, dependence, and withdrawal for quetiapine (from 2005 to 2016) compared with 4,178 for olanzapine (from 2004 to 2016).⁸⁰ These reports identified 368 fatalities associated with quetiapine.

The rate of quetiapine M/A appears to be increasing sharply. Reports of quetiapine M/A to poison centers in Australia increased nearly 7-fold from 2006 to 2016.⁸¹ Based on reports to the Drug Abuse Warning System, US emergency department visits for M/A of quetiapine increased from 19,195 in 2005 to 32,024 in 2011 (an average of 27,114 visits/year), with 75% of cases involving quetiapine taken in combination with other prescription drugs, alcohol, or illicit drugs.⁸² Consistent with poison center data, M/A was reported for other antipsychotics, but none nearly as frequently as for quetiapine.

With increasingly frequent quetiapine M/A, clinicians should be vigilant in monitoring for medical morbidity related to quetiapine and cumulative toxicity with other drugs. The most frequent adverse events associated with quetiapine M/A reported to US Poison Control Centers are presented in Table 4.^78,79

Continue to: Unlike bupropion...

Unlike bupropion, quetiapine’s dopamine antagonism makes it unlikely to be a truly addictive drug, although this mechanism of action could mediate an increase in concurrent psychostimulant use.⁸³ A few case reports have described a quetiapine discontinuation syndrome similar to that of antidepressants,^60,65,84-88 but withdrawal symptoms suggestive of physiologic dependence may be mediated by non-dopaminergic effects through histamine and serotonin receptors.^84,89 Evidence for quetiapine misuse being associated with craving and compulsive use is lacking, and true quetiapine addiction is probably rare.

Similar to bupropion, preliminary findings have suggested promise for quetiapine as a putative therapy for other SUDs.^90-93 However, subsequent RCTs have failed to demonstrate a therapeutic effect for alcohol and cocaine use disorders.^94-96 Given these negative results and the clear M/A potential of quetiapine, off-label use of quetiapine for the treatment of SUDs and psychiatric symptoms among those with SUDs must be considered judiciously, with an eye towards possible diversion and avoiding the substitution of one drug of abuse for another.

Gabapentinoids

In 1997, the first published case report of gabapentin M/A described a woman who self-administered her husband’s gabapentin to reduce cravings for and withdrawal from cocaine.⁹⁷ The authors highlighted the possible therapeutic benefit of gabapentin in this regard rather than raising concerns about diversion and M/A. By 2004, however, reports of recreational gabapentin M/A emerged among inmates incarcerated within Florida correctional facilities who self-administered intranasal gabapentin to achieve a “high” that was “reminiscent of prior effects from intranasal ingestion of cocaine powder.”⁹⁸ In 2007, a single case of gabapentin misuse up to 7,200 mg/d (recommended dosing is ≤3,600 mg/d) was reported, with documentation of both tolerance and withdrawal symptoms.⁹⁹ As of 2017, a total of 36 cases of gabapentin M/A and 19 cases of pregabalin M/A have been published.¹⁰⁰

In the past decade, anecdotal reports have given way to larger-scale epidemiologic data painting a clear picture of the now-widespread M/A of gabapentin and other gabapentinoids. For example, a study of online descriptions of gabapentin and pregabalin M/A from 2008 to 2010 documented:

• oral and IM use (gabapentin)
• IV and rectal (“plugging”) use (pregabalin)
• “parachuting” (emptying the contents of capsules for a larger dose) (pregabalin)
• euphoric, entactogenic, stimulant, calming/anxiolytic, and dissociative subjective effects (gabapentin/pregabalin)
• rapid development of tolerance to euphoric effects leading to self-administration of increasing doses (gabapentin/pregabalin)
• frequent co-administration with other drugs of abuse, including alcohol, benzodiazepines, cannabis, stimulants, opiates, hallucinogens, gamma-hydroxybutyrate, mephedrone, and Salvia divinorum (gabapentin/pregabalin)¹⁰¹

Several systematic reviews of both anecdotal reports and epidemiologic studies published in the past few years provide additional evidence of the above, such as:

• excessive dosing with self-administration
• intranasal and inhaled routes of administration
• diversion and “street value”
• greater M/A potential of pregabalin than gabapentin
• the presence of gabapentinoids in postmortem toxicology analyses, suggesting a role in overdose fatalities when combined with other drugs.^100,102,103

Continue to: The European Medicine Agency's EudraVigilance database...

The European Medicine Agency’s EudraVigilance database included 4,301 reports of gabapentin misuse, abuse, or dependence, and 7,639 such reports for pregabalin, from 2006 to 2015 (rising sharply after 2012), with 86 gabapentin-related and 27 pregabalin-related fatalities.¹⁰⁴ Data from the Drug Diversion Program of the Researched Abuse, Diversion, and Addiction-Related Surveillance System from 2002 to 2015 have likewise revealed that gabapentin diversion increased significantly in 2013.¹⁰⁵

While the prevalence of gabapentinoid M/A is not known, rates appear to be significantly lower than for traditional drugs of abuse such as cannabis, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), and opioids.^106,107 However, gabapentin and pregabalin M/A appears to be increasingly common among individuals with SUDs and in particular among those with opioid use disorders (OUDs). For example, a 2015 report indicated that 15% of an adult cohort in Appalachian Kentucky with nonmedical use of diverted prescription opioids reported gabapentin M/A, an increase of nearly 3,000% since 2008.¹⁰⁸ Based on data from a US insurance enrollment and claims database, researchers found that the rate of gabapentin overuse among those also overusing opioids was 12% compared with only 2% for those using gabapentin alone.¹⁰⁹ It has also been reported that gabapentin is sometimes used as a “cutting agent” for heroin.¹¹⁰

Those who use gabapentinoids together with opioids report that gabapentin and pregabalin potentiate the euphoric effects of methadone¹¹¹ and endorse specific beliefs that pregabalin increases both the desired effects of heroin as well as negative effects such as “blackouts,” loss of control, and risk of overdose.¹¹² Indeed, sustained M/A of gabapentin and opioids together has been found to increase emergency department utilization, drug-related hospitalization, and respiratory depression.¹¹³ Based on a case-control study of opioid users in Canada, co-prescription of gabapentin and opioids was associated with a 50% increase in death from opioid-related causes compared with prescription of opioids alone.¹¹⁴

Case reports documenting tolerance, withdrawal, craving, and loss of control suggest a true addictive potential for gabapentinoids, but Bonnet and Sherbaum¹⁰⁰ concluded that while there is robust evidence of abusers “liking” gabapentin and pregabalin (eg, reward), evidence of “wanting” them (eg, psychological dependence) in the absence of other SUDs has been limited to only a few anecdotal reports with pregabalin. Accordingly, the risk of true addiction to gabapentinoids by those without preexisting SUDs appears to be low. Nonetheless, the M/A potential of both gabapentin and pregabalin is clear and in the context of a nationwide opioid epidemic, the increased morbidity/mortality risk related to combined use of gabapentinoids and opioids is both striking and concerning. Consequently, the state of Kentucky recently recognized the M/A potential of gabapentin by designating it a Schedule V controlled substance (pregabalin is already a Schedule V drug according to the US Drug Enforcement Agency),^103,113 and several other states now mandate the reporting of gabapentin prescriptions to prescription drug monitoring programs.¹¹⁵

Following a similar pattern to antidepressants and antipsychotics, a potential role for gabapentin in the treatment of cocaine use disorders was supported in preliminary studies,^116-118 but not in subsequent RCTs.^119-121 However, there is evidence from RCTs to support the use of gabapentin and pregabalin in the treatment of alcohol use disorders.^122-124 Gabapentin was also found to significantly reduce cannabis use and withdrawal symptoms in patients compared with placebo in an RCT of individuals with cannabis use disorders.¹²⁵ The perceived safety of gabapentinoids by clinicians, their subjective desirability by patients with SUDs, and efficacy data supporting a therapeutic role in SUDs must be balanced with recognition that approximately 80% of gabapentin prescriptions are written for off-label indications for which there is little supporting evidence,¹⁰⁹ such as low back pain.¹²⁶ Clinicians considering prescribing gabapentinoids to manage psychiatric symptoms, such as anxiety and insomnia, should carefully consider the risk of M/A and other potential morbidities, especially in the setting of SUDs and OUD in particular.

Continue to: Problematic, even if not addictive

Problematic, even if not addictive

It is sometimes claimed that “addiction” to psychiatric medications is not limited to stimulants and benzodiazepines.^27,127 Although anticholinergics, antidepressants, antipsychotics, and gabapentinoids can be drugs of abuse, with some users reporting physiologic withdrawal upon discontinuation, there is only limited evidence that the M/A of these psychiatric medications is associated with the characteristic features of a more complete definition of “addiction,” which may include:

• inability to consistently abstain
• impairment in behavioral control
• diminished recognition of significant problems associated with use
• a dysfunctional emotional response to chronic use.¹²⁸

Nonetheless, the literature documenting anticholinergic, antidepressant, antipsychotic, and gabapentinoid M/A includes several common features, including:

• initial reports among those with limited access to illicit drugs (eg, young people and incarcerated individuals) and subsequent spread to a wider population with more unconventional routes of administration
• use for recreational purposes and other subjective pseudo-therapeutic effects, often in combination with alcohol and illicit drugs
• greater M/A potential of certain medications within each of these drug classes (eg, trihexyphenidyl, bupropion, quetiapine)
• malingering psychiatric symptoms in order to obtain medications from prescribers and diversion for black market sale
• observations that medications might constitute therapy for SUDs that were not supported in subsequent RCTs (with the exception of gabapentin for alcohol and cannabis use disorders)
• increasing evidence of toxicity related to M/A, which suggests that prescription by clinicians has limited benefit and high risk for patients with SUDs.

Bottom Line

Some psychiatric medications are taken as drugs of abuse. Clinicians should be particularly aware of the misuse/abuse potential of anticholinergics, antidepressants, antipsychotics, and gabapentinoids, and use them cautiously, if at all, when treating patients with existing substance use disorders.

Related Resources

• Substance Abuse and Mental Health Services Administration. Prescription drug misuse and abuse. https://www.samhsa.gov/topics/prescription-drug-misuse-abuse.
• Substance Abuse and Mental Health Services Administration. Types of commonly misused or abused drugs. https://www.samhsa.gov/prescription-drug-misuse-abuse/types.
• National Institute on Drug Abuse. Misuse of prescription drugs. https://www.drugabuse.gov/publications/research-reports/misuse-prescription-drugs/summary.
• National Institute on Drug Abuse. New clinician screening tool available for substance use. https://www.drugabuse.gov/news-events/news-releases/2018/06/newclinician-screening-tool-available-substance-use.

Drug Brand Names

Amitriptyline • Elavil, Endep
Benztropine • Cogentin
Biperiden • Akineton
Bupropion • Wellbutrin, Zyban
Chlorpromazine • Thorzine
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Orphenadrine • Disipal, Norflex
Pregabalin • Lyrica, Lyrica CR
Procyclidine • Kemadrin
Quetiapine • Seroquel
Tianeptine • Coaxil, Stablon
Tranylcypromine • Parnate
Trifluoperazine • Stelazine
Trihexyphenidyl • Artane, Tremin
Venlafaxine • Effexor

While some classes of medications used to treat psychi­atric disorders, such as stimulants and benzodiazepines, are well-recognized as controlled substances and drugs of abuse, clinicians may be less familiar with the potential misuse/abuse of other psychiatric medications. This article reviews the evidence related to the misuse/abuse of anticholinergics, antidepressants, antipsychotics, and gabapentinoids.

The terms “misuse,” “abuse,” and “addiction” are used variably in the literature without standardized definitions. For this review, “misuse/abuse (M/A)” will be used to collectively describe self-administration that is recreational or otherwise inconsistent with legal or medical guidelines, unless a specific distinction is made. Whether or not the medications reviewed are truly “addictive” will be briefly discussed for each drug class, but the focus will be on clinically relevant aspects of M/A, including:

• excessive self-administration
• self-administration by non-oral routes
• co-administration with other drugs of abuse
• malingering of psychiatric symptoms to obtain prescriptions
• diversion for sale to third parties
• toxicity from overdose.

Anticholinergic medications

The first case describing the deliberate M/A of an anticholinergic medication for its euphoric effects was published in 1960.Further reportsfollowed in Europe before the M/A potential of prescription anticholinergic medications among psychiatric patients with an overdose syndrome characterized by atropinism and toxic psychosis was more widely recognized in the United States in the 1970s. Most reported cases of M/A to date have occurred among patients with psychiatric illness because anticholinergic medications, including trihexyphenidyl, benztropine, biperiden, procyclidine, and orphenadrine, were commonly prescribed for the management of first-generation and high dopamine D2-affinity antipsychotic-induced extrapyramidal symptoms (EPS). For example, one study of 234 consecutively hospitalized patients with schizophrenia noted an anticholinergic M/A incidence of 6.5%.¹

However, anticholinergic M/A is not limited to individuals with psychotic disorders. A UK study of 154 admissions to an inpatient unit specializing in behavioral disturbances found a 12-month trihexyphenidyl M/A incidence of 17%; the most common diagnosis among abusers was antisocial personality disorder.² Anticholinergic M/A has also been reported among patients with a primary diagnosis of substance use disorders (SUDs)³ as well as more indiscriminately in prison settings,⁴ with some inmates exchanging trihexyphenidyl as currency and using it recreationally by crushing it into powder and smoking it with tobacco.⁵ Others have noted that abusers sometimes take anticholinergics with alcohol in order to “potentiate” the effects of each substance.^6,7 Pullen et al⁸ described individuals with and without psychiatric illness who stole anticholinergic medications, purchased them from other patients, or bought them “on the street.” Malingering EPS in order to obtain anticholinergic medications has also been well documented.⁹ Clearly, anticholinergic M/A can occur in psychiatric and non-psychiatric populations, both within and outside of clinical settings. Although anticholinergic M/A appears to be less frequent in the United States now that second-generation antipsychotics (SGAs) are more frequently prescribed, M/A remains common in some settings outside of the United States.⁷

Among the various anticholinergic medications prescribed for EPS, trihexyphenidyl has been reported to have the greatest M/A potential, which has been attributed to its potency,¹⁰ its stimulating effects (whereas benztropine is more sedating),¹¹ and its former popularity among prescribers.⁸ Marken et al¹¹ published a review of 110 reports of M/A occurring in patients receiving anticholinergic medications as part of psychiatric treatment in which 69% of cases involved taking trihexyphenidyl 15 to 60 mg at a time (recommended dosing is 6 to 10 mg/d in divided doses).Most of these patients were prescribed anticholinergic medications for diagnostically appropriate reasons—only 7% were described as “true abusers” with no medical indication. Anticholinergic M/A was typically driven by a desire for euphoric and psychedelic/hallucinogenic effects, although in some cases, anticholinergic M/A was attributed to self-medication of EPS and depressive symptoms. These findings illustrate the blurred distinction between recreational use and perceived subjective benefit, and match those of a subsequent study of 50 psychiatric patients who reported anticholinergic M/A not only to “get high,” but to “decrease depression,” “increase energy,” and decrease antipsychotic adverse effects.¹² Once again, trihexyphenidyl was the most frequently misused anticholinergic in this sample.

Table 1^{2,3,7,8,10-15} outlines the subjective effects sought and experienced by anticholinergic abusers as well as potential toxic effects; there is the potential for overlap. Several authors have also described physiologic dependence with long-term trihexyphenidyl use, including tolerance and a withdrawal/abstinence syndrome.^7,16 In addition, there have been several reports of coma¹³ and death in the setting of intended suicide by overdose of anticholinergic medications.^14,15

Although anticholinergic M/A in the United States now appears to be less common, clinicians should remain aware of the M/A potential of anticholinergic medications prescribed for EPS. Management of M/A involves:

• detection
• reducing anticholinergic exposure by managing EPS with alternative strategies, such as switching or reducing the dose of the antipsychotic medication
• gradual tapering of anticholinergic medications to minimize withdrawal.¹¹

Continue to: Antidepressants

Haddad¹⁷ published a review of 21 English-language case reports from 1966 to 1998 describing antidepressant use in which individuals met DSM-IV criteria for substance dependence to the medication. An additional 14 cases of antidepressant M/A were excluded based on insufficient details to support a diagnosis of dependence. The 21 reported cases involved:

• tranylcypromine (a monoamine oxidase inhibitor [MAOI])
• amitriptyline (a tricyclic antidepressant [TCA])
• fluoxetine (a selective serotonin reuptake inhibitor [SSRI])
• amineptine (a TCA previously available in France but removed from the market in 1999 in part due to its abuse potential)
• nomifensine (a norepinephrine/dopamine reuptake inhibitor previously available in the United Kingdom but removed in 1986 due to hemolytic anemia).

In 95% of cases, the antidepressants were prescribed for treatment of an affective disorder but were abused for stimulant effects or the perceived ability to lift mood, cause euphoria or a “high,” or to improve functioning. Two-thirds of cases involved patients with preexisting substance misuse. Placing the case reports in the context of the millions of patients prescribed antidepressants during this period, Haddad concluded the “incidence of [antidepressant] addiction [is] so low as to be clinically irrelevant.”¹⁷

Despite this conclusion, Haddad singled out amineptine and tranylcypromine as antidepressants with some evidence of true addictive potential.^17,18 A more recent case series described 14 patients who met DSM-IV criteria for substance abuse of tertiary amine TCAs (which have strong anticholinergic activity) and concluded that “misuse of [TCAs] is more common than generally appreciated.”¹⁹ In keeping with that claim, a study of 54 outpatients taking unspecified antidepressants found that up to 15% met DSM-III-R criteria for substance dependence (for the antidepressant) in the past year, although that rate was much lower than the rate of benzodiazepine dependence (47%) in a comparative sample.²⁰ Finally, a comprehensive review by Evans and Sullivan²¹ found anecdotal reports published before 2014 that detailed misuse, abuse, and dependence with MAOIs, TCAs, fluoxetine, venlafaxine, bupropion, tianeptine, and amineptine. Taken together, existing evidence indicates that select individuals—typically those with other SUD comorbidity—sometimes misuse antidepressants in a way that suggests addiction.

Still, while it is well known that abrupt cessation of antidepressants can result in a discontinuation syndrome characterized by flu-like symptoms, nausea, and dizziness,²² physiologic withdrawal effects must be distinguished from historical definitions of substance “abuse” and the broader concept of psychological “addiction” or drug dependence^18,23 now incorporated into the DSM-5 definition of SUDs.²⁴ Indeed, although withdrawal symptoms were reported by more than half of those who took antidepressants and responded to a recent online survey,²⁵ evidence to support the existence of significant antidepressant tolerance, craving, or compulsive use is lacking.^17,18 Antidepressants as a class do not appear to be significantly rewarding or reinforcing and, on the contrary, discontinuation by patients is common in clinical practice.²⁶ The popular claim that some individuals taking antidepressants “can’t quit”²⁷ must also be disentangled from loss of therapeutic effects upon cessation.

Bupropion. A more convincing argument for antidepressant addiction can be made for bupropion, a weak norepinephrine and dopamine reuptake inhibitor with an otherwise unclear mechanism of action.²⁸ In 2002, the first report of recreational bupropion M/A described a 13-year-old girl who took 2,400 mg orally (recommended maximum dose is 450 mg/d in divided doses) after being told it would give her “a better high than amphetamine.”²⁹ This was followed in the same year by the first report of recreational M/A of bupropion via nasal insufflation (snorting), resulting in a seizure,³⁰ and in 2013 by the first published case of M/A by IV self-administration.³¹

Continue to: The M/A potential of bupropion...

The M/A potential of bupropion, most commonly via intranasal administration, is now broadly recognized based on several case reports describing desired effects that include a euphoric high and a stimulating “buzz” similar to that of cocaine or methamphetamine but less intense.^29-36 Among recreational users, bupropion tablets are referred to as “welbys,” “wellies,” “dubs,” or “barnies.”³⁷ Media coverage of a 2013 outbreak of bupropion M/A in Toronto detailed administration by snorting, smoking, and injection, and described bupropion as “poor man’s cocaine.”³⁸ Between 2003 and 2016, 2,232 cases of bupropion misuse/abuse/dependence adverse drug reactions were reported to the European Monitoring Agency.³⁷ A review of intentional bupropion M/A reported to US Poison Control Centers between 2000 to 2013 found 975 such cases, with the yearly number tripling between 2000 and 2012.³⁹ In this sample, nearly half (45%) of the users were age 13 to 19, and 76% of cases involved oral ingestion. In addition to bupropion M/A among younger people, individuals who misuse bupropion often include those with existing SUDs but limited access to illicit stimulants and those trying to evade detection by urine toxicology screening.³³ For example, widespread use and diversion has been well documented within correctional settings, and as a result, many facilities have removed bupropion from their formularies.^{21,28,33,34,40}

Beyond desired effects, the most common adverse events associated with bupropion M/A are listed in Table 2,^{28,30,32-34,36,39} along with their incidence based on cases brought to the attention of US Poison Control Centers.³⁹ With relatively little evidence of a significant bupropion withdrawal syndrome,³⁷ the argument in favor of modeling bupropion as a truly addictive drug is limited to anecdotal reports of cravings and compulsive self-administration³⁵ and pro-dopaminergic activity (reuptake inhibition) that might provide a mechanism for potential rewarding and reinforcing effects.⁴⁰ While early preclinical studies of bupropion failed to provide evidence of amphetamine-like abuse potential,^41,42 non-oral administration in amounts well beyond therapeutic dosing could account for euphoric effects and a greater risk of psychological dependence and addiction.^21,28,40

Bupropion also has an FDA indication as an aid to smoking cessation treatment, and the medication demonstrated early promise in the pharmacologic treatment of psycho­stimulant use disorders, with reported improvements in cravings and other SUD outcomes.^43-45 However, subsequent randomized controlled trials (RCTs) failed to demonstrate a clear therapeutic role for bupropion in the treatment of cocaine^46,47 and methamphetamine use disorders (although some secondary analyses suggest possible therapeutic effects among non-daily stimulant users who are able to maintain good adherence with bupropion).^48-51 Given these overall discouraging results, the additive seizure risk of bupropion use with concomitant psychostimulant use, and the potential for M/A and diversion of bupropion (particularly among those with existing SUDs), the use of bupropion for the off-label treatment of stimulant use disorders is not advised.

Antipsychotics

As dopamine antagonists, antipsychotics are typically considered to have low potential for rewarding or reinforcing effects. Indeed, misuse of antipsychotics was a rarity in the first-generation era, with only a few published reports of haloperidol M/A within a small cluster of naïve young people who developed acute EPS,⁵² and a report of diversion in a prison with the “sadistic” intent of inflicting dystonic reactions on others.⁵³ A more recent report described 2additional cases of M/A involving haloperidol and trifluoperazine.⁵⁴ Some authors have described occasional drug-seeking behavior for low-potency D2 blockers such as chlorpromazine, presumably based on their M/A as anticholinergic medications.⁵⁵

The potential for antipsychotic M/A has gained wider recognition since the advent of the SGAs. Three cases of prescription olanzapine M/A have been published to date. One involved a man who malingered manic symptoms to obtain olanzapine, taking ≥40 mg at a time (beyond his prescribed dose of 20 mg twice daily) to get a “buzz,” and combining it with alcohol and benzodiazepines for additive effects or to “come down” from cocaine.⁵⁶ This patient noted that olanzapine was “a popular drug at parties” and was bought, sold, or traded among users, and occasionally administered intravenously. Two other cases described women who self-administered olanzapine, 40 to 50 mg/d, for euphoric and anxiolytic effects.^57,58 James et al⁵⁹ detailed a sample of 28 adults who reported “non-medical use” of olanzapine for anxiolytic effects, as a sleep aid, or to “escape from worries.”

Continue to: Quetiapine

Quetiapine. In contrast to some reports of olanzapine M/A in which the line between M/A and “self-medication” was blurred, quetiapine has become a more convincing example of clear recreational antipsychotic M/A. Since the first report of oral and intranasal quetiapine M/A in the Los Angeles County Jail published in 2004,⁵⁵ subsequent cases have detailed other novel methods of recreational self-administration^60-68 (Table 3^55,60-68), and additional reports have been published in non-English language journals.^69,70 Collectively, these case reports have detailed that quetiapine is:

• misused for primary subjective effects as well as to mitigate the unpleasant effects of other drugs^60,67
• referred to as “quell,”“Q,” “Susie-Q,” “squirrel,” and “baby heroin”^55,71,72
• often obtained by malingering psychiatric symptoms^55,61,63,65
• diverted/sold with “street value” both within and outside of psychiatric facilities and correctional settings.^{55,60-62,67,68,73}

These anecdotal accounts of quetiapine M/A have since been corroborated on a larger scale based on several retrospective studies. Although early reports of quetiapine M/A occurring in correctional settings have resulted in formulary removal,^71,74 quetiapine M/A is by no means limited to forensic populations and is especially common among those with comorbid SUDs. A survey of 74 patients enrolled in a Canadian methadone program reported that nearly 60% had misused quetiapine at some point.⁷⁵ Among an Australian sample of 868 individuals with active IV drug abuse, 31% reported having misused quetiapine.⁷⁶ Finally, within a small sample of patients with SUDs admitted to a detoxification unit in New York City, 17% reported M/A of SGAs.⁷⁷ In this study, SGAs were often taken in conjunction with other drugs of abuse in order to “recover” from or “enhance” the effects of other drugs or to “experiment.” Quetiapine was by far the most frequently abused SGA, reported in 96% of the sample; the most frequently reported SGA/drug combinations were quetiapine/alcohol/opioids, quetiapine/cocaine, and quetiapine/opioids.

Looking more broadly at poison center data, reports to the US National Poison Data System (NPDS) from 2005 to 2011 included 3,116 cases of quetiapine abuse (37.5%, defined as intentional recreational use in order to obtain a “high”) or misuse (62.5%, defined as improper use or dosing for non-recreational purposes).⁷⁸ A more recent analysis of NPDS reports from 2003 to 2013 found 2,118 cases of quetiapine abuse, representing 61% of all cases of reported SGA abuse.⁷⁹ An analysis of the European Medicines Agency Adverse Drug Database yielded 18,112 reports of quetia­pine misuse, abuse, dependence, and withdrawal for quetiapine (from 2005 to 2016) compared with 4,178 for olanzapine (from 2004 to 2016).⁸⁰ These reports identified 368 fatalities associated with quetiapine.

The rate of quetiapine M/A appears to be increasing sharply. Reports of quetiapine M/A to poison centers in Australia increased nearly 7-fold from 2006 to 2016.⁸¹ Based on reports to the Drug Abuse Warning System, US emergency department visits for M/A of quetiapine increased from 19,195 in 2005 to 32,024 in 2011 (an average of 27,114 visits/year), with 75% of cases involving quetiapine taken in combination with other prescription drugs, alcohol, or illicit drugs.⁸² Consistent with poison center data, M/A was reported for other antipsychotics, but none nearly as frequently as for quetiapine.

With increasingly frequent quetiapine M/A, clinicians should be vigilant in monitoring for medical morbidity related to quetiapine and cumulative toxicity with other drugs. The most frequent adverse events associated with quetiapine M/A reported to US Poison Control Centers are presented in Table 4.^78,79

Continue to: Unlike bupropion...

Unlike bupropion, quetiapine’s dopamine antagonism makes it unlikely to be a truly addictive drug, although this mechanism of action could mediate an increase in concurrent psychostimulant use.⁸³ A few case reports have described a quetiapine discontinuation syndrome similar to that of antidepressants,^60,65,84-88 but withdrawal symptoms suggestive of physiologic dependence may be mediated by non-dopaminergic effects through histamine and serotonin receptors.^84,89 Evidence for quetiapine misuse being associated with craving and compulsive use is lacking, and true quetiapine addiction is probably rare.

Similar to bupropion, preliminary findings have suggested promise for quetiapine as a putative therapy for other SUDs.^90-93 However, subsequent RCTs have failed to demonstrate a therapeutic effect for alcohol and cocaine use disorders.^94-96 Given these negative results and the clear M/A potential of quetiapine, off-label use of quetiapine for the treatment of SUDs and psychiatric symptoms among those with SUDs must be considered judiciously, with an eye towards possible diversion and avoiding the substitution of one drug of abuse for another.

Gabapentinoids

In 1997, the first published case report of gabapentin M/A described a woman who self-administered her husband’s gabapentin to reduce cravings for and withdrawal from cocaine.⁹⁷ The authors highlighted the possible therapeutic benefit of gabapentin in this regard rather than raising concerns about diversion and M/A. By 2004, however, reports of recreational gabapentin M/A emerged among inmates incarcerated within Florida correctional facilities who self-administered intranasal gabapentin to achieve a “high” that was “reminiscent of prior effects from intranasal ingestion of cocaine powder.”⁹⁸ In 2007, a single case of gabapentin misuse up to 7,200 mg/d (recommended dosing is ≤3,600 mg/d) was reported, with documentation of both tolerance and withdrawal symptoms.⁹⁹ As of 2017, a total of 36 cases of gabapentin M/A and 19 cases of pregabalin M/A have been published.¹⁰⁰

In the past decade, anecdotal reports have given way to larger-scale epidemiologic data painting a clear picture of the now-widespread M/A of gabapentin and other gabapentinoids. For example, a study of online descriptions of gabapentin and pregabalin M/A from 2008 to 2010 documented:

• oral and IM use (gabapentin)
• IV and rectal (“plugging”) use (pregabalin)
• “parachuting” (emptying the contents of capsules for a larger dose) (pregabalin)
• euphoric, entactogenic, stimulant, calming/anxiolytic, and dissociative subjective effects (gabapentin/pregabalin)
• rapid development of tolerance to euphoric effects leading to self-administration of increasing doses (gabapentin/pregabalin)
• frequent co-administration with other drugs of abuse, including alcohol, benzodiazepines, cannabis, stimulants, opiates, hallucinogens, gamma-hydroxybutyrate, mephedrone, and Salvia divinorum (gabapentin/pregabalin)¹⁰¹

Several systematic reviews of both anecdotal reports and epidemiologic studies published in the past few years provide additional evidence of the above, such as:

• excessive dosing with self-administration
• intranasal and inhaled routes of administration
• diversion and “street value”
• greater M/A potential of pregabalin than gabapentin
• the presence of gabapentinoids in postmortem toxicology analyses, suggesting a role in overdose fatalities when combined with other drugs.^100,102,103

Continue to: The European Medicine Agency's EudraVigilance database...

The European Medicine Agency’s EudraVigilance database included 4,301 reports of gabapentin misuse, abuse, or dependence, and 7,639 such reports for pregabalin, from 2006 to 2015 (rising sharply after 2012), with 86 gabapentin-related and 27 pregabalin-related fatalities.¹⁰⁴ Data from the Drug Diversion Program of the Researched Abuse, Diversion, and Addiction-Related Surveillance System from 2002 to 2015 have likewise revealed that gabapentin diversion increased significantly in 2013.¹⁰⁵

While the prevalence of gabapentinoid M/A is not known, rates appear to be significantly lower than for traditional drugs of abuse such as cannabis, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), and opioids.^106,107 However, gabapentin and pregabalin M/A appears to be increasingly common among individuals with SUDs and in particular among those with opioid use disorders (OUDs). For example, a 2015 report indicated that 15% of an adult cohort in Appalachian Kentucky with nonmedical use of diverted prescription opioids reported gabapentin M/A, an increase of nearly 3,000% since 2008.¹⁰⁸ Based on data from a US insurance enrollment and claims database, researchers found that the rate of gabapentin overuse among those also overusing opioids was 12% compared with only 2% for those using gabapentin alone.¹⁰⁹ It has also been reported that gabapentin is sometimes used as a “cutting agent” for heroin.¹¹⁰

Those who use gabapentinoids together with opioids report that gabapentin and pregabalin potentiate the euphoric effects of methadone¹¹¹ and endorse specific beliefs that pregabalin increases both the desired effects of heroin as well as negative effects such as “blackouts,” loss of control, and risk of overdose.¹¹² Indeed, sustained M/A of gabapentin and opioids together has been found to increase emergency department utilization, drug-related hospitalization, and respiratory depression.¹¹³ Based on a case-control study of opioid users in Canada, co-prescription of gabapentin and opioids was associated with a 50% increase in death from opioid-related causes compared with prescription of opioids alone.¹¹⁴

Case reports documenting tolerance, withdrawal, craving, and loss of control suggest a true addictive potential for gabapentinoids, but Bonnet and Sherbaum¹⁰⁰ concluded that while there is robust evidence of abusers “liking” gabapentin and pregabalin (eg, reward), evidence of “wanting” them (eg, psychological dependence) in the absence of other SUDs has been limited to only a few anecdotal reports with pregabalin. Accordingly, the risk of true addiction to gabapentinoids by those without preexisting SUDs appears to be low. Nonetheless, the M/A potential of both gabapentin and pregabalin is clear and in the context of a nationwide opioid epidemic, the increased morbidity/mortality risk related to combined use of gabapentinoids and opioids is both striking and concerning. Consequently, the state of Kentucky recently recognized the M/A potential of gabapentin by designating it a Schedule V controlled substance (pregabalin is already a Schedule V drug according to the US Drug Enforcement Agency),^103,113 and several other states now mandate the reporting of gabapentin prescriptions to prescription drug monitoring programs.¹¹⁵

Following a similar pattern to antidepressants and antipsychotics, a potential role for gabapentin in the treatment of cocaine use disorders was supported in preliminary studies,^116-118 but not in subsequent RCTs.^119-121 However, there is evidence from RCTs to support the use of gabapentin and pregabalin in the treatment of alcohol use disorders.^122-124 Gabapentin was also found to significantly reduce cannabis use and withdrawal symptoms in patients compared with placebo in an RCT of individuals with cannabis use disorders.¹²⁵ The perceived safety of gabapentinoids by clinicians, their subjective desirability by patients with SUDs, and efficacy data supporting a therapeutic role in SUDs must be balanced with recognition that approximately 80% of gabapentin prescriptions are written for off-label indications for which there is little supporting evidence,¹⁰⁹ such as low back pain.¹²⁶ Clinicians considering prescribing gabapentinoids to manage psychiatric symptoms, such as anxiety and insomnia, should carefully consider the risk of M/A and other potential morbidities, especially in the setting of SUDs and OUD in particular.

Continue to: Problematic, even if not addictive

Problematic, even if not addictive

It is sometimes claimed that “addiction” to psychiatric medications is not limited to stimulants and benzodiazepines.^27,127 Although anticholinergics, antidepressants, antipsychotics, and gabapentinoids can be drugs of abuse, with some users reporting physiologic withdrawal upon discontinuation, there is only limited evidence that the M/A of these psychiatric medications is associated with the characteristic features of a more complete definition of “addiction,” which may include:

• inability to consistently abstain
• impairment in behavioral control
• diminished recognition of significant problems associated with use
• a dysfunctional emotional response to chronic use.¹²⁸

Nonetheless, the literature documenting anticholinergic, antidepressant, antipsychotic, and gabapentinoid M/A includes several common features, including:

• initial reports among those with limited access to illicit drugs (eg, young people and incarcerated individuals) and subsequent spread to a wider population with more unconventional routes of administration
• use for recreational purposes and other subjective pseudo-therapeutic effects, often in combination with alcohol and illicit drugs
• greater M/A potential of certain medications within each of these drug classes (eg, trihexyphenidyl, bupropion, quetiapine)
• malingering psychiatric symptoms in order to obtain medications from prescribers and diversion for black market sale
• observations that medications might constitute therapy for SUDs that were not supported in subsequent RCTs (with the exception of gabapentin for alcohol and cannabis use disorders)
• increasing evidence of toxicity related to M/A, which suggests that prescription by clinicians has limited benefit and high risk for patients with SUDs.

Bottom Line

Some psychiatric medications are taken as drugs of abuse. Clinicians should be particularly aware of the misuse/abuse potential of anticholinergics, antidepressants, antipsychotics, and gabapentinoids, and use them cautiously, if at all, when treating patients with existing substance use disorders.

Related Resources

• Substance Abuse and Mental Health Services Administration. Prescription drug misuse and abuse. https://www.samhsa.gov/topics/prescription-drug-misuse-abuse.
• Substance Abuse and Mental Health Services Administration. Types of commonly misused or abused drugs. https://www.samhsa.gov/prescription-drug-misuse-abuse/types.
• National Institute on Drug Abuse. Misuse of prescription drugs. https://www.drugabuse.gov/publications/research-reports/misuse-prescription-drugs/summary.
• National Institute on Drug Abuse. New clinician screening tool available for substance use. https://www.drugabuse.gov/news-events/news-releases/2018/06/newclinician-screening-tool-available-substance-use.

Drug Brand Names

Amitriptyline • Elavil, Endep
Benztropine • Cogentin
Biperiden • Akineton
Bupropion • Wellbutrin, Zyban
Chlorpromazine • Thorzine
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Orphenadrine • Disipal, Norflex
Pregabalin • Lyrica, Lyrica CR
Procyclidine • Kemadrin
Quetiapine • Seroquel
Tianeptine • Coaxil, Stablon
Tranylcypromine • Parnate
Trifluoperazine • Stelazine
Trihexyphenidyl • Artane, Tremin
Venlafaxine • Effexor

While some classes of medications used to treat psychi­atric disorders, such as stimulants and benzodiazepines, are well-recognized as controlled substances and drugs of abuse, clinicians may be less familiar with the potential misuse/abuse of other psychiatric medications. This article reviews the evidence related to the misuse/abuse of anticholinergics, antidepressants, antipsychotics, and gabapentinoids.

The terms “misuse,” “abuse,” and “addiction” are used variably in the literature without standardized definitions. For this review, “misuse/abuse (M/A)” will be used to collectively describe self-administration that is recreational or otherwise inconsistent with legal or medical guidelines, unless a specific distinction is made. Whether or not the medications reviewed are truly “addictive” will be briefly discussed for each drug class, but the focus will be on clinically relevant aspects of M/A, including:

• excessive self-administration
• self-administration by non-oral routes
• co-administration with other drugs of abuse
• malingering of psychiatric symptoms to obtain prescriptions
• diversion for sale to third parties
• toxicity from overdose.

Anticholinergic medications

The first case describing the deliberate M/A of an anticholinergic medication for its euphoric effects was published in 1960.Further reportsfollowed in Europe before the M/A potential of prescription anticholinergic medications among psychiatric patients with an overdose syndrome characterized by atropinism and toxic psychosis was more widely recognized in the United States in the 1970s. Most reported cases of M/A to date have occurred among patients with psychiatric illness because anticholinergic medications, including trihexyphenidyl, benztropine, biperiden, procyclidine, and orphenadrine, were commonly prescribed for the management of first-generation and high dopamine D2-affinity antipsychotic-induced extrapyramidal symptoms (EPS). For example, one study of 234 consecutively hospitalized patients with schizophrenia noted an anticholinergic M/A incidence of 6.5%.¹

However, anticholinergic M/A is not limited to individuals with psychotic disorders. A UK study of 154 admissions to an inpatient unit specializing in behavioral disturbances found a 12-month trihexyphenidyl M/A incidence of 17%; the most common diagnosis among abusers was antisocial personality disorder.² Anticholinergic M/A has also been reported among patients with a primary diagnosis of substance use disorders (SUDs)³ as well as more indiscriminately in prison settings,⁴ with some inmates exchanging trihexyphenidyl as currency and using it recreationally by crushing it into powder and smoking it with tobacco.⁵ Others have noted that abusers sometimes take anticholinergics with alcohol in order to “potentiate” the effects of each substance.^6,7 Pullen et al⁸ described individuals with and without psychiatric illness who stole anticholinergic medications, purchased them from other patients, or bought them “on the street.” Malingering EPS in order to obtain anticholinergic medications has also been well documented.⁹ Clearly, anticholinergic M/A can occur in psychiatric and non-psychiatric populations, both within and outside of clinical settings. Although anticholinergic M/A appears to be less frequent in the United States now that second-generation antipsychotics (SGAs) are more frequently prescribed, M/A remains common in some settings outside of the United States.⁷

Among the various anticholinergic medications prescribed for EPS, trihexyphenidyl has been reported to have the greatest M/A potential, which has been attributed to its potency,¹⁰ its stimulating effects (whereas benztropine is more sedating),¹¹ and its former popularity among prescribers.⁸ Marken et al¹¹ published a review of 110 reports of M/A occurring in patients receiving anticholinergic medications as part of psychiatric treatment in which 69% of cases involved taking trihexyphenidyl 15 to 60 mg at a time (recommended dosing is 6 to 10 mg/d in divided doses).Most of these patients were prescribed anticholinergic medications for diagnostically appropriate reasons—only 7% were described as “true abusers” with no medical indication. Anticholinergic M/A was typically driven by a desire for euphoric and psychedelic/hallucinogenic effects, although in some cases, anticholinergic M/A was attributed to self-medication of EPS and depressive symptoms. These findings illustrate the blurred distinction between recreational use and perceived subjective benefit, and match those of a subsequent study of 50 psychiatric patients who reported anticholinergic M/A not only to “get high,” but to “decrease depression,” “increase energy,” and decrease antipsychotic adverse effects.¹² Once again, trihexyphenidyl was the most frequently misused anticholinergic in this sample.

Table 1^{2,3,7,8,10-15} outlines the subjective effects sought and experienced by anticholinergic abusers as well as potential toxic effects; there is the potential for overlap. Several authors have also described physiologic dependence with long-term trihexyphenidyl use, including tolerance and a withdrawal/abstinence syndrome.^7,16 In addition, there have been several reports of coma¹³ and death in the setting of intended suicide by overdose of anticholinergic medications.^14,15

Although anticholinergic M/A in the United States now appears to be less common, clinicians should remain aware of the M/A potential of anticholinergic medications prescribed for EPS. Management of M/A involves:

• detection
• reducing anticholinergic exposure by managing EPS with alternative strategies, such as switching or reducing the dose of the antipsychotic medication
• gradual tapering of anticholinergic medications to minimize withdrawal.¹¹

Continue to: Antidepressants

Haddad¹⁷ published a review of 21 English-language case reports from 1966 to 1998 describing antidepressant use in which individuals met DSM-IV criteria for substance dependence to the medication. An additional 14 cases of antidepressant M/A were excluded based on insufficient details to support a diagnosis of dependence. The 21 reported cases involved:

• tranylcypromine (a monoamine oxidase inhibitor [MAOI])
• amitriptyline (a tricyclic antidepressant [TCA])
• fluoxetine (a selective serotonin reuptake inhibitor [SSRI])
• amineptine (a TCA previously available in France but removed from the market in 1999 in part due to its abuse potential)
• nomifensine (a norepinephrine/dopamine reuptake inhibitor previously available in the United Kingdom but removed in 1986 due to hemolytic anemia).

In 95% of cases, the antidepressants were prescribed for treatment of an affective disorder but were abused for stimulant effects or the perceived ability to lift mood, cause euphoria or a “high,” or to improve functioning. Two-thirds of cases involved patients with preexisting substance misuse. Placing the case reports in the context of the millions of patients prescribed antidepressants during this period, Haddad concluded the “incidence of [antidepressant] addiction [is] so low as to be clinically irrelevant.”¹⁷

Despite this conclusion, Haddad singled out amineptine and tranylcypromine as antidepressants with some evidence of true addictive potential.^17,18 A more recent case series described 14 patients who met DSM-IV criteria for substance abuse of tertiary amine TCAs (which have strong anticholinergic activity) and concluded that “misuse of [TCAs] is more common than generally appreciated.”¹⁹ In keeping with that claim, a study of 54 outpatients taking unspecified antidepressants found that up to 15% met DSM-III-R criteria for substance dependence (for the antidepressant) in the past year, although that rate was much lower than the rate of benzodiazepine dependence (47%) in a comparative sample.²⁰ Finally, a comprehensive review by Evans and Sullivan²¹ found anecdotal reports published before 2014 that detailed misuse, abuse, and dependence with MAOIs, TCAs, fluoxetine, venlafaxine, bupropion, tianeptine, and amineptine. Taken together, existing evidence indicates that select individuals—typically those with other SUD comorbidity—sometimes misuse antidepressants in a way that suggests addiction.

Still, while it is well known that abrupt cessation of antidepressants can result in a discontinuation syndrome characterized by flu-like symptoms, nausea, and dizziness,²² physiologic withdrawal effects must be distinguished from historical definitions of substance “abuse” and the broader concept of psychological “addiction” or drug dependence^18,23 now incorporated into the DSM-5 definition of SUDs.²⁴ Indeed, although withdrawal symptoms were reported by more than half of those who took antidepressants and responded to a recent online survey,²⁵ evidence to support the existence of significant antidepressant tolerance, craving, or compulsive use is lacking.^17,18 Antidepressants as a class do not appear to be significantly rewarding or reinforcing and, on the contrary, discontinuation by patients is common in clinical practice.²⁶ The popular claim that some individuals taking antidepressants “can’t quit”²⁷ must also be disentangled from loss of therapeutic effects upon cessation.

Bupropion. A more convincing argument for antidepressant addiction can be made for bupropion, a weak norepinephrine and dopamine reuptake inhibitor with an otherwise unclear mechanism of action.²⁸ In 2002, the first report of recreational bupropion M/A described a 13-year-old girl who took 2,400 mg orally (recommended maximum dose is 450 mg/d in divided doses) after being told it would give her “a better high than amphetamine.”²⁹ This was followed in the same year by the first report of recreational M/A of bupropion via nasal insufflation (snorting), resulting in a seizure,³⁰ and in 2013 by the first published case of M/A by IV self-administration.³¹

Continue to: The M/A potential of bupropion...

The M/A potential of bupropion, most commonly via intranasal administration, is now broadly recognized based on several case reports describing desired effects that include a euphoric high and a stimulating “buzz” similar to that of cocaine or methamphetamine but less intense.^29-36 Among recreational users, bupropion tablets are referred to as “welbys,” “wellies,” “dubs,” or “barnies.”³⁷ Media coverage of a 2013 outbreak of bupropion M/A in Toronto detailed administration by snorting, smoking, and injection, and described bupropion as “poor man’s cocaine.”³⁸ Between 2003 and 2016, 2,232 cases of bupropion misuse/abuse/dependence adverse drug reactions were reported to the European Monitoring Agency.³⁷ A review of intentional bupropion M/A reported to US Poison Control Centers between 2000 to 2013 found 975 such cases, with the yearly number tripling between 2000 and 2012.³⁹ In this sample, nearly half (45%) of the users were age 13 to 19, and 76% of cases involved oral ingestion. In addition to bupropion M/A among younger people, individuals who misuse bupropion often include those with existing SUDs but limited access to illicit stimulants and those trying to evade detection by urine toxicology screening.³³ For example, widespread use and diversion has been well documented within correctional settings, and as a result, many facilities have removed bupropion from their formularies.^{21,28,33,34,40}

Beyond desired effects, the most common adverse events associated with bupropion M/A are listed in Table 2,^{28,30,32-34,36,39} along with their incidence based on cases brought to the attention of US Poison Control Centers.³⁹ With relatively little evidence of a significant bupropion withdrawal syndrome,³⁷ the argument in favor of modeling bupropion as a truly addictive drug is limited to anecdotal reports of cravings and compulsive self-administration³⁵ and pro-dopaminergic activity (reuptake inhibition) that might provide a mechanism for potential rewarding and reinforcing effects.⁴⁰ While early preclinical studies of bupropion failed to provide evidence of amphetamine-like abuse potential,^41,42 non-oral administration in amounts well beyond therapeutic dosing could account for euphoric effects and a greater risk of psychological dependence and addiction.^21,28,40

Bupropion also has an FDA indication as an aid to smoking cessation treatment, and the medication demonstrated early promise in the pharmacologic treatment of psycho­stimulant use disorders, with reported improvements in cravings and other SUD outcomes.^43-45 However, subsequent randomized controlled trials (RCTs) failed to demonstrate a clear therapeutic role for bupropion in the treatment of cocaine^46,47 and methamphetamine use disorders (although some secondary analyses suggest possible therapeutic effects among non-daily stimulant users who are able to maintain good adherence with bupropion).^48-51 Given these overall discouraging results, the additive seizure risk of bupropion use with concomitant psychostimulant use, and the potential for M/A and diversion of bupropion (particularly among those with existing SUDs), the use of bupropion for the off-label treatment of stimulant use disorders is not advised.

Antipsychotics

As dopamine antagonists, antipsychotics are typically considered to have low potential for rewarding or reinforcing effects. Indeed, misuse of antipsychotics was a rarity in the first-generation era, with only a few published reports of haloperidol M/A within a small cluster of naïve young people who developed acute EPS,⁵² and a report of diversion in a prison with the “sadistic” intent of inflicting dystonic reactions on others.⁵³ A more recent report described 2additional cases of M/A involving haloperidol and trifluoperazine.⁵⁴ Some authors have described occasional drug-seeking behavior for low-potency D2 blockers such as chlorpromazine, presumably based on their M/A as anticholinergic medications.⁵⁵

The potential for antipsychotic M/A has gained wider recognition since the advent of the SGAs. Three cases of prescription olanzapine M/A have been published to date. One involved a man who malingered manic symptoms to obtain olanzapine, taking ≥40 mg at a time (beyond his prescribed dose of 20 mg twice daily) to get a “buzz,” and combining it with alcohol and benzodiazepines for additive effects or to “come down” from cocaine.⁵⁶ This patient noted that olanzapine was “a popular drug at parties” and was bought, sold, or traded among users, and occasionally administered intravenously. Two other cases described women who self-administered olanzapine, 40 to 50 mg/d, for euphoric and anxiolytic effects.^57,58 James et al⁵⁹ detailed a sample of 28 adults who reported “non-medical use” of olanzapine for anxiolytic effects, as a sleep aid, or to “escape from worries.”

Continue to: Quetiapine

Quetiapine. In contrast to some reports of olanzapine M/A in which the line between M/A and “self-medication” was blurred, quetiapine has become a more convincing example of clear recreational antipsychotic M/A. Since the first report of oral and intranasal quetiapine M/A in the Los Angeles County Jail published in 2004,⁵⁵ subsequent cases have detailed other novel methods of recreational self-administration^60-68 (Table 3^55,60-68), and additional reports have been published in non-English language journals.^69,70 Collectively, these case reports have detailed that quetiapine is:

• misused for primary subjective effects as well as to mitigate the unpleasant effects of other drugs^60,67
• referred to as “quell,”“Q,” “Susie-Q,” “squirrel,” and “baby heroin”^55,71,72
• often obtained by malingering psychiatric symptoms^55,61,63,65
• diverted/sold with “street value” both within and outside of psychiatric facilities and correctional settings.^{55,60-62,67,68,73}

These anecdotal accounts of quetiapine M/A have since been corroborated on a larger scale based on several retrospective studies. Although early reports of quetiapine M/A occurring in correctional settings have resulted in formulary removal,^71,74 quetiapine M/A is by no means limited to forensic populations and is especially common among those with comorbid SUDs. A survey of 74 patients enrolled in a Canadian methadone program reported that nearly 60% had misused quetiapine at some point.⁷⁵ Among an Australian sample of 868 individuals with active IV drug abuse, 31% reported having misused quetiapine.⁷⁶ Finally, within a small sample of patients with SUDs admitted to a detoxification unit in New York City, 17% reported M/A of SGAs.⁷⁷ In this study, SGAs were often taken in conjunction with other drugs of abuse in order to “recover” from or “enhance” the effects of other drugs or to “experiment.” Quetiapine was by far the most frequently abused SGA, reported in 96% of the sample; the most frequently reported SGA/drug combinations were quetiapine/alcohol/opioids, quetiapine/cocaine, and quetiapine/opioids.

Looking more broadly at poison center data, reports to the US National Poison Data System (NPDS) from 2005 to 2011 included 3,116 cases of quetiapine abuse (37.5%, defined as intentional recreational use in order to obtain a “high”) or misuse (62.5%, defined as improper use or dosing for non-recreational purposes).⁷⁸ A more recent analysis of NPDS reports from 2003 to 2013 found 2,118 cases of quetiapine abuse, representing 61% of all cases of reported SGA abuse.⁷⁹ An analysis of the European Medicines Agency Adverse Drug Database yielded 18,112 reports of quetia­pine misuse, abuse, dependence, and withdrawal for quetiapine (from 2005 to 2016) compared with 4,178 for olanzapine (from 2004 to 2016).⁸⁰ These reports identified 368 fatalities associated with quetiapine.

The rate of quetiapine M/A appears to be increasing sharply. Reports of quetiapine M/A to poison centers in Australia increased nearly 7-fold from 2006 to 2016.⁸¹ Based on reports to the Drug Abuse Warning System, US emergency department visits for M/A of quetiapine increased from 19,195 in 2005 to 32,024 in 2011 (an average of 27,114 visits/year), with 75% of cases involving quetiapine taken in combination with other prescription drugs, alcohol, or illicit drugs.⁸² Consistent with poison center data, M/A was reported for other antipsychotics, but none nearly as frequently as for quetiapine.

With increasingly frequent quetiapine M/A, clinicians should be vigilant in monitoring for medical morbidity related to quetiapine and cumulative toxicity with other drugs. The most frequent adverse events associated with quetiapine M/A reported to US Poison Control Centers are presented in Table 4.^78,79

Continue to: Unlike bupropion...

Unlike bupropion, quetiapine’s dopamine antagonism makes it unlikely to be a truly addictive drug, although this mechanism of action could mediate an increase in concurrent psychostimulant use.⁸³ A few case reports have described a quetiapine discontinuation syndrome similar to that of antidepressants,^60,65,84-88 but withdrawal symptoms suggestive of physiologic dependence may be mediated by non-dopaminergic effects through histamine and serotonin receptors.^84,89 Evidence for quetiapine misuse being associated with craving and compulsive use is lacking, and true quetiapine addiction is probably rare.

Similar to bupropion, preliminary findings have suggested promise for quetiapine as a putative therapy for other SUDs.^90-93 However, subsequent RCTs have failed to demonstrate a therapeutic effect for alcohol and cocaine use disorders.^94-96 Given these negative results and the clear M/A potential of quetiapine, off-label use of quetiapine for the treatment of SUDs and psychiatric symptoms among those with SUDs must be considered judiciously, with an eye towards possible diversion and avoiding the substitution of one drug of abuse for another.

Gabapentinoids

In 1997, the first published case report of gabapentin M/A described a woman who self-administered her husband’s gabapentin to reduce cravings for and withdrawal from cocaine.⁹⁷ The authors highlighted the possible therapeutic benefit of gabapentin in this regard rather than raising concerns about diversion and M/A. By 2004, however, reports of recreational gabapentin M/A emerged among inmates incarcerated within Florida correctional facilities who self-administered intranasal gabapentin to achieve a “high” that was “reminiscent of prior effects from intranasal ingestion of cocaine powder.”⁹⁸ In 2007, a single case of gabapentin misuse up to 7,200 mg/d (recommended dosing is ≤3,600 mg/d) was reported, with documentation of both tolerance and withdrawal symptoms.⁹⁹ As of 2017, a total of 36 cases of gabapentin M/A and 19 cases of pregabalin M/A have been published.¹⁰⁰

In the past decade, anecdotal reports have given way to larger-scale epidemiologic data painting a clear picture of the now-widespread M/A of gabapentin and other gabapentinoids. For example, a study of online descriptions of gabapentin and pregabalin M/A from 2008 to 2010 documented:

• oral and IM use (gabapentin)
• IV and rectal (“plugging”) use (pregabalin)
• “parachuting” (emptying the contents of capsules for a larger dose) (pregabalin)
• euphoric, entactogenic, stimulant, calming/anxiolytic, and dissociative subjective effects (gabapentin/pregabalin)
• rapid development of tolerance to euphoric effects leading to self-administration of increasing doses (gabapentin/pregabalin)
• frequent co-administration with other drugs of abuse, including alcohol, benzodiazepines, cannabis, stimulants, opiates, hallucinogens, gamma-hydroxybutyrate, mephedrone, and Salvia divinorum (gabapentin/pregabalin)¹⁰¹

Several systematic reviews of both anecdotal reports and epidemiologic studies published in the past few years provide additional evidence of the above, such as:

• excessive dosing with self-administration
• intranasal and inhaled routes of administration
• diversion and “street value”
• greater M/A potential of pregabalin than gabapentin
• the presence of gabapentinoids in postmortem toxicology analyses, suggesting a role in overdose fatalities when combined with other drugs.^100,102,103

Continue to: The European Medicine Agency's EudraVigilance database...

The European Medicine Agency’s EudraVigilance database included 4,301 reports of gabapentin misuse, abuse, or dependence, and 7,639 such reports for pregabalin, from 2006 to 2015 (rising sharply after 2012), with 86 gabapentin-related and 27 pregabalin-related fatalities.¹⁰⁴ Data from the Drug Diversion Program of the Researched Abuse, Diversion, and Addiction-Related Surveillance System from 2002 to 2015 have likewise revealed that gabapentin diversion increased significantly in 2013.¹⁰⁵

While the prevalence of gabapentinoid M/A is not known, rates appear to be significantly lower than for traditional drugs of abuse such as cannabis, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), and opioids.^106,107 However, gabapentin and pregabalin M/A appears to be increasingly common among individuals with SUDs and in particular among those with opioid use disorders (OUDs). For example, a 2015 report indicated that 15% of an adult cohort in Appalachian Kentucky with nonmedical use of diverted prescription opioids reported gabapentin M/A, an increase of nearly 3,000% since 2008.¹⁰⁸ Based on data from a US insurance enrollment and claims database, researchers found that the rate of gabapentin overuse among those also overusing opioids was 12% compared with only 2% for those using gabapentin alone.¹⁰⁹ It has also been reported that gabapentin is sometimes used as a “cutting agent” for heroin.¹¹⁰

Those who use gabapentinoids together with opioids report that gabapentin and pregabalin potentiate the euphoric effects of methadone¹¹¹ and endorse specific beliefs that pregabalin increases both the desired effects of heroin as well as negative effects such as “blackouts,” loss of control, and risk of overdose.¹¹² Indeed, sustained M/A of gabapentin and opioids together has been found to increase emergency department utilization, drug-related hospitalization, and respiratory depression.¹¹³ Based on a case-control study of opioid users in Canada, co-prescription of gabapentin and opioids was associated with a 50% increase in death from opioid-related causes compared with prescription of opioids alone.¹¹⁴

Case reports documenting tolerance, withdrawal, craving, and loss of control suggest a true addictive potential for gabapentinoids, but Bonnet and Sherbaum¹⁰⁰ concluded that while there is robust evidence of abusers “liking” gabapentin and pregabalin (eg, reward), evidence of “wanting” them (eg, psychological dependence) in the absence of other SUDs has been limited to only a few anecdotal reports with pregabalin. Accordingly, the risk of true addiction to gabapentinoids by those without preexisting SUDs appears to be low. Nonetheless, the M/A potential of both gabapentin and pregabalin is clear and in the context of a nationwide opioid epidemic, the increased morbidity/mortality risk related to combined use of gabapentinoids and opioids is both striking and concerning. Consequently, the state of Kentucky recently recognized the M/A potential of gabapentin by designating it a Schedule V controlled substance (pregabalin is already a Schedule V drug according to the US Drug Enforcement Agency),^103,113 and several other states now mandate the reporting of gabapentin prescriptions to prescription drug monitoring programs.¹¹⁵

Following a similar pattern to antidepressants and antipsychotics, a potential role for gabapentin in the treatment of cocaine use disorders was supported in preliminary studies,^116-118 but not in subsequent RCTs.^119-121 However, there is evidence from RCTs to support the use of gabapentin and pregabalin in the treatment of alcohol use disorders.^122-124 Gabapentin was also found to significantly reduce cannabis use and withdrawal symptoms in patients compared with placebo in an RCT of individuals with cannabis use disorders.¹²⁵ The perceived safety of gabapentinoids by clinicians, their subjective desirability by patients with SUDs, and efficacy data supporting a therapeutic role in SUDs must be balanced with recognition that approximately 80% of gabapentin prescriptions are written for off-label indications for which there is little supporting evidence,¹⁰⁹ such as low back pain.¹²⁶ Clinicians considering prescribing gabapentinoids to manage psychiatric symptoms, such as anxiety and insomnia, should carefully consider the risk of M/A and other potential morbidities, especially in the setting of SUDs and OUD in particular.

Continue to: Problematic, even if not addictive

Problematic, even if not addictive

It is sometimes claimed that “addiction” to psychiatric medications is not limited to stimulants and benzodiazepines.^27,127 Although anticholinergics, antidepressants, antipsychotics, and gabapentinoids can be drugs of abuse, with some users reporting physiologic withdrawal upon discontinuation, there is only limited evidence that the M/A of these psychiatric medications is associated with the characteristic features of a more complete definition of “addiction,” which may include:

• inability to consistently abstain
• impairment in behavioral control
• diminished recognition of significant problems associated with use
• a dysfunctional emotional response to chronic use.¹²⁸

Nonetheless, the literature documenting anticholinergic, antidepressant, antipsychotic, and gabapentinoid M/A includes several common features, including:

• initial reports among those with limited access to illicit drugs (eg, young people and incarcerated individuals) and subsequent spread to a wider population with more unconventional routes of administration
• use for recreational purposes and other subjective pseudo-therapeutic effects, often in combination with alcohol and illicit drugs
• greater M/A potential of certain medications within each of these drug classes (eg, trihexyphenidyl, bupropion, quetiapine)
• malingering psychiatric symptoms in order to obtain medications from prescribers and diversion for black market sale
• observations that medications might constitute therapy for SUDs that were not supported in subsequent RCTs (with the exception of gabapentin for alcohol and cannabis use disorders)
• increasing evidence of toxicity related to M/A, which suggests that prescription by clinicians has limited benefit and high risk for patients with SUDs.

Bottom Line

Some psychiatric medications are taken as drugs of abuse. Clinicians should be particularly aware of the misuse/abuse potential of anticholinergics, antidepressants, antipsychotics, and gabapentinoids, and use them cautiously, if at all, when treating patients with existing substance use disorders.

Related Resources

• Substance Abuse and Mental Health Services Administration. Prescription drug misuse and abuse. https://www.samhsa.gov/topics/prescription-drug-misuse-abuse.
• Substance Abuse and Mental Health Services Administration. Types of commonly misused or abused drugs. https://www.samhsa.gov/prescription-drug-misuse-abuse/types.
• National Institute on Drug Abuse. Misuse of prescription drugs. https://www.drugabuse.gov/publications/research-reports/misuse-prescription-drugs/summary.
• National Institute on Drug Abuse. New clinician screening tool available for substance use. https://www.drugabuse.gov/news-events/news-releases/2018/06/newclinician-screening-tool-available-substance-use.

Drug Brand Names

Amitriptyline • Elavil, Endep
Benztropine • Cogentin
Biperiden • Akineton
Bupropion • Wellbutrin, Zyban
Chlorpromazine • Thorzine
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Orphenadrine • Disipal, Norflex
Pregabalin • Lyrica, Lyrica CR
Procyclidine • Kemadrin
Quetiapine • Seroquel
Tianeptine • Coaxil, Stablon
Tranylcypromine • Parnate
Trifluoperazine • Stelazine
Trihexyphenidyl • Artane, Tremin
Venlafaxine • Effexor