TOPLINE:

Researchers detected single-nucleotide polymorphisms (SNPs) tied to osteoporosis risk from a drop of blood, in a 15-minute, inexpensive test using an investigational electrochemical device.

METHODOLOGY:

• 10-mcL finger-prick blood samples from 15 people were diluted 1:5 and subjected to rapid thermolysis (30 seconds at 95° C) to extract the DNA.
• Blood samples with the lysed DNA, and negative controls, were applied to an investigational, generic, portable electrochemical device (Labman Automation), in which individual gold electrodes were covered with reverse primers for each of five osteoporosis-associated SNPs.
• DNA in the blood samples that matched the SNPs bound to these electrodes, and the reaction was amplified with recombinase polymerase labeled with ferrocene, which facilitates electrochemical detection.
• Five SNPs associated with an increased risk of developing osteoporosis and risk for fracture were detected in the 15 blood samples, and the results were validated using TaqMan SNP genotyping assays and Sanger sequencing.

TAKEAWAYS:

• Measuring bone mineral density by dual-energy x-ray absorptiometry reliably predicts fracture risk, but only when a significant amount of bone is already lost.
• Researchers developed and validated a generic, battery-operable, portable device to detect osteoporosis-associated SNPs from a finger-prick blood sample, with no need for DNA extraction or purification.
• The entire assay from the addition of the thermolyzed blood sample to the readout of the results was complete in just 15 minutes, with a cost per SNP, on a laboratory scale, including the cost of the electrode array and all reagents, of 0.3 euro (0.33 USD).
• The researchers previously showed that the device identified an SNP associated with rifampicin resistance in Mycobacterium tuberculosis in a sputum sample, and an SNP linked with cardiomyopathy in blood; they plan to test a scaled-up version of the device.

IN PRACTICE:

“The platform is completely generic and has immense potential for deployment at the point of need in an automated device for targeted SNP genotyping with the only required end-user intervention being sample addition,” said the authors in their report.

STUDY DETAILS:

The authors, from INTERFIBIO Research Group, Tarragona, Spain, as well as Austria, the Czech Republic, and the Netherlands, published their findings in ACS Central Science.

LIMITATIONS:

The researchers did not report any study limitations.

DISCLOSURES:

The study received no commercial funding. The authors reported no relevant financial relationships.

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

TOPLINE:

Researchers detected single-nucleotide polymorphisms (SNPs) tied to osteoporosis risk from a drop of blood, in a 15-minute, inexpensive test using an investigational electrochemical device.

METHODOLOGY:

• 10-mcL finger-prick blood samples from 15 people were diluted 1:5 and subjected to rapid thermolysis (30 seconds at 95° C) to extract the DNA.
• Blood samples with the lysed DNA, and negative controls, were applied to an investigational, generic, portable electrochemical device (Labman Automation), in which individual gold electrodes were covered with reverse primers for each of five osteoporosis-associated SNPs.
• DNA in the blood samples that matched the SNPs bound to these electrodes, and the reaction was amplified with recombinase polymerase labeled with ferrocene, which facilitates electrochemical detection.
• Five SNPs associated with an increased risk of developing osteoporosis and risk for fracture were detected in the 15 blood samples, and the results were validated using TaqMan SNP genotyping assays and Sanger sequencing.

TAKEAWAYS:

• Measuring bone mineral density by dual-energy x-ray absorptiometry reliably predicts fracture risk, but only when a significant amount of bone is already lost.
• Researchers developed and validated a generic, battery-operable, portable device to detect osteoporosis-associated SNPs from a finger-prick blood sample, with no need for DNA extraction or purification.
• The entire assay from the addition of the thermolyzed blood sample to the readout of the results was complete in just 15 minutes, with a cost per SNP, on a laboratory scale, including the cost of the electrode array and all reagents, of 0.3 euro (0.33 USD).
• The researchers previously showed that the device identified an SNP associated with rifampicin resistance in Mycobacterium tuberculosis in a sputum sample, and an SNP linked with cardiomyopathy in blood; they plan to test a scaled-up version of the device.

IN PRACTICE:

“The platform is completely generic and has immense potential for deployment at the point of need in an automated device for targeted SNP genotyping with the only required end-user intervention being sample addition,” said the authors in their report.

STUDY DETAILS:

The authors, from INTERFIBIO Research Group, Tarragona, Spain, as well as Austria, the Czech Republic, and the Netherlands, published their findings in ACS Central Science.

LIMITATIONS:

The researchers did not report any study limitations.

DISCLOSURES:

The study received no commercial funding. The authors reported no relevant financial relationships.

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

TOPLINE:

Researchers detected single-nucleotide polymorphisms (SNPs) tied to osteoporosis risk from a drop of blood, in a 15-minute, inexpensive test using an investigational electrochemical device.

METHODOLOGY:

• 10-mcL finger-prick blood samples from 15 people were diluted 1:5 and subjected to rapid thermolysis (30 seconds at 95° C) to extract the DNA.
• Blood samples with the lysed DNA, and negative controls, were applied to an investigational, generic, portable electrochemical device (Labman Automation), in which individual gold electrodes were covered with reverse primers for each of five osteoporosis-associated SNPs.
• DNA in the blood samples that matched the SNPs bound to these electrodes, and the reaction was amplified with recombinase polymerase labeled with ferrocene, which facilitates electrochemical detection.
• Five SNPs associated with an increased risk of developing osteoporosis and risk for fracture were detected in the 15 blood samples, and the results were validated using TaqMan SNP genotyping assays and Sanger sequencing.

TAKEAWAYS:

• Measuring bone mineral density by dual-energy x-ray absorptiometry reliably predicts fracture risk, but only when a significant amount of bone is already lost.
• Researchers developed and validated a generic, battery-operable, portable device to detect osteoporosis-associated SNPs from a finger-prick blood sample, with no need for DNA extraction or purification.
• The entire assay from the addition of the thermolyzed blood sample to the readout of the results was complete in just 15 minutes, with a cost per SNP, on a laboratory scale, including the cost of the electrode array and all reagents, of 0.3 euro (0.33 USD).
• The researchers previously showed that the device identified an SNP associated with rifampicin resistance in Mycobacterium tuberculosis in a sputum sample, and an SNP linked with cardiomyopathy in blood; they plan to test a scaled-up version of the device.

IN PRACTICE:

“The platform is completely generic and has immense potential for deployment at the point of need in an automated device for targeted SNP genotyping with the only required end-user intervention being sample addition,” said the authors in their report.

STUDY DETAILS:

The authors, from INTERFIBIO Research Group, Tarragona, Spain, as well as Austria, the Czech Republic, and the Netherlands, published their findings in ACS Central Science.

LIMITATIONS:

The researchers did not report any study limitations.

DISCLOSURES:

The study received no commercial funding. The authors reported no relevant financial relationships.

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

At the new Walnut Creek Clinic in the East Bay of the San Francisco Bay area, kids get a “Comfort Promise.”

The clinic extends the work of the Stad Center for Pediatric Pain, Palliative & Integrative Medicine beyond the locations in University of California San Francisco Benioff Children’s Hospitals in San Francisco and Oakland.

At Walnut Creek, clinical acupuncturists, massage therapists, and specialists in hypnosis complement advanced medical care with integrative techniques.

The “Comfort Promise” program, which is being rolled out at that clinic and other UCSF pediatric clinics through the end of 2024, is the clinicians’ pledge to do everything in their power to make tests, infusions, and vaccinations “practically pain free.”

Needle sticks, for example, can be a common source of pain and anxiety for kids. Techniques to minimize pain vary by age. Among the ways the clinicians minimize needle pain for a child 6- to 12-years-old are:

• Giving the child control options to pick which arm; and watch the injection, pause it, or stop it with a communication sign.
• Introducing memory shaping by asking the child about the experience afterward and presenting it in a positive way by praising the acts of sitting still, breathing deeply, or being brave.
• Using distractors such as asking the child to hold a favorite item from home, storytelling, coloring, singing, or using breathing exercises.

Stefan Friedrichsdorf, MD, chief of the UCSF division of pediatric pain, palliative & integrative medicine, said in a statement: “For kids with chronic pain, complex pain medications can cause more harm than benefit. Our goal is to combine exercise and physical therapy with integrative medicine and skills-based psychotherapy to help them become pain free in their everyday life.”
 

Bundling appointments for early impact

At Lurie Children’s Hospital of Chicago, the chronic pain treatment program bundles visits with experts in several disciplines, include social workers, psychologists, and physical therapists, in addition to the medical team, so that patients can complete a first round of visits with multiple specialists in a short period, as opposed to several months.

Natalie Weatherred, APRN-NP, CPNP-PC, a pediatric nurse practitioner in anesthesiology and the pain clinic coordinator, said in an interview that the up-front visits involve between four and eight follow-up sessions in a short period with everybody in the multidisciplinary team “to really help jump-start their pain treatment.”

She pointed out that many families come from distant parts of the state or beyond so the bundled appointments are also important for easing burden on families.

Sarah Duggan, APRN-NP, CPNP-PC, also a pediatric nurse practitioner in anesthesiology at Lurie’s, pointed out that patients at their clinic often have other chronic conditions as well, such as such as postural orthostatic tachycardia syndrome so the care integration is particularly important.

“We can get them the appropriate care that they need and the resources they need, much sooner than we would have been able to do 5 or 10 years ago,” Ms. Duggan said.
 

Virtual reality distraction instead of sedation

Henry Huang, MD, anesthesiologist and pain physician at Texas Children’s Hospital, Houston, said a special team there collaborates with the Chariot Program at Stanford (Calif.) University and incorporates virtual reality to distract children from pain and anxiety and harness their imaginations during induction for anesthesia, intravenous placement, and vaccinations.

“At our institution we’ve been recruiting patients to do a proof of concept to do virtual reality distraction for pain procedures, such as nerve blocks or steroid injections,” Dr. Huang said.

Traditionally, kids would have received oral or intravenous sedation to help them cope with the fear and pain.

“We’ve been successful in several cases without relying on any sedation,” he said. “The next target is to expand that to the chronic pain population.”

The distraction techniques are promising for a wide range of ages, he said, and the programming is tailored to the child’s ability to interact with the technology.

He said he is also part of a group promoting use of ultrasound instead of x-rays to guide injections to the spine and chest to reduce children’s exposure to radiation. His group is helping teach these methods to other clinicians nationally.

Dr. Huang said the most important development in chronic pediatric pain has been the growth of rehab centers that include the medical team, and practitioners from psychology as well as occupational and physical therapy.

“More and more hospitals are recognizing the importance of these pain rehab centers,” he said.

The problem, Dr. Huang said, is that these programs have always been resource intensive and involve highly specialized clinicians. The cost and the limited number of specialists make it difficult for widespread rollout.

“That’s always been the challenge from the pediatric pain world,” he said.
 

Recognizing the complexity of kids’ chronic pain

Angela Garcia, MD, a consulting physician for pediatric rehabilitation medicine at UPMC Children’s Hospital of Pittsburgh said recognizing the validity and complexity of pediatric pain has led to multidisciplinary approaches and specialty clinics for chronic pain instead of primarily pharmaceutical solutions.

Techniques such as biofeedback and acupuncture are becoming more mainstream in pediatric chronic care, she said.

At the UPMC clinic, children and their families talk with a care team about their values and what they want to accomplish in managing the child’s pain. They ask what the pain is preventing the child from doing.

“Their goals really are our goals,” she said.

She said she also refers almost all patients to one of the center’s pain psychologists.

“Pain is biopsychosocial,” she said. “We want to make sure we’re addressing how to cope with pain.”

Dr. Garcia said she hopes nutritional therapy is one of the next approaches the clinic will incorporate, particularly surrounding how dietary changes can reduce inflammation “and heal the body from the inside out.”

She said the hospital is also looking at developing an inpatient pain program for kids whose functioning has changed so drastically that they need more intensive therapies.

Whatever the treatment approach, she said, addressing the pain early is critical.

“There is an increased risk of a child with chronic pain becoming an adult with chronic pain,” Dr. Garcia pointed out, “and that can lead to a decrease in the ability to participate in society.”

Ms. Weatherred, Ms. Duggan, Dr. Huang, and Dr. Garcia reported no relevant financial relationships.

At the new Walnut Creek Clinic in the East Bay of the San Francisco Bay area, kids get a “Comfort Promise.”

The clinic extends the work of the Stad Center for Pediatric Pain, Palliative & Integrative Medicine beyond the locations in University of California San Francisco Benioff Children’s Hospitals in San Francisco and Oakland.

At Walnut Creek, clinical acupuncturists, massage therapists, and specialists in hypnosis complement advanced medical care with integrative techniques.

The “Comfort Promise” program, which is being rolled out at that clinic and other UCSF pediatric clinics through the end of 2024, is the clinicians’ pledge to do everything in their power to make tests, infusions, and vaccinations “practically pain free.”

Needle sticks, for example, can be a common source of pain and anxiety for kids. Techniques to minimize pain vary by age. Among the ways the clinicians minimize needle pain for a child 6- to 12-years-old are:

• Giving the child control options to pick which arm; and watch the injection, pause it, or stop it with a communication sign.
• Introducing memory shaping by asking the child about the experience afterward and presenting it in a positive way by praising the acts of sitting still, breathing deeply, or being brave.
• Using distractors such as asking the child to hold a favorite item from home, storytelling, coloring, singing, or using breathing exercises.

Stefan Friedrichsdorf, MD, chief of the UCSF division of pediatric pain, palliative & integrative medicine, said in a statement: “For kids with chronic pain, complex pain medications can cause more harm than benefit. Our goal is to combine exercise and physical therapy with integrative medicine and skills-based psychotherapy to help them become pain free in their everyday life.”
 

Bundling appointments for early impact

At Lurie Children’s Hospital of Chicago, the chronic pain treatment program bundles visits with experts in several disciplines, include social workers, psychologists, and physical therapists, in addition to the medical team, so that patients can complete a first round of visits with multiple specialists in a short period, as opposed to several months.

Natalie Weatherred, APRN-NP, CPNP-PC, a pediatric nurse practitioner in anesthesiology and the pain clinic coordinator, said in an interview that the up-front visits involve between four and eight follow-up sessions in a short period with everybody in the multidisciplinary team “to really help jump-start their pain treatment.”

She pointed out that many families come from distant parts of the state or beyond so the bundled appointments are also important for easing burden on families.

Sarah Duggan, APRN-NP, CPNP-PC, also a pediatric nurse practitioner in anesthesiology at Lurie’s, pointed out that patients at their clinic often have other chronic conditions as well, such as such as postural orthostatic tachycardia syndrome so the care integration is particularly important.

“We can get them the appropriate care that they need and the resources they need, much sooner than we would have been able to do 5 or 10 years ago,” Ms. Duggan said.
 

Virtual reality distraction instead of sedation

Henry Huang, MD, anesthesiologist and pain physician at Texas Children’s Hospital, Houston, said a special team there collaborates with the Chariot Program at Stanford (Calif.) University and incorporates virtual reality to distract children from pain and anxiety and harness their imaginations during induction for anesthesia, intravenous placement, and vaccinations.

“At our institution we’ve been recruiting patients to do a proof of concept to do virtual reality distraction for pain procedures, such as nerve blocks or steroid injections,” Dr. Huang said.

Traditionally, kids would have received oral or intravenous sedation to help them cope with the fear and pain.

“We’ve been successful in several cases without relying on any sedation,” he said. “The next target is to expand that to the chronic pain population.”

The distraction techniques are promising for a wide range of ages, he said, and the programming is tailored to the child’s ability to interact with the technology.

He said he is also part of a group promoting use of ultrasound instead of x-rays to guide injections to the spine and chest to reduce children’s exposure to radiation. His group is helping teach these methods to other clinicians nationally.

Dr. Huang said the most important development in chronic pediatric pain has been the growth of rehab centers that include the medical team, and practitioners from psychology as well as occupational and physical therapy.

“More and more hospitals are recognizing the importance of these pain rehab centers,” he said.

The problem, Dr. Huang said, is that these programs have always been resource intensive and involve highly specialized clinicians. The cost and the limited number of specialists make it difficult for widespread rollout.

“That’s always been the challenge from the pediatric pain world,” he said.
 

Recognizing the complexity of kids’ chronic pain

Angela Garcia, MD, a consulting physician for pediatric rehabilitation medicine at UPMC Children’s Hospital of Pittsburgh said recognizing the validity and complexity of pediatric pain has led to multidisciplinary approaches and specialty clinics for chronic pain instead of primarily pharmaceutical solutions.

Techniques such as biofeedback and acupuncture are becoming more mainstream in pediatric chronic care, she said.

At the UPMC clinic, children and their families talk with a care team about their values and what they want to accomplish in managing the child’s pain. They ask what the pain is preventing the child from doing.

“Their goals really are our goals,” she said.

She said she also refers almost all patients to one of the center’s pain psychologists.

“Pain is biopsychosocial,” she said. “We want to make sure we’re addressing how to cope with pain.”

Dr. Garcia said she hopes nutritional therapy is one of the next approaches the clinic will incorporate, particularly surrounding how dietary changes can reduce inflammation “and heal the body from the inside out.”

She said the hospital is also looking at developing an inpatient pain program for kids whose functioning has changed so drastically that they need more intensive therapies.

Whatever the treatment approach, she said, addressing the pain early is critical.

“There is an increased risk of a child with chronic pain becoming an adult with chronic pain,” Dr. Garcia pointed out, “and that can lead to a decrease in the ability to participate in society.”

Ms. Weatherred, Ms. Duggan, Dr. Huang, and Dr. Garcia reported no relevant financial relationships.

At the new Walnut Creek Clinic in the East Bay of the San Francisco Bay area, kids get a “Comfort Promise.”

The clinic extends the work of the Stad Center for Pediatric Pain, Palliative & Integrative Medicine beyond the locations in University of California San Francisco Benioff Children’s Hospitals in San Francisco and Oakland.

At Walnut Creek, clinical acupuncturists, massage therapists, and specialists in hypnosis complement advanced medical care with integrative techniques.

The “Comfort Promise” program, which is being rolled out at that clinic and other UCSF pediatric clinics through the end of 2024, is the clinicians’ pledge to do everything in their power to make tests, infusions, and vaccinations “practically pain free.”

Needle sticks, for example, can be a common source of pain and anxiety for kids. Techniques to minimize pain vary by age. Among the ways the clinicians minimize needle pain for a child 6- to 12-years-old are:

• Giving the child control options to pick which arm; and watch the injection, pause it, or stop it with a communication sign.
• Introducing memory shaping by asking the child about the experience afterward and presenting it in a positive way by praising the acts of sitting still, breathing deeply, or being brave.
• Using distractors such as asking the child to hold a favorite item from home, storytelling, coloring, singing, or using breathing exercises.

Stefan Friedrichsdorf, MD, chief of the UCSF division of pediatric pain, palliative & integrative medicine, said in a statement: “For kids with chronic pain, complex pain medications can cause more harm than benefit. Our goal is to combine exercise and physical therapy with integrative medicine and skills-based psychotherapy to help them become pain free in their everyday life.”
 

Bundling appointments for early impact

At Lurie Children’s Hospital of Chicago, the chronic pain treatment program bundles visits with experts in several disciplines, include social workers, psychologists, and physical therapists, in addition to the medical team, so that patients can complete a first round of visits with multiple specialists in a short period, as opposed to several months.

Natalie Weatherred, APRN-NP, CPNP-PC, a pediatric nurse practitioner in anesthesiology and the pain clinic coordinator, said in an interview that the up-front visits involve between four and eight follow-up sessions in a short period with everybody in the multidisciplinary team “to really help jump-start their pain treatment.”

She pointed out that many families come from distant parts of the state or beyond so the bundled appointments are also important for easing burden on families.

Sarah Duggan, APRN-NP, CPNP-PC, also a pediatric nurse practitioner in anesthesiology at Lurie’s, pointed out that patients at their clinic often have other chronic conditions as well, such as such as postural orthostatic tachycardia syndrome so the care integration is particularly important.

“We can get them the appropriate care that they need and the resources they need, much sooner than we would have been able to do 5 or 10 years ago,” Ms. Duggan said.
 

Virtual reality distraction instead of sedation

Henry Huang, MD, anesthesiologist and pain physician at Texas Children’s Hospital, Houston, said a special team there collaborates with the Chariot Program at Stanford (Calif.) University and incorporates virtual reality to distract children from pain and anxiety and harness their imaginations during induction for anesthesia, intravenous placement, and vaccinations.

“At our institution we’ve been recruiting patients to do a proof of concept to do virtual reality distraction for pain procedures, such as nerve blocks or steroid injections,” Dr. Huang said.

Traditionally, kids would have received oral or intravenous sedation to help them cope with the fear and pain.

“We’ve been successful in several cases without relying on any sedation,” he said. “The next target is to expand that to the chronic pain population.”

The distraction techniques are promising for a wide range of ages, he said, and the programming is tailored to the child’s ability to interact with the technology.

He said he is also part of a group promoting use of ultrasound instead of x-rays to guide injections to the spine and chest to reduce children’s exposure to radiation. His group is helping teach these methods to other clinicians nationally.

Dr. Huang said the most important development in chronic pediatric pain has been the growth of rehab centers that include the medical team, and practitioners from psychology as well as occupational and physical therapy.

“More and more hospitals are recognizing the importance of these pain rehab centers,” he said.

The problem, Dr. Huang said, is that these programs have always been resource intensive and involve highly specialized clinicians. The cost and the limited number of specialists make it difficult for widespread rollout.

“That’s always been the challenge from the pediatric pain world,” he said.
 

Recognizing the complexity of kids’ chronic pain

Angela Garcia, MD, a consulting physician for pediatric rehabilitation medicine at UPMC Children’s Hospital of Pittsburgh said recognizing the validity and complexity of pediatric pain has led to multidisciplinary approaches and specialty clinics for chronic pain instead of primarily pharmaceutical solutions.

Techniques such as biofeedback and acupuncture are becoming more mainstream in pediatric chronic care, she said.

At the UPMC clinic, children and their families talk with a care team about their values and what they want to accomplish in managing the child’s pain. They ask what the pain is preventing the child from doing.

“Their goals really are our goals,” she said.

She said she also refers almost all patients to one of the center’s pain psychologists.

“Pain is biopsychosocial,” she said. “We want to make sure we’re addressing how to cope with pain.”

Dr. Garcia said she hopes nutritional therapy is one of the next approaches the clinic will incorporate, particularly surrounding how dietary changes can reduce inflammation “and heal the body from the inside out.”

She said the hospital is also looking at developing an inpatient pain program for kids whose functioning has changed so drastically that they need more intensive therapies.

Whatever the treatment approach, she said, addressing the pain early is critical.

“There is an increased risk of a child with chronic pain becoming an adult with chronic pain,” Dr. Garcia pointed out, “and that can lead to a decrease in the ability to participate in society.”

Ms. Weatherred, Ms. Duggan, Dr. Huang, and Dr. Garcia reported no relevant financial relationships.

Off-label prescribing (OLP) refers to the practice of using medications for indications outside of those approved by the FDA, or in dosages, dose forms, or patient populations that have not been approved by the FDA.¹ OLP is common, occurring in many practice settings and nearly every medical specialty. In a 2006 review, Radley et al² found OLP accounted for 21% of the overall use of 160 common medications. The frequency of OLP varies between medication classes. Off-label use of anticonvulsants, antidepressants, and antipsychotics tends to be higher than that of other medications.^3,4 OLP is often more common in patient populations unlikely to be included in clinical trials due to ethical or logistical difficulties, such as pediatric patients and individuals who are pregnant. The Box summarizes several components that contribute to the prevalence of OLP and explains why this practice is often necessary for treating certain substance-related and addictive disorders.

Box

Several important medicolegal and ethical considerations surround OLP. The FDA prohibits off-label promotion, in which manufacturers advertise the use of a medication for off-label use.⁵ However, regulations allow physicians to use their best clinical judgment when prescribing medications for off-label use. When considering off-label use of any medication, physicians should review the most up-to-date research, including clinical trials, case reports, and reviews to safely support their decision-making. OLP should be guided by ethical principles such as autonomy, beneficence, nonmaleficence, and justice. Physicians should obtain informed consent by conducting an appropriate discussion of the risks, benefits, and alternatives of off-label medications. This conversation should be clearly documented, and physicians should provide written material regarding off-label options to patients when available. Finally, physicians should verify their patients’ understanding of this discussion, and allow patients to accept or decline off-label medications without pressure.

This article focuses on current and potential future medications available for OLP to treat patients with alcohol use disorder (AUD), gambling disorder (GD), stimulant use disorder, and cannabis use disorder.

Alcohol use disorder

CASE 1

Ms. X, age 67, has a history of severe AUD, mild renal impairment, and migraines. She presents to the outpatient clinic seeking help to drink less alcohol. Ms. X reports drinking 1 to 2 bottles of wine each day. She was previously treated for AUD but was not helped by naltrexone and did not tolerate disulfiram (abstinence was not her goal and she experienced significant adverse effects). Ms. X says she has a medical history of chronic migraines but denies other medical issues. The treatment team discusses alternative pharmacologic options, including acamprosate and topiramate. After outlining the dosing schedule and risks/benefits with Ms. X, you make the joint decision to start topiramate to reduce alcohol cravings and target her migraine symptoms.

Only 3 medications are FDA-approved for treating AUD: disulfiram, naltrexone (oral and injectable formulations), and acamprosate. Off-label options for AUD treatment include gabapentin, topiramate, and baclofen.

Gabapentin is FDA-approved for treating postherpetic neuralgia and partial seizures in patients age ≥3. The exact mechanism of action is unclear, though its effects are possibly related to its activity as a calcium channel ligand. It also carries a structural resemblance to gamma-aminobutyric acid (GABA), though it lacks activity at GABA receptors.

Several randomized controlled trials (RCTs) evaluating the efficacy of gabapentin for AUD produced promising results. In a comparison of gabapentin vs placebo for AUD, Anton et al⁶ found gabapentin led to significant increases in the number of participants with total alcohol abstinence and participants who reported reduced drinking. Notably, the effect was most prominent in those with heavy drinking patterns and pretreatment alcohol withdrawal symptoms. A total of 41% of participants with high alcohol withdrawal scores on pretreatment evaluation achieved total abstinence while taking gabapentin, compared to 1% in the placebo group.⁶ A meta-analysis of gabapentin for AUD by Kranzler et al⁷ included 7 RCTs and 32 effect measures. It found that although all outcome measures favored gabapentin over placebo, only the percentage of heavy drinking days was significantly different.

Gabapentin is dosed between 300 to 600 mg 3 times per day, but 1 study found that a higher dose (1,800 mg/d) was associated with better outcomes.⁸ Common adverse effects include sedation, dizziness, peripheral edema, and ataxia.

Continue to: Topiramate

Topiramate blocks voltage-gated sodium channels and enhances GABA-A receptor activity.⁹ It is indicated for the treatment of seizures, migraine prophylaxis, weight management, and weight loss. Several clinical trials, including RCTs,^10-12 demonstrated that topiramate was superior to placebo in reducing the percentage of heavy drinking days and overall drinking days. Some also showed that topiramate was associated with abstinence and reduced craving levels.^12,13 A meta-analysis by Blodgett et al¹⁴ found that compared to placebo, topiramate lowered the rate of heavy drinking and increased abstinence.

Topiramate is dosed from 50 to 150 mg twice daily, although some studies suggest a lower dose (≤75 mg/d) may be associated with clinical benefits.^15,16 One important clinical consideration: topiramate must follow a slow titration schedule (4 to 6 weeks) to increase tolerability and avoid adverse effects. Common adverse effects include sedation, word-finding difficulty, paresthesia, increased risk for renal calculi, dizziness, anorexia, and alterations in taste.

Baclofen is a GABA-B agonist FDA-approved for the treatment of muscle spasticity related to multiple sclerosis and reversible spasticity related to spinal cord lesions and multiple sclerosis. Of note, it is approved for treatment of AUD in Europe.

In a meta-analysis of 13 RCTs, Pierce et al¹⁷ found a greater likelihood of abstinence and greater time to first lapse of drinking with baclofen compared to placebo. Interestingly, a subgroup analysis found that the positive effects were limited to trials that used 30 to 60 mg/d of baclofen, and not evident in those that used higher doses. Additionally, there was no difference between baclofen and placebo with regard to several important outcomes, including alcohol cravings, anxiety, depression, or number of total abstinent days. A review by Andrade¹⁸ proposed that individualized treatment with high-dose baclofen (30 to 300 mg/d) may be a useful second-line approach in heavy drinkers who wish to reduce their alcohol intake.

Continue to: Before starting baclofen...

Before starting baclofen, patients should be informed about its adverse effects. Common adverse effects include sedation and motor impairment. More serious but less common adverse effects include seizures, respiratory depression with sleep apnea, severe mood disorders (ie, mania, depression, or suicide risk), and mental confusion. Baclofen should be gradually discontinued, because there is some risk of clinical withdrawal symptoms (ie, agitation, confusion, seizures, or delirium).

Among the medications discussed in this section, the evidence for gabapentin and topiramate is moderate to strong, while the evidence for baclofen is overall weaker or mixed. The American Psychiatric Association’s Practice Guideline suggests offering gabapentin or topiramate to patients with moderate to severe AUD whose goal is to achieve abstinence or reduce alcohol use, or those who prefer gabapentin or topiramate or cannot tolerate or have not responded to naltrexone and acamprosate.¹⁹ Clinicians must ensure patients have no contra­indications to the use of these medications. Due to the moderate quality evidence for a significant reduction in heavy drinking and increased abstinence,^14,20 a practice guideline from the US Department of Veterans Affairs and US Department of Defense²¹ recommends topiramate as 1 of 2 first-line treatments (the other is naltrexone). This guideline suggests gabapentin as a second-line treatment for AUD.²¹

Gambling disorder

CASE 2

Mr. P, age 28, seeks treatment for GD and cocaine use disorder. He reports a 7-year history of sports betting that has increasingly impaired his functioning over the past year. He lost his job, savings, and familial relationships due to his impulsive and risky behavior. Mr. P also reports frequent cocaine use, about 2 to 3 days per week, mostly on the weekends. The psychiatrist tells Mr. P there is no FDA-approved pharmacologic treatment for GD or cocaine use disorder. The psychiatrist discusses the option of naltrexone as off-label treatment for GD with the goal of reducing Mr. P’s urges to gamble, and points to possible benefits for cocaine use disorder.

GD impacts approximately 0.5% of the adult US population and is often co-occurring with substance use disorders.²² It is thought to share neurobiological and clinical similarities with substance use disorders.²³ There are currently no FDA-approved medications to treat the disorder. In studies of GD, treatment success with antidepressants and mood stabilizers has not been consistent,^23,24 but some promising results have been published for the opioid receptor antagonist naltrexone^24-29and N-acetylcysteine (NAC).^30-32

Naltrexone is thought to reduce gambling behavior and urges via downstream modulation of mesolimbic dopamine circuitry.²⁴ It is FDA-approved for the treatment of AUD and opioid use disorder. Open-label RCTs have found a reduction in gambling urges and behavior with daily naltrexone.^25-27 Dosing at 50 mg/d appears to be just as efficacious as higher doses such as 100 and 150 mg/d.²⁷ When used as a daily as-needed medication for strong gambling urges or if an individual was planning to gamble, naltrexone 50 mg/d was not effective.²⁸

Continue to: Naltrexone typically is started...

Naltrexone typically is started at 25 mg/d to assess tolerability and quickly titrated to 50 mg/d. When titrating, common adverse effects include nausea, vomiting, and transient elevations in transaminases. Another opioid antagonist, nalmefene, has also been studied in patients with GD. An RCT by Grant et al²⁹ that evaluated 207 patients found that compared with placebo, nalmefene 25 mg/d for 16 weeks was associated with a significant reduction in gambling assessment scores. In Europe, nalmefene is approved for treating AUD but the oral formulation is not currently available in the US.

N-acetylcysteine is thought to potentially reverse neuronal dysfunction seen in addictive disorders by glutamatergic modulation.³⁰ Research investigating NAC for GD is scarce. A pilot study found 16 of 27 patients with GD reduced gambling behavior with a mean dose of 1,476.9 mg/d.³¹ An additional study investigating the addition of NAC to behavioral therapy in nicotine-dependent individuals with pathologic gambling found a reduction in problem gambling after 18 weeks (6 weeks + 3 months follow-up).³² Common but mild adverse effects associated with NAC are nausea, vomiting, and diarrhea.

A meta-analysis by Goslar et al³³ that reviewed 34 studies (1,340 participants) found pharmacologic treatments were associated with large and medium pre-post reductions in global severity, frequency, and financial loss in patients with GD. RCTs studying opioid antagonists and mood stabilizers (combined with a cognitive intervention) as well as lithium for patients with comorbid bipolar disorder and GD demonstrated promising results.³³

Stimulant use disorder

There are no FDA-approved medications for stimulant use disorder. Multiple off-label options have been studied for the treatment of methamphetamine abuse and cocaine abuse.

Methamphetamine use has been expanding over the past decade with a 3.6-fold increase in positive methamphetamine screens in overdose deaths from 2011 to 2016.³⁴ Pharmacologic options studied for OLP of methamphetamine use disorder include mirtazapine, bupropion, naltrexone, and topiramate.

Continue to: Mirtazapine

Mirtazapine is an atypical antidepressant whose mechanism of action includes modulation of the serotonin, norepinephrine, and alpha-2 adrenergic systems. It is FDA-approved for the treatment of major depressive disorder (MDD). In a randomized placebo-controlled study, mirtazapine 30 mg/d at night was found to decrease methamphetamine use for active users and led to decreased sexual risk in men who have sex with men.³⁵ These results were supported by an additional RCT in which mirtazapine 30 mg/d significantly reduced rates of methamphetamine use vs placebo at 24 and 36 weeks despite poor medication adherence.³⁶ Adverse effects to monitor in patients treated with mirtazapine include increased appetite, weight gain, sedation, and constipation.

Bupropion is a norepinephrine dopamine reuptake inhibitor that produces increased neurotransmission of norepinephrine and dopamine in the CNS. It is FDA-approved for the treatment of MDD and as an aid for smoking cessation. Bupropion has been studied for methamphetamine use disorder with mixed results. In a randomized placebo-controlled trial, bupropion sustained release 150 mg twice daily was not more effective than placebo in reducing methamphetamine use.³⁷ However, the extended-release formulation of bupropion 450 mg/d combined with long-acting injectable naltrexone was associated with a reduction in methamphetamine use over 12 weeks.³⁸ Bupropion is generally well tolerated; common adverse effects include insomnia, tremor, headache, and dizziness.

Naltrexone. Data about using oral naltrexone to treat stimulant use disorders are limited. A randomized, placebo-controlled trial by Jayaram-Lindström et al³⁹ found naltrexone 50 mg/d significantly reduced amphetamine use compared to placebo. Additionally, naltrexone 50 and 150 mg/d have been shown to reduce cocaine use over time in combination with therapy for cocaine-dependent patients and those dependent on alcohol and cocaine.^40,41

Topiramate has been studied for the treatment of cocaine use disorder. It is hypothesized that modulation of the mesocorticolimbic dopamine system may contribute to decreased cocaine cravings.⁴² A pilot study by Kampman et al⁴³ found that after an 8-week titration of topiramate to 200 mg/d, individuals were more likely to achieve cocaine abstinence compared to those who receive placebo. In an RCT, Elkashef et al⁴⁴ did not find topiramate assisted with increased abstinence of methamphetamine in active users at a target dose of 200 mg/d. However, it was associated with reduced relapse rates in individuals who were abstinent prior to the study.⁴⁴ At a target dose of 300 mg/d, topiramate also outperformed placebo in decreasing days of cocaine use.⁴² Adverse effects of topiramate included paresthesia, alteration in taste, and difficulty with concentration.

Cannabis use disorder

In recent years, cannabis use in the US has greatly increased⁴⁵ but no medications are FDA-approved for treating cannabis use disorder. Studies of pharmacologic options for cannabis use disorder have had mixed results.⁴⁶ A meta-analysis by Bahji et al⁴⁷ of 24 studies investigating pharmacotherapies for cannabis use disorder highlighted the lack of adequate evidence. In this section, we focus on a few positive trials of NAC and gabapentin.

Continue to: N-acetylcysteine

N-acetylcysteine. Studies investigating NAC 1,200 mg twice daily have been promising in adolescent and adult populations.^48-50 There are some mixed results, however. A large RCT found NAC 1,200 mg twice daily was not better than placebo in helping adults achieve abstinence from cannabis.⁵¹

Gabapentin may be a viable option for treating cannabis use disorder. A pilot study by Mason et al⁵² found gabapentin 1,200 mg/d was more effective than placebo at reducing cannabis use among treatment-seeking adults.

When and how to consider OLP

OLP for addictive disorders is common and often necessary. This is primarily due to limitations of the FDA-approved medications and because there are no FDA-approved medications for many substance-related and addictive disorders (ie, GD, cannabis use disorder, and stimulant use disorder). When assessing pharmacotherapy options, if FDA-approved medications are available for certain diagnoses, clinicians should first consider them. The off-label medications discussed in this article are outlined in the Table.^{6-21,24-28,30-33,35-44,48-52}

The overall level of evidence to support the use of off-label medications is lower than that of FDA-approved medications, which contributes to potential medicolegal concerns of OLP. Off-label medications should be considered when there are no FDA-approved medications available, and the decision to use off-label medications should be based on evidence from the literature and current standard of care. Additionally, OLP is necessary if a patient cannot tolerate FDA-approved medications, is not helped by FDA-approved treatments, or when there are other clinical reasons to choose a particular off-label medication. For example, if a patient has comorbid AUD and obesity (or migraines), using topiramate may be appropriate because it may target alcohol cravings and can be helpful for weight loss (and migraine prophylaxis). Similarly, for patients with AUD and neuropathic pain, using gabapentin can be considered for its dual therapeutic effects.

It is critical for clinicians to understand the landscape of off-label options for treating addictive disorders. Additional research in the form of RCTs is needed to better clarify the efficacy and adverse effects of these treatments.

Continue to: Bottom Line

Off-label prescribing is prevalent in practice, including in the treatment of substance-related and addictive disorders. When considering off-label use of any medication, clinicians should review the most recent research, obtain informed consent from patients, and verify patients’ understanding of the potential risks and adverse effects associated with the particular medication.

Related Resources

• Joshi KG, Frierson RL. Off-label prescribing: how to limit your liability. Current Psychiatry. 2020;19(9):12,39. doi:10.12788/ cp.0035
• Stanciu CN, Gnanasegaram SA. Don’t balk at using medical therapy to manage alcohol use disorder. Current Psychiatry. 2017;16(2):50-52.

Drug Brand Names

Acamprosate • Campral
Baclofen • Ozobax
Bupropion • Wellbutrin, Zyban
Disulfiram • Antabuse
Gabapentin • Neurontin
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Naltrexone • ReVia, Vivitrol
Topiramate • Topamax

Off-label prescribing (OLP) refers to the practice of using medications for indications outside of those approved by the FDA, or in dosages, dose forms, or patient populations that have not been approved by the FDA.¹ OLP is common, occurring in many practice settings and nearly every medical specialty. In a 2006 review, Radley et al² found OLP accounted for 21% of the overall use of 160 common medications. The frequency of OLP varies between medication classes. Off-label use of anticonvulsants, antidepressants, and antipsychotics tends to be higher than that of other medications.^3,4 OLP is often more common in patient populations unlikely to be included in clinical trials due to ethical or logistical difficulties, such as pediatric patients and individuals who are pregnant. The Box summarizes several components that contribute to the prevalence of OLP and explains why this practice is often necessary for treating certain substance-related and addictive disorders.

Box

Several important medicolegal and ethical considerations surround OLP. The FDA prohibits off-label promotion, in which manufacturers advertise the use of a medication for off-label use.⁵ However, regulations allow physicians to use their best clinical judgment when prescribing medications for off-label use. When considering off-label use of any medication, physicians should review the most up-to-date research, including clinical trials, case reports, and reviews to safely support their decision-making. OLP should be guided by ethical principles such as autonomy, beneficence, nonmaleficence, and justice. Physicians should obtain informed consent by conducting an appropriate discussion of the risks, benefits, and alternatives of off-label medications. This conversation should be clearly documented, and physicians should provide written material regarding off-label options to patients when available. Finally, physicians should verify their patients’ understanding of this discussion, and allow patients to accept or decline off-label medications without pressure.

This article focuses on current and potential future medications available for OLP to treat patients with alcohol use disorder (AUD), gambling disorder (GD), stimulant use disorder, and cannabis use disorder.

Alcohol use disorder

CASE 1

Ms. X, age 67, has a history of severe AUD, mild renal impairment, and migraines. She presents to the outpatient clinic seeking help to drink less alcohol. Ms. X reports drinking 1 to 2 bottles of wine each day. She was previously treated for AUD but was not helped by naltrexone and did not tolerate disulfiram (abstinence was not her goal and she experienced significant adverse effects). Ms. X says she has a medical history of chronic migraines but denies other medical issues. The treatment team discusses alternative pharmacologic options, including acamprosate and topiramate. After outlining the dosing schedule and risks/benefits with Ms. X, you make the joint decision to start topiramate to reduce alcohol cravings and target her migraine symptoms.

Only 3 medications are FDA-approved for treating AUD: disulfiram, naltrexone (oral and injectable formulations), and acamprosate. Off-label options for AUD treatment include gabapentin, topiramate, and baclofen.

Gabapentin is FDA-approved for treating postherpetic neuralgia and partial seizures in patients age ≥3. The exact mechanism of action is unclear, though its effects are possibly related to its activity as a calcium channel ligand. It also carries a structural resemblance to gamma-aminobutyric acid (GABA), though it lacks activity at GABA receptors.

Several randomized controlled trials (RCTs) evaluating the efficacy of gabapentin for AUD produced promising results. In a comparison of gabapentin vs placebo for AUD, Anton et al⁶ found gabapentin led to significant increases in the number of participants with total alcohol abstinence and participants who reported reduced drinking. Notably, the effect was most prominent in those with heavy drinking patterns and pretreatment alcohol withdrawal symptoms. A total of 41% of participants with high alcohol withdrawal scores on pretreatment evaluation achieved total abstinence while taking gabapentin, compared to 1% in the placebo group.⁶ A meta-analysis of gabapentin for AUD by Kranzler et al⁷ included 7 RCTs and 32 effect measures. It found that although all outcome measures favored gabapentin over placebo, only the percentage of heavy drinking days was significantly different.

Gabapentin is dosed between 300 to 600 mg 3 times per day, but 1 study found that a higher dose (1,800 mg/d) was associated with better outcomes.⁸ Common adverse effects include sedation, dizziness, peripheral edema, and ataxia.

Continue to: Topiramate

Topiramate blocks voltage-gated sodium channels and enhances GABA-A receptor activity.⁹ It is indicated for the treatment of seizures, migraine prophylaxis, weight management, and weight loss. Several clinical trials, including RCTs,^10-12 demonstrated that topiramate was superior to placebo in reducing the percentage of heavy drinking days and overall drinking days. Some also showed that topiramate was associated with abstinence and reduced craving levels.^12,13 A meta-analysis by Blodgett et al¹⁴ found that compared to placebo, topiramate lowered the rate of heavy drinking and increased abstinence.

Topiramate is dosed from 50 to 150 mg twice daily, although some studies suggest a lower dose (≤75 mg/d) may be associated with clinical benefits.^15,16 One important clinical consideration: topiramate must follow a slow titration schedule (4 to 6 weeks) to increase tolerability and avoid adverse effects. Common adverse effects include sedation, word-finding difficulty, paresthesia, increased risk for renal calculi, dizziness, anorexia, and alterations in taste.

Baclofen is a GABA-B agonist FDA-approved for the treatment of muscle spasticity related to multiple sclerosis and reversible spasticity related to spinal cord lesions and multiple sclerosis. Of note, it is approved for treatment of AUD in Europe.

In a meta-analysis of 13 RCTs, Pierce et al¹⁷ found a greater likelihood of abstinence and greater time to first lapse of drinking with baclofen compared to placebo. Interestingly, a subgroup analysis found that the positive effects were limited to trials that used 30 to 60 mg/d of baclofen, and not evident in those that used higher doses. Additionally, there was no difference between baclofen and placebo with regard to several important outcomes, including alcohol cravings, anxiety, depression, or number of total abstinent days. A review by Andrade¹⁸ proposed that individualized treatment with high-dose baclofen (30 to 300 mg/d) may be a useful second-line approach in heavy drinkers who wish to reduce their alcohol intake.

Continue to: Before starting baclofen...

Before starting baclofen, patients should be informed about its adverse effects. Common adverse effects include sedation and motor impairment. More serious but less common adverse effects include seizures, respiratory depression with sleep apnea, severe mood disorders (ie, mania, depression, or suicide risk), and mental confusion. Baclofen should be gradually discontinued, because there is some risk of clinical withdrawal symptoms (ie, agitation, confusion, seizures, or delirium).

Among the medications discussed in this section, the evidence for gabapentin and topiramate is moderate to strong, while the evidence for baclofen is overall weaker or mixed. The American Psychiatric Association’s Practice Guideline suggests offering gabapentin or topiramate to patients with moderate to severe AUD whose goal is to achieve abstinence or reduce alcohol use, or those who prefer gabapentin or topiramate or cannot tolerate or have not responded to naltrexone and acamprosate.¹⁹ Clinicians must ensure patients have no contra­indications to the use of these medications. Due to the moderate quality evidence for a significant reduction in heavy drinking and increased abstinence,^14,20 a practice guideline from the US Department of Veterans Affairs and US Department of Defense²¹ recommends topiramate as 1 of 2 first-line treatments (the other is naltrexone). This guideline suggests gabapentin as a second-line treatment for AUD.²¹

Gambling disorder

CASE 2

Mr. P, age 28, seeks treatment for GD and cocaine use disorder. He reports a 7-year history of sports betting that has increasingly impaired his functioning over the past year. He lost his job, savings, and familial relationships due to his impulsive and risky behavior. Mr. P also reports frequent cocaine use, about 2 to 3 days per week, mostly on the weekends. The psychiatrist tells Mr. P there is no FDA-approved pharmacologic treatment for GD or cocaine use disorder. The psychiatrist discusses the option of naltrexone as off-label treatment for GD with the goal of reducing Mr. P’s urges to gamble, and points to possible benefits for cocaine use disorder.

GD impacts approximately 0.5% of the adult US population and is often co-occurring with substance use disorders.²² It is thought to share neurobiological and clinical similarities with substance use disorders.²³ There are currently no FDA-approved medications to treat the disorder. In studies of GD, treatment success with antidepressants and mood stabilizers has not been consistent,^23,24 but some promising results have been published for the opioid receptor antagonist naltrexone^24-29and N-acetylcysteine (NAC).^30-32

Naltrexone is thought to reduce gambling behavior and urges via downstream modulation of mesolimbic dopamine circuitry.²⁴ It is FDA-approved for the treatment of AUD and opioid use disorder. Open-label RCTs have found a reduction in gambling urges and behavior with daily naltrexone.^25-27 Dosing at 50 mg/d appears to be just as efficacious as higher doses such as 100 and 150 mg/d.²⁷ When used as a daily as-needed medication for strong gambling urges or if an individual was planning to gamble, naltrexone 50 mg/d was not effective.²⁸

Continue to: Naltrexone typically is started...

Naltrexone typically is started at 25 mg/d to assess tolerability and quickly titrated to 50 mg/d. When titrating, common adverse effects include nausea, vomiting, and transient elevations in transaminases. Another opioid antagonist, nalmefene, has also been studied in patients with GD. An RCT by Grant et al²⁹ that evaluated 207 patients found that compared with placebo, nalmefene 25 mg/d for 16 weeks was associated with a significant reduction in gambling assessment scores. In Europe, nalmefene is approved for treating AUD but the oral formulation is not currently available in the US.

N-acetylcysteine is thought to potentially reverse neuronal dysfunction seen in addictive disorders by glutamatergic modulation.³⁰ Research investigating NAC for GD is scarce. A pilot study found 16 of 27 patients with GD reduced gambling behavior with a mean dose of 1,476.9 mg/d.³¹ An additional study investigating the addition of NAC to behavioral therapy in nicotine-dependent individuals with pathologic gambling found a reduction in problem gambling after 18 weeks (6 weeks + 3 months follow-up).³² Common but mild adverse effects associated with NAC are nausea, vomiting, and diarrhea.

A meta-analysis by Goslar et al³³ that reviewed 34 studies (1,340 participants) found pharmacologic treatments were associated with large and medium pre-post reductions in global severity, frequency, and financial loss in patients with GD. RCTs studying opioid antagonists and mood stabilizers (combined with a cognitive intervention) as well as lithium for patients with comorbid bipolar disorder and GD demonstrated promising results.³³

Stimulant use disorder

There are no FDA-approved medications for stimulant use disorder. Multiple off-label options have been studied for the treatment of methamphetamine abuse and cocaine abuse.

Methamphetamine use has been expanding over the past decade with a 3.6-fold increase in positive methamphetamine screens in overdose deaths from 2011 to 2016.³⁴ Pharmacologic options studied for OLP of methamphetamine use disorder include mirtazapine, bupropion, naltrexone, and topiramate.

Continue to: Mirtazapine

Mirtazapine is an atypical antidepressant whose mechanism of action includes modulation of the serotonin, norepinephrine, and alpha-2 adrenergic systems. It is FDA-approved for the treatment of major depressive disorder (MDD). In a randomized placebo-controlled study, mirtazapine 30 mg/d at night was found to decrease methamphetamine use for active users and led to decreased sexual risk in men who have sex with men.³⁵ These results were supported by an additional RCT in which mirtazapine 30 mg/d significantly reduced rates of methamphetamine use vs placebo at 24 and 36 weeks despite poor medication adherence.³⁶ Adverse effects to monitor in patients treated with mirtazapine include increased appetite, weight gain, sedation, and constipation.

Bupropion is a norepinephrine dopamine reuptake inhibitor that produces increased neurotransmission of norepinephrine and dopamine in the CNS. It is FDA-approved for the treatment of MDD and as an aid for smoking cessation. Bupropion has been studied for methamphetamine use disorder with mixed results. In a randomized placebo-controlled trial, bupropion sustained release 150 mg twice daily was not more effective than placebo in reducing methamphetamine use.³⁷ However, the extended-release formulation of bupropion 450 mg/d combined with long-acting injectable naltrexone was associated with a reduction in methamphetamine use over 12 weeks.³⁸ Bupropion is generally well tolerated; common adverse effects include insomnia, tremor, headache, and dizziness.

Naltrexone. Data about using oral naltrexone to treat stimulant use disorders are limited. A randomized, placebo-controlled trial by Jayaram-Lindström et al³⁹ found naltrexone 50 mg/d significantly reduced amphetamine use compared to placebo. Additionally, naltrexone 50 and 150 mg/d have been shown to reduce cocaine use over time in combination with therapy for cocaine-dependent patients and those dependent on alcohol and cocaine.^40,41

Topiramate has been studied for the treatment of cocaine use disorder. It is hypothesized that modulation of the mesocorticolimbic dopamine system may contribute to decreased cocaine cravings.⁴² A pilot study by Kampman et al⁴³ found that after an 8-week titration of topiramate to 200 mg/d, individuals were more likely to achieve cocaine abstinence compared to those who receive placebo. In an RCT, Elkashef et al⁴⁴ did not find topiramate assisted with increased abstinence of methamphetamine in active users at a target dose of 200 mg/d. However, it was associated with reduced relapse rates in individuals who were abstinent prior to the study.⁴⁴ At a target dose of 300 mg/d, topiramate also outperformed placebo in decreasing days of cocaine use.⁴² Adverse effects of topiramate included paresthesia, alteration in taste, and difficulty with concentration.

Cannabis use disorder

In recent years, cannabis use in the US has greatly increased⁴⁵ but no medications are FDA-approved for treating cannabis use disorder. Studies of pharmacologic options for cannabis use disorder have had mixed results.⁴⁶ A meta-analysis by Bahji et al⁴⁷ of 24 studies investigating pharmacotherapies for cannabis use disorder highlighted the lack of adequate evidence. In this section, we focus on a few positive trials of NAC and gabapentin.

Continue to: N-acetylcysteine

N-acetylcysteine. Studies investigating NAC 1,200 mg twice daily have been promising in adolescent and adult populations.^48-50 There are some mixed results, however. A large RCT found NAC 1,200 mg twice daily was not better than placebo in helping adults achieve abstinence from cannabis.⁵¹

Gabapentin may be a viable option for treating cannabis use disorder. A pilot study by Mason et al⁵² found gabapentin 1,200 mg/d was more effective than placebo at reducing cannabis use among treatment-seeking adults.

When and how to consider OLP

OLP for addictive disorders is common and often necessary. This is primarily due to limitations of the FDA-approved medications and because there are no FDA-approved medications for many substance-related and addictive disorders (ie, GD, cannabis use disorder, and stimulant use disorder). When assessing pharmacotherapy options, if FDA-approved medications are available for certain diagnoses, clinicians should first consider them. The off-label medications discussed in this article are outlined in the Table.^{6-21,24-28,30-33,35-44,48-52}

The overall level of evidence to support the use of off-label medications is lower than that of FDA-approved medications, which contributes to potential medicolegal concerns of OLP. Off-label medications should be considered when there are no FDA-approved medications available, and the decision to use off-label medications should be based on evidence from the literature and current standard of care. Additionally, OLP is necessary if a patient cannot tolerate FDA-approved medications, is not helped by FDA-approved treatments, or when there are other clinical reasons to choose a particular off-label medication. For example, if a patient has comorbid AUD and obesity (or migraines), using topiramate may be appropriate because it may target alcohol cravings and can be helpful for weight loss (and migraine prophylaxis). Similarly, for patients with AUD and neuropathic pain, using gabapentin can be considered for its dual therapeutic effects.

It is critical for clinicians to understand the landscape of off-label options for treating addictive disorders. Additional research in the form of RCTs is needed to better clarify the efficacy and adverse effects of these treatments.

Continue to: Bottom Line

Off-label prescribing is prevalent in practice, including in the treatment of substance-related and addictive disorders. When considering off-label use of any medication, clinicians should review the most recent research, obtain informed consent from patients, and verify patients’ understanding of the potential risks and adverse effects associated with the particular medication.

Related Resources

• Joshi KG, Frierson RL. Off-label prescribing: how to limit your liability. Current Psychiatry. 2020;19(9):12,39. doi:10.12788/ cp.0035
• Stanciu CN, Gnanasegaram SA. Don’t balk at using medical therapy to manage alcohol use disorder. Current Psychiatry. 2017;16(2):50-52.

Drug Brand Names

Acamprosate • Campral
Baclofen • Ozobax
Bupropion • Wellbutrin, Zyban
Disulfiram • Antabuse
Gabapentin • Neurontin
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Naltrexone • ReVia, Vivitrol
Topiramate • Topamax

Off-label prescribing (OLP) refers to the practice of using medications for indications outside of those approved by the FDA, or in dosages, dose forms, or patient populations that have not been approved by the FDA.¹ OLP is common, occurring in many practice settings and nearly every medical specialty. In a 2006 review, Radley et al² found OLP accounted for 21% of the overall use of 160 common medications. The frequency of OLP varies between medication classes. Off-label use of anticonvulsants, antidepressants, and antipsychotics tends to be higher than that of other medications.^3,4 OLP is often more common in patient populations unlikely to be included in clinical trials due to ethical or logistical difficulties, such as pediatric patients and individuals who are pregnant. The Box summarizes several components that contribute to the prevalence of OLP and explains why this practice is often necessary for treating certain substance-related and addictive disorders.

Box

Several important medicolegal and ethical considerations surround OLP. The FDA prohibits off-label promotion, in which manufacturers advertise the use of a medication for off-label use.⁵ However, regulations allow physicians to use their best clinical judgment when prescribing medications for off-label use. When considering off-label use of any medication, physicians should review the most up-to-date research, including clinical trials, case reports, and reviews to safely support their decision-making. OLP should be guided by ethical principles such as autonomy, beneficence, nonmaleficence, and justice. Physicians should obtain informed consent by conducting an appropriate discussion of the risks, benefits, and alternatives of off-label medications. This conversation should be clearly documented, and physicians should provide written material regarding off-label options to patients when available. Finally, physicians should verify their patients’ understanding of this discussion, and allow patients to accept or decline off-label medications without pressure.

This article focuses on current and potential future medications available for OLP to treat patients with alcohol use disorder (AUD), gambling disorder (GD), stimulant use disorder, and cannabis use disorder.

Alcohol use disorder

CASE 1

Ms. X, age 67, has a history of severe AUD, mild renal impairment, and migraines. She presents to the outpatient clinic seeking help to drink less alcohol. Ms. X reports drinking 1 to 2 bottles of wine each day. She was previously treated for AUD but was not helped by naltrexone and did not tolerate disulfiram (abstinence was not her goal and she experienced significant adverse effects). Ms. X says she has a medical history of chronic migraines but denies other medical issues. The treatment team discusses alternative pharmacologic options, including acamprosate and topiramate. After outlining the dosing schedule and risks/benefits with Ms. X, you make the joint decision to start topiramate to reduce alcohol cravings and target her migraine symptoms.

Only 3 medications are FDA-approved for treating AUD: disulfiram, naltrexone (oral and injectable formulations), and acamprosate. Off-label options for AUD treatment include gabapentin, topiramate, and baclofen.

Gabapentin is FDA-approved for treating postherpetic neuralgia and partial seizures in patients age ≥3. The exact mechanism of action is unclear, though its effects are possibly related to its activity as a calcium channel ligand. It also carries a structural resemblance to gamma-aminobutyric acid (GABA), though it lacks activity at GABA receptors.

Several randomized controlled trials (RCTs) evaluating the efficacy of gabapentin for AUD produced promising results. In a comparison of gabapentin vs placebo for AUD, Anton et al⁶ found gabapentin led to significant increases in the number of participants with total alcohol abstinence and participants who reported reduced drinking. Notably, the effect was most prominent in those with heavy drinking patterns and pretreatment alcohol withdrawal symptoms. A total of 41% of participants with high alcohol withdrawal scores on pretreatment evaluation achieved total abstinence while taking gabapentin, compared to 1% in the placebo group.⁶ A meta-analysis of gabapentin for AUD by Kranzler et al⁷ included 7 RCTs and 32 effect measures. It found that although all outcome measures favored gabapentin over placebo, only the percentage of heavy drinking days was significantly different.

Gabapentin is dosed between 300 to 600 mg 3 times per day, but 1 study found that a higher dose (1,800 mg/d) was associated with better outcomes.⁸ Common adverse effects include sedation, dizziness, peripheral edema, and ataxia.

Continue to: Topiramate

Topiramate blocks voltage-gated sodium channels and enhances GABA-A receptor activity.⁹ It is indicated for the treatment of seizures, migraine prophylaxis, weight management, and weight loss. Several clinical trials, including RCTs,^10-12 demonstrated that topiramate was superior to placebo in reducing the percentage of heavy drinking days and overall drinking days. Some also showed that topiramate was associated with abstinence and reduced craving levels.^12,13 A meta-analysis by Blodgett et al¹⁴ found that compared to placebo, topiramate lowered the rate of heavy drinking and increased abstinence.

Topiramate is dosed from 50 to 150 mg twice daily, although some studies suggest a lower dose (≤75 mg/d) may be associated with clinical benefits.^15,16 One important clinical consideration: topiramate must follow a slow titration schedule (4 to 6 weeks) to increase tolerability and avoid adverse effects. Common adverse effects include sedation, word-finding difficulty, paresthesia, increased risk for renal calculi, dizziness, anorexia, and alterations in taste.

Baclofen is a GABA-B agonist FDA-approved for the treatment of muscle spasticity related to multiple sclerosis and reversible spasticity related to spinal cord lesions and multiple sclerosis. Of note, it is approved for treatment of AUD in Europe.

In a meta-analysis of 13 RCTs, Pierce et al¹⁷ found a greater likelihood of abstinence and greater time to first lapse of drinking with baclofen compared to placebo. Interestingly, a subgroup analysis found that the positive effects were limited to trials that used 30 to 60 mg/d of baclofen, and not evident in those that used higher doses. Additionally, there was no difference between baclofen and placebo with regard to several important outcomes, including alcohol cravings, anxiety, depression, or number of total abstinent days. A review by Andrade¹⁸ proposed that individualized treatment with high-dose baclofen (30 to 300 mg/d) may be a useful second-line approach in heavy drinkers who wish to reduce their alcohol intake.

Continue to: Before starting baclofen...

Before starting baclofen, patients should be informed about its adverse effects. Common adverse effects include sedation and motor impairment. More serious but less common adverse effects include seizures, respiratory depression with sleep apnea, severe mood disorders (ie, mania, depression, or suicide risk), and mental confusion. Baclofen should be gradually discontinued, because there is some risk of clinical withdrawal symptoms (ie, agitation, confusion, seizures, or delirium).

Among the medications discussed in this section, the evidence for gabapentin and topiramate is moderate to strong, while the evidence for baclofen is overall weaker or mixed. The American Psychiatric Association’s Practice Guideline suggests offering gabapentin or topiramate to patients with moderate to severe AUD whose goal is to achieve abstinence or reduce alcohol use, or those who prefer gabapentin or topiramate or cannot tolerate or have not responded to naltrexone and acamprosate.¹⁹ Clinicians must ensure patients have no contra­indications to the use of these medications. Due to the moderate quality evidence for a significant reduction in heavy drinking and increased abstinence,^14,20 a practice guideline from the US Department of Veterans Affairs and US Department of Defense²¹ recommends topiramate as 1 of 2 first-line treatments (the other is naltrexone). This guideline suggests gabapentin as a second-line treatment for AUD.²¹

Gambling disorder

CASE 2

Mr. P, age 28, seeks treatment for GD and cocaine use disorder. He reports a 7-year history of sports betting that has increasingly impaired his functioning over the past year. He lost his job, savings, and familial relationships due to his impulsive and risky behavior. Mr. P also reports frequent cocaine use, about 2 to 3 days per week, mostly on the weekends. The psychiatrist tells Mr. P there is no FDA-approved pharmacologic treatment for GD or cocaine use disorder. The psychiatrist discusses the option of naltrexone as off-label treatment for GD with the goal of reducing Mr. P’s urges to gamble, and points to possible benefits for cocaine use disorder.

GD impacts approximately 0.5% of the adult US population and is often co-occurring with substance use disorders.²² It is thought to share neurobiological and clinical similarities with substance use disorders.²³ There are currently no FDA-approved medications to treat the disorder. In studies of GD, treatment success with antidepressants and mood stabilizers has not been consistent,^23,24 but some promising results have been published for the opioid receptor antagonist naltrexone^24-29and N-acetylcysteine (NAC).^30-32

Naltrexone is thought to reduce gambling behavior and urges via downstream modulation of mesolimbic dopamine circuitry.²⁴ It is FDA-approved for the treatment of AUD and opioid use disorder. Open-label RCTs have found a reduction in gambling urges and behavior with daily naltrexone.^25-27 Dosing at 50 mg/d appears to be just as efficacious as higher doses such as 100 and 150 mg/d.²⁷ When used as a daily as-needed medication for strong gambling urges or if an individual was planning to gamble, naltrexone 50 mg/d was not effective.²⁸

Continue to: Naltrexone typically is started...

Naltrexone typically is started at 25 mg/d to assess tolerability and quickly titrated to 50 mg/d. When titrating, common adverse effects include nausea, vomiting, and transient elevations in transaminases. Another opioid antagonist, nalmefene, has also been studied in patients with GD. An RCT by Grant et al²⁹ that evaluated 207 patients found that compared with placebo, nalmefene 25 mg/d for 16 weeks was associated with a significant reduction in gambling assessment scores. In Europe, nalmefene is approved for treating AUD but the oral formulation is not currently available in the US.

N-acetylcysteine is thought to potentially reverse neuronal dysfunction seen in addictive disorders by glutamatergic modulation.³⁰ Research investigating NAC for GD is scarce. A pilot study found 16 of 27 patients with GD reduced gambling behavior with a mean dose of 1,476.9 mg/d.³¹ An additional study investigating the addition of NAC to behavioral therapy in nicotine-dependent individuals with pathologic gambling found a reduction in problem gambling after 18 weeks (6 weeks + 3 months follow-up).³² Common but mild adverse effects associated with NAC are nausea, vomiting, and diarrhea.

A meta-analysis by Goslar et al³³ that reviewed 34 studies (1,340 participants) found pharmacologic treatments were associated with large and medium pre-post reductions in global severity, frequency, and financial loss in patients with GD. RCTs studying opioid antagonists and mood stabilizers (combined with a cognitive intervention) as well as lithium for patients with comorbid bipolar disorder and GD demonstrated promising results.³³

Stimulant use disorder

There are no FDA-approved medications for stimulant use disorder. Multiple off-label options have been studied for the treatment of methamphetamine abuse and cocaine abuse.

Methamphetamine use has been expanding over the past decade with a 3.6-fold increase in positive methamphetamine screens in overdose deaths from 2011 to 2016.³⁴ Pharmacologic options studied for OLP of methamphetamine use disorder include mirtazapine, bupropion, naltrexone, and topiramate.

Continue to: Mirtazapine

Mirtazapine is an atypical antidepressant whose mechanism of action includes modulation of the serotonin, norepinephrine, and alpha-2 adrenergic systems. It is FDA-approved for the treatment of major depressive disorder (MDD). In a randomized placebo-controlled study, mirtazapine 30 mg/d at night was found to decrease methamphetamine use for active users and led to decreased sexual risk in men who have sex with men.³⁵ These results were supported by an additional RCT in which mirtazapine 30 mg/d significantly reduced rates of methamphetamine use vs placebo at 24 and 36 weeks despite poor medication adherence.³⁶ Adverse effects to monitor in patients treated with mirtazapine include increased appetite, weight gain, sedation, and constipation.

Bupropion is a norepinephrine dopamine reuptake inhibitor that produces increased neurotransmission of norepinephrine and dopamine in the CNS. It is FDA-approved for the treatment of MDD and as an aid for smoking cessation. Bupropion has been studied for methamphetamine use disorder with mixed results. In a randomized placebo-controlled trial, bupropion sustained release 150 mg twice daily was not more effective than placebo in reducing methamphetamine use.³⁷ However, the extended-release formulation of bupropion 450 mg/d combined with long-acting injectable naltrexone was associated with a reduction in methamphetamine use over 12 weeks.³⁸ Bupropion is generally well tolerated; common adverse effects include insomnia, tremor, headache, and dizziness.

Naltrexone. Data about using oral naltrexone to treat stimulant use disorders are limited. A randomized, placebo-controlled trial by Jayaram-Lindström et al³⁹ found naltrexone 50 mg/d significantly reduced amphetamine use compared to placebo. Additionally, naltrexone 50 and 150 mg/d have been shown to reduce cocaine use over time in combination with therapy for cocaine-dependent patients and those dependent on alcohol and cocaine.^40,41

Topiramate has been studied for the treatment of cocaine use disorder. It is hypothesized that modulation of the mesocorticolimbic dopamine system may contribute to decreased cocaine cravings.⁴² A pilot study by Kampman et al⁴³ found that after an 8-week titration of topiramate to 200 mg/d, individuals were more likely to achieve cocaine abstinence compared to those who receive placebo. In an RCT, Elkashef et al⁴⁴ did not find topiramate assisted with increased abstinence of methamphetamine in active users at a target dose of 200 mg/d. However, it was associated with reduced relapse rates in individuals who were abstinent prior to the study.⁴⁴ At a target dose of 300 mg/d, topiramate also outperformed placebo in decreasing days of cocaine use.⁴² Adverse effects of topiramate included paresthesia, alteration in taste, and difficulty with concentration.

Cannabis use disorder

In recent years, cannabis use in the US has greatly increased⁴⁵ but no medications are FDA-approved for treating cannabis use disorder. Studies of pharmacologic options for cannabis use disorder have had mixed results.⁴⁶ A meta-analysis by Bahji et al⁴⁷ of 24 studies investigating pharmacotherapies for cannabis use disorder highlighted the lack of adequate evidence. In this section, we focus on a few positive trials of NAC and gabapentin.

Continue to: N-acetylcysteine

N-acetylcysteine. Studies investigating NAC 1,200 mg twice daily have been promising in adolescent and adult populations.^48-50 There are some mixed results, however. A large RCT found NAC 1,200 mg twice daily was not better than placebo in helping adults achieve abstinence from cannabis.⁵¹

Gabapentin may be a viable option for treating cannabis use disorder. A pilot study by Mason et al⁵² found gabapentin 1,200 mg/d was more effective than placebo at reducing cannabis use among treatment-seeking adults.

When and how to consider OLP

OLP for addictive disorders is common and often necessary. This is primarily due to limitations of the FDA-approved medications and because there are no FDA-approved medications for many substance-related and addictive disorders (ie, GD, cannabis use disorder, and stimulant use disorder). When assessing pharmacotherapy options, if FDA-approved medications are available for certain diagnoses, clinicians should first consider them. The off-label medications discussed in this article are outlined in the Table.^{6-21,24-28,30-33,35-44,48-52}

The overall level of evidence to support the use of off-label medications is lower than that of FDA-approved medications, which contributes to potential medicolegal concerns of OLP. Off-label medications should be considered when there are no FDA-approved medications available, and the decision to use off-label medications should be based on evidence from the literature and current standard of care. Additionally, OLP is necessary if a patient cannot tolerate FDA-approved medications, is not helped by FDA-approved treatments, or when there are other clinical reasons to choose a particular off-label medication. For example, if a patient has comorbid AUD and obesity (or migraines), using topiramate may be appropriate because it may target alcohol cravings and can be helpful for weight loss (and migraine prophylaxis). Similarly, for patients with AUD and neuropathic pain, using gabapentin can be considered for its dual therapeutic effects.

It is critical for clinicians to understand the landscape of off-label options for treating addictive disorders. Additional research in the form of RCTs is needed to better clarify the efficacy and adverse effects of these treatments.

Continue to: Bottom Line

Off-label prescribing is prevalent in practice, including in the treatment of substance-related and addictive disorders. When considering off-label use of any medication, clinicians should review the most recent research, obtain informed consent from patients, and verify patients’ understanding of the potential risks and adverse effects associated with the particular medication.

Related Resources

• Joshi KG, Frierson RL. Off-label prescribing: how to limit your liability. Current Psychiatry. 2020;19(9):12,39. doi:10.12788/ cp.0035
• Stanciu CN, Gnanasegaram SA. Don’t balk at using medical therapy to manage alcohol use disorder. Current Psychiatry. 2017;16(2):50-52.

Drug Brand Names

Acamprosate • Campral
Baclofen • Ozobax
Bupropion • Wellbutrin, Zyban
Disulfiram • Antabuse
Gabapentin • Neurontin
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Naltrexone • ReVia, Vivitrol
Topiramate • Topamax

Burnout is an occupational phenomenon and a syndrome resulting from unsuccessfully managed chronic workplace stress. The characteristic features of burnout include feelings of exhaustion, cynicism, and reduced professional efficacy.¹ A career in surgery is associated with demanding and unpredictable work hours in a high-stress environment.^2-8 Research indicates that surgeons are at an elevated risk for developing burnout and mental health problems that can compromise patient care. A survey of the fellows of the American College of Surgeons found that 40% of surgeons experience burnout, 30% experience symptoms of depression, and 28% have a mental quality of life (QOL) score greater than one-half an SD below the population norm.^9,10 Surgeon burnout was also found to compromise the delivery of medical care.^9,10

To prevent serious harm to surgeons and patients, it is critical to understand the causative factors of burnout among surgeons and how they can be addressed. We conducted this systematic review to identify factors linked to burnout across surgical specialties and to suggest ways to mitigate these risk factors.  

Methods

To identify studies of burnout among surgeons, we conducted an electronic search of Ovid MEDLINE, Ovid PsycInfo, SCOPUS, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. The headings and keywords used are listed in Supplemental Table 1. Studies met the inclusion criteria if they evaluated residents or attendings, used a tool to measure burnout, and examined any surgical specialty. Studies were excluded if they were published before 2010; were conducted outside the United States; were review articles, commentaries, or abstracts without full text articles; evaluated medical school students; were published in a language other than English; did not use a tool to measure burnout; or examined a nonsurgical specialty.  Our analysis was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)¹¹ and is outlined in the Supplemental Figure.

Results

Surgical specialties and burnout

We identified 56 studies^2-10,12-58 that focused on specific surgical specialties in relation to burnout. Supplemental Table 2^2-10,12-58 lists these studies and the surgical specialties they evaluated.

Work/life balance factors

Fifteen studies^{2-5,14,15,18,19,22,32,34,38,39,47,57} examined the role of work/life balance in burnout. Table 1^{2-5,14,15,18,19,22,32,34,38,39,47,57} lists the work/life factors these studies identified as being linked to burnout. Six studies^{2,4,18,22,32,47} discussed how decreased leisure time was linked to burnout. Eleven studies^{2,4,14,15,19,22,34,38,39,42,57} associated inabilities to meet family commitments with burnout. A lack of time to spend with family and not having adequate time to raise children was more prevalent among women. Seven studies^{2,3,18,22,32,34,47} implicated increased time commitment to work as playing a role in burnout. This increased time commitment was also found to be a compounding variable for other factors, such as limited time for family and leisure.

Work hours

Fifteen studies^{2,7,14,20,21,30,34,41,42,44-46,50,52,56} examined work hours and burnout. Of these, 14^{2,7,14,20,21,30,34,42,44-46,50,52,56} found a correlation between increased work hours and burnout, while only 1 study⁴¹ found no correlation between these factors. 

Medical errors

Six studies^{2,14,18,43,49,52} discussed the role of burnout in medical errors. Of these, 5^{2,14,43,49,52} reported a correlation between burnout and medical errors, while 1 study¹⁸ found no link between burnout and medical errors. The medical errors were self-reported.^14,49 They included actions that resulted in patient harm, sample collection error, and errors in medication orders and laboratory test orders.²

Continue to: Institutional and organizational factors

Eighteen studies^{3,13,14,18,20,22,23,29,30,36-38,44,45,47,54,56,57} examined how different organizational factors play a role in burnout. Four studies^3,13,20,37 discussed administrative/bureaucratic work, 4^20,45,54,57 mentioned electronic medical documentation, 2^22,30 covered duty hour regulations, 3^18,45,57 discussed mistreatment of physicians, and 6^{13,18,23,44,47,56} described the importance of workplace support in addressing burnout.

Physical and mental health factors

Eighteen studies^{6,7,14,15,17,20,26,27,29,34,43,44,48,52,54,57-59} discussed aspects of physical and mental health linked to burnout. Among these, 3^34,43,59 discussed the importance of physical health and focused on how improving physical health can reduce stress and burnout. Three studies^6,17,58 noted the prevalence of suicidal ideation in both residents and attendings experiencing prolonged burnout. Five studies^{26,29,43,44,48} described the systematic barriers that inhibit physicians from getting professional help. Two studies^7,27 reported marital status as a factor for burnout; participants who were single reported higher levels of depression and suicidal ideation. Five studies^{6,14,15,54,57} outlined how depression is associated with burnout.

Strategies to mitigate burnout

Fifteen studies^{2,4,5,14,20,22,33,36,47,51,53,55-58} described strategies physicians use to cope with burnout. Table 2^{2,4,5,14,20,22,33,36,47,51,53,55-58} outlines the strategies postulated and reported by these studies as helpful in reducing burnout. Two studies^2,4 mentioned that physicians may turn to maladaptive behaviors, such as substance abuse, to cope with stress and burnout. Four studies^2,4,53,56 mentioned the importance of social support in fighting burnout and building resilience. Ten studies^{2,5,14,20,22,33,36,47,57,58} described the benefits of institutional interventions, such as what administrators can do to reduce the rate of burnout. Three studies^5,36,53 postulated different adaptive behaviors physicians can implement to reduce burnout.

Take-home points 

Research that focused on work/life balance and burnout found excessive time commitment to work is a major factor associated with poor work/life balance. Residents who worked >80 hours a week had a significantly higher burnout rate.⁵⁶ One study found that 70% of residents reported not getting enough sleep, 30% reported not having enough energy for relationships, and 39% reported that they were not eating or exercising due to time constraints.⁴ A high correlation was found between the number of hours worked per week and rates of burnout, emotional exhaustion, and depersonalization. Emotional exhaustion and depersonalization are aspects of burnout measured by the Maslach Burnout Inventory (MBI).²⁴ The excessive time commitment to work not only contributes to burnout but also prevents physicians from getting professional help. In 1 study, both residents (56%) and attendings (24%) reported that 1 of the biggest barriers to getting help for their burnout symptoms was the inability to take time off.³⁴ Research indicates that the hours worked per week and work/home conflicts were independently associated with burnout and career satisfaction.¹⁵ A decrease of weekly work hours may give physicians time to meet their responsibilities at work and home, allowing for a decrease in burnout and an increase in career satisfaction.

Increased work hours have also been found to be correlated with medical errors. One study found that those who worked 60 hours per week were significantly less likely to report any major medical errors in the previous 3 months compared with those who worked 80 hours per week.⁹ The risk for the number of medical errors has been reported as being 2-fold if surgeons are unable to combat the burnout.⁴⁹ On the other hand, a positive and supportive environment with easy access to resources to combat burnout and burnout prevention programs can reduce the frequency of medical errors, which also can reduce the risk of malpractice, thus further reducing stress and burnout.⁴³

Continue to: In response to resident complaints...

In response to resident complaints about long duty hours, a new rule has been implemented that states residents cannot work >16 hours per shift.³⁰ This rule has been found to increase quality of life and prevent burnout.³⁰

The amount of time spent on electronic medical records and documentation has been a major complaint from doctors and was identified as a factor contributing to burnout.⁴⁵ It can act as a time drain that impedes the physician from providing optimal patient care and cause additional stress. This suggests the need for organizations to find solutions to minimize this strain.

A concerning issue reported as an institutional factor and associated with burnout is mistreatment through discrimination, harassment, and physical or verbal abuse. A recent study found 45% of general and vascular surgeons reported being mistreated in some fashion.⁵⁷ The strategies reported as helpful for institutions to combat mistreatment include resilience training, improved mentorship, and implicit bias training.⁵⁷

Burnout has been positively correlated with anxiety and depression.⁶ A recent study reported that 13% of orthopedic surgery residents screened positive for depression.⁴⁴ Higher levels of burnout and depersonalization have been found to be closely associated with increased rates of suicidal ideation.¹⁷ In a study of vascular surgeons, 8% were found to report suicidal ideation, and this increased to 15% among vascular surgeons who had higher levels of depersonalization and emotional exhaustion,⁵⁸ both of which are associated with burnout. In another study, surgery residents and fellows were found to have lower levels of personal achievement and higher levels of depersonalization, depressive symptoms, alcohol abuse, and suicidal ideation compared to attending physicians and the general population.⁵⁴ These findings spell out the association between burnout and depressive symptoms among surgeons and emphasize the need for institutions to create a culture that supports the mental health needs of their physicians. Without access to supportive resources, residents resort to alternative methods that may be detrimental in the long run. In a recent study, 17% of residents admitted to using alcohol, including binge drinking, to cope with their stress.⁴

Burnout and depression are linked to physical health risks such as cardiovascular disease, diabetes, substance abuse, and male infertility.⁶ Exercise has been shown to be beneficial for stress reduction, which can lead to changes in metabolism, inflammation, coagulation, and autonomic function.⁶ One study of surgeons found aerobic exercise and strength training were associated with lower rates of burnout and a higher quality of life.⁵⁹

Continue to: The amount of burnout physicians...

The amount of burnout physicians experience can be determined by how they respond to adversities. Adaptive behaviors such as socializing, mindfulness, volunteering, and exercising have been found to be protective against burnout.^6,37,54 Resilience training and maintaining low stress at work can decrease burnout.³⁷ These findings highlight the need for physicians to be trained in the appropriate ways to combat their burnout symptoms.

Unfortunately, seeking help by health care professionals to improve mental health has been stigmatized, causing physicians to not seek help and instead resort to other ways to cope with their distress.^26,34 While some of these coping methods may be positive, others—such as substance abuse or stress eating—can be maladaptive, leading to a poor quality of life, and in some cases, suicide.⁵⁴ It is vital that effective mental health services become more accessible and for health care professionals to become aware of their maladaptive behaviors.³⁴

Institutions finding ways to ease the path for their physicians to seek professional help to combat burnout may mitigate its negative impact. One strategy is to embed access to mental health services within regular wellness checks. Institutions can use wellness checks to provide resources to physicians who need it. These interventions have been found to be effective because they give physicians a safe space to seek help and become aware of any factors that could lead to burnout.¹⁸ Apart from these direct attempts to combat burnout, program-sponsored social events would also promote social connectedness with colleagues and contribute to a sense of well-being that could help decrease levels of burnout and depression.¹³ Mentorship has been shown to play a crucial role in decreasing burnout among residents. One study that examined the role of mentorship reported that 55% of residents felt supported, and of these, 96% felt mentorship was critical to their success.¹⁸ The role of institutions in helping to improve the well-being of surgeons is highlighted by the finding that increasing workplace support results in psychological resilience that can mitigate burnout at its roots.²⁹

Bottom Line

Surgeons are at risk for burnout, which can impact their mental health and reduce their professional efficacy. Both institutions and surgeons themselves can take action to prevent burnout and treat burnout early when it occurs.

Related Resources

• Pahal P, Lippmann S. Building a better work/life balance. Current Psychiatry. 2021;20(8):e1-e2. doi:10.12788/cp.0158
• Gibson R, Hategan A. Physician burnout vs depression: recognize the signs. Current Psychiatry. 2019;18(10):41-42.

Burnout is an occupational phenomenon and a syndrome resulting from unsuccessfully managed chronic workplace stress. The characteristic features of burnout include feelings of exhaustion, cynicism, and reduced professional efficacy.¹ A career in surgery is associated with demanding and unpredictable work hours in a high-stress environment.^2-8 Research indicates that surgeons are at an elevated risk for developing burnout and mental health problems that can compromise patient care. A survey of the fellows of the American College of Surgeons found that 40% of surgeons experience burnout, 30% experience symptoms of depression, and 28% have a mental quality of life (QOL) score greater than one-half an SD below the population norm.^9,10 Surgeon burnout was also found to compromise the delivery of medical care.^9,10

To prevent serious harm to surgeons and patients, it is critical to understand the causative factors of burnout among surgeons and how they can be addressed. We conducted this systematic review to identify factors linked to burnout across surgical specialties and to suggest ways to mitigate these risk factors.  

Methods

To identify studies of burnout among surgeons, we conducted an electronic search of Ovid MEDLINE, Ovid PsycInfo, SCOPUS, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. The headings and keywords used are listed in Supplemental Table 1. Studies met the inclusion criteria if they evaluated residents or attendings, used a tool to measure burnout, and examined any surgical specialty. Studies were excluded if they were published before 2010; were conducted outside the United States; were review articles, commentaries, or abstracts without full text articles; evaluated medical school students; were published in a language other than English; did not use a tool to measure burnout; or examined a nonsurgical specialty.  Our analysis was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)¹¹ and is outlined in the Supplemental Figure.

Results

Surgical specialties and burnout

We identified 56 studies^2-10,12-58 that focused on specific surgical specialties in relation to burnout. Supplemental Table 2^2-10,12-58 lists these studies and the surgical specialties they evaluated.

Work/life balance factors

Fifteen studies^{2-5,14,15,18,19,22,32,34,38,39,47,57} examined the role of work/life balance in burnout. Table 1^{2-5,14,15,18,19,22,32,34,38,39,47,57} lists the work/life factors these studies identified as being linked to burnout. Six studies^{2,4,18,22,32,47} discussed how decreased leisure time was linked to burnout. Eleven studies^{2,4,14,15,19,22,34,38,39,42,57} associated inabilities to meet family commitments with burnout. A lack of time to spend with family and not having adequate time to raise children was more prevalent among women. Seven studies^{2,3,18,22,32,34,47} implicated increased time commitment to work as playing a role in burnout. This increased time commitment was also found to be a compounding variable for other factors, such as limited time for family and leisure.

Work hours

Fifteen studies^{2,7,14,20,21,30,34,41,42,44-46,50,52,56} examined work hours and burnout. Of these, 14^{2,7,14,20,21,30,34,42,44-46,50,52,56} found a correlation between increased work hours and burnout, while only 1 study⁴¹ found no correlation between these factors. 

Medical errors

Six studies^{2,14,18,43,49,52} discussed the role of burnout in medical errors. Of these, 5^{2,14,43,49,52} reported a correlation between burnout and medical errors, while 1 study¹⁸ found no link between burnout and medical errors. The medical errors were self-reported.^14,49 They included actions that resulted in patient harm, sample collection error, and errors in medication orders and laboratory test orders.²

Continue to: Institutional and organizational factors

Eighteen studies^{3,13,14,18,20,22,23,29,30,36-38,44,45,47,54,56,57} examined how different organizational factors play a role in burnout. Four studies^3,13,20,37 discussed administrative/bureaucratic work, 4^20,45,54,57 mentioned electronic medical documentation, 2^22,30 covered duty hour regulations, 3^18,45,57 discussed mistreatment of physicians, and 6^{13,18,23,44,47,56} described the importance of workplace support in addressing burnout.

Physical and mental health factors

Eighteen studies^{6,7,14,15,17,20,26,27,29,34,43,44,48,52,54,57-59} discussed aspects of physical and mental health linked to burnout. Among these, 3^34,43,59 discussed the importance of physical health and focused on how improving physical health can reduce stress and burnout. Three studies^6,17,58 noted the prevalence of suicidal ideation in both residents and attendings experiencing prolonged burnout. Five studies^{26,29,43,44,48} described the systematic barriers that inhibit physicians from getting professional help. Two studies^7,27 reported marital status as a factor for burnout; participants who were single reported higher levels of depression and suicidal ideation. Five studies^{6,14,15,54,57} outlined how depression is associated with burnout.

Strategies to mitigate burnout

Fifteen studies^{2,4,5,14,20,22,33,36,47,51,53,55-58} described strategies physicians use to cope with burnout. Table 2^{2,4,5,14,20,22,33,36,47,51,53,55-58} outlines the strategies postulated and reported by these studies as helpful in reducing burnout. Two studies^2,4 mentioned that physicians may turn to maladaptive behaviors, such as substance abuse, to cope with stress and burnout. Four studies^2,4,53,56 mentioned the importance of social support in fighting burnout and building resilience. Ten studies^{2,5,14,20,22,33,36,47,57,58} described the benefits of institutional interventions, such as what administrators can do to reduce the rate of burnout. Three studies^5,36,53 postulated different adaptive behaviors physicians can implement to reduce burnout.

Take-home points 

Research that focused on work/life balance and burnout found excessive time commitment to work is a major factor associated with poor work/life balance. Residents who worked >80 hours a week had a significantly higher burnout rate.⁵⁶ One study found that 70% of residents reported not getting enough sleep, 30% reported not having enough energy for relationships, and 39% reported that they were not eating or exercising due to time constraints.⁴ A high correlation was found between the number of hours worked per week and rates of burnout, emotional exhaustion, and depersonalization. Emotional exhaustion and depersonalization are aspects of burnout measured by the Maslach Burnout Inventory (MBI).²⁴ The excessive time commitment to work not only contributes to burnout but also prevents physicians from getting professional help. In 1 study, both residents (56%) and attendings (24%) reported that 1 of the biggest barriers to getting help for their burnout symptoms was the inability to take time off.³⁴ Research indicates that the hours worked per week and work/home conflicts were independently associated with burnout and career satisfaction.¹⁵ A decrease of weekly work hours may give physicians time to meet their responsibilities at work and home, allowing for a decrease in burnout and an increase in career satisfaction.

Increased work hours have also been found to be correlated with medical errors. One study found that those who worked 60 hours per week were significantly less likely to report any major medical errors in the previous 3 months compared with those who worked 80 hours per week.⁹ The risk for the number of medical errors has been reported as being 2-fold if surgeons are unable to combat the burnout.⁴⁹ On the other hand, a positive and supportive environment with easy access to resources to combat burnout and burnout prevention programs can reduce the frequency of medical errors, which also can reduce the risk of malpractice, thus further reducing stress and burnout.⁴³

Continue to: In response to resident complaints...

In response to resident complaints about long duty hours, a new rule has been implemented that states residents cannot work >16 hours per shift.³⁰ This rule has been found to increase quality of life and prevent burnout.³⁰

The amount of time spent on electronic medical records and documentation has been a major complaint from doctors and was identified as a factor contributing to burnout.⁴⁵ It can act as a time drain that impedes the physician from providing optimal patient care and cause additional stress. This suggests the need for organizations to find solutions to minimize this strain.

A concerning issue reported as an institutional factor and associated with burnout is mistreatment through discrimination, harassment, and physical or verbal abuse. A recent study found 45% of general and vascular surgeons reported being mistreated in some fashion.⁵⁷ The strategies reported as helpful for institutions to combat mistreatment include resilience training, improved mentorship, and implicit bias training.⁵⁷

Burnout has been positively correlated with anxiety and depression.⁶ A recent study reported that 13% of orthopedic surgery residents screened positive for depression.⁴⁴ Higher levels of burnout and depersonalization have been found to be closely associated with increased rates of suicidal ideation.¹⁷ In a study of vascular surgeons, 8% were found to report suicidal ideation, and this increased to 15% among vascular surgeons who had higher levels of depersonalization and emotional exhaustion,⁵⁸ both of which are associated with burnout. In another study, surgery residents and fellows were found to have lower levels of personal achievement and higher levels of depersonalization, depressive symptoms, alcohol abuse, and suicidal ideation compared to attending physicians and the general population.⁵⁴ These findings spell out the association between burnout and depressive symptoms among surgeons and emphasize the need for institutions to create a culture that supports the mental health needs of their physicians. Without access to supportive resources, residents resort to alternative methods that may be detrimental in the long run. In a recent study, 17% of residents admitted to using alcohol, including binge drinking, to cope with their stress.⁴

Burnout and depression are linked to physical health risks such as cardiovascular disease, diabetes, substance abuse, and male infertility.⁶ Exercise has been shown to be beneficial for stress reduction, which can lead to changes in metabolism, inflammation, coagulation, and autonomic function.⁶ One study of surgeons found aerobic exercise and strength training were associated with lower rates of burnout and a higher quality of life.⁵⁹

Continue to: The amount of burnout physicians...

The amount of burnout physicians experience can be determined by how they respond to adversities. Adaptive behaviors such as socializing, mindfulness, volunteering, and exercising have been found to be protective against burnout.^6,37,54 Resilience training and maintaining low stress at work can decrease burnout.³⁷ These findings highlight the need for physicians to be trained in the appropriate ways to combat their burnout symptoms.

Unfortunately, seeking help by health care professionals to improve mental health has been stigmatized, causing physicians to not seek help and instead resort to other ways to cope with their distress.^26,34 While some of these coping methods may be positive, others—such as substance abuse or stress eating—can be maladaptive, leading to a poor quality of life, and in some cases, suicide.⁵⁴ It is vital that effective mental health services become more accessible and for health care professionals to become aware of their maladaptive behaviors.³⁴

Institutions finding ways to ease the path for their physicians to seek professional help to combat burnout may mitigate its negative impact. One strategy is to embed access to mental health services within regular wellness checks. Institutions can use wellness checks to provide resources to physicians who need it. These interventions have been found to be effective because they give physicians a safe space to seek help and become aware of any factors that could lead to burnout.¹⁸ Apart from these direct attempts to combat burnout, program-sponsored social events would also promote social connectedness with colleagues and contribute to a sense of well-being that could help decrease levels of burnout and depression.¹³ Mentorship has been shown to play a crucial role in decreasing burnout among residents. One study that examined the role of mentorship reported that 55% of residents felt supported, and of these, 96% felt mentorship was critical to their success.¹⁸ The role of institutions in helping to improve the well-being of surgeons is highlighted by the finding that increasing workplace support results in psychological resilience that can mitigate burnout at its roots.²⁹

Bottom Line

Surgeons are at risk for burnout, which can impact their mental health and reduce their professional efficacy. Both institutions and surgeons themselves can take action to prevent burnout and treat burnout early when it occurs.

Related Resources

• Pahal P, Lippmann S. Building a better work/life balance. Current Psychiatry. 2021;20(8):e1-e2. doi:10.12788/cp.0158
• Gibson R, Hategan A. Physician burnout vs depression: recognize the signs. Current Psychiatry. 2019;18(10):41-42.

Burnout is an occupational phenomenon and a syndrome resulting from unsuccessfully managed chronic workplace stress. The characteristic features of burnout include feelings of exhaustion, cynicism, and reduced professional efficacy.¹ A career in surgery is associated with demanding and unpredictable work hours in a high-stress environment.^2-8 Research indicates that surgeons are at an elevated risk for developing burnout and mental health problems that can compromise patient care. A survey of the fellows of the American College of Surgeons found that 40% of surgeons experience burnout, 30% experience symptoms of depression, and 28% have a mental quality of life (QOL) score greater than one-half an SD below the population norm.^9,10 Surgeon burnout was also found to compromise the delivery of medical care.^9,10

To prevent serious harm to surgeons and patients, it is critical to understand the causative factors of burnout among surgeons and how they can be addressed. We conducted this systematic review to identify factors linked to burnout across surgical specialties and to suggest ways to mitigate these risk factors.  

Methods

To identify studies of burnout among surgeons, we conducted an electronic search of Ovid MEDLINE, Ovid PsycInfo, SCOPUS, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. The headings and keywords used are listed in Supplemental Table 1. Studies met the inclusion criteria if they evaluated residents or attendings, used a tool to measure burnout, and examined any surgical specialty. Studies were excluded if they were published before 2010; were conducted outside the United States; were review articles, commentaries, or abstracts without full text articles; evaluated medical school students; were published in a language other than English; did not use a tool to measure burnout; or examined a nonsurgical specialty.  Our analysis was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)¹¹ and is outlined in the Supplemental Figure.

Results

Surgical specialties and burnout

We identified 56 studies^2-10,12-58 that focused on specific surgical specialties in relation to burnout. Supplemental Table 2^2-10,12-58 lists these studies and the surgical specialties they evaluated.

Work/life balance factors

Fifteen studies^{2-5,14,15,18,19,22,32,34,38,39,47,57} examined the role of work/life balance in burnout. Table 1^{2-5,14,15,18,19,22,32,34,38,39,47,57} lists the work/life factors these studies identified as being linked to burnout. Six studies^{2,4,18,22,32,47} discussed how decreased leisure time was linked to burnout. Eleven studies^{2,4,14,15,19,22,34,38,39,42,57} associated inabilities to meet family commitments with burnout. A lack of time to spend with family and not having adequate time to raise children was more prevalent among women. Seven studies^{2,3,18,22,32,34,47} implicated increased time commitment to work as playing a role in burnout. This increased time commitment was also found to be a compounding variable for other factors, such as limited time for family and leisure.

Work hours

Fifteen studies^{2,7,14,20,21,30,34,41,42,44-46,50,52,56} examined work hours and burnout. Of these, 14^{2,7,14,20,21,30,34,42,44-46,50,52,56} found a correlation between increased work hours and burnout, while only 1 study⁴¹ found no correlation between these factors. 

Medical errors

Six studies^{2,14,18,43,49,52} discussed the role of burnout in medical errors. Of these, 5^{2,14,43,49,52} reported a correlation between burnout and medical errors, while 1 study¹⁸ found no link between burnout and medical errors. The medical errors were self-reported.^14,49 They included actions that resulted in patient harm, sample collection error, and errors in medication orders and laboratory test orders.²

Continue to: Institutional and organizational factors

Eighteen studies^{3,13,14,18,20,22,23,29,30,36-38,44,45,47,54,56,57} examined how different organizational factors play a role in burnout. Four studies^3,13,20,37 discussed administrative/bureaucratic work, 4^20,45,54,57 mentioned electronic medical documentation, 2^22,30 covered duty hour regulations, 3^18,45,57 discussed mistreatment of physicians, and 6^{13,18,23,44,47,56} described the importance of workplace support in addressing burnout.

Physical and mental health factors

Eighteen studies^{6,7,14,15,17,20,26,27,29,34,43,44,48,52,54,57-59} discussed aspects of physical and mental health linked to burnout. Among these, 3^34,43,59 discussed the importance of physical health and focused on how improving physical health can reduce stress and burnout. Three studies^6,17,58 noted the prevalence of suicidal ideation in both residents and attendings experiencing prolonged burnout. Five studies^{26,29,43,44,48} described the systematic barriers that inhibit physicians from getting professional help. Two studies^7,27 reported marital status as a factor for burnout; participants who were single reported higher levels of depression and suicidal ideation. Five studies^{6,14,15,54,57} outlined how depression is associated with burnout.

Strategies to mitigate burnout

Fifteen studies^{2,4,5,14,20,22,33,36,47,51,53,55-58} described strategies physicians use to cope with burnout. Table 2^{2,4,5,14,20,22,33,36,47,51,53,55-58} outlines the strategies postulated and reported by these studies as helpful in reducing burnout. Two studies^2,4 mentioned that physicians may turn to maladaptive behaviors, such as substance abuse, to cope with stress and burnout. Four studies^2,4,53,56 mentioned the importance of social support in fighting burnout and building resilience. Ten studies^{2,5,14,20,22,33,36,47,57,58} described the benefits of institutional interventions, such as what administrators can do to reduce the rate of burnout. Three studies^5,36,53 postulated different adaptive behaviors physicians can implement to reduce burnout.

Take-home points 

Research that focused on work/life balance and burnout found excessive time commitment to work is a major factor associated with poor work/life balance. Residents who worked >80 hours a week had a significantly higher burnout rate.⁵⁶ One study found that 70% of residents reported not getting enough sleep, 30% reported not having enough energy for relationships, and 39% reported that they were not eating or exercising due to time constraints.⁴ A high correlation was found between the number of hours worked per week and rates of burnout, emotional exhaustion, and depersonalization. Emotional exhaustion and depersonalization are aspects of burnout measured by the Maslach Burnout Inventory (MBI).²⁴ The excessive time commitment to work not only contributes to burnout but also prevents physicians from getting professional help. In 1 study, both residents (56%) and attendings (24%) reported that 1 of the biggest barriers to getting help for their burnout symptoms was the inability to take time off.³⁴ Research indicates that the hours worked per week and work/home conflicts were independently associated with burnout and career satisfaction.¹⁵ A decrease of weekly work hours may give physicians time to meet their responsibilities at work and home, allowing for a decrease in burnout and an increase in career satisfaction.

Increased work hours have also been found to be correlated with medical errors. One study found that those who worked 60 hours per week were significantly less likely to report any major medical errors in the previous 3 months compared with those who worked 80 hours per week.⁹ The risk for the number of medical errors has been reported as being 2-fold if surgeons are unable to combat the burnout.⁴⁹ On the other hand, a positive and supportive environment with easy access to resources to combat burnout and burnout prevention programs can reduce the frequency of medical errors, which also can reduce the risk of malpractice, thus further reducing stress and burnout.⁴³

Continue to: In response to resident complaints...

In response to resident complaints about long duty hours, a new rule has been implemented that states residents cannot work >16 hours per shift.³⁰ This rule has been found to increase quality of life and prevent burnout.³⁰

The amount of time spent on electronic medical records and documentation has been a major complaint from doctors and was identified as a factor contributing to burnout.⁴⁵ It can act as a time drain that impedes the physician from providing optimal patient care and cause additional stress. This suggests the need for organizations to find solutions to minimize this strain.

A concerning issue reported as an institutional factor and associated with burnout is mistreatment through discrimination, harassment, and physical or verbal abuse. A recent study found 45% of general and vascular surgeons reported being mistreated in some fashion.⁵⁷ The strategies reported as helpful for institutions to combat mistreatment include resilience training, improved mentorship, and implicit bias training.⁵⁷

Burnout has been positively correlated with anxiety and depression.⁶ A recent study reported that 13% of orthopedic surgery residents screened positive for depression.⁴⁴ Higher levels of burnout and depersonalization have been found to be closely associated with increased rates of suicidal ideation.¹⁷ In a study of vascular surgeons, 8% were found to report suicidal ideation, and this increased to 15% among vascular surgeons who had higher levels of depersonalization and emotional exhaustion,⁵⁸ both of which are associated with burnout. In another study, surgery residents and fellows were found to have lower levels of personal achievement and higher levels of depersonalization, depressive symptoms, alcohol abuse, and suicidal ideation compared to attending physicians and the general population.⁵⁴ These findings spell out the association between burnout and depressive symptoms among surgeons and emphasize the need for institutions to create a culture that supports the mental health needs of their physicians. Without access to supportive resources, residents resort to alternative methods that may be detrimental in the long run. In a recent study, 17% of residents admitted to using alcohol, including binge drinking, to cope with their stress.⁴

Burnout and depression are linked to physical health risks such as cardiovascular disease, diabetes, substance abuse, and male infertility.⁶ Exercise has been shown to be beneficial for stress reduction, which can lead to changes in metabolism, inflammation, coagulation, and autonomic function.⁶ One study of surgeons found aerobic exercise and strength training were associated with lower rates of burnout and a higher quality of life.⁵⁹

Continue to: The amount of burnout physicians...

The amount of burnout physicians experience can be determined by how they respond to adversities. Adaptive behaviors such as socializing, mindfulness, volunteering, and exercising have been found to be protective against burnout.^6,37,54 Resilience training and maintaining low stress at work can decrease burnout.³⁷ These findings highlight the need for physicians to be trained in the appropriate ways to combat their burnout symptoms.

Unfortunately, seeking help by health care professionals to improve mental health has been stigmatized, causing physicians to not seek help and instead resort to other ways to cope with their distress.^26,34 While some of these coping methods may be positive, others—such as substance abuse or stress eating—can be maladaptive, leading to a poor quality of life, and in some cases, suicide.⁵⁴ It is vital that effective mental health services become more accessible and for health care professionals to become aware of their maladaptive behaviors.³⁴

Institutions finding ways to ease the path for their physicians to seek professional help to combat burnout may mitigate its negative impact. One strategy is to embed access to mental health services within regular wellness checks. Institutions can use wellness checks to provide resources to physicians who need it. These interventions have been found to be effective because they give physicians a safe space to seek help and become aware of any factors that could lead to burnout.¹⁸ Apart from these direct attempts to combat burnout, program-sponsored social events would also promote social connectedness with colleagues and contribute to a sense of well-being that could help decrease levels of burnout and depression.¹³ Mentorship has been shown to play a crucial role in decreasing burnout among residents. One study that examined the role of mentorship reported that 55% of residents felt supported, and of these, 96% felt mentorship was critical to their success.¹⁸ The role of institutions in helping to improve the well-being of surgeons is highlighted by the finding that increasing workplace support results in psychological resilience that can mitigate burnout at its roots.²⁹

Bottom Line

Surgeons are at risk for burnout, which can impact their mental health and reduce their professional efficacy. Both institutions and surgeons themselves can take action to prevent burnout and treat burnout early when it occurs.

Related Resources

• Pahal P, Lippmann S. Building a better work/life balance. Current Psychiatry. 2021;20(8):e1-e2. doi:10.12788/cp.0158
• Gibson R, Hategan A. Physician burnout vs depression: recognize the signs. Current Psychiatry. 2019;18(10):41-42.

Bipolar disorder (BD) is a psychotic mood disorder. Like schizophrenia, it has been shown to be associated with significant degeneration and structural brain abnormalities with multiple relapses.^1,2

Just as I have always advocated preventing recurrences in schizophrenia by using long-acting injectable (LAI) antipsychotic formulations immediately after the first episode to prevent psychotic relapses and progressive brain damage,³ I strongly recommend using LAIs right after hospital discharge from the first manic episode. It is the most rational management approach for bipolar mania given the grave consequences of multiple episodes, which are so common in this psychotic mood disorder due to poor medication adherence.

In contrast to the depressive episodes of BD I, where patients have insight into their depression and seek psychiatric treatment, during a manic episode patients often have no insight (anosognosia) that they suffer from a serious brain disorder, and refuse treatment.⁴ In addition, young patients with BD I frequently discontinue their oral mood stabilizer or second-generation antipsychotic (which are approved for mania) because they miss the blissful euphoria and the buoyant physical and mental energy of their manic episodes. They are completely oblivious to (and uninformed about) the grave neurobiological damage of further manic episodes, which can condemn them to clinical, functional, and cognitive deterioration. These patients are also likely to become treatment-resistant, which has been labeled as “the malignant transformation of bipolar disorder.”⁵

The evidence for progressive brain tissue loss, clinical deterioration, functional decline, and treatment resistance is abundant.⁶ I was the lead investigator of the first study to report ventricular dilatation (which is a proxy for cortical atrophy) in bipolar mania,⁷ a discovery that was subsequently replicated by 2 dozen researchers. This was followed by numerous neuroimaging studies reporting a loss of volume across multiple brain regions, including the frontal lobe, temporal lobe, cerebellum, thalamus, hippocampus, and basal ganglia. BD is heterogeneous⁸ with 4 stages (Table 1⁹), and patients experience progressively worse brain structure and function with each stage.

Many patients with bipolar mania end up with poor clinical and functional outcomes, even when they respond well to initial treatment with lithium, anticonvulsant mood stabilizers, or second-generation antipsychotics. With their intentional nonadherence to oral medications leading to multiple recurrent relapses, these patients are at serious risk for neuroprogression and brain atrophic changes driven by multiple factors: inflammatory cytokines, increased cortical steroids, decreased neurotrophins, deceased neurogenesis, increased oxidative stress, and mitochondrial energy dysfunction. The consequences include progressive shortening of the interval between episodes with every relapse and loss of responsiveness to pharmacotherapy as the illness progresses.^6,10 Predictors of a downhill progression include genetic vulnerability, perinatal complication during fetal life, childhood trauma (physical, sexual, emotional, or neglect), substance use, stress, psychiatric/medial comorbidities, and especially the number of episodes.^9,11

Biomarkers have been reported in both the early and late stages of BD (Table 2¹²) as well as in postmortem studies (Table 3^8,13). They reflect the progressive neurodegenerative nature of recurrent BD I episodes as the disorder moves to the advanced stages. I summarize these stages in Table 1⁹ and Table 2¹² for the benefit of psychiatric clinicians who do not have access to the neuroscience journals where such findings are usually published.

BD I is also believed to be associated with accelerated aging^14,15 and an increased risk for dementia¹⁶ or cognitive deterioration.¹⁷ There is also an emerging hypothesis that neuroprogression and treatment resistance in BD is frequently associated with insulin resistance,¹⁸ peripheral inflammation,¹⁹ and blood-brain barrier permeability dysfunction.²⁰

The bottom line is that like patients with schizophrenia, where relapses lead to devastating consequences,²¹ those with BD are at a similar high risk for neuroprogression, which includes atrophy in several brain regions, treatment resistance, and functional disability. This underscores the urgency for implementing LAI therapy early in the illness, when the first manic episode (Stage 2) emerges after the prodrome (Stage 1). This is the best strategy to preserve brain health in persons with BD²² and to allow them to remain functional with their many intellectual gifts, such as eloquence, poetry, artistic talents, humor, and social skills. It is unfortunate that the combination of patients’ and clinicians’ reluctance to use an LAI early in the illness dooms many patients with BD to a potentially avoidable malignant outcome.

Bipolar disorder (BD) is a psychotic mood disorder. Like schizophrenia, it has been shown to be associated with significant degeneration and structural brain abnormalities with multiple relapses.^1,2

Just as I have always advocated preventing recurrences in schizophrenia by using long-acting injectable (LAI) antipsychotic formulations immediately after the first episode to prevent psychotic relapses and progressive brain damage,³ I strongly recommend using LAIs right after hospital discharge from the first manic episode. It is the most rational management approach for bipolar mania given the grave consequences of multiple episodes, which are so common in this psychotic mood disorder due to poor medication adherence.

In contrast to the depressive episodes of BD I, where patients have insight into their depression and seek psychiatric treatment, during a manic episode patients often have no insight (anosognosia) that they suffer from a serious brain disorder, and refuse treatment.⁴ In addition, young patients with BD I frequently discontinue their oral mood stabilizer or second-generation antipsychotic (which are approved for mania) because they miss the blissful euphoria and the buoyant physical and mental energy of their manic episodes. They are completely oblivious to (and uninformed about) the grave neurobiological damage of further manic episodes, which can condemn them to clinical, functional, and cognitive deterioration. These patients are also likely to become treatment-resistant, which has been labeled as “the malignant transformation of bipolar disorder.”⁵

The evidence for progressive brain tissue loss, clinical deterioration, functional decline, and treatment resistance is abundant.⁶ I was the lead investigator of the first study to report ventricular dilatation (which is a proxy for cortical atrophy) in bipolar mania,⁷ a discovery that was subsequently replicated by 2 dozen researchers. This was followed by numerous neuroimaging studies reporting a loss of volume across multiple brain regions, including the frontal lobe, temporal lobe, cerebellum, thalamus, hippocampus, and basal ganglia. BD is heterogeneous⁸ with 4 stages (Table 1⁹), and patients experience progressively worse brain structure and function with each stage.

Many patients with bipolar mania end up with poor clinical and functional outcomes, even when they respond well to initial treatment with lithium, anticonvulsant mood stabilizers, or second-generation antipsychotics. With their intentional nonadherence to oral medications leading to multiple recurrent relapses, these patients are at serious risk for neuroprogression and brain atrophic changes driven by multiple factors: inflammatory cytokines, increased cortical steroids, decreased neurotrophins, deceased neurogenesis, increased oxidative stress, and mitochondrial energy dysfunction. The consequences include progressive shortening of the interval between episodes with every relapse and loss of responsiveness to pharmacotherapy as the illness progresses.^6,10 Predictors of a downhill progression include genetic vulnerability, perinatal complication during fetal life, childhood trauma (physical, sexual, emotional, or neglect), substance use, stress, psychiatric/medial comorbidities, and especially the number of episodes.^9,11

Biomarkers have been reported in both the early and late stages of BD (Table 2¹²) as well as in postmortem studies (Table 3^8,13). They reflect the progressive neurodegenerative nature of recurrent BD I episodes as the disorder moves to the advanced stages. I summarize these stages in Table 1⁹ and Table 2¹² for the benefit of psychiatric clinicians who do not have access to the neuroscience journals where such findings are usually published.

BD I is also believed to be associated with accelerated aging^14,15 and an increased risk for dementia¹⁶ or cognitive deterioration.¹⁷ There is also an emerging hypothesis that neuroprogression and treatment resistance in BD is frequently associated with insulin resistance,¹⁸ peripheral inflammation,¹⁹ and blood-brain barrier permeability dysfunction.²⁰

The bottom line is that like patients with schizophrenia, where relapses lead to devastating consequences,²¹ those with BD are at a similar high risk for neuroprogression, which includes atrophy in several brain regions, treatment resistance, and functional disability. This underscores the urgency for implementing LAI therapy early in the illness, when the first manic episode (Stage 2) emerges after the prodrome (Stage 1). This is the best strategy to preserve brain health in persons with BD²² and to allow them to remain functional with their many intellectual gifts, such as eloquence, poetry, artistic talents, humor, and social skills. It is unfortunate that the combination of patients’ and clinicians’ reluctance to use an LAI early in the illness dooms many patients with BD to a potentially avoidable malignant outcome.

Bipolar disorder (BD) is a psychotic mood disorder. Like schizophrenia, it has been shown to be associated with significant degeneration and structural brain abnormalities with multiple relapses.^1,2

Just as I have always advocated preventing recurrences in schizophrenia by using long-acting injectable (LAI) antipsychotic formulations immediately after the first episode to prevent psychotic relapses and progressive brain damage,³ I strongly recommend using LAIs right after hospital discharge from the first manic episode. It is the most rational management approach for bipolar mania given the grave consequences of multiple episodes, which are so common in this psychotic mood disorder due to poor medication adherence.

In contrast to the depressive episodes of BD I, where patients have insight into their depression and seek psychiatric treatment, during a manic episode patients often have no insight (anosognosia) that they suffer from a serious brain disorder, and refuse treatment.⁴ In addition, young patients with BD I frequently discontinue their oral mood stabilizer or second-generation antipsychotic (which are approved for mania) because they miss the blissful euphoria and the buoyant physical and mental energy of their manic episodes. They are completely oblivious to (and uninformed about) the grave neurobiological damage of further manic episodes, which can condemn them to clinical, functional, and cognitive deterioration. These patients are also likely to become treatment-resistant, which has been labeled as “the malignant transformation of bipolar disorder.”⁵

The evidence for progressive brain tissue loss, clinical deterioration, functional decline, and treatment resistance is abundant.⁶ I was the lead investigator of the first study to report ventricular dilatation (which is a proxy for cortical atrophy) in bipolar mania,⁷ a discovery that was subsequently replicated by 2 dozen researchers. This was followed by numerous neuroimaging studies reporting a loss of volume across multiple brain regions, including the frontal lobe, temporal lobe, cerebellum, thalamus, hippocampus, and basal ganglia. BD is heterogeneous⁸ with 4 stages (Table 1⁹), and patients experience progressively worse brain structure and function with each stage.

Many patients with bipolar mania end up with poor clinical and functional outcomes, even when they respond well to initial treatment with lithium, anticonvulsant mood stabilizers, or second-generation antipsychotics. With their intentional nonadherence to oral medications leading to multiple recurrent relapses, these patients are at serious risk for neuroprogression and brain atrophic changes driven by multiple factors: inflammatory cytokines, increased cortical steroids, decreased neurotrophins, deceased neurogenesis, increased oxidative stress, and mitochondrial energy dysfunction. The consequences include progressive shortening of the interval between episodes with every relapse and loss of responsiveness to pharmacotherapy as the illness progresses.^6,10 Predictors of a downhill progression include genetic vulnerability, perinatal complication during fetal life, childhood trauma (physical, sexual, emotional, or neglect), substance use, stress, psychiatric/medial comorbidities, and especially the number of episodes.^9,11

Biomarkers have been reported in both the early and late stages of BD (Table 2¹²) as well as in postmortem studies (Table 3^8,13). They reflect the progressive neurodegenerative nature of recurrent BD I episodes as the disorder moves to the advanced stages. I summarize these stages in Table 1⁹ and Table 2¹² for the benefit of psychiatric clinicians who do not have access to the neuroscience journals where such findings are usually published.

BD I is also believed to be associated with accelerated aging^14,15 and an increased risk for dementia¹⁶ or cognitive deterioration.¹⁷ There is also an emerging hypothesis that neuroprogression and treatment resistance in BD is frequently associated with insulin resistance,¹⁸ peripheral inflammation,¹⁹ and blood-brain barrier permeability dysfunction.²⁰

The bottom line is that like patients with schizophrenia, where relapses lead to devastating consequences,²¹ those with BD are at a similar high risk for neuroprogression, which includes atrophy in several brain regions, treatment resistance, and functional disability. This underscores the urgency for implementing LAI therapy early in the illness, when the first manic episode (Stage 2) emerges after the prodrome (Stage 1). This is the best strategy to preserve brain health in persons with BD²² and to allow them to remain functional with their many intellectual gifts, such as eloquence, poetry, artistic talents, humor, and social skills. It is unfortunate that the combination of patients’ and clinicians’ reluctance to use an LAI early in the illness dooms many patients with BD to a potentially avoidable malignant outcome.

CASE Detoxification and preoccupation with parasites

Mr. H, age 51, has an extensive history of alcohol and methamphetamine use. He presents to the emergency department (ED) requesting inpatient detoxification. He says he had been drinking alcohol but is unable to say how much. His blood ethanol level is 61 mg/dL (unintoxicated level: <50 mg/dL), and a urine drug screen is positive for methamphetamine; Mr. H also admits to using fentanyl. The ED team treats Mr. H’s electrolyte abnormalities, initiates thiamine supplementation, and transfers him to a unit for inpatient withdrawal management.

On the detoxification unit, Mr. H receives a total of 1,950 mg of phenobarbital for alcohol withdrawal and stabilizes on a buprenorphine/naloxone maintenance dose of 8 mg/2 mg twice daily for methamphetamine and fentanyl use. Though he was not taking any psychiatric medications prior to his arrival at the ED, Mr. H agrees to restart quetiapine—which he took when he was younger for suspected bipolar depression—50 mg/d at bedtime.

During Mr. H’s 3-day detoxification, the psychiatry team evaluates him. Mr. H says he believes he is infested with worms. He describes a prior sensation of “meth mites,” or the feeling of bugs crawling under his skin, while using methamphetamines. However, Mr. H says his current infestation feels distinctively different, and he had continued to experience these sensations during prior periods of abstinence.

The psychiatry team expresses concern over his preoccupation with infestations, disheveled appearance, poor hygiene, and healed scars from excoriation. Mr. H also reports poor sleep and appetite and was observed writing an incomprehensible “experiment” on a paper towel. Due to his bizarre behavior, delusional thoughts, and concerns about his inability to care for himself, the team admits Mr. H to the acute inpatient psychiatric unit on a voluntary commitment.

HISTORY Long-standing drug use and repeated hospital visits

Mr. H reports a history of drug use. His first documented ED visit was >5 years before his current admission. He has a family history of substance abuse and reports previously using methamphetamine, heroin, and alcohol. Mr. H was never diagnosed with a psychiatric illness, but when he was younger, there were suspicions of bipolar depression, with no contributing family psychiatric history. Though he took quetiapine at an unspecified younger age, Mr. H did not follow through with any outpatient mental health services or medications.

Mr. H first reported infestation symptoms 6 months before his current inpatient admission, when he came to the ED with complaints of bumps on his arms and legs and reported seeing bugs in his carpet. He was prescribed permethrin 5% topical cream for suspected bedbug infestation.

In the 6 months prior to his current admission, Mr. H came to the hospital >20 times for various reasons, including methamphetamine abuse, alcohol withdrawal, opiate overdose, cellulitis, wound checks, and 3 visits for hallucinations for which he requested physical evaluation and medical care. His substance use was the suspected cause of his tactile and visual hallucinations of infestation because formication—the sensation of something crawling on your skin—is commonly associated with substance use. Although the etiology of Mr. H’s hallucinations was unclear, his substance use may have either precipitated them, or, as the team suspects, masked an underlying pathology that eventually became more evident and required psychiatric treatment.

Continue to: The authors' observations

The authors’ observations

Delusional parasitosis (DP), also known as delusional infestation or Ekbom Syndrome, is a condition characterized by the fixed, false belief of an infestation without any objective evidence. This condition was previously defined in DSM-IV, but was removed from DSM-5-TR. In DSM-5-TR, DP is most closely associated with delusional disorder—somatic type (Table 1¹). It describes a patient with ≥1 month of delusions who does not meet the criteria for schizophrenia with a central theme of delusions involving bodily functions or sensations such as infestation of insects or internal parasites.¹

DP is rare, affecting approximately 1.9 per 100,000 people. There has not been consistent data supporting differences in prevalence between sexes, but there is evidence for increasing incidence with age, with a mean age of diagnosis of 61.4.^2,3 DP can be divided into 2 types based on the history and etiology of the symptoms: primary DP and secondary DP. Primary DP occurs when there is a failure to identify an organic cause for the occurrence of the symptoms. Therefore, primary DP requires an extensive investigation by a multidisciplinary team that commonly includes medical specialists for a nonpsychiatric workup. Secondary DP occurs when the patient has delusional symptoms associated with a primary diagnosis of schizophrenia, depression, stroke, diabetes, vitamin B12 deficiency, or substance use.⁴

Though Mr. H initially presented to the ED, patients with DP commonly present to a primary care physician or dermatologist with the complaint of itching or feelings of insects, worms, or unclear organisms inside them. Patients with DP may often develop poor working relationships with physicians while obtaining multiple negative results. They may seek opinions from multiple specialists; however, patients typically do not consider psychiatrists as a source of help. When patients seek psychiatric care, often after a recommendation from a primary care physician or dermatologist, mental health clinicians should listen to and evaluate the patient holistically, continuing to rule out other possible etiologies.

[polldaddy:12570072]

TREATMENT Finding the right antipsychotic

In the psychiatric unit, Mr. H says he believes worms are exiting his ears, mouth, toenail, and self-inflicted scratch wounds. He believes he has been dealing with the parasites for >1 year and they are slowly draining his energy. Mr. H insists he contracted the “infection” from his home carpet, which was wet due to a flood in his house, and after he had fallen asleep following drug use. He also believes he acquired the parasites while walking barefoot along the beach and collecting rocks, and that there are multiple species living inside him, all intelligent enough to hide, making it difficult to prove their existence. He notes they vary in size, and some have red eyes.

During admission, Mr. H voices his frustration that clinicians had not found the worms he has been seeing. He continuously requests to review imaging performed during his visit and wants a multidisciplinary team to evaluate his case. He demands to test a cup with spit-up “samples,” believing the parasites would be visible under a microscope. Throughout his admission, Mr. H continues to take buprenorphine/naloxone and does not experience withdrawal symptoms. The treatment team titrates his quetiapine to 400 mg/d. Due to the lack of improvement, the team initiates olanzapine 5 mg/d at bedtime. However, Mr. H reports significant tinnitus and requests a medication change. He is started on haloperidol 5 mg twice daily.

Continue to: Mr. H begins to see improvements...

Mr. H begins to see improvements on Day 7 of taking haloperidol. He no longer brings up infestation but still acknowledges having worms inside him when directly asked. He says the worms cause him less distress than before and he is hopeful to live without discomfort. He also demonstrates an ability to conduct activities of daily living. Because Mr. H is being monitored on an acute inpatient psychiatric basis, he is deemed appropriate for discharge even though his symptoms have not yet fully resolved. After a 19-day hospital stay, Mr. H is discharged on haloperidol 15 mg/d and quetiapine 200 mg/d.

[polldaddy:12570074]

The authors’ observations

Mr. H asked to have his sputum examined. The “specimen sign,” also called “matchbox sign” or “Ziploc bag sign,” in which patients collect what they believe to be infected tissue or organisms in a container, is a well-studied part of DP.⁵ Such samples should be considered during initial encounters and can be examined for formal evaluation, but cautiously. Overtesting may incur a financial burden or reinforce deleterious beliefs and behaviors.

It can be difficult to identify triggers of DP. Research shows DP may arise from nonorganic and stressful life events, home floods, or contact with people infected with parasites.^6,7 Organic causes have also been found, such as patients taking multiple medications for Parkinson disease who developed delusional symptoms.⁸ Buscarino et al⁹ reported the case of a woman who started to develop symptoms of delusions and hallucinations after being on high-dose amphetamines for attention-deficit/hyperactivity disorder. Research shows that stopping the suspected medication commonly improves such symptoms.^9,10 Although methamphetamine can remain detectable in urine for up to 4 days after use and potentially a few days longer for chronic users due to circulating levels,¹¹ Mr. H’s symptoms continued for weeks after all substances of abuse should have been cleared from his system. This suggests he was experiencing a psychiatric illness and was accurate in distinguishing methamphetamine-induced from psychiatric-induced sensations. Regardless, polysubstance use has been shown to potentially increase the risk and play a role in the onset and progression of delusional illness, as seen in prior cases as well as in this case.⁹

It has been hypothesized that the pathophysiology of DP is associated with the deterioration of the striatal dopaminergic pathway, leading to an increase in extracellular dopamine levels. The striatum is responsible for most dopamine reuptake in the brain; therefore, certain drugs such as cocaine, methamphetamine, and methyl­phenidate may precipitate symptoms of DP due to their blockade of presynaptic dopamine reuptake.¹² Additionally, conditions that decrease the functioning of striatal dopamine transporters, such as schizophrenia or depression, may be underlying causes of DP.¹³

Treatment of DP remains a topic of debate. Most current recommendations appear to be based on a small, nonrandomized placebo-controlled trial.¹⁴ The first-generation antipsychotic pimozide had been a first-line treatment for DP, but its adverse effect profile, which includes QTc prolongation and extrapyramidal symptoms, led to the exploration of second-generation antipsychotics such as olanzapine and risperidone.^15,16 There is a dearth of literature about the use of haloperidol, quetiapine, or a combination of both as treatment options for DP, though the combination of these 2 medications proved effective for Mr. H. Further research is necessary to justify changes to current treatment standards, but this finding highlights a successful symptom reduction achieved with this combination.

Continue to: Patients may experience genuine symptoms...

Patients may experience genuine symptoms despite the delusional nature of DP, and it is important for clinicians to recognize the potential burden and anxiety these individuals face. Patients may present with self-inflicted bruises, cuts, and erosions to gain access to infected areas, which may be confused with skin picking disorder. Excessive cleansing or use of irritant products can also cause skin damage, leading to other dermatological conditions that reinforce the patient’s belief that something is medically wrong. During treatment, consider medications for relief of pruritus or pain. Focus on offering patients the opportunity to express their concerns, treat them with empathy, avoid stigmatizing language such as “delusions” or “psychosis,” and refrain from contradicting them until a strong rapport has been established (Table 2¹⁷).

Symptoms of DP can persist for months to years. Patients who fully recovered experienced a median duration of 0.5 years until symptom resolution, compared to incompletely recovered patients, who took approximately 1 year.¹⁸ Primary DP has slower improvement rates compared to secondary DP, with the median onset of effects occurring at Week 1.5 and peak improvements occurring at Week 6.¹⁶

OUTCOME Continued ED visits

Unfortunately, Mr. H does not follow through with his outpatient psychiatry appointments. In the 7 months following discharge, he visits the ED 8 times for alcohol intoxication, alcohol withdrawal, and methamphetamine abuse, in addition to 2 admissions for inpatient detoxification, during which he was still receiving the same scheduled medications (haloperidol 15 mg/d and quetiapine 200 mg/d). At each of his ED visits, there was no documentation of DP symptoms, which suggests his symptoms may have resolved.

Bottom Line

Because delusional parasitosis symptoms feel real to patients, it is crucial to build rapport to recommend and successfully initiate treatment. After ruling out nonpsychiatric etiologies, consider traditional treatment with antipsychotics, and consider medications for relief of pruritus or pain.

Related Resources

• Sellman D, Phan SV, Inyang M. Bugs on her skin—but nobody else sees them. Current Psychiatry. 2018;17(8):48,50-53.
• Campbell EH, Elston DM, Hawthorne JD, et al. Diagnosis and management of delusional parasitosis. J Am Acad Dermatol. 2019;80(5):1428-1434. doi:10.1016/j.jaad.2018.12.012

Drug Brand Names

Buprenorphine/naloxone • Suboxone
Haloperidol • Haldol
Hydroxyzine • Vistaril
Lithium • Eskalith, Lithobid
Methylphenidate • Concerta
Olanzapine • Zyprexa
Permethrin • Elimite
Phenobarbital • Solfoton, Tedral, Luminal
Pimozide • Orap
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Valproic acid • Depakote

CASE Detoxification and preoccupation with parasites

Mr. H, age 51, has an extensive history of alcohol and methamphetamine use. He presents to the emergency department (ED) requesting inpatient detoxification. He says he had been drinking alcohol but is unable to say how much. His blood ethanol level is 61 mg/dL (unintoxicated level: <50 mg/dL), and a urine drug screen is positive for methamphetamine; Mr. H also admits to using fentanyl. The ED team treats Mr. H’s electrolyte abnormalities, initiates thiamine supplementation, and transfers him to a unit for inpatient withdrawal management.

On the detoxification unit, Mr. H receives a total of 1,950 mg of phenobarbital for alcohol withdrawal and stabilizes on a buprenorphine/naloxone maintenance dose of 8 mg/2 mg twice daily for methamphetamine and fentanyl use. Though he was not taking any psychiatric medications prior to his arrival at the ED, Mr. H agrees to restart quetiapine—which he took when he was younger for suspected bipolar depression—50 mg/d at bedtime.

During Mr. H’s 3-day detoxification, the psychiatry team evaluates him. Mr. H says he believes he is infested with worms. He describes a prior sensation of “meth mites,” or the feeling of bugs crawling under his skin, while using methamphetamines. However, Mr. H says his current infestation feels distinctively different, and he had continued to experience these sensations during prior periods of abstinence.

The psychiatry team expresses concern over his preoccupation with infestations, disheveled appearance, poor hygiene, and healed scars from excoriation. Mr. H also reports poor sleep and appetite and was observed writing an incomprehensible “experiment” on a paper towel. Due to his bizarre behavior, delusional thoughts, and concerns about his inability to care for himself, the team admits Mr. H to the acute inpatient psychiatric unit on a voluntary commitment.

HISTORY Long-standing drug use and repeated hospital visits

Mr. H reports a history of drug use. His first documented ED visit was >5 years before his current admission. He has a family history of substance abuse and reports previously using methamphetamine, heroin, and alcohol. Mr. H was never diagnosed with a psychiatric illness, but when he was younger, there were suspicions of bipolar depression, with no contributing family psychiatric history. Though he took quetiapine at an unspecified younger age, Mr. H did not follow through with any outpatient mental health services or medications.

Mr. H first reported infestation symptoms 6 months before his current inpatient admission, when he came to the ED with complaints of bumps on his arms and legs and reported seeing bugs in his carpet. He was prescribed permethrin 5% topical cream for suspected bedbug infestation.

In the 6 months prior to his current admission, Mr. H came to the hospital >20 times for various reasons, including methamphetamine abuse, alcohol withdrawal, opiate overdose, cellulitis, wound checks, and 3 visits for hallucinations for which he requested physical evaluation and medical care. His substance use was the suspected cause of his tactile and visual hallucinations of infestation because formication—the sensation of something crawling on your skin—is commonly associated with substance use. Although the etiology of Mr. H’s hallucinations was unclear, his substance use may have either precipitated them, or, as the team suspects, masked an underlying pathology that eventually became more evident and required psychiatric treatment.

Continue to: The authors' observations

The authors’ observations

Delusional parasitosis (DP), also known as delusional infestation or Ekbom Syndrome, is a condition characterized by the fixed, false belief of an infestation without any objective evidence. This condition was previously defined in DSM-IV, but was removed from DSM-5-TR. In DSM-5-TR, DP is most closely associated with delusional disorder—somatic type (Table 1¹). It describes a patient with ≥1 month of delusions who does not meet the criteria for schizophrenia with a central theme of delusions involving bodily functions or sensations such as infestation of insects or internal parasites.¹

DP is rare, affecting approximately 1.9 per 100,000 people. There has not been consistent data supporting differences in prevalence between sexes, but there is evidence for increasing incidence with age, with a mean age of diagnosis of 61.4.^2,3 DP can be divided into 2 types based on the history and etiology of the symptoms: primary DP and secondary DP. Primary DP occurs when there is a failure to identify an organic cause for the occurrence of the symptoms. Therefore, primary DP requires an extensive investigation by a multidisciplinary team that commonly includes medical specialists for a nonpsychiatric workup. Secondary DP occurs when the patient has delusional symptoms associated with a primary diagnosis of schizophrenia, depression, stroke, diabetes, vitamin B12 deficiency, or substance use.⁴

Though Mr. H initially presented to the ED, patients with DP commonly present to a primary care physician or dermatologist with the complaint of itching or feelings of insects, worms, or unclear organisms inside them. Patients with DP may often develop poor working relationships with physicians while obtaining multiple negative results. They may seek opinions from multiple specialists; however, patients typically do not consider psychiatrists as a source of help. When patients seek psychiatric care, often after a recommendation from a primary care physician or dermatologist, mental health clinicians should listen to and evaluate the patient holistically, continuing to rule out other possible etiologies.

[polldaddy:12570072]

TREATMENT Finding the right antipsychotic

In the psychiatric unit, Mr. H says he believes worms are exiting his ears, mouth, toenail, and self-inflicted scratch wounds. He believes he has been dealing with the parasites for >1 year and they are slowly draining his energy. Mr. H insists he contracted the “infection” from his home carpet, which was wet due to a flood in his house, and after he had fallen asleep following drug use. He also believes he acquired the parasites while walking barefoot along the beach and collecting rocks, and that there are multiple species living inside him, all intelligent enough to hide, making it difficult to prove their existence. He notes they vary in size, and some have red eyes.

During admission, Mr. H voices his frustration that clinicians had not found the worms he has been seeing. He continuously requests to review imaging performed during his visit and wants a multidisciplinary team to evaluate his case. He demands to test a cup with spit-up “samples,” believing the parasites would be visible under a microscope. Throughout his admission, Mr. H continues to take buprenorphine/naloxone and does not experience withdrawal symptoms. The treatment team titrates his quetiapine to 400 mg/d. Due to the lack of improvement, the team initiates olanzapine 5 mg/d at bedtime. However, Mr. H reports significant tinnitus and requests a medication change. He is started on haloperidol 5 mg twice daily.

Continue to: Mr. H begins to see improvements...

Mr. H begins to see improvements on Day 7 of taking haloperidol. He no longer brings up infestation but still acknowledges having worms inside him when directly asked. He says the worms cause him less distress than before and he is hopeful to live without discomfort. He also demonstrates an ability to conduct activities of daily living. Because Mr. H is being monitored on an acute inpatient psychiatric basis, he is deemed appropriate for discharge even though his symptoms have not yet fully resolved. After a 19-day hospital stay, Mr. H is discharged on haloperidol 15 mg/d and quetiapine 200 mg/d.

[polldaddy:12570074]

The authors’ observations

Mr. H asked to have his sputum examined. The “specimen sign,” also called “matchbox sign” or “Ziploc bag sign,” in which patients collect what they believe to be infected tissue or organisms in a container, is a well-studied part of DP.⁵ Such samples should be considered during initial encounters and can be examined for formal evaluation, but cautiously. Overtesting may incur a financial burden or reinforce deleterious beliefs and behaviors.

It can be difficult to identify triggers of DP. Research shows DP may arise from nonorganic and stressful life events, home floods, or contact with people infected with parasites.^6,7 Organic causes have also been found, such as patients taking multiple medications for Parkinson disease who developed delusional symptoms.⁸ Buscarino et al⁹ reported the case of a woman who started to develop symptoms of delusions and hallucinations after being on high-dose amphetamines for attention-deficit/hyperactivity disorder. Research shows that stopping the suspected medication commonly improves such symptoms.^9,10 Although methamphetamine can remain detectable in urine for up to 4 days after use and potentially a few days longer for chronic users due to circulating levels,¹¹ Mr. H’s symptoms continued for weeks after all substances of abuse should have been cleared from his system. This suggests he was experiencing a psychiatric illness and was accurate in distinguishing methamphetamine-induced from psychiatric-induced sensations. Regardless, polysubstance use has been shown to potentially increase the risk and play a role in the onset and progression of delusional illness, as seen in prior cases as well as in this case.⁹

It has been hypothesized that the pathophysiology of DP is associated with the deterioration of the striatal dopaminergic pathway, leading to an increase in extracellular dopamine levels. The striatum is responsible for most dopamine reuptake in the brain; therefore, certain drugs such as cocaine, methamphetamine, and methyl­phenidate may precipitate symptoms of DP due to their blockade of presynaptic dopamine reuptake.¹² Additionally, conditions that decrease the functioning of striatal dopamine transporters, such as schizophrenia or depression, may be underlying causes of DP.¹³

Treatment of DP remains a topic of debate. Most current recommendations appear to be based on a small, nonrandomized placebo-controlled trial.¹⁴ The first-generation antipsychotic pimozide had been a first-line treatment for DP, but its adverse effect profile, which includes QTc prolongation and extrapyramidal symptoms, led to the exploration of second-generation antipsychotics such as olanzapine and risperidone.^15,16 There is a dearth of literature about the use of haloperidol, quetiapine, or a combination of both as treatment options for DP, though the combination of these 2 medications proved effective for Mr. H. Further research is necessary to justify changes to current treatment standards, but this finding highlights a successful symptom reduction achieved with this combination.

Continue to: Patients may experience genuine symptoms...

Patients may experience genuine symptoms despite the delusional nature of DP, and it is important for clinicians to recognize the potential burden and anxiety these individuals face. Patients may present with self-inflicted bruises, cuts, and erosions to gain access to infected areas, which may be confused with skin picking disorder. Excessive cleansing or use of irritant products can also cause skin damage, leading to other dermatological conditions that reinforce the patient’s belief that something is medically wrong. During treatment, consider medications for relief of pruritus or pain. Focus on offering patients the opportunity to express their concerns, treat them with empathy, avoid stigmatizing language such as “delusions” or “psychosis,” and refrain from contradicting them until a strong rapport has been established (Table 2¹⁷).

Symptoms of DP can persist for months to years. Patients who fully recovered experienced a median duration of 0.5 years until symptom resolution, compared to incompletely recovered patients, who took approximately 1 year.¹⁸ Primary DP has slower improvement rates compared to secondary DP, with the median onset of effects occurring at Week 1.5 and peak improvements occurring at Week 6.¹⁶

OUTCOME Continued ED visits

Unfortunately, Mr. H does not follow through with his outpatient psychiatry appointments. In the 7 months following discharge, he visits the ED 8 times for alcohol intoxication, alcohol withdrawal, and methamphetamine abuse, in addition to 2 admissions for inpatient detoxification, during which he was still receiving the same scheduled medications (haloperidol 15 mg/d and quetiapine 200 mg/d). At each of his ED visits, there was no documentation of DP symptoms, which suggests his symptoms may have resolved.

Bottom Line

Because delusional parasitosis symptoms feel real to patients, it is crucial to build rapport to recommend and successfully initiate treatment. After ruling out nonpsychiatric etiologies, consider traditional treatment with antipsychotics, and consider medications for relief of pruritus or pain.

Related Resources

• Sellman D, Phan SV, Inyang M. Bugs on her skin—but nobody else sees them. Current Psychiatry. 2018;17(8):48,50-53.
• Campbell EH, Elston DM, Hawthorne JD, et al. Diagnosis and management of delusional parasitosis. J Am Acad Dermatol. 2019;80(5):1428-1434. doi:10.1016/j.jaad.2018.12.012

Drug Brand Names

Buprenorphine/naloxone • Suboxone
Haloperidol • Haldol
Hydroxyzine • Vistaril
Lithium • Eskalith, Lithobid
Methylphenidate • Concerta
Olanzapine • Zyprexa
Permethrin • Elimite
Phenobarbital • Solfoton, Tedral, Luminal
Pimozide • Orap
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Valproic acid • Depakote

CASE Detoxification and preoccupation with parasites

Mr. H, age 51, has an extensive history of alcohol and methamphetamine use. He presents to the emergency department (ED) requesting inpatient detoxification. He says he had been drinking alcohol but is unable to say how much. His blood ethanol level is 61 mg/dL (unintoxicated level: <50 mg/dL), and a urine drug screen is positive for methamphetamine; Mr. H also admits to using fentanyl. The ED team treats Mr. H’s electrolyte abnormalities, initiates thiamine supplementation, and transfers him to a unit for inpatient withdrawal management.

On the detoxification unit, Mr. H receives a total of 1,950 mg of phenobarbital for alcohol withdrawal and stabilizes on a buprenorphine/naloxone maintenance dose of 8 mg/2 mg twice daily for methamphetamine and fentanyl use. Though he was not taking any psychiatric medications prior to his arrival at the ED, Mr. H agrees to restart quetiapine—which he took when he was younger for suspected bipolar depression—50 mg/d at bedtime.

During Mr. H’s 3-day detoxification, the psychiatry team evaluates him. Mr. H says he believes he is infested with worms. He describes a prior sensation of “meth mites,” or the feeling of bugs crawling under his skin, while using methamphetamines. However, Mr. H says his current infestation feels distinctively different, and he had continued to experience these sensations during prior periods of abstinence.

The psychiatry team expresses concern over his preoccupation with infestations, disheveled appearance, poor hygiene, and healed scars from excoriation. Mr. H also reports poor sleep and appetite and was observed writing an incomprehensible “experiment” on a paper towel. Due to his bizarre behavior, delusional thoughts, and concerns about his inability to care for himself, the team admits Mr. H to the acute inpatient psychiatric unit on a voluntary commitment.

HISTORY Long-standing drug use and repeated hospital visits

Mr. H reports a history of drug use. His first documented ED visit was >5 years before his current admission. He has a family history of substance abuse and reports previously using methamphetamine, heroin, and alcohol. Mr. H was never diagnosed with a psychiatric illness, but when he was younger, there were suspicions of bipolar depression, with no contributing family psychiatric history. Though he took quetiapine at an unspecified younger age, Mr. H did not follow through with any outpatient mental health services or medications.

Mr. H first reported infestation symptoms 6 months before his current inpatient admission, when he came to the ED with complaints of bumps on his arms and legs and reported seeing bugs in his carpet. He was prescribed permethrin 5% topical cream for suspected bedbug infestation.

In the 6 months prior to his current admission, Mr. H came to the hospital >20 times for various reasons, including methamphetamine abuse, alcohol withdrawal, opiate overdose, cellulitis, wound checks, and 3 visits for hallucinations for which he requested physical evaluation and medical care. His substance use was the suspected cause of his tactile and visual hallucinations of infestation because formication—the sensation of something crawling on your skin—is commonly associated with substance use. Although the etiology of Mr. H’s hallucinations was unclear, his substance use may have either precipitated them, or, as the team suspects, masked an underlying pathology that eventually became more evident and required psychiatric treatment.

Continue to: The authors' observations

The authors’ observations

Delusional parasitosis (DP), also known as delusional infestation or Ekbom Syndrome, is a condition characterized by the fixed, false belief of an infestation without any objective evidence. This condition was previously defined in DSM-IV, but was removed from DSM-5-TR. In DSM-5-TR, DP is most closely associated with delusional disorder—somatic type (Table 1¹). It describes a patient with ≥1 month of delusions who does not meet the criteria for schizophrenia with a central theme of delusions involving bodily functions or sensations such as infestation of insects or internal parasites.¹

DP is rare, affecting approximately 1.9 per 100,000 people. There has not been consistent data supporting differences in prevalence between sexes, but there is evidence for increasing incidence with age, with a mean age of diagnosis of 61.4.^2,3 DP can be divided into 2 types based on the history and etiology of the symptoms: primary DP and secondary DP. Primary DP occurs when there is a failure to identify an organic cause for the occurrence of the symptoms. Therefore, primary DP requires an extensive investigation by a multidisciplinary team that commonly includes medical specialists for a nonpsychiatric workup. Secondary DP occurs when the patient has delusional symptoms associated with a primary diagnosis of schizophrenia, depression, stroke, diabetes, vitamin B12 deficiency, or substance use.⁴

Though Mr. H initially presented to the ED, patients with DP commonly present to a primary care physician or dermatologist with the complaint of itching or feelings of insects, worms, or unclear organisms inside them. Patients with DP may often develop poor working relationships with physicians while obtaining multiple negative results. They may seek opinions from multiple specialists; however, patients typically do not consider psychiatrists as a source of help. When patients seek psychiatric care, often after a recommendation from a primary care physician or dermatologist, mental health clinicians should listen to and evaluate the patient holistically, continuing to rule out other possible etiologies.

[polldaddy:12570072]

TREATMENT Finding the right antipsychotic

In the psychiatric unit, Mr. H says he believes worms are exiting his ears, mouth, toenail, and self-inflicted scratch wounds. He believes he has been dealing with the parasites for >1 year and they are slowly draining his energy. Mr. H insists he contracted the “infection” from his home carpet, which was wet due to a flood in his house, and after he had fallen asleep following drug use. He also believes he acquired the parasites while walking barefoot along the beach and collecting rocks, and that there are multiple species living inside him, all intelligent enough to hide, making it difficult to prove their existence. He notes they vary in size, and some have red eyes.

During admission, Mr. H voices his frustration that clinicians had not found the worms he has been seeing. He continuously requests to review imaging performed during his visit and wants a multidisciplinary team to evaluate his case. He demands to test a cup with spit-up “samples,” believing the parasites would be visible under a microscope. Throughout his admission, Mr. H continues to take buprenorphine/naloxone and does not experience withdrawal symptoms. The treatment team titrates his quetiapine to 400 mg/d. Due to the lack of improvement, the team initiates olanzapine 5 mg/d at bedtime. However, Mr. H reports significant tinnitus and requests a medication change. He is started on haloperidol 5 mg twice daily.

Continue to: Mr. H begins to see improvements...

Mr. H begins to see improvements on Day 7 of taking haloperidol. He no longer brings up infestation but still acknowledges having worms inside him when directly asked. He says the worms cause him less distress than before and he is hopeful to live without discomfort. He also demonstrates an ability to conduct activities of daily living. Because Mr. H is being monitored on an acute inpatient psychiatric basis, he is deemed appropriate for discharge even though his symptoms have not yet fully resolved. After a 19-day hospital stay, Mr. H is discharged on haloperidol 15 mg/d and quetiapine 200 mg/d.

[polldaddy:12570074]

The authors’ observations

Mr. H asked to have his sputum examined. The “specimen sign,” also called “matchbox sign” or “Ziploc bag sign,” in which patients collect what they believe to be infected tissue or organisms in a container, is a well-studied part of DP.⁵ Such samples should be considered during initial encounters and can be examined for formal evaluation, but cautiously. Overtesting may incur a financial burden or reinforce deleterious beliefs and behaviors.

It can be difficult to identify triggers of DP. Research shows DP may arise from nonorganic and stressful life events, home floods, or contact with people infected with parasites.^6,7 Organic causes have also been found, such as patients taking multiple medications for Parkinson disease who developed delusional symptoms.⁸ Buscarino et al⁹ reported the case of a woman who started to develop symptoms of delusions and hallucinations after being on high-dose amphetamines for attention-deficit/hyperactivity disorder. Research shows that stopping the suspected medication commonly improves such symptoms.^9,10 Although methamphetamine can remain detectable in urine for up to 4 days after use and potentially a few days longer for chronic users due to circulating levels,¹¹ Mr. H’s symptoms continued for weeks after all substances of abuse should have been cleared from his system. This suggests he was experiencing a psychiatric illness and was accurate in distinguishing methamphetamine-induced from psychiatric-induced sensations. Regardless, polysubstance use has been shown to potentially increase the risk and play a role in the onset and progression of delusional illness, as seen in prior cases as well as in this case.⁹

It has been hypothesized that the pathophysiology of DP is associated with the deterioration of the striatal dopaminergic pathway, leading to an increase in extracellular dopamine levels. The striatum is responsible for most dopamine reuptake in the brain; therefore, certain drugs such as cocaine, methamphetamine, and methyl­phenidate may precipitate symptoms of DP due to their blockade of presynaptic dopamine reuptake.¹² Additionally, conditions that decrease the functioning of striatal dopamine transporters, such as schizophrenia or depression, may be underlying causes of DP.¹³

Treatment of DP remains a topic of debate. Most current recommendations appear to be based on a small, nonrandomized placebo-controlled trial.¹⁴ The first-generation antipsychotic pimozide had been a first-line treatment for DP, but its adverse effect profile, which includes QTc prolongation and extrapyramidal symptoms, led to the exploration of second-generation antipsychotics such as olanzapine and risperidone.^15,16 There is a dearth of literature about the use of haloperidol, quetiapine, or a combination of both as treatment options for DP, though the combination of these 2 medications proved effective for Mr. H. Further research is necessary to justify changes to current treatment standards, but this finding highlights a successful symptom reduction achieved with this combination.

Continue to: Patients may experience genuine symptoms...

Patients may experience genuine symptoms despite the delusional nature of DP, and it is important for clinicians to recognize the potential burden and anxiety these individuals face. Patients may present with self-inflicted bruises, cuts, and erosions to gain access to infected areas, which may be confused with skin picking disorder. Excessive cleansing or use of irritant products can also cause skin damage, leading to other dermatological conditions that reinforce the patient’s belief that something is medically wrong. During treatment, consider medications for relief of pruritus or pain. Focus on offering patients the opportunity to express their concerns, treat them with empathy, avoid stigmatizing language such as “delusions” or “psychosis,” and refrain from contradicting them until a strong rapport has been established (Table 2¹⁷).

Symptoms of DP can persist for months to years. Patients who fully recovered experienced a median duration of 0.5 years until symptom resolution, compared to incompletely recovered patients, who took approximately 1 year.¹⁸ Primary DP has slower improvement rates compared to secondary DP, with the median onset of effects occurring at Week 1.5 and peak improvements occurring at Week 6.¹⁶

OUTCOME Continued ED visits

Unfortunately, Mr. H does not follow through with his outpatient psychiatry appointments. In the 7 months following discharge, he visits the ED 8 times for alcohol intoxication, alcohol withdrawal, and methamphetamine abuse, in addition to 2 admissions for inpatient detoxification, during which he was still receiving the same scheduled medications (haloperidol 15 mg/d and quetiapine 200 mg/d). At each of his ED visits, there was no documentation of DP symptoms, which suggests his symptoms may have resolved.

Bottom Line

Because delusional parasitosis symptoms feel real to patients, it is crucial to build rapport to recommend and successfully initiate treatment. After ruling out nonpsychiatric etiologies, consider traditional treatment with antipsychotics, and consider medications for relief of pruritus or pain.

Related Resources

• Sellman D, Phan SV, Inyang M. Bugs on her skin—but nobody else sees them. Current Psychiatry. 2018;17(8):48,50-53.
• Campbell EH, Elston DM, Hawthorne JD, et al. Diagnosis and management of delusional parasitosis. J Am Acad Dermatol. 2019;80(5):1428-1434. doi:10.1016/j.jaad.2018.12.012

Drug Brand Names

Buprenorphine/naloxone • Suboxone
Haloperidol • Haldol
Hydroxyzine • Vistaril
Lithium • Eskalith, Lithobid
Methylphenidate • Concerta
Olanzapine • Zyprexa
Permethrin • Elimite
Phenobarbital • Solfoton, Tedral, Luminal
Pimozide • Orap
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Valproic acid • Depakote

Perinatal mood and anxiety disorders are the most common complication of pregnancy and childbirth.¹ Mental health concerns are a leading cause of maternal mortality in the United States, which has rising maternal mortality rates and glaring racial and socioeconomic disparities.² Inconsistent perinatal psychiatry training likely contributes to perceived discomfort of patients who are pregnant.³ This is why it is critical for all psychiatrists to understand the principles of perinatal psychiatry. Here is a brief description of 5 key principles.

1. Discuss preconception planning

Reproductive life planning should occur with all patients who are capable of becoming pregnant. This planning should include not just a risks/benefits analysis and anticipatory planning regarding medications but also a discussion of prior perinatal symptoms, pregnancy intentions and contraception (especially in light of increasingly limited access to abortion), and the bidirectional nature of pregnancy and mental health conditions.

The acronym PATH provides a framework for these conversations:

• Pregnancy Attitudes: “Do you think you might like to have (more) children at some point?”
• Timing: “If considering future parenthood, when do you think that might be?”
• How important is prevention: “How important is it to you to prevent pregnancy (until then)?”⁴

2. Focus on perinatal mental health

Discussion often centers on medication risks to the fetus at the expense of considering risks of under- or nontreatment for both members of the dyad. Undertreating perinatal mental health conditions results in dual exposures (medication and illness), and untreated illness is associated with negative effects on obstetric and neonatal outcomes and the well-being of the parent and offspring.¹

3. Resist experimentation

It is common for clinicians to reflexively switch patients who are pregnant from an effective medication to one viewed as the “safest” or “best” because it has more data. This exposes the fetus to 2 medications and the dyad to potential symptoms of the illness. Decisions about medication changes should instead be made on an individual basis considering the risks and benefits of all exposures as well as the patient’s current symptoms, previous treatment, and family history.

4. Collaborate and communicate

Despite effective interventions, many perinatal mental health conditions go untreated.¹ Normalize perinatal mental health symptoms with patients to reduce stigma and barriers to disclosure, and respect their decisions regarding perinatal medication use. Proper communication with the obstetric team ensures appropriate perinatal mental health screening and fetal monitoring (eg, possible fetal growth ultrasounds for a patient taking prazosin, or assessing for neonatal adaptation syndrome if there is selective serotonin reuptake inhibitor exposure in utero).

5. Recognize your limitations

Our understanding of psychotropics’ teratogenicity is constantly evolving, and we must recognize when we don’t know something. In addition to medication databases such as Reprotox (https://reprotox.org/) and LactMed (https://www.ncbi.nlm.nih.gov/books/NBK501922/), several perinatal psychiatry resources are available for both patients and clinicians (Table). Additionally, Postpartum Support International maintains a National Perinatal Consult Line (1-877-499-4773) as well as a list of state perinatal psychiatry access lines (https://www.postpartum.net/professionals/state-perinatal-psychiatry-access-lines/) for clinicians. The Massachusetts General Hospital Center for Women’s Mental Health (https://womensmentalhealth.org) is also a helpful resource for clinicians.

Perinatal mood and anxiety disorders are the most common complication of pregnancy and childbirth.¹ Mental health concerns are a leading cause of maternal mortality in the United States, which has rising maternal mortality rates and glaring racial and socioeconomic disparities.² Inconsistent perinatal psychiatry training likely contributes to perceived discomfort of patients who are pregnant.³ This is why it is critical for all psychiatrists to understand the principles of perinatal psychiatry. Here is a brief description of 5 key principles.

1. Discuss preconception planning

Reproductive life planning should occur with all patients who are capable of becoming pregnant. This planning should include not just a risks/benefits analysis and anticipatory planning regarding medications but also a discussion of prior perinatal symptoms, pregnancy intentions and contraception (especially in light of increasingly limited access to abortion), and the bidirectional nature of pregnancy and mental health conditions.

The acronym PATH provides a framework for these conversations:

• Pregnancy Attitudes: “Do you think you might like to have (more) children at some point?”
• Timing: “If considering future parenthood, when do you think that might be?”
• How important is prevention: “How important is it to you to prevent pregnancy (until then)?”⁴

2. Focus on perinatal mental health

Discussion often centers on medication risks to the fetus at the expense of considering risks of under- or nontreatment for both members of the dyad. Undertreating perinatal mental health conditions results in dual exposures (medication and illness), and untreated illness is associated with negative effects on obstetric and neonatal outcomes and the well-being of the parent and offspring.¹

3. Resist experimentation

It is common for clinicians to reflexively switch patients who are pregnant from an effective medication to one viewed as the “safest” or “best” because it has more data. This exposes the fetus to 2 medications and the dyad to potential symptoms of the illness. Decisions about medication changes should instead be made on an individual basis considering the risks and benefits of all exposures as well as the patient’s current symptoms, previous treatment, and family history.

4. Collaborate and communicate

Despite effective interventions, many perinatal mental health conditions go untreated.¹ Normalize perinatal mental health symptoms with patients to reduce stigma and barriers to disclosure, and respect their decisions regarding perinatal medication use. Proper communication with the obstetric team ensures appropriate perinatal mental health screening and fetal monitoring (eg, possible fetal growth ultrasounds for a patient taking prazosin, or assessing for neonatal adaptation syndrome if there is selective serotonin reuptake inhibitor exposure in utero).

5. Recognize your limitations

Our understanding of psychotropics’ teratogenicity is constantly evolving, and we must recognize when we don’t know something. In addition to medication databases such as Reprotox (https://reprotox.org/) and LactMed (https://www.ncbi.nlm.nih.gov/books/NBK501922/), several perinatal psychiatry resources are available for both patients and clinicians (Table). Additionally, Postpartum Support International maintains a National Perinatal Consult Line (1-877-499-4773) as well as a list of state perinatal psychiatry access lines (https://www.postpartum.net/professionals/state-perinatal-psychiatry-access-lines/) for clinicians. The Massachusetts General Hospital Center for Women’s Mental Health (https://womensmentalhealth.org) is also a helpful resource for clinicians.

Perinatal mood and anxiety disorders are the most common complication of pregnancy and childbirth.¹ Mental health concerns are a leading cause of maternal mortality in the United States, which has rising maternal mortality rates and glaring racial and socioeconomic disparities.² Inconsistent perinatal psychiatry training likely contributes to perceived discomfort of patients who are pregnant.³ This is why it is critical for all psychiatrists to understand the principles of perinatal psychiatry. Here is a brief description of 5 key principles.

1. Discuss preconception planning

Reproductive life planning should occur with all patients who are capable of becoming pregnant. This planning should include not just a risks/benefits analysis and anticipatory planning regarding medications but also a discussion of prior perinatal symptoms, pregnancy intentions and contraception (especially in light of increasingly limited access to abortion), and the bidirectional nature of pregnancy and mental health conditions.

The acronym PATH provides a framework for these conversations:

• Pregnancy Attitudes: “Do you think you might like to have (more) children at some point?”
• Timing: “If considering future parenthood, when do you think that might be?”
• How important is prevention: “How important is it to you to prevent pregnancy (until then)?”⁴

2. Focus on perinatal mental health

Discussion often centers on medication risks to the fetus at the expense of considering risks of under- or nontreatment for both members of the dyad. Undertreating perinatal mental health conditions results in dual exposures (medication and illness), and untreated illness is associated with negative effects on obstetric and neonatal outcomes and the well-being of the parent and offspring.¹

3. Resist experimentation

It is common for clinicians to reflexively switch patients who are pregnant from an effective medication to one viewed as the “safest” or “best” because it has more data. This exposes the fetus to 2 medications and the dyad to potential symptoms of the illness. Decisions about medication changes should instead be made on an individual basis considering the risks and benefits of all exposures as well as the patient’s current symptoms, previous treatment, and family history.

4. Collaborate and communicate

Despite effective interventions, many perinatal mental health conditions go untreated.¹ Normalize perinatal mental health symptoms with patients to reduce stigma and barriers to disclosure, and respect their decisions regarding perinatal medication use. Proper communication with the obstetric team ensures appropriate perinatal mental health screening and fetal monitoring (eg, possible fetal growth ultrasounds for a patient taking prazosin, or assessing for neonatal adaptation syndrome if there is selective serotonin reuptake inhibitor exposure in utero).

5. Recognize your limitations

Our understanding of psychotropics’ teratogenicity is constantly evolving, and we must recognize when we don’t know something. In addition to medication databases such as Reprotox (https://reprotox.org/) and LactMed (https://www.ncbi.nlm.nih.gov/books/NBK501922/), several perinatal psychiatry resources are available for both patients and clinicians (Table). Additionally, Postpartum Support International maintains a National Perinatal Consult Line (1-877-499-4773) as well as a list of state perinatal psychiatry access lines (https://www.postpartum.net/professionals/state-perinatal-psychiatry-access-lines/) for clinicians. The Massachusetts General Hospital Center for Women’s Mental Health (https://womensmentalhealth.org) is also a helpful resource for clinicians.

Borderline personality disorder (BPD) is associated with impaired psychosocial functioning, reduced quality of life, increased use of health care services, and excess mortality.¹ Unfortunately, this disorder is often underrecognized and underdiagnosed, and patients with BPD may not receive an accurate diagnosis for years after first seeking treatment.¹ Problems in diagnosing BPD include:

Stigma. Some patients may view the term “borderline” as stigmatizing, as if we are calling these patients borderline human beings. One of the symptoms of BPD is a “markedly and persistently unstable self-image.”² Such patients do not need a stigmatizing label to worsen their self-image.

Terminology. The word borderline may also imply relatively mild psychiatric symptoms. However, “borderline personality disorder” does not refer to a mild personality disorder. DSM-5 describes potential BPD symptoms as “intense,” “marked,” or “severe,” and 1 of the symptoms is suicidal behavior.²

Symptoms. To meet the criteria for a BPD diagnosis, a patient must exhibit ≥5 of 9 severe symptoms²:

• frantic efforts to avoid abandonment
• unstable and intense interpersonal relationships
• unstable self-image
• impulsivity in ≥2 areas that are potentially self-damaging
• suicidal behavior
• affective instability
• chronic feelings of emptiness
• inappropriate anger
• transient paranoid ideation or dissociative symptoms.

Asking about all 9 of these criteria and their severity is not part of a routine psychiatric evaluation. A patient might not volunteer any of this information because they are concerned about potential stigma. Additionally, perhaps most of the general population has had a “BPD-like” symptom at least once during their lives. This symptom might not have been severe enough to qualify as a true BPD symptom. Clinicians might have difficulty discerning BPD-like symptoms from true BPD symptoms.

Comorbidities. Many patients with BPD also have a comorbid mood disorder or substance use disorder.^1,3 Clinicians might focus on a comorbid diagnosis and not recognize BPD.

Stress. BPD symptoms may become more severe when the patient faces a stressful situation. The BPD symptoms might seem more severe than the stress would warrant.² However, clinicians might blame the BPD symptoms solely on stress and not acknowledge the underlying BPD diagnosis.

Awareness of these factors can help clinicians keep BPD in the differential diagnosis when conducting a psychiatric evaluation, thus reducing the chances of overlooking this serious disorder.

Borderline personality disorder (BPD) is associated with impaired psychosocial functioning, reduced quality of life, increased use of health care services, and excess mortality.¹ Unfortunately, this disorder is often underrecognized and underdiagnosed, and patients with BPD may not receive an accurate diagnosis for years after first seeking treatment.¹ Problems in diagnosing BPD include:

Stigma. Some patients may view the term “borderline” as stigmatizing, as if we are calling these patients borderline human beings. One of the symptoms of BPD is a “markedly and persistently unstable self-image.”² Such patients do not need a stigmatizing label to worsen their self-image.

Terminology. The word borderline may also imply relatively mild psychiatric symptoms. However, “borderline personality disorder” does not refer to a mild personality disorder. DSM-5 describes potential BPD symptoms as “intense,” “marked,” or “severe,” and 1 of the symptoms is suicidal behavior.²

Symptoms. To meet the criteria for a BPD diagnosis, a patient must exhibit ≥5 of 9 severe symptoms²:

• frantic efforts to avoid abandonment
• unstable and intense interpersonal relationships
• unstable self-image
• impulsivity in ≥2 areas that are potentially self-damaging
• suicidal behavior
• affective instability
• chronic feelings of emptiness
• inappropriate anger
• transient paranoid ideation or dissociative symptoms.

Asking about all 9 of these criteria and their severity is not part of a routine psychiatric evaluation. A patient might not volunteer any of this information because they are concerned about potential stigma. Additionally, perhaps most of the general population has had a “BPD-like” symptom at least once during their lives. This symptom might not have been severe enough to qualify as a true BPD symptom. Clinicians might have difficulty discerning BPD-like symptoms from true BPD symptoms.

Comorbidities. Many patients with BPD also have a comorbid mood disorder or substance use disorder.^1,3 Clinicians might focus on a comorbid diagnosis and not recognize BPD.

Stress. BPD symptoms may become more severe when the patient faces a stressful situation. The BPD symptoms might seem more severe than the stress would warrant.² However, clinicians might blame the BPD symptoms solely on stress and not acknowledge the underlying BPD diagnosis.

Awareness of these factors can help clinicians keep BPD in the differential diagnosis when conducting a psychiatric evaluation, thus reducing the chances of overlooking this serious disorder.

Borderline personality disorder (BPD) is associated with impaired psychosocial functioning, reduced quality of life, increased use of health care services, and excess mortality.¹ Unfortunately, this disorder is often underrecognized and underdiagnosed, and patients with BPD may not receive an accurate diagnosis for years after first seeking treatment.¹ Problems in diagnosing BPD include:

Stigma. Some patients may view the term “borderline” as stigmatizing, as if we are calling these patients borderline human beings. One of the symptoms of BPD is a “markedly and persistently unstable self-image.”² Such patients do not need a stigmatizing label to worsen their self-image.

Terminology. The word borderline may also imply relatively mild psychiatric symptoms. However, “borderline personality disorder” does not refer to a mild personality disorder. DSM-5 describes potential BPD symptoms as “intense,” “marked,” or “severe,” and 1 of the symptoms is suicidal behavior.²

Symptoms. To meet the criteria for a BPD diagnosis, a patient must exhibit ≥5 of 9 severe symptoms²:

• frantic efforts to avoid abandonment
• unstable and intense interpersonal relationships
• unstable self-image
• impulsivity in ≥2 areas that are potentially self-damaging
• suicidal behavior
• affective instability
• chronic feelings of emptiness
• inappropriate anger
• transient paranoid ideation or dissociative symptoms.

Asking about all 9 of these criteria and their severity is not part of a routine psychiatric evaluation. A patient might not volunteer any of this information because they are concerned about potential stigma. Additionally, perhaps most of the general population has had a “BPD-like” symptom at least once during their lives. This symptom might not have been severe enough to qualify as a true BPD symptom. Clinicians might have difficulty discerning BPD-like symptoms from true BPD symptoms.

Comorbidities. Many patients with BPD also have a comorbid mood disorder or substance use disorder.^1,3 Clinicians might focus on a comorbid diagnosis and not recognize BPD.

Stress. BPD symptoms may become more severe when the patient faces a stressful situation. The BPD symptoms might seem more severe than the stress would warrant.² However, clinicians might blame the BPD symptoms solely on stress and not acknowledge the underlying BPD diagnosis.

Awareness of these factors can help clinicians keep BPD in the differential diagnosis when conducting a psychiatric evaluation, thus reducing the chances of overlooking this serious disorder.

We appreciate the important review by Gluck et al (“Managing patients with comorbid opioid and alcohol use disorders,” Current Psychiatry, February 2023, p. 20-28, doi:10.12788/cp.0327) addressing the common co-occurrence of opioid use disorder (OUD) and alcohol use disorder (AUD) among hospitalized patients, and we offer a friendly amendment to the algorithm they presented. Early in their algorithm, the authors suggest asking patients whether they want pharmacologic treatment for OUD. We recommend that if the patient affirms interest in OUD medication, the next question should be whether the patient prefers to be opioid-free. If the patient says “yes,” extended-release injectable naltrexone (XR-NTX) is offered. If the patient answers “no,” they can be offered buprenorphine or methadone.

XR-NTX should be considered an equal OUD treatment alternative to buprenorphine-naloxone, especially for patients who prefer an opioid-free option.^1,2 It has the added advantage of being FDA-approved for both AUD and OUD.

One obstacle to the success of XR-NTX is the induction period. The National Institute on Drug Abuse Clinical Trials Network X:BOT trial found that once the induction hurdle was surmounted, XR-NTX and buprenorphine were equally effective in a population of approximately 80% heroin users and two-thirds injection drug users.² Patient variables that predict successful induction include young age, baseline preference for XR-NTX, fewer drug complications, and fewer family/social complications.³ If the length of the induction (usually 7 to 10 days) is a deterrent, a study supported the feasibility of a 5-day outpatient XR-NTX induction.⁴ Further research is needed to improve successful induction for XR-NTX.

Ashmeer Ogbuchi, MD
Karen Drexler, MD
Atlanta, Georgia

References

1. Tanum L, Solli KK, Latif Z, et al. Effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence. JAMA Psychiatry. 2017;74(12):1197-1205. doi:10.1001/ jamapsychiatry.2017.3206

2. Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318. doi:10.1016/s0140-6736(17)32812-x

3. Murphy SM, Jeng PJ, McCollister KE, et al. Cost‐effectiveness implications of increasing the efficiency of the extended‐release naltrexone induction process for the treatment of opioid use disorder: a secondary analysis. Addiction. 2021;116(12)3444-3453. doi:10.1111/add.15531

4. Sibai M, Mishlen K, Nunes EV, et al. A week-long outpatient induction onto XR-naltrexone in patients with opioid use disorder. Am J Drug Alcohol Abuse. 2020;46(3):289-296. doi:10.1080/00952990.2019.1700265

Continue to: The authors respond

We appreciate Drs. Ogbuchi and Drexler for their thoughtful attention to our review. They proposed amending our original algorithm, recommending that XR-NTX be considered as another first-line option for patients with OUD. We agree with this suggestion, particularly for inpatients. However, we have some reservations about applying this suggestion to outpatient treatment. Though research evidence from Lee et al¹ indicates that once initiation is completed, both medications are equally safe and effective, the initial attrition rate in the XR-NTX group was much higher (28% vs 6%, P < .0001), which suggests lower acceptability/tolerability compared with buprenorphine. Notably, the initiation of both medications in Lee et al¹ was done in an inpatient setting. Moreover, although some medications are endorsed as “first-line,” the actual utilization rate is often influenced by many factors, including the ease of treatment initiation. Wakeman et al² found the most common treatment modality received by patients with OUD was nonintensive behavioral health (59.5%), followed by inpatient withdrawal management and residential treatment (15.2%). Among all patients in the Wakeman study,² only 12.5% received buprenorphine or methadone, and 2.4% received naltrexone.

Data from our clinic corroborate this trend. Currently, in our clinic approximately 300 patients with OUD are receiving medications, including approximately 250 on buprenorphine (including 5 to 10 on the long-acting injectable formulation), 50 on methadone, and only 1 or 2 on XR-NTX. Though this disparity may reflect bias in our clinicians’ prescribing practices, in the past few years we have had many unsuccessful attempts at initiating XR-NTX. To our disappointment, a theoretically excellent medication has not translated clinically. The recent surge in fentanyl use further complicates XR-NTX initiation for OUD, because the length of induction may be longer.

In conclusion, we agree that XR-NTX is a potential treatment option for patients with OUD, but clinicians should be cognizant of the potential barriers; inform patients of the advantages, expectations, and challenges; and respect patients’ informed decisions.

Rachel Gluck, MD
Karen Hochman, MD
Yi-lang Tang, MD, PhD
Atlanta, Georgia

References

1. Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318. doi:10.1016/s0140-6736(17)32812-x

2. Wakeman SE, Larochelle MR, Ameli O, et al. Comparative effectiveness of different treatment pathways for opioid use disorder. JAMA Netw Open. 2020;3(2):e1920622. doi:10.1001/jamanetworkopen.2019.20622

We appreciate the important review by Gluck et al (“Managing patients with comorbid opioid and alcohol use disorders,” Current Psychiatry, February 2023, p. 20-28, doi:10.12788/cp.0327) addressing the common co-occurrence of opioid use disorder (OUD) and alcohol use disorder (AUD) among hospitalized patients, and we offer a friendly amendment to the algorithm they presented. Early in their algorithm, the authors suggest asking patients whether they want pharmacologic treatment for OUD. We recommend that if the patient affirms interest in OUD medication, the next question should be whether the patient prefers to be opioid-free. If the patient says “yes,” extended-release injectable naltrexone (XR-NTX) is offered. If the patient answers “no,” they can be offered buprenorphine or methadone.

XR-NTX should be considered an equal OUD treatment alternative to buprenorphine-naloxone, especially for patients who prefer an opioid-free option.^1,2 It has the added advantage of being FDA-approved for both AUD and OUD.

One obstacle to the success of XR-NTX is the induction period. The National Institute on Drug Abuse Clinical Trials Network X:BOT trial found that once the induction hurdle was surmounted, XR-NTX and buprenorphine were equally effective in a population of approximately 80% heroin users and two-thirds injection drug users.² Patient variables that predict successful induction include young age, baseline preference for XR-NTX, fewer drug complications, and fewer family/social complications.³ If the length of the induction (usually 7 to 10 days) is a deterrent, a study supported the feasibility of a 5-day outpatient XR-NTX induction.⁴ Further research is needed to improve successful induction for XR-NTX.

Ashmeer Ogbuchi, MD
Karen Drexler, MD
Atlanta, Georgia

References

1. Tanum L, Solli KK, Latif Z, et al. Effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence. JAMA Psychiatry. 2017;74(12):1197-1205. doi:10.1001/ jamapsychiatry.2017.3206

2. Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318. doi:10.1016/s0140-6736(17)32812-x

3. Murphy SM, Jeng PJ, McCollister KE, et al. Cost‐effectiveness implications of increasing the efficiency of the extended‐release naltrexone induction process for the treatment of opioid use disorder: a secondary analysis. Addiction. 2021;116(12)3444-3453. doi:10.1111/add.15531

4. Sibai M, Mishlen K, Nunes EV, et al. A week-long outpatient induction onto XR-naltrexone in patients with opioid use disorder. Am J Drug Alcohol Abuse. 2020;46(3):289-296. doi:10.1080/00952990.2019.1700265

Continue to: The authors respond

We appreciate Drs. Ogbuchi and Drexler for their thoughtful attention to our review. They proposed amending our original algorithm, recommending that XR-NTX be considered as another first-line option for patients with OUD. We agree with this suggestion, particularly for inpatients. However, we have some reservations about applying this suggestion to outpatient treatment. Though research evidence from Lee et al¹ indicates that once initiation is completed, both medications are equally safe and effective, the initial attrition rate in the XR-NTX group was much higher (28% vs 6%, P < .0001), which suggests lower acceptability/tolerability compared with buprenorphine. Notably, the initiation of both medications in Lee et al¹ was done in an inpatient setting. Moreover, although some medications are endorsed as “first-line,” the actual utilization rate is often influenced by many factors, including the ease of treatment initiation. Wakeman et al² found the most common treatment modality received by patients with OUD was nonintensive behavioral health (59.5%), followed by inpatient withdrawal management and residential treatment (15.2%). Among all patients in the Wakeman study,² only 12.5% received buprenorphine or methadone, and 2.4% received naltrexone.

Data from our clinic corroborate this trend. Currently, in our clinic approximately 300 patients with OUD are receiving medications, including approximately 250 on buprenorphine (including 5 to 10 on the long-acting injectable formulation), 50 on methadone, and only 1 or 2 on XR-NTX. Though this disparity may reflect bias in our clinicians’ prescribing practices, in the past few years we have had many unsuccessful attempts at initiating XR-NTX. To our disappointment, a theoretically excellent medication has not translated clinically. The recent surge in fentanyl use further complicates XR-NTX initiation for OUD, because the length of induction may be longer.

In conclusion, we agree that XR-NTX is a potential treatment option for patients with OUD, but clinicians should be cognizant of the potential barriers; inform patients of the advantages, expectations, and challenges; and respect patients’ informed decisions.

Rachel Gluck, MD
Karen Hochman, MD
Yi-lang Tang, MD, PhD
Atlanta, Georgia

References

1. Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318. doi:10.1016/s0140-6736(17)32812-x

2. Wakeman SE, Larochelle MR, Ameli O, et al. Comparative effectiveness of different treatment pathways for opioid use disorder. JAMA Netw Open. 2020;3(2):e1920622. doi:10.1001/jamanetworkopen.2019.20622

We appreciate the important review by Gluck et al (“Managing patients with comorbid opioid and alcohol use disorders,” Current Psychiatry, February 2023, p. 20-28, doi:10.12788/cp.0327) addressing the common co-occurrence of opioid use disorder (OUD) and alcohol use disorder (AUD) among hospitalized patients, and we offer a friendly amendment to the algorithm they presented. Early in their algorithm, the authors suggest asking patients whether they want pharmacologic treatment for OUD. We recommend that if the patient affirms interest in OUD medication, the next question should be whether the patient prefers to be opioid-free. If the patient says “yes,” extended-release injectable naltrexone (XR-NTX) is offered. If the patient answers “no,” they can be offered buprenorphine or methadone.

XR-NTX should be considered an equal OUD treatment alternative to buprenorphine-naloxone, especially for patients who prefer an opioid-free option.^1,2 It has the added advantage of being FDA-approved for both AUD and OUD.

One obstacle to the success of XR-NTX is the induction period. The National Institute on Drug Abuse Clinical Trials Network X:BOT trial found that once the induction hurdle was surmounted, XR-NTX and buprenorphine were equally effective in a population of approximately 80% heroin users and two-thirds injection drug users.² Patient variables that predict successful induction include young age, baseline preference for XR-NTX, fewer drug complications, and fewer family/social complications.³ If the length of the induction (usually 7 to 10 days) is a deterrent, a study supported the feasibility of a 5-day outpatient XR-NTX induction.⁴ Further research is needed to improve successful induction for XR-NTX.

Ashmeer Ogbuchi, MD
Karen Drexler, MD
Atlanta, Georgia

References

1. Tanum L, Solli KK, Latif Z, et al. Effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence. JAMA Psychiatry. 2017;74(12):1197-1205. doi:10.1001/ jamapsychiatry.2017.3206

2. Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318. doi:10.1016/s0140-6736(17)32812-x

3. Murphy SM, Jeng PJ, McCollister KE, et al. Cost‐effectiveness implications of increasing the efficiency of the extended‐release naltrexone induction process for the treatment of opioid use disorder: a secondary analysis. Addiction. 2021;116(12)3444-3453. doi:10.1111/add.15531

4. Sibai M, Mishlen K, Nunes EV, et al. A week-long outpatient induction onto XR-naltrexone in patients with opioid use disorder. Am J Drug Alcohol Abuse. 2020;46(3):289-296. doi:10.1080/00952990.2019.1700265

Continue to: The authors respond

We appreciate Drs. Ogbuchi and Drexler for their thoughtful attention to our review. They proposed amending our original algorithm, recommending that XR-NTX be considered as another first-line option for patients with OUD. We agree with this suggestion, particularly for inpatients. However, we have some reservations about applying this suggestion to outpatient treatment. Though research evidence from Lee et al¹ indicates that once initiation is completed, both medications are equally safe and effective, the initial attrition rate in the XR-NTX group was much higher (28% vs 6%, P < .0001), which suggests lower acceptability/tolerability compared with buprenorphine. Notably, the initiation of both medications in Lee et al¹ was done in an inpatient setting. Moreover, although some medications are endorsed as “first-line,” the actual utilization rate is often influenced by many factors, including the ease of treatment initiation. Wakeman et al² found the most common treatment modality received by patients with OUD was nonintensive behavioral health (59.5%), followed by inpatient withdrawal management and residential treatment (15.2%). Among all patients in the Wakeman study,² only 12.5% received buprenorphine or methadone, and 2.4% received naltrexone.

Data from our clinic corroborate this trend. Currently, in our clinic approximately 300 patients with OUD are receiving medications, including approximately 250 on buprenorphine (including 5 to 10 on the long-acting injectable formulation), 50 on methadone, and only 1 or 2 on XR-NTX. Though this disparity may reflect bias in our clinicians’ prescribing practices, in the past few years we have had many unsuccessful attempts at initiating XR-NTX. To our disappointment, a theoretically excellent medication has not translated clinically. The recent surge in fentanyl use further complicates XR-NTX initiation for OUD, because the length of induction may be longer.

In conclusion, we agree that XR-NTX is a potential treatment option for patients with OUD, but clinicians should be cognizant of the potential barriers; inform patients of the advantages, expectations, and challenges; and respect patients’ informed decisions.

Rachel Gluck, MD
Karen Hochman, MD
Yi-lang Tang, MD, PhD
Atlanta, Georgia

References

1. Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318. doi:10.1016/s0140-6736(17)32812-x

2. Wakeman SE, Larochelle MR, Ameli O, et al. Comparative effectiveness of different treatment pathways for opioid use disorder. JAMA Netw Open. 2020;3(2):e1920622. doi:10.1001/jamanetworkopen.2019.20622

Burden of NAFLD in the U.S.

Nonalcoholic fatty liver disease (NAFLD) has become a rapidly increasing public health burden in the U.S. and elsewhere. NAFLD is a manifestation of systemic metabolic abnormalities, including insulin resistance, dyslipidemia, central obesity, and hypertension. In this short review, we summarize data on the burden of NAFLD in the U.S. and its prognostic determinants and review what clinical and public health approaches may be needed to mitigating its impact.

Epidemiology of NAFLD

Worldwide, the prevalence of NAFLD is estimated at 6% to 35%, with biopsy-based studies reporting NASH in 3% to 5%.¹ U.S. estimates for the prevalence of NAFLD range from 10% to 46%.² In our own analysis of the National Health and Nutrition Examination Survey (NHANES) data, transient elastography-detected steatosis was found in 36%, which projected to a minimum of 73 million American adults.³

Dr. Mai Sedki

NAFLD represents a spectrum of disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), the latter leading, in some cases, to progressive hepatic fibrosis and cirrhosis.⁴ Out of a large number of subjects with NAFLD, the proportions of NASH patients that develop severe liver problems such as end-stage liver disease (ESLD) or hepatocellular carcinoma (HCC) are progressively smaller. For example, we recently reported that less than 2,000 liver-related deaths are attributable to NAFLD in the U.S. per annum, which corresponds to a crude case fatality rate of < 0.005% per year.⁵

According to the Centers for Disease Control and Prevention (CDC), there have been substantial increases in liver-related deaths over the last 2 decades. Mortality from liver disease including hepatobiliary cancers more than doubled from 41,966 deaths (including 15,321 women and 26,645 men) in 2000 to 85,884 deaths (33,000 women and 52,884 men) in 2020. The proportion of deaths specifically attributed to NAFLD among liver-related deaths was miniscule in 2000, accounting for 1.1% in women and 0.7% in men. By 2020, the proportions increased several folds in both sexes (7.4% in women and 2.7% in men).⁶ Moreover, it is likely that a substantial portion of deaths from chronic liver disease from unknown causes (“cryptogenic”) are likely end-stage NAFLD, making these figures underestimates of the true impact of NAFLD in the U.S.

From a comparative epidemiologic perspective, there are significant racial and ethnic and socioeconomic disparities in NAFLD prevalence, wherein Hispanic persons and individuals experiencing food insecurity – independent of poverty status, education level, race and ethnicity – are disproportionately more affected by NAFLD.^7,8 Furthermore, these disparities persist when examining long-term complications of NAFLD, such as developing HCC.
 

Prognosis in NAFLD: NASH versus fibrosis

Given the enormous prevalence and increasing public health burden of NAFLD, systematic interventions to mitigate its impact are urgently needed. Clearly, patients who already have developed advanced liver disease need to be directed to specialty care so the disease progression may be halted and complications of ESLD may be prevented or managed. On the other hand, in order to mitigate the future impact of ESLD, prompt identification of at-risk patients and proactive interventions to improve liver health are needed.

Stanford University

In the assessment of disease progression, prior data have shown that the presence of NASH and increasing stages of liver fibrosis are important predictors of disease progression. Fibrosis is a component of NASH, while NASH is thought to be a prerequisite for fibrosis. In a prospective, multicenter follow-up study of NAFLD evaluated by liver biopsies (n = 1,773), over a median follow-up of 4 years, 37 (2%) developed hepatic decompensation, while 47 (3%) died from any cause, which included ESLD (n = 12), cardiovascular complications (n = 4), and malignancies (n = 12), including HCC (n = 9).⁹ It is not entirely surprising that advanced fibrosis and cirrhosis was highly associated with the development of hepatic decompensation. In their multivariable analysis, patients with F3-4 had a 13.8-fold (95% confidence interval [CI]: 4.6, 41.0) increase in the hazard of reaching a MELD score of 15 compared to those with F0-2. In addition, all-cause mortality was 17.2-fold (95% CI: 5.2, 56.6) higher with F3-4 compared to F0-2.

These data have been borne out by a larger body of literature on the topic. In a recent meta-analysis assessing the relation between liver fibrosis and future mortality, which included 17,301 subjects with NAFLD, patients with at least stage 2 fibrosis experience a significantly increased risk of liver-related and overall mortality, a trend that accelerates at higher fibrosis stages.¹⁰ These point to liver fibrosis as the singular determinant of long-term prognosis, in comparison, for example, with the diagnosis of NASH. Hagström conducted a retrospective cohort study of patients with biopsy-proven NAFLD in Sweden. When fibrosis stage and histological diagnosis of NASH were considered together, NASH did not have an impact on overall mortality (hazard ratio [HR] = 0.83, P = .29) or liver morbidity (HR = 0.62, P = .25).¹¹

On an individual level, factors that affect fibrosis progression are not as well studied. It is commonly believed that demographic factors (e.g., age, sex and race), genetic polymorphisms (e.g., PNPLA3, TM6SF2), clinical comorbidities (e.g., obesity, DM, and sleep apnea), and environmental factors (e.g., smoking) may accelerate fibrosis and disease outcomes, although prospective data are sparse to estimate the extent these individual variables affect progression.¹² Recent guidelines remain silent about whether and how these data may be incorporated in screening for NAFLD in the population.
 

Assessment of liver fibrosis

The traditional means to detect liver fibrosis is liver histology, which also assesses steatosis, individual components of NASH and, often importantly, other concomitant liver pathology. In reality, however, liver biopsies have several limitations including the risk of complications, patient discomfort, economic costs, and sampling variability. Increasingly, “noninvasive” methods have been used to estimate liver fibrosis in patients with NAFLD. Liver elastography estimates the physical stiffness of the organ, which may be measured by MRI or ultrasound. Among ultrasound-based technologies, vibration-controlled transient elastography (VCTE) is more widely accepted and affordable although it may not be as accurate as MR elastography.¹³

In general, these elastographic tests are not readily accessible to most physicians outside hepatology specialty practices. Instead, blood test-based markers have been developed and widely recommended as the initial modality to assess liver fibrosis. Figure 1 represents a partial list of blood test-based markers. Traditionally, FIB-4 and NFS have been considered the most widely recommended by society guidelines. The AGA Pathway for evaluation of patients with NAFLD recommends first to apply the FIB-4 score and, in patients considered to be at intermediate risk of fibrosis for advanced fibrosis (stage 3 or 4, FIB-4 = 1.3-2.67), to assess liver stiffness by VCTE.¹⁴

More recently, the accumulating natural history data have highlighted the inflection in the risk of future outcomes coinciding with F2 and therapeutic trials that target patients with “at risk NASH,” thus more attention has been paid to the identification of patients with stage 2 (or higher). The steatosis-associated fibrosis estimator (SAFE) was developed for this specific purpose. The score has been validated in multiple data sets, in all of which SAFE outperformed FIB-4 and NFS (Figure 1). When the score was applied to assess overall survival in participants of the NHANES, patients with NAFLD deemed to be high risk (SAFE > 100) had significantly lower survival (37% Kaplan-Meier survival at 20 years), compared to those with intermediate (SAFE 0-100, 61% survival) and low (SAFE < 0, 86% survival). In comparison, the 20-year survival of subjects without NAFLD survival was 79%.¹⁵

Mai Sedki, MD, MPH and W. Ray Kim, MD

Mai Sedki, MD, MPH and W. Ray Kim, MD

Partnership between primary care and specialty

The insights expressed in Figure 2 can be utilized to guide management decisions. In patients without evidence of liver fibrosis, emphasis may primarily be on screening, stratification and management of metabolic syndrome. For patients with evidence of incipient liver fibrosis, medical management of NAFLD needs to be implemented including lifestyle changes and pharmacological interventions as appropriate. For patients unresponsive to medical therapy, an endoscopic or surgical bariatric procedure should be considered. Management of patients with evidence of cirrhosis includes screening for portal hypertension, surveillance for HCC, medical management of cirrhosis, and finally, in suitable cases, referral for liver transplant evaluation. The reader is referred to the latest treatment guidelines for detailed discussion of these individual management modalities [ref, AGA and AASLD guidelines].^14,17

Given the spectrum of management modalities needed to successfully manage patients with NAFLD, it is unrealistic to expect that hepatologists and gastroenterologists are able to manage the large number of patients with NAFLD. In general, clinical activities on the left side of the figure are in the domain of primary care providers, whereas management of patients with progressive liver fibrosis is conducted by the specialist. An important aspect of the overall management of these patients is risk management in terms of the metabolic syndrome, including cardiovascular risk reduction and diabetes management, as appropriate. Many patients with NAFLD are burdened with several comorbidities and likely to benefit from a multidisciplinary team consisting of primary care, endocrinology, preventive cardiology, pharmacy, nutrition/dietetics, social services, and addiction specialists, as well as hepatology and gastroenterology. Prospective, high-quality data to define these teams and their function are yet to be generated.
 

Conclusion

NAFLD is an important and increasing public health concern in the U.S. Once diagnosed, assessing liver fibrosis and evaluating the presence of the components of metabolic syndrome in these patients, constitute the key components in the care in terms of risk stratification, medical management, and referral decisions. Noninvasive tests have been increasingly utilized including liver stiffness measurements and various blood test-based indicators. For patients in specialty GI/hepatology care, transient elastography is a widely accepted tool, with which standardized recommendations may be made for screening, stratification, and medical and surgical interventions in patients with NAFLD.

Mai Sedki, MD, MPH, is a doctoral candidate at the University of California, San Francisco. W. Ray Kim, MD, is professor of medicine (gastroenterology and hepatology) at Stanford (Calif.) University. Address correspondence to: [email protected]. The authors disclosed no conflicts of interest. Twitter: @SedkiMD and @WRayKimMD.

References

1. Younossi ZM et al. Epidemiology of chronic liver diseases in the USA in the past three decades. Gut. 2020 Mar;69(3):564-8.

2. Lazo M et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol. 2013 Jul 1;178(1):38-45.

3. Kim D et al. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology. 2013 Apr;57:1357-65.

4. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002 Apr 18;346:1221-31.

5. Kim D et al. Changing trends in etiology-based annual mortality from chronic liver disease, from 2007 through 2016. Gastroenterology. 2018;155(4):1154-63.e3.

6. FastStats. Chronic Liver Disease and Cirrhosis. Centers for Disease Control and Prevention.

7. Rich NE et al. Racial and ethnic disparities in nonalcoholic fatty liver disease prevalence, severity, and outcomes in the United States: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16(2):198-210. e2.

8. Coleman-Jensen A et al. Household food security in the United States in 2020 (ERR-298). Washington, DC: U.S. Department of Agriculture; Sep 2021.

9. Sanyal AJ et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med. 2021 Oct 21;385(17):1559-69.

10. Ng CH et al. Mortality outcomes by fibrosis stage in nonalcoholic fatty liver disease: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2023 Apr;21(4):931-9.e5.

11. Hagström H et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67(6):1265-73.

12. Rinella ME et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023 May 1;77(5):1797-835.

13. Singh S et al. Diagnostic performance of magnetic resonance elastography in staging liver fibrosis: A systematic review and meta-analysis of individual participant data. Clin Gastroenterol Hepatol. 2015 Mar;13(3):440-51.e6.

14. Kanwal F et al. Clinical Care Pathway for the risk stratification and management of patients with nonalcoholic fatty liver disease. Gastroenterology. 2021 Nov;161(5):1657-69.

15. Sripongpun P et al. The steatosis-associated fibrosis estimator (SAFE) score: A tool to detect low-risk NAFLD in primary care. .

16. de Franchis R et al. Baveno VII: Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76(4):959-74.

17. Rinella ME et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023 May 1;77(5):1797-835.

Burden of NAFLD in the U.S.

Nonalcoholic fatty liver disease (NAFLD) has become a rapidly increasing public health burden in the U.S. and elsewhere. NAFLD is a manifestation of systemic metabolic abnormalities, including insulin resistance, dyslipidemia, central obesity, and hypertension. In this short review, we summarize data on the burden of NAFLD in the U.S. and its prognostic determinants and review what clinical and public health approaches may be needed to mitigating its impact.

Epidemiology of NAFLD

Worldwide, the prevalence of NAFLD is estimated at 6% to 35%, with biopsy-based studies reporting NASH in 3% to 5%.¹ U.S. estimates for the prevalence of NAFLD range from 10% to 46%.² In our own analysis of the National Health and Nutrition Examination Survey (NHANES) data, transient elastography-detected steatosis was found in 36%, which projected to a minimum of 73 million American adults.³

Dr. Mai Sedki

NAFLD represents a spectrum of disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), the latter leading, in some cases, to progressive hepatic fibrosis and cirrhosis.⁴ Out of a large number of subjects with NAFLD, the proportions of NASH patients that develop severe liver problems such as end-stage liver disease (ESLD) or hepatocellular carcinoma (HCC) are progressively smaller. For example, we recently reported that less than 2,000 liver-related deaths are attributable to NAFLD in the U.S. per annum, which corresponds to a crude case fatality rate of < 0.005% per year.⁵

According to the Centers for Disease Control and Prevention (CDC), there have been substantial increases in liver-related deaths over the last 2 decades. Mortality from liver disease including hepatobiliary cancers more than doubled from 41,966 deaths (including 15,321 women and 26,645 men) in 2000 to 85,884 deaths (33,000 women and 52,884 men) in 2020. The proportion of deaths specifically attributed to NAFLD among liver-related deaths was miniscule in 2000, accounting for 1.1% in women and 0.7% in men. By 2020, the proportions increased several folds in both sexes (7.4% in women and 2.7% in men).⁶ Moreover, it is likely that a substantial portion of deaths from chronic liver disease from unknown causes (“cryptogenic”) are likely end-stage NAFLD, making these figures underestimates of the true impact of NAFLD in the U.S.

From a comparative epidemiologic perspective, there are significant racial and ethnic and socioeconomic disparities in NAFLD prevalence, wherein Hispanic persons and individuals experiencing food insecurity – independent of poverty status, education level, race and ethnicity – are disproportionately more affected by NAFLD.^7,8 Furthermore, these disparities persist when examining long-term complications of NAFLD, such as developing HCC.
 

Prognosis in NAFLD: NASH versus fibrosis

Given the enormous prevalence and increasing public health burden of NAFLD, systematic interventions to mitigate its impact are urgently needed. Clearly, patients who already have developed advanced liver disease need to be directed to specialty care so the disease progression may be halted and complications of ESLD may be prevented or managed. On the other hand, in order to mitigate the future impact of ESLD, prompt identification of at-risk patients and proactive interventions to improve liver health are needed.

Stanford University

In the assessment of disease progression, prior data have shown that the presence of NASH and increasing stages of liver fibrosis are important predictors of disease progression. Fibrosis is a component of NASH, while NASH is thought to be a prerequisite for fibrosis. In a prospective, multicenter follow-up study of NAFLD evaluated by liver biopsies (n = 1,773), over a median follow-up of 4 years, 37 (2%) developed hepatic decompensation, while 47 (3%) died from any cause, which included ESLD (n = 12), cardiovascular complications (n = 4), and malignancies (n = 12), including HCC (n = 9).⁹ It is not entirely surprising that advanced fibrosis and cirrhosis was highly associated with the development of hepatic decompensation. In their multivariable analysis, patients with F3-4 had a 13.8-fold (95% confidence interval [CI]: 4.6, 41.0) increase in the hazard of reaching a MELD score of 15 compared to those with F0-2. In addition, all-cause mortality was 17.2-fold (95% CI: 5.2, 56.6) higher with F3-4 compared to F0-2.

These data have been borne out by a larger body of literature on the topic. In a recent meta-analysis assessing the relation between liver fibrosis and future mortality, which included 17,301 subjects with NAFLD, patients with at least stage 2 fibrosis experience a significantly increased risk of liver-related and overall mortality, a trend that accelerates at higher fibrosis stages.¹⁰ These point to liver fibrosis as the singular determinant of long-term prognosis, in comparison, for example, with the diagnosis of NASH. Hagström conducted a retrospective cohort study of patients with biopsy-proven NAFLD in Sweden. When fibrosis stage and histological diagnosis of NASH were considered together, NASH did not have an impact on overall mortality (hazard ratio [HR] = 0.83, P = .29) or liver morbidity (HR = 0.62, P = .25).¹¹

On an individual level, factors that affect fibrosis progression are not as well studied. It is commonly believed that demographic factors (e.g., age, sex and race), genetic polymorphisms (e.g., PNPLA3, TM6SF2), clinical comorbidities (e.g., obesity, DM, and sleep apnea), and environmental factors (e.g., smoking) may accelerate fibrosis and disease outcomes, although prospective data are sparse to estimate the extent these individual variables affect progression.¹² Recent guidelines remain silent about whether and how these data may be incorporated in screening for NAFLD in the population.
 

Assessment of liver fibrosis

The traditional means to detect liver fibrosis is liver histology, which also assesses steatosis, individual components of NASH and, often importantly, other concomitant liver pathology. In reality, however, liver biopsies have several limitations including the risk of complications, patient discomfort, economic costs, and sampling variability. Increasingly, “noninvasive” methods have been used to estimate liver fibrosis in patients with NAFLD. Liver elastography estimates the physical stiffness of the organ, which may be measured by MRI or ultrasound. Among ultrasound-based technologies, vibration-controlled transient elastography (VCTE) is more widely accepted and affordable although it may not be as accurate as MR elastography.¹³

In general, these elastographic tests are not readily accessible to most physicians outside hepatology specialty practices. Instead, blood test-based markers have been developed and widely recommended as the initial modality to assess liver fibrosis. Figure 1 represents a partial list of blood test-based markers. Traditionally, FIB-4 and NFS have been considered the most widely recommended by society guidelines. The AGA Pathway for evaluation of patients with NAFLD recommends first to apply the FIB-4 score and, in patients considered to be at intermediate risk of fibrosis for advanced fibrosis (stage 3 or 4, FIB-4 = 1.3-2.67), to assess liver stiffness by VCTE.¹⁴

More recently, the accumulating natural history data have highlighted the inflection in the risk of future outcomes coinciding with F2 and therapeutic trials that target patients with “at risk NASH,” thus more attention has been paid to the identification of patients with stage 2 (or higher). The steatosis-associated fibrosis estimator (SAFE) was developed for this specific purpose. The score has been validated in multiple data sets, in all of which SAFE outperformed FIB-4 and NFS (Figure 1). When the score was applied to assess overall survival in participants of the NHANES, patients with NAFLD deemed to be high risk (SAFE > 100) had significantly lower survival (37% Kaplan-Meier survival at 20 years), compared to those with intermediate (SAFE 0-100, 61% survival) and low (SAFE < 0, 86% survival). In comparison, the 20-year survival of subjects without NAFLD survival was 79%.¹⁵

Mai Sedki, MD, MPH and W. Ray Kim, MD

Mai Sedki, MD, MPH and W. Ray Kim, MD

Partnership between primary care and specialty

The insights expressed in Figure 2 can be utilized to guide management decisions. In patients without evidence of liver fibrosis, emphasis may primarily be on screening, stratification and management of metabolic syndrome. For patients with evidence of incipient liver fibrosis, medical management of NAFLD needs to be implemented including lifestyle changes and pharmacological interventions as appropriate. For patients unresponsive to medical therapy, an endoscopic or surgical bariatric procedure should be considered. Management of patients with evidence of cirrhosis includes screening for portal hypertension, surveillance for HCC, medical management of cirrhosis, and finally, in suitable cases, referral for liver transplant evaluation. The reader is referred to the latest treatment guidelines for detailed discussion of these individual management modalities [ref, AGA and AASLD guidelines].^14,17

Given the spectrum of management modalities needed to successfully manage patients with NAFLD, it is unrealistic to expect that hepatologists and gastroenterologists are able to manage the large number of patients with NAFLD. In general, clinical activities on the left side of the figure are in the domain of primary care providers, whereas management of patients with progressive liver fibrosis is conducted by the specialist. An important aspect of the overall management of these patients is risk management in terms of the metabolic syndrome, including cardiovascular risk reduction and diabetes management, as appropriate. Many patients with NAFLD are burdened with several comorbidities and likely to benefit from a multidisciplinary team consisting of primary care, endocrinology, preventive cardiology, pharmacy, nutrition/dietetics, social services, and addiction specialists, as well as hepatology and gastroenterology. Prospective, high-quality data to define these teams and their function are yet to be generated.
 

Conclusion

NAFLD is an important and increasing public health concern in the U.S. Once diagnosed, assessing liver fibrosis and evaluating the presence of the components of metabolic syndrome in these patients, constitute the key components in the care in terms of risk stratification, medical management, and referral decisions. Noninvasive tests have been increasingly utilized including liver stiffness measurements and various blood test-based indicators. For patients in specialty GI/hepatology care, transient elastography is a widely accepted tool, with which standardized recommendations may be made for screening, stratification, and medical and surgical interventions in patients with NAFLD.

Mai Sedki, MD, MPH, is a doctoral candidate at the University of California, San Francisco. W. Ray Kim, MD, is professor of medicine (gastroenterology and hepatology) at Stanford (Calif.) University. Address correspondence to: [email protected]. The authors disclosed no conflicts of interest. Twitter: @SedkiMD and @WRayKimMD.

References

1. Younossi ZM et al. Epidemiology of chronic liver diseases in the USA in the past three decades. Gut. 2020 Mar;69(3):564-8.

2. Lazo M et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol. 2013 Jul 1;178(1):38-45.

3. Kim D et al. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology. 2013 Apr;57:1357-65.

4. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002 Apr 18;346:1221-31.

5. Kim D et al. Changing trends in etiology-based annual mortality from chronic liver disease, from 2007 through 2016. Gastroenterology. 2018;155(4):1154-63.e3.

6. FastStats. Chronic Liver Disease and Cirrhosis. Centers for Disease Control and Prevention.

7. Rich NE et al. Racial and ethnic disparities in nonalcoholic fatty liver disease prevalence, severity, and outcomes in the United States: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16(2):198-210. e2.

8. Coleman-Jensen A et al. Household food security in the United States in 2020 (ERR-298). Washington, DC: U.S. Department of Agriculture; Sep 2021.

9. Sanyal AJ et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med. 2021 Oct 21;385(17):1559-69.

10. Ng CH et al. Mortality outcomes by fibrosis stage in nonalcoholic fatty liver disease: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2023 Apr;21(4):931-9.e5.

11. Hagström H et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67(6):1265-73.

12. Rinella ME et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023 May 1;77(5):1797-835.

13. Singh S et al. Diagnostic performance of magnetic resonance elastography in staging liver fibrosis: A systematic review and meta-analysis of individual participant data. Clin Gastroenterol Hepatol. 2015 Mar;13(3):440-51.e6.

14. Kanwal F et al. Clinical Care Pathway for the risk stratification and management of patients with nonalcoholic fatty liver disease. Gastroenterology. 2021 Nov;161(5):1657-69.

15. Sripongpun P et al. The steatosis-associated fibrosis estimator (SAFE) score: A tool to detect low-risk NAFLD in primary care. .

16. de Franchis R et al. Baveno VII: Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76(4):959-74.

17. Rinella ME et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023 May 1;77(5):1797-835.

Burden of NAFLD in the U.S.

Nonalcoholic fatty liver disease (NAFLD) has become a rapidly increasing public health burden in the U.S. and elsewhere. NAFLD is a manifestation of systemic metabolic abnormalities, including insulin resistance, dyslipidemia, central obesity, and hypertension. In this short review, we summarize data on the burden of NAFLD in the U.S. and its prognostic determinants and review what clinical and public health approaches may be needed to mitigating its impact.

Epidemiology of NAFLD

Worldwide, the prevalence of NAFLD is estimated at 6% to 35%, with biopsy-based studies reporting NASH in 3% to 5%.¹ U.S. estimates for the prevalence of NAFLD range from 10% to 46%.² In our own analysis of the National Health and Nutrition Examination Survey (NHANES) data, transient elastography-detected steatosis was found in 36%, which projected to a minimum of 73 million American adults.³

Dr. Mai Sedki

NAFLD represents a spectrum of disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), the latter leading, in some cases, to progressive hepatic fibrosis and cirrhosis.⁴ Out of a large number of subjects with NAFLD, the proportions of NASH patients that develop severe liver problems such as end-stage liver disease (ESLD) or hepatocellular carcinoma (HCC) are progressively smaller. For example, we recently reported that less than 2,000 liver-related deaths are attributable to NAFLD in the U.S. per annum, which corresponds to a crude case fatality rate of < 0.005% per year.⁵

According to the Centers for Disease Control and Prevention (CDC), there have been substantial increases in liver-related deaths over the last 2 decades. Mortality from liver disease including hepatobiliary cancers more than doubled from 41,966 deaths (including 15,321 women and 26,645 men) in 2000 to 85,884 deaths (33,000 women and 52,884 men) in 2020. The proportion of deaths specifically attributed to NAFLD among liver-related deaths was miniscule in 2000, accounting for 1.1% in women and 0.7% in men. By 2020, the proportions increased several folds in both sexes (7.4% in women and 2.7% in men).⁶ Moreover, it is likely that a substantial portion of deaths from chronic liver disease from unknown causes (“cryptogenic”) are likely end-stage NAFLD, making these figures underestimates of the true impact of NAFLD in the U.S.

From a comparative epidemiologic perspective, there are significant racial and ethnic and socioeconomic disparities in NAFLD prevalence, wherein Hispanic persons and individuals experiencing food insecurity – independent of poverty status, education level, race and ethnicity – are disproportionately more affected by NAFLD.^7,8 Furthermore, these disparities persist when examining long-term complications of NAFLD, such as developing HCC.
 

Prognosis in NAFLD: NASH versus fibrosis

Given the enormous prevalence and increasing public health burden of NAFLD, systematic interventions to mitigate its impact are urgently needed. Clearly, patients who already have developed advanced liver disease need to be directed to specialty care so the disease progression may be halted and complications of ESLD may be prevented or managed. On the other hand, in order to mitigate the future impact of ESLD, prompt identification of at-risk patients and proactive interventions to improve liver health are needed.

Stanford University

In the assessment of disease progression, prior data have shown that the presence of NASH and increasing stages of liver fibrosis are important predictors of disease progression. Fibrosis is a component of NASH, while NASH is thought to be a prerequisite for fibrosis. In a prospective, multicenter follow-up study of NAFLD evaluated by liver biopsies (n = 1,773), over a median follow-up of 4 years, 37 (2%) developed hepatic decompensation, while 47 (3%) died from any cause, which included ESLD (n = 12), cardiovascular complications (n = 4), and malignancies (n = 12), including HCC (n = 9).⁹ It is not entirely surprising that advanced fibrosis and cirrhosis was highly associated with the development of hepatic decompensation. In their multivariable analysis, patients with F3-4 had a 13.8-fold (95% confidence interval [CI]: 4.6, 41.0) increase in the hazard of reaching a MELD score of 15 compared to those with F0-2. In addition, all-cause mortality was 17.2-fold (95% CI: 5.2, 56.6) higher with F3-4 compared to F0-2.

These data have been borne out by a larger body of literature on the topic. In a recent meta-analysis assessing the relation between liver fibrosis and future mortality, which included 17,301 subjects with NAFLD, patients with at least stage 2 fibrosis experience a significantly increased risk of liver-related and overall mortality, a trend that accelerates at higher fibrosis stages.¹⁰ These point to liver fibrosis as the singular determinant of long-term prognosis, in comparison, for example, with the diagnosis of NASH. Hagström conducted a retrospective cohort study of patients with biopsy-proven NAFLD in Sweden. When fibrosis stage and histological diagnosis of NASH were considered together, NASH did not have an impact on overall mortality (hazard ratio [HR] = 0.83, P = .29) or liver morbidity (HR = 0.62, P = .25).¹¹

On an individual level, factors that affect fibrosis progression are not as well studied. It is commonly believed that demographic factors (e.g., age, sex and race), genetic polymorphisms (e.g., PNPLA3, TM6SF2), clinical comorbidities (e.g., obesity, DM, and sleep apnea), and environmental factors (e.g., smoking) may accelerate fibrosis and disease outcomes, although prospective data are sparse to estimate the extent these individual variables affect progression.¹² Recent guidelines remain silent about whether and how these data may be incorporated in screening for NAFLD in the population.
 

Assessment of liver fibrosis

The traditional means to detect liver fibrosis is liver histology, which also assesses steatosis, individual components of NASH and, often importantly, other concomitant liver pathology. In reality, however, liver biopsies have several limitations including the risk of complications, patient discomfort, economic costs, and sampling variability. Increasingly, “noninvasive” methods have been used to estimate liver fibrosis in patients with NAFLD. Liver elastography estimates the physical stiffness of the organ, which may be measured by MRI or ultrasound. Among ultrasound-based technologies, vibration-controlled transient elastography (VCTE) is more widely accepted and affordable although it may not be as accurate as MR elastography.¹³

In general, these elastographic tests are not readily accessible to most physicians outside hepatology specialty practices. Instead, blood test-based markers have been developed and widely recommended as the initial modality to assess liver fibrosis. Figure 1 represents a partial list of blood test-based markers. Traditionally, FIB-4 and NFS have been considered the most widely recommended by society guidelines. The AGA Pathway for evaluation of patients with NAFLD recommends first to apply the FIB-4 score and, in patients considered to be at intermediate risk of fibrosis for advanced fibrosis (stage 3 or 4, FIB-4 = 1.3-2.67), to assess liver stiffness by VCTE.¹⁴

More recently, the accumulating natural history data have highlighted the inflection in the risk of future outcomes coinciding with F2 and therapeutic trials that target patients with “at risk NASH,” thus more attention has been paid to the identification of patients with stage 2 (or higher). The steatosis-associated fibrosis estimator (SAFE) was developed for this specific purpose. The score has been validated in multiple data sets, in all of which SAFE outperformed FIB-4 and NFS (Figure 1). When the score was applied to assess overall survival in participants of the NHANES, patients with NAFLD deemed to be high risk (SAFE > 100) had significantly lower survival (37% Kaplan-Meier survival at 20 years), compared to those with intermediate (SAFE 0-100, 61% survival) and low (SAFE < 0, 86% survival). In comparison, the 20-year survival of subjects without NAFLD survival was 79%.¹⁵

Mai Sedki, MD, MPH and W. Ray Kim, MD

Mai Sedki, MD, MPH and W. Ray Kim, MD

Partnership between primary care and specialty

The insights expressed in Figure 2 can be utilized to guide management decisions. In patients without evidence of liver fibrosis, emphasis may primarily be on screening, stratification and management of metabolic syndrome. For patients with evidence of incipient liver fibrosis, medical management of NAFLD needs to be implemented including lifestyle changes and pharmacological interventions as appropriate. For patients unresponsive to medical therapy, an endoscopic or surgical bariatric procedure should be considered. Management of patients with evidence of cirrhosis includes screening for portal hypertension, surveillance for HCC, medical management of cirrhosis, and finally, in suitable cases, referral for liver transplant evaluation. The reader is referred to the latest treatment guidelines for detailed discussion of these individual management modalities [ref, AGA and AASLD guidelines].^14,17

Given the spectrum of management modalities needed to successfully manage patients with NAFLD, it is unrealistic to expect that hepatologists and gastroenterologists are able to manage the large number of patients with NAFLD. In general, clinical activities on the left side of the figure are in the domain of primary care providers, whereas management of patients with progressive liver fibrosis is conducted by the specialist. An important aspect of the overall management of these patients is risk management in terms of the metabolic syndrome, including cardiovascular risk reduction and diabetes management, as appropriate. Many patients with NAFLD are burdened with several comorbidities and likely to benefit from a multidisciplinary team consisting of primary care, endocrinology, preventive cardiology, pharmacy, nutrition/dietetics, social services, and addiction specialists, as well as hepatology and gastroenterology. Prospective, high-quality data to define these teams and their function are yet to be generated.
 

Conclusion

NAFLD is an important and increasing public health concern in the U.S. Once diagnosed, assessing liver fibrosis and evaluating the presence of the components of metabolic syndrome in these patients, constitute the key components in the care in terms of risk stratification, medical management, and referral decisions. Noninvasive tests have been increasingly utilized including liver stiffness measurements and various blood test-based indicators. For patients in specialty GI/hepatology care, transient elastography is a widely accepted tool, with which standardized recommendations may be made for screening, stratification, and medical and surgical interventions in patients with NAFLD.

Mai Sedki, MD, MPH, is a doctoral candidate at the University of California, San Francisco. W. Ray Kim, MD, is professor of medicine (gastroenterology and hepatology) at Stanford (Calif.) University. Address correspondence to: [email protected]. The authors disclosed no conflicts of interest. Twitter: @SedkiMD and @WRayKimMD.

References

1. Younossi ZM et al. Epidemiology of chronic liver diseases in the USA in the past three decades. Gut. 2020 Mar;69(3):564-8.

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