CASE Withdrawn and confused

Mr. J, age 54, is brought to the emergency department from a correctional treatment facility where he is reported to be displaying new, unusual behavior. He has a history of schizoaffective disorder, which has been stable with haloperidol, 10 mg/d, for more than a year.

Although previously Mr. J openly discussed his long-standing delusions about the FBI coming to release him from prison, he no longer mentions this or any other delusional beliefs, and has become less communicative with staff and peers. Mr. J no longer accompanies the other patients to the cafeteria for meals and eats in his room alone and appears to be losing weight. He says, “I do not feel good,” but otherwise does not communicate spontaneously. Intermittently, he is irritable, without known triggers. The staff notices that Mr. J often lays on his bed, sometimes in a fetal position. Over time, he becomes confused and is seen attempting to open his room door with a toothbrush. His personal hygiene is poor, and he often urinates through his clothes, on the floor, and in his bed. Recently, Mr. J’s eczema has worsened. His gait has become unsteady, and he has orthostasis.

What could be causing these new symptoms?

a) worsening schizoaffective disorder
b) illicit drug use in the prison
c) atypical dementia
d) cardiac etiology

The author’s observations

The differential diagnosis for Mr. J appeared to be wide and without specific etiology. Because of the complex types of symptoms that Mr. J was experiencing, the emergency department managed his care and specialty clinic referrals were ordered.

It was reported that Mr. J started complaining of lightheadedness a few months ago, which worsened (unsteady gait, near falls). In the context of Mr. J’s history of lightheadedness and orthostasis, the cardiology clinic ordered a tilt table test, which was within normal limits:

• 70º head-up tilt: blood pressure, 91/67 to 102/62 mm Hg, and pulse, 70 to 79 beats per minute (bpm)
• with isoproterenol, 1 μg/minute: blood pressure, 90/66 to 110/70 mm Hg, and pulse, 77 to 124 bpm
• with isoproterenol, 2 μg/minute: blood pressure, 98/58 to 111/66 mm Hg, and pulse, 121 to 134 bpm.

The neurologist’s diagnostic impression was atypical dementia; however, Mr. J showed no memory deficits. Parkinsonism also was considered, but Mr. J had no unilateral tremor, masked facies, or micrographia. Mr. J showed some restriction in his movement, but he was not bradykinetic. The team suspected haloperidol could be causing his stiff movement.

Although it was possible that Mr. J’s schizoaffective disorder was worsening and led to the new symptoms, Mr. J appeared to be less delusional because he was no longer talking to the staff about his delusions. There seemed to be no outward evidence of progression of psychotic symptoms.

Mr. J had a history of substance abuse, including alcohol, cocaine, and Cannabis. Although prison inmates have been known to manufacture and drink “hooch,” the new symptoms Mr. J was experiencing were severe enough that his social interactions with other inmates diminished substantially. Because Mr. J had not been communicating with the other inmates and had no recent visitors, the team felt that it was unlikely that drugs were causing these symptoms. Also, a urine drug screen for cocaine, amphetamines, benzodiazepines, Cannabis, and opioids was negative.

HISTORY Substance use, violence

Mr. J was diagnosed with bipolar disorder at age 18. After later hospitalizations, his diagnosis was changed to schizoaffective disorder as a matter of diagnostic clarification. He has a long history of non-compliance with treatment, homelessness, and drug abuse.

Mr. J is serving a 20-year sentence for first-degree reckless homicide. A year after he was incarcerated, Mr. J was sent to a specialized mental health facility for inmates whose illness cannot be managed in a typical correctional setting. While at the treatment facility, Mr. J was non-compliant with medications and because of concerns about dangerousness and psychosis, the court found probable cause for involuntary commitment.

His medication regimen is trihexyphenidyl, 2 mg/d, for extrapyramidal symptoms; haloperidol, 10 mg/d, for psychosis; trazodone, 150 mg/d, for insomnia; vitamin D₃, 2,000 IU/d; vitamin E, 400 IU/d, for symptoms of tardive dyskinesia; IM ziprasidone, 20 mg, because he refused oral haliperidol; and hydrocortisone cream 1% for eczema.

EVALUATION Additional tests

Mr. J’s blood pressure is 124/72 mm Hg, and pulse, 104 bpm, laying down; blood pressure, 110/84 mm Hg, and pulse, 112 bpm, sitting; and blood pressure, 108/82 mm Hg, and pulse, 129 bpm, standing. With repeated readings: blood pressure, 128/84 mm Hg, and pulse, 98 bpm, laying down; blood pressure, 125/86 mm Hg, and pulse, 113 bpm, sitting; and blood pressure, 105/76 mm Hg, and pulse, 130 bpm, standing.

Laboratory tests, including complete blood count, chemistry panel, thyroid-stimulating hormone, are within normal limits. The team feels that the investigation for an etiology for Mr. J’s symptoms needs to be more exhaustive and additional tests are ordered, including vitamin levels (C, B₁, B₁₂, B₆), rapid plasma reagin for syphilis, and arbovirus testing (eastern equine encephalitis virus, western equine encephalitis, West Nile virus, La Crosse encephalitis, St. Louis encephalitis), which are negative.

What’s the next best step in managing Mr. J’s care?

a) adjust his medication

b) eliminate a mediation

c) order further testing

The author’s observations

To determine if Mr. J’s new-onset symptoms might be related to the progression of his psychiatric illness, the haloperidol dosage was increased to 20 mg/d; however, we saw no positive response to this change. His tardive dyskinesia symptoms (bruxism and other oral buccal movements) worsened. Haloperidol was reduced to 10 mg/d.

Trihexyphenidyl then was suspected to contribute to Mr. J’s confusion. Unfortunately, lowering the dosage of trihexyphenidyl to 1 mg/d, did not affect Mr. J’s current symptoms and exacerbated extrapyramidal symptoms.

The treatment team then questioned if porphyria—known as the “little imitator”—might be considered because of the variety of symptoms without an etiology, despite extensive testing. A 24-hour urine collection was ordered.

What is the correct method of collecting a urine sample for porphyrins?

a) collect a small sample and expose it to light before testing

b) collect a 24-hour sample with the sample kept in ambient temperature and light

c) collect a 24-hour sample with the sample kept on ice in a light-blocking container and frozen when sent to the laboratory

EVALUATION Diagnosis revealed

The 24-hour urine collection is obtained. However, it needed to be collected twice, because the first sample was not a full sample. Interestingly, the first sample, which is exposed to light and not kept on ice, turned dark in color. The second sample is obtained properly and sent to the laboratory. When the laboratory results are returned (Figure 1), Mr. J is diagnosed with hereditary coproporphyria (HCP).

The author’s observations

There are several types of porphyria, each associated with a different step in the chain of enzymes associated with synthesis of a heme molecule in the mitochondria. A defect in any single enzyme step will create a build up of porphyrins—a precursor to heme molecules—in erythrocytes or hepatic cells.

It is important to differentiate hepatic from erythropoietic porphyrias. The acute porphyrias (acute intermittent porphyria [AIP], HCP, and variegate porphyria generally are hepatic in origin with neuropsychiatric and neurovisceral symptoms. Cutaneous porphyrias originate in bone marrow and therefore are erythropoietic. However, there are exceptions such as porphyria cutanea tarda (PCT), which is hepatic in origin but the manifestations mainly are cutaneous¹ (Figure 2).²

• muscle spasms (commonly abdominal, but can be any muscle group)
• confusion
• disorientation
• autonomic instability
• lightheadness
• disorientation
• diarrhea
• light sensitivity
• dermatologic conditions
• weakness (particularly peripheral weakness)
• hypesthesia
• allodynia
• severe nausea and vomiting
• emotional lability
• psychosis as well as general malaise.

The attack could result in death.

Mr. J had many differing symptoms and was evaluated by several specialty providers. He had a chronic dermatologic condition; he was confused, disoriented, and complained of nausea, weakness, orthostasis, and loose stools. With the variety of possible symptoms that patients such as Mr. J could experience, one can see why it would lead to many different providers being involved in the diagnosis. It is not uncommon for psychiatrists to be the last providers to care for such patients who could have been evaluated by hematology, cardiology, gastroenterology, dermatology, and/or neurology.

Hereditary coproporphyria

The team considered hepatic porphyias because of new-onset symptoms of mood lability, confusion, orthostasis, unsteady gait, weakness, dermatologic conditions on hands not responsive to treatment, and general malaise. Mr. J was diagnosed with HCP, a type of porphyria caused by a defect in coproporphyrinogen oxidase that leads to an accumulation of coproporphyrinogen III. This precursor, as are many porphyrin precursors, is neurotoxic, leading to neurovisceral or neuropsychiatric effects. Although in Mr. J’s case the coproporphyrinogen III value from the 24-hour drug screen was only modestly elevated, it has been noted that levels of excreted prophyrins do not necessarily correlate with symptom severity.³

In the past, porphyria testing was performed using the Watson-Schwartz test, which used Ehrlich’s reagent to precipitate porphyrins in a urine sample,⁴ and was used as a “bedside” test. Interestingly, porphyrins—not the iron found in the heme molecule—are precipitated in this test and cause the reddish-purple coloration of the urine sample. When quantitative testing was developed, a 24-hour sample of urine—kept on ice and away from ambient light, later to be frozen when sent to the laboratory—became the standard tool for testing for porphyrins. Now DNA testing can be used to diagnose HCP.

OUTCOME Symptoms resolve

Mr. J is started on loxapine, 20 mg at bedtime, and his symptoms resolve within 2 weeks. He maintains some baseline delusional ideation consistent with his history of schizoaffective disorder, but he is more social, his personal hygiene improves, he attends groups, eats in the cafeteria with his peers, and is no longer confused.

The author’s observations

In the 1950s, chlorpromazine was used to treat AIP.⁵ Mr. J received loxapine, a mid-potency first-generation antipsychotic, although it has been this author’s observation that high-potency first-generation antipsychotics are not effective for treating porphyria.

CASE Withdrawn and confused

Mr. J, age 54, is brought to the emergency department from a correctional treatment facility where he is reported to be displaying new, unusual behavior. He has a history of schizoaffective disorder, which has been stable with haloperidol, 10 mg/d, for more than a year.

Although previously Mr. J openly discussed his long-standing delusions about the FBI coming to release him from prison, he no longer mentions this or any other delusional beliefs, and has become less communicative with staff and peers. Mr. J no longer accompanies the other patients to the cafeteria for meals and eats in his room alone and appears to be losing weight. He says, “I do not feel good,” but otherwise does not communicate spontaneously. Intermittently, he is irritable, without known triggers. The staff notices that Mr. J often lays on his bed, sometimes in a fetal position. Over time, he becomes confused and is seen attempting to open his room door with a toothbrush. His personal hygiene is poor, and he often urinates through his clothes, on the floor, and in his bed. Recently, Mr. J’s eczema has worsened. His gait has become unsteady, and he has orthostasis.

What could be causing these new symptoms?

a) worsening schizoaffective disorder
b) illicit drug use in the prison
c) atypical dementia
d) cardiac etiology

The author’s observations

The differential diagnosis for Mr. J appeared to be wide and without specific etiology. Because of the complex types of symptoms that Mr. J was experiencing, the emergency department managed his care and specialty clinic referrals were ordered.

It was reported that Mr. J started complaining of lightheadedness a few months ago, which worsened (unsteady gait, near falls). In the context of Mr. J’s history of lightheadedness and orthostasis, the cardiology clinic ordered a tilt table test, which was within normal limits:

• 70º head-up tilt: blood pressure, 91/67 to 102/62 mm Hg, and pulse, 70 to 79 beats per minute (bpm)
• with isoproterenol, 1 μg/minute: blood pressure, 90/66 to 110/70 mm Hg, and pulse, 77 to 124 bpm
• with isoproterenol, 2 μg/minute: blood pressure, 98/58 to 111/66 mm Hg, and pulse, 121 to 134 bpm.

The neurologist’s diagnostic impression was atypical dementia; however, Mr. J showed no memory deficits. Parkinsonism also was considered, but Mr. J had no unilateral tremor, masked facies, or micrographia. Mr. J showed some restriction in his movement, but he was not bradykinetic. The team suspected haloperidol could be causing his stiff movement.

Although it was possible that Mr. J’s schizoaffective disorder was worsening and led to the new symptoms, Mr. J appeared to be less delusional because he was no longer talking to the staff about his delusions. There seemed to be no outward evidence of progression of psychotic symptoms.

Mr. J had a history of substance abuse, including alcohol, cocaine, and Cannabis. Although prison inmates have been known to manufacture and drink “hooch,” the new symptoms Mr. J was experiencing were severe enough that his social interactions with other inmates diminished substantially. Because Mr. J had not been communicating with the other inmates and had no recent visitors, the team felt that it was unlikely that drugs were causing these symptoms. Also, a urine drug screen for cocaine, amphetamines, benzodiazepines, Cannabis, and opioids was negative.

HISTORY Substance use, violence

Mr. J was diagnosed with bipolar disorder at age 18. After later hospitalizations, his diagnosis was changed to schizoaffective disorder as a matter of diagnostic clarification. He has a long history of non-compliance with treatment, homelessness, and drug abuse.

Mr. J is serving a 20-year sentence for first-degree reckless homicide. A year after he was incarcerated, Mr. J was sent to a specialized mental health facility for inmates whose illness cannot be managed in a typical correctional setting. While at the treatment facility, Mr. J was non-compliant with medications and because of concerns about dangerousness and psychosis, the court found probable cause for involuntary commitment.

His medication regimen is trihexyphenidyl, 2 mg/d, for extrapyramidal symptoms; haloperidol, 10 mg/d, for psychosis; trazodone, 150 mg/d, for insomnia; vitamin D₃, 2,000 IU/d; vitamin E, 400 IU/d, for symptoms of tardive dyskinesia; IM ziprasidone, 20 mg, because he refused oral haliperidol; and hydrocortisone cream 1% for eczema.

EVALUATION Additional tests

Mr. J’s blood pressure is 124/72 mm Hg, and pulse, 104 bpm, laying down; blood pressure, 110/84 mm Hg, and pulse, 112 bpm, sitting; and blood pressure, 108/82 mm Hg, and pulse, 129 bpm, standing. With repeated readings: blood pressure, 128/84 mm Hg, and pulse, 98 bpm, laying down; blood pressure, 125/86 mm Hg, and pulse, 113 bpm, sitting; and blood pressure, 105/76 mm Hg, and pulse, 130 bpm, standing.

Laboratory tests, including complete blood count, chemistry panel, thyroid-stimulating hormone, are within normal limits. The team feels that the investigation for an etiology for Mr. J’s symptoms needs to be more exhaustive and additional tests are ordered, including vitamin levels (C, B₁, B₁₂, B₆), rapid plasma reagin for syphilis, and arbovirus testing (eastern equine encephalitis virus, western equine encephalitis, West Nile virus, La Crosse encephalitis, St. Louis encephalitis), which are negative.

What’s the next best step in managing Mr. J’s care?

a) adjust his medication

b) eliminate a mediation

c) order further testing

The author’s observations

To determine if Mr. J’s new-onset symptoms might be related to the progression of his psychiatric illness, the haloperidol dosage was increased to 20 mg/d; however, we saw no positive response to this change. His tardive dyskinesia symptoms (bruxism and other oral buccal movements) worsened. Haloperidol was reduced to 10 mg/d.

Trihexyphenidyl then was suspected to contribute to Mr. J’s confusion. Unfortunately, lowering the dosage of trihexyphenidyl to 1 mg/d, did not affect Mr. J’s current symptoms and exacerbated extrapyramidal symptoms.

The treatment team then questioned if porphyria—known as the “little imitator”—might be considered because of the variety of symptoms without an etiology, despite extensive testing. A 24-hour urine collection was ordered.

What is the correct method of collecting a urine sample for porphyrins?

a) collect a small sample and expose it to light before testing

b) collect a 24-hour sample with the sample kept in ambient temperature and light

c) collect a 24-hour sample with the sample kept on ice in a light-blocking container and frozen when sent to the laboratory

EVALUATION Diagnosis revealed

The 24-hour urine collection is obtained. However, it needed to be collected twice, because the first sample was not a full sample. Interestingly, the first sample, which is exposed to light and not kept on ice, turned dark in color. The second sample is obtained properly and sent to the laboratory. When the laboratory results are returned (Figure 1), Mr. J is diagnosed with hereditary coproporphyria (HCP).

The author’s observations

There are several types of porphyria, each associated with a different step in the chain of enzymes associated with synthesis of a heme molecule in the mitochondria. A defect in any single enzyme step will create a build up of porphyrins—a precursor to heme molecules—in erythrocytes or hepatic cells.

It is important to differentiate hepatic from erythropoietic porphyrias. The acute porphyrias (acute intermittent porphyria [AIP], HCP, and variegate porphyria generally are hepatic in origin with neuropsychiatric and neurovisceral symptoms. Cutaneous porphyrias originate in bone marrow and therefore are erythropoietic. However, there are exceptions such as porphyria cutanea tarda (PCT), which is hepatic in origin but the manifestations mainly are cutaneous¹ (Figure 2).²

• muscle spasms (commonly abdominal, but can be any muscle group)
• confusion
• disorientation
• autonomic instability
• lightheadness
• disorientation
• diarrhea
• light sensitivity
• dermatologic conditions
• weakness (particularly peripheral weakness)
• hypesthesia
• allodynia
• severe nausea and vomiting
• emotional lability
• psychosis as well as general malaise.

The attack could result in death.

Mr. J had many differing symptoms and was evaluated by several specialty providers. He had a chronic dermatologic condition; he was confused, disoriented, and complained of nausea, weakness, orthostasis, and loose stools. With the variety of possible symptoms that patients such as Mr. J could experience, one can see why it would lead to many different providers being involved in the diagnosis. It is not uncommon for psychiatrists to be the last providers to care for such patients who could have been evaluated by hematology, cardiology, gastroenterology, dermatology, and/or neurology.

Hereditary coproporphyria

The team considered hepatic porphyias because of new-onset symptoms of mood lability, confusion, orthostasis, unsteady gait, weakness, dermatologic conditions on hands not responsive to treatment, and general malaise. Mr. J was diagnosed with HCP, a type of porphyria caused by a defect in coproporphyrinogen oxidase that leads to an accumulation of coproporphyrinogen III. This precursor, as are many porphyrin precursors, is neurotoxic, leading to neurovisceral or neuropsychiatric effects. Although in Mr. J’s case the coproporphyrinogen III value from the 24-hour drug screen was only modestly elevated, it has been noted that levels of excreted prophyrins do not necessarily correlate with symptom severity.³

In the past, porphyria testing was performed using the Watson-Schwartz test, which used Ehrlich’s reagent to precipitate porphyrins in a urine sample,⁴ and was used as a “bedside” test. Interestingly, porphyrins—not the iron found in the heme molecule—are precipitated in this test and cause the reddish-purple coloration of the urine sample. When quantitative testing was developed, a 24-hour sample of urine—kept on ice and away from ambient light, later to be frozen when sent to the laboratory—became the standard tool for testing for porphyrins. Now DNA testing can be used to diagnose HCP.

OUTCOME Symptoms resolve

Mr. J is started on loxapine, 20 mg at bedtime, and his symptoms resolve within 2 weeks. He maintains some baseline delusional ideation consistent with his history of schizoaffective disorder, but he is more social, his personal hygiene improves, he attends groups, eats in the cafeteria with his peers, and is no longer confused.

The author’s observations

In the 1950s, chlorpromazine was used to treat AIP.⁵ Mr. J received loxapine, a mid-potency first-generation antipsychotic, although it has been this author’s observation that high-potency first-generation antipsychotics are not effective for treating porphyria.

CASE Withdrawn and confused

Mr. J, age 54, is brought to the emergency department from a correctional treatment facility where he is reported to be displaying new, unusual behavior. He has a history of schizoaffective disorder, which has been stable with haloperidol, 10 mg/d, for more than a year.

Although previously Mr. J openly discussed his long-standing delusions about the FBI coming to release him from prison, he no longer mentions this or any other delusional beliefs, and has become less communicative with staff and peers. Mr. J no longer accompanies the other patients to the cafeteria for meals and eats in his room alone and appears to be losing weight. He says, “I do not feel good,” but otherwise does not communicate spontaneously. Intermittently, he is irritable, without known triggers. The staff notices that Mr. J often lays on his bed, sometimes in a fetal position. Over time, he becomes confused and is seen attempting to open his room door with a toothbrush. His personal hygiene is poor, and he often urinates through his clothes, on the floor, and in his bed. Recently, Mr. J’s eczema has worsened. His gait has become unsteady, and he has orthostasis.

What could be causing these new symptoms?

a) worsening schizoaffective disorder
b) illicit drug use in the prison
c) atypical dementia
d) cardiac etiology

The author’s observations

The differential diagnosis for Mr. J appeared to be wide and without specific etiology. Because of the complex types of symptoms that Mr. J was experiencing, the emergency department managed his care and specialty clinic referrals were ordered.

It was reported that Mr. J started complaining of lightheadedness a few months ago, which worsened (unsteady gait, near falls). In the context of Mr. J’s history of lightheadedness and orthostasis, the cardiology clinic ordered a tilt table test, which was within normal limits:

• 70º head-up tilt: blood pressure, 91/67 to 102/62 mm Hg, and pulse, 70 to 79 beats per minute (bpm)
• with isoproterenol, 1 μg/minute: blood pressure, 90/66 to 110/70 mm Hg, and pulse, 77 to 124 bpm
• with isoproterenol, 2 μg/minute: blood pressure, 98/58 to 111/66 mm Hg, and pulse, 121 to 134 bpm.

The neurologist’s diagnostic impression was atypical dementia; however, Mr. J showed no memory deficits. Parkinsonism also was considered, but Mr. J had no unilateral tremor, masked facies, or micrographia. Mr. J showed some restriction in his movement, but he was not bradykinetic. The team suspected haloperidol could be causing his stiff movement.

Although it was possible that Mr. J’s schizoaffective disorder was worsening and led to the new symptoms, Mr. J appeared to be less delusional because he was no longer talking to the staff about his delusions. There seemed to be no outward evidence of progression of psychotic symptoms.

Mr. J had a history of substance abuse, including alcohol, cocaine, and Cannabis. Although prison inmates have been known to manufacture and drink “hooch,” the new symptoms Mr. J was experiencing were severe enough that his social interactions with other inmates diminished substantially. Because Mr. J had not been communicating with the other inmates and had no recent visitors, the team felt that it was unlikely that drugs were causing these symptoms. Also, a urine drug screen for cocaine, amphetamines, benzodiazepines, Cannabis, and opioids was negative.

HISTORY Substance use, violence

Mr. J was diagnosed with bipolar disorder at age 18. After later hospitalizations, his diagnosis was changed to schizoaffective disorder as a matter of diagnostic clarification. He has a long history of non-compliance with treatment, homelessness, and drug abuse.

Mr. J is serving a 20-year sentence for first-degree reckless homicide. A year after he was incarcerated, Mr. J was sent to a specialized mental health facility for inmates whose illness cannot be managed in a typical correctional setting. While at the treatment facility, Mr. J was non-compliant with medications and because of concerns about dangerousness and psychosis, the court found probable cause for involuntary commitment.

His medication regimen is trihexyphenidyl, 2 mg/d, for extrapyramidal symptoms; haloperidol, 10 mg/d, for psychosis; trazodone, 150 mg/d, for insomnia; vitamin D₃, 2,000 IU/d; vitamin E, 400 IU/d, for symptoms of tardive dyskinesia; IM ziprasidone, 20 mg, because he refused oral haliperidol; and hydrocortisone cream 1% for eczema.

EVALUATION Additional tests

Mr. J’s blood pressure is 124/72 mm Hg, and pulse, 104 bpm, laying down; blood pressure, 110/84 mm Hg, and pulse, 112 bpm, sitting; and blood pressure, 108/82 mm Hg, and pulse, 129 bpm, standing. With repeated readings: blood pressure, 128/84 mm Hg, and pulse, 98 bpm, laying down; blood pressure, 125/86 mm Hg, and pulse, 113 bpm, sitting; and blood pressure, 105/76 mm Hg, and pulse, 130 bpm, standing.

Laboratory tests, including complete blood count, chemistry panel, thyroid-stimulating hormone, are within normal limits. The team feels that the investigation for an etiology for Mr. J’s symptoms needs to be more exhaustive and additional tests are ordered, including vitamin levels (C, B₁, B₁₂, B₆), rapid plasma reagin for syphilis, and arbovirus testing (eastern equine encephalitis virus, western equine encephalitis, West Nile virus, La Crosse encephalitis, St. Louis encephalitis), which are negative.

What’s the next best step in managing Mr. J’s care?

a) adjust his medication

b) eliminate a mediation

c) order further testing

The author’s observations

To determine if Mr. J’s new-onset symptoms might be related to the progression of his psychiatric illness, the haloperidol dosage was increased to 20 mg/d; however, we saw no positive response to this change. His tardive dyskinesia symptoms (bruxism and other oral buccal movements) worsened. Haloperidol was reduced to 10 mg/d.

Trihexyphenidyl then was suspected to contribute to Mr. J’s confusion. Unfortunately, lowering the dosage of trihexyphenidyl to 1 mg/d, did not affect Mr. J’s current symptoms and exacerbated extrapyramidal symptoms.

The treatment team then questioned if porphyria—known as the “little imitator”—might be considered because of the variety of symptoms without an etiology, despite extensive testing. A 24-hour urine collection was ordered.

What is the correct method of collecting a urine sample for porphyrins?

a) collect a small sample and expose it to light before testing

b) collect a 24-hour sample with the sample kept in ambient temperature and light

c) collect a 24-hour sample with the sample kept on ice in a light-blocking container and frozen when sent to the laboratory

EVALUATION Diagnosis revealed

The 24-hour urine collection is obtained. However, it needed to be collected twice, because the first sample was not a full sample. Interestingly, the first sample, which is exposed to light and not kept on ice, turned dark in color. The second sample is obtained properly and sent to the laboratory. When the laboratory results are returned (Figure 1), Mr. J is diagnosed with hereditary coproporphyria (HCP).

The author’s observations

There are several types of porphyria, each associated with a different step in the chain of enzymes associated with synthesis of a heme molecule in the mitochondria. A defect in any single enzyme step will create a build up of porphyrins—a precursor to heme molecules—in erythrocytes or hepatic cells.

It is important to differentiate hepatic from erythropoietic porphyrias. The acute porphyrias (acute intermittent porphyria [AIP], HCP, and variegate porphyria generally are hepatic in origin with neuropsychiatric and neurovisceral symptoms. Cutaneous porphyrias originate in bone marrow and therefore are erythropoietic. However, there are exceptions such as porphyria cutanea tarda (PCT), which is hepatic in origin but the manifestations mainly are cutaneous¹ (Figure 2).²

• muscle spasms (commonly abdominal, but can be any muscle group)
• confusion
• disorientation
• autonomic instability
• lightheadness
• disorientation
• diarrhea
• light sensitivity
• dermatologic conditions
• weakness (particularly peripheral weakness)
• hypesthesia
• allodynia
• severe nausea and vomiting
• emotional lability
• psychosis as well as general malaise.

The attack could result in death.

Mr. J had many differing symptoms and was evaluated by several specialty providers. He had a chronic dermatologic condition; he was confused, disoriented, and complained of nausea, weakness, orthostasis, and loose stools. With the variety of possible symptoms that patients such as Mr. J could experience, one can see why it would lead to many different providers being involved in the diagnosis. It is not uncommon for psychiatrists to be the last providers to care for such patients who could have been evaluated by hematology, cardiology, gastroenterology, dermatology, and/or neurology.

Hereditary coproporphyria

The team considered hepatic porphyias because of new-onset symptoms of mood lability, confusion, orthostasis, unsteady gait, weakness, dermatologic conditions on hands not responsive to treatment, and general malaise. Mr. J was diagnosed with HCP, a type of porphyria caused by a defect in coproporphyrinogen oxidase that leads to an accumulation of coproporphyrinogen III. This precursor, as are many porphyrin precursors, is neurotoxic, leading to neurovisceral or neuropsychiatric effects. Although in Mr. J’s case the coproporphyrinogen III value from the 24-hour drug screen was only modestly elevated, it has been noted that levels of excreted prophyrins do not necessarily correlate with symptom severity.³

In the past, porphyria testing was performed using the Watson-Schwartz test, which used Ehrlich’s reagent to precipitate porphyrins in a urine sample,⁴ and was used as a “bedside” test. Interestingly, porphyrins—not the iron found in the heme molecule—are precipitated in this test and cause the reddish-purple coloration of the urine sample. When quantitative testing was developed, a 24-hour sample of urine—kept on ice and away from ambient light, later to be frozen when sent to the laboratory—became the standard tool for testing for porphyrins. Now DNA testing can be used to diagnose HCP.

OUTCOME Symptoms resolve

Mr. J is started on loxapine, 20 mg at bedtime, and his symptoms resolve within 2 weeks. He maintains some baseline delusional ideation consistent with his history of schizoaffective disorder, but he is more social, his personal hygiene improves, he attends groups, eats in the cafeteria with his peers, and is no longer confused.

The author’s observations

In the 1950s, chlorpromazine was used to treat AIP.⁵ Mr. J received loxapine, a mid-potency first-generation antipsychotic, although it has been this author’s observation that high-potency first-generation antipsychotics are not effective for treating porphyria.

Dear Dr. Mossman,
Last week, I hospitalized a patient against her will, based in part on what her family members told me she had threatened to do. The patient threatened to sue me and said I should have known that her relatives were lying. What if my patient is right? Could I face liability if I involuntarily hospitalized her based on bad collateral information?

Submitted by “Dr. R”

In all U.S. states, laws permit psychiatrists to involuntarily hospitalize persons who pose a danger to themselves or others because of mental illness.¹ But taking this step can be tough. Deciding to hospitalize a patient against her will involves weighing her wants and freedom against your duty to look out for her long-term welfare and the community’s safety.^2,3 Often, psychiatrists make these decisions under pressure because the family wants something done immediately, other patients also need attention, the clinical picture is incomplete, or potential dispositions (eg, crisis care and inpatient beds) are limited.³ Given such constraints, you can’t always make perfect decisions.

Dr. R’s question has 2 parts:

• What liabilities can a clinician face if a patient is wrongfully committed?
• What liabilities could arise from relying on inaccurate information or making a false petition in order to hospitalize a patient?

We hope that as you and Dr. R read our answers, you’ll have a clearer understanding of:

• the rationale for civil commitment
• how patients, doctors, and courts view civil commitment
• the role of collateral information in decision-making
• relevant legal concepts and case law.

Rationale for civil commitment

For centuries, society has used civil commitment as one of its legal methods for intervening when persons pose a danger to themselves or others because of their mental illness.⁴ Because incapacitation or death could result from a “false-negative” decision to release a dangerous patient, psychiatrists err on the side of caution and tolerate many “false-positive” hospitalizations of persons who wouldn’t have hurt anyone.⁵

We can never know if a patient would have done harm had she not been hospitalized. Measures of suicidality and hostility tend to subside during involuntary hospital treatment.⁶ After hospitalization, many patients cite protection from harm as a reason they are thankful for their treatment.^7-9 Some involuntary inpatients want to be hospitalized but hide this for conscious or unconscious reasons,^10,11 and involuntary treatment sometimes is the only way to help persons whose illness-induced anosognosia¹² prevents them from understanding why they need treatment.¹³ Involuntary inpatient care leads to modest symptom reduction^14,15 and produces treatment outcomes no worse than those of non-coerced patients.¹⁰

Patients’ views

Patients often view commitment as unjustified.¹⁶ They and their advocates object to what some view as the ultimate infringement on civil liberty.^7,17 By its nature, involuntary commitment eliminates patients’ involvement in a major treatment decision,⁸ disempowers them,¹⁸ and influences their relationship with the treatment team.¹⁵

Some involuntary patients feel disrespected by staff members⁸ or experience inadvertent psychological harm, including “loss of self-esteem, identity, self-control, and self-efficacy, as well as diminished hope in the possibility of recovery.”¹⁵ Involuntary hospitalization also can have serious practical consequences. Commitment can lead to social stigma, loss of gun rights, increased risks of losing child custody, housing problems, and possible disqualification from some professions.¹⁹

Having seen many involuntary patients undergo a change of heart after treatment, psychiatrist Alan Stone proposed the “Thank You Theory” of civil commitment: involuntary hospitalization can be justified by showing that the patient is grateful after recovering.²⁰ Studies show, however, that gratitude is far from universal.¹

How coercion is experienced often depends on how it is communicated. The less coercion patients perceive, the better they feel about the treatment they received.²¹ Satisfaction is important because it leads to less compulsory readmission,²² and dissatisfaction makes malpractice lawsuits more likely.²³

Commitment decision-making

States’ laws, judges’ attitudes, and court decisions establish each jurisdiction’s legal methods for instituting emergency holds and willingness to tolerate “false-positive” involuntary hospitalization,^4,24 all of which create variation between and within states in how civil commitment laws are applied. As a result, clinicians’ decisions are influenced “by a range of social, political, and economic factors,”²⁵ including patients’ sex, race, age, homelessness, employment status, living situation, diagnoses, previous involuntary treatment, and dissatisfaction with mental health treatment.^22,26-32 Furthermore, the potential for coercion often blurs the line between an offer of voluntary admission and an involuntary hospitalization.¹⁸

Collateral information

Psychiatrists owe each patient a sound clinical assessment before deciding to initiate involuntarily hospitalization. During a psychiatric crisis, a patient might not be forthcoming or could have impaired memory or judgment. Information from friends or family can help fill in gaps in a patient’s self-report.³³ As Dr. R’s question illustrates, adequate assessment often includes seeking information from persons familiar with the patient.¹ A report on the Virginia Tech shootings by the Virginia Office of the Inspector General describes how collateral sources can provide otherwise missing evidence of dangerousness,³⁴ and it often leads clinicians toward favoring admission.³⁵

Yet clinicians should regard third-party reports with caution.³⁶ As one attorney warns, “Psychiatrists should be cautious of the underlying motives of well-meaning family members and relatives.”³⁷ If you make a decision to hospitalize a patient involuntarily based on collateral information that turns out to be flawed, are you at fault and potentially liable for harm to the patient?

False petitions and liability

If you’re in a situation similar to the one Dr. R describes, you can take solace in knowing that courts generally provide immunity to a psychiatrist who makes a reasonable, well-intentioned decision to commit someone. The degree of immunity offered varies by jurisdiction. Table 1 provides examples of immunity language from several states’ statutes.

Many states’ statutes also lay out the potential consequences if a psychiatrist takes action to involuntarily hospitalize someone in bad faith or with malicious intent. In some jurisdictions, such actions can lead to criminal sanctions against the doctor or against the party who made a false petition (eg, a devious family member) (Table 2). Commenting on Texas’s statute, attorney Jeffrey Anderson explains, “The touchstone for causes of action based upon a wrongful civil commitment require that the psychiatrist[’s] conduct be found to be unreasonable and negligent. [Immunity…] still requires that a psychiatrist[’s] diagnosis of a patient[’s] threat to harm himself or others be a reasonable and prudent one.”³⁷

Ways to reduce liability risk

Although an involuntary hospitalization could have an uncertain basis, psychiatrists can reduce the risk of legal liability for their decisions. Good documentation is important. Admitting psychiatrists usually make sound decisions, but the corresponding documentation frequently lacks clinical justification.^42-44 As the rate of appropriate documentation of admission decision-making improves, the rate of commitment falls,⁴⁴ and patients’ legal rights enjoy greater protection.⁴³ Poor communication can decrease the quality of care and increase the risk of a malpractice lawsuit.⁴⁵ This is just one of many reasons why you should explain your reasons for involuntary hospitalization and inform patients of the procedures for judicial review.^8,9 Table 3 summarizes other steps to reduce liability risk when committing patients to the hospital.^{1,8,15,21,33,35-37,42,45-47}

Dear Dr. Mossman,
Last week, I hospitalized a patient against her will, based in part on what her family members told me she had threatened to do. The patient threatened to sue me and said I should have known that her relatives were lying. What if my patient is right? Could I face liability if I involuntarily hospitalized her based on bad collateral information?

Submitted by “Dr. R”

In all U.S. states, laws permit psychiatrists to involuntarily hospitalize persons who pose a danger to themselves or others because of mental illness.¹ But taking this step can be tough. Deciding to hospitalize a patient against her will involves weighing her wants and freedom against your duty to look out for her long-term welfare and the community’s safety.^2,3 Often, psychiatrists make these decisions under pressure because the family wants something done immediately, other patients also need attention, the clinical picture is incomplete, or potential dispositions (eg, crisis care and inpatient beds) are limited.³ Given such constraints, you can’t always make perfect decisions.

Dr. R’s question has 2 parts:

• What liabilities can a clinician face if a patient is wrongfully committed?
• What liabilities could arise from relying on inaccurate information or making a false petition in order to hospitalize a patient?

We hope that as you and Dr. R read our answers, you’ll have a clearer understanding of:

• the rationale for civil commitment
• how patients, doctors, and courts view civil commitment
• the role of collateral information in decision-making
• relevant legal concepts and case law.

Rationale for civil commitment

For centuries, society has used civil commitment as one of its legal methods for intervening when persons pose a danger to themselves or others because of their mental illness.⁴ Because incapacitation or death could result from a “false-negative” decision to release a dangerous patient, psychiatrists err on the side of caution and tolerate many “false-positive” hospitalizations of persons who wouldn’t have hurt anyone.⁵

We can never know if a patient would have done harm had she not been hospitalized. Measures of suicidality and hostility tend to subside during involuntary hospital treatment.⁶ After hospitalization, many patients cite protection from harm as a reason they are thankful for their treatment.^7-9 Some involuntary inpatients want to be hospitalized but hide this for conscious or unconscious reasons,^10,11 and involuntary treatment sometimes is the only way to help persons whose illness-induced anosognosia¹² prevents them from understanding why they need treatment.¹³ Involuntary inpatient care leads to modest symptom reduction^14,15 and produces treatment outcomes no worse than those of non-coerced patients.¹⁰

Patients’ views

Patients often view commitment as unjustified.¹⁶ They and their advocates object to what some view as the ultimate infringement on civil liberty.^7,17 By its nature, involuntary commitment eliminates patients’ involvement in a major treatment decision,⁸ disempowers them,¹⁸ and influences their relationship with the treatment team.¹⁵

Some involuntary patients feel disrespected by staff members⁸ or experience inadvertent psychological harm, including “loss of self-esteem, identity, self-control, and self-efficacy, as well as diminished hope in the possibility of recovery.”¹⁵ Involuntary hospitalization also can have serious practical consequences. Commitment can lead to social stigma, loss of gun rights, increased risks of losing child custody, housing problems, and possible disqualification from some professions.¹⁹

Having seen many involuntary patients undergo a change of heart after treatment, psychiatrist Alan Stone proposed the “Thank You Theory” of civil commitment: involuntary hospitalization can be justified by showing that the patient is grateful after recovering.²⁰ Studies show, however, that gratitude is far from universal.¹

How coercion is experienced often depends on how it is communicated. The less coercion patients perceive, the better they feel about the treatment they received.²¹ Satisfaction is important because it leads to less compulsory readmission,²² and dissatisfaction makes malpractice lawsuits more likely.²³

Commitment decision-making

States’ laws, judges’ attitudes, and court decisions establish each jurisdiction’s legal methods for instituting emergency holds and willingness to tolerate “false-positive” involuntary hospitalization,^4,24 all of which create variation between and within states in how civil commitment laws are applied. As a result, clinicians’ decisions are influenced “by a range of social, political, and economic factors,”²⁵ including patients’ sex, race, age, homelessness, employment status, living situation, diagnoses, previous involuntary treatment, and dissatisfaction with mental health treatment.^22,26-32 Furthermore, the potential for coercion often blurs the line between an offer of voluntary admission and an involuntary hospitalization.¹⁸

Collateral information

Psychiatrists owe each patient a sound clinical assessment before deciding to initiate involuntarily hospitalization. During a psychiatric crisis, a patient might not be forthcoming or could have impaired memory or judgment. Information from friends or family can help fill in gaps in a patient’s self-report.³³ As Dr. R’s question illustrates, adequate assessment often includes seeking information from persons familiar with the patient.¹ A report on the Virginia Tech shootings by the Virginia Office of the Inspector General describes how collateral sources can provide otherwise missing evidence of dangerousness,³⁴ and it often leads clinicians toward favoring admission.³⁵

Yet clinicians should regard third-party reports with caution.³⁶ As one attorney warns, “Psychiatrists should be cautious of the underlying motives of well-meaning family members and relatives.”³⁷ If you make a decision to hospitalize a patient involuntarily based on collateral information that turns out to be flawed, are you at fault and potentially liable for harm to the patient?

False petitions and liability

If you’re in a situation similar to the one Dr. R describes, you can take solace in knowing that courts generally provide immunity to a psychiatrist who makes a reasonable, well-intentioned decision to commit someone. The degree of immunity offered varies by jurisdiction. Table 1 provides examples of immunity language from several states’ statutes.

Many states’ statutes also lay out the potential consequences if a psychiatrist takes action to involuntarily hospitalize someone in bad faith or with malicious intent. In some jurisdictions, such actions can lead to criminal sanctions against the doctor or against the party who made a false petition (eg, a devious family member) (Table 2). Commenting on Texas’s statute, attorney Jeffrey Anderson explains, “The touchstone for causes of action based upon a wrongful civil commitment require that the psychiatrist[’s] conduct be found to be unreasonable and negligent. [Immunity…] still requires that a psychiatrist[’s] diagnosis of a patient[’s] threat to harm himself or others be a reasonable and prudent one.”³⁷

Ways to reduce liability risk

Although an involuntary hospitalization could have an uncertain basis, psychiatrists can reduce the risk of legal liability for their decisions. Good documentation is important. Admitting psychiatrists usually make sound decisions, but the corresponding documentation frequently lacks clinical justification.^42-44 As the rate of appropriate documentation of admission decision-making improves, the rate of commitment falls,⁴⁴ and patients’ legal rights enjoy greater protection.⁴³ Poor communication can decrease the quality of care and increase the risk of a malpractice lawsuit.⁴⁵ This is just one of many reasons why you should explain your reasons for involuntary hospitalization and inform patients of the procedures for judicial review.^8,9 Table 3 summarizes other steps to reduce liability risk when committing patients to the hospital.^{1,8,15,21,33,35-37,42,45-47}

Dear Dr. Mossman,
Last week, I hospitalized a patient against her will, based in part on what her family members told me she had threatened to do. The patient threatened to sue me and said I should have known that her relatives were lying. What if my patient is right? Could I face liability if I involuntarily hospitalized her based on bad collateral information?

Submitted by “Dr. R”

In all U.S. states, laws permit psychiatrists to involuntarily hospitalize persons who pose a danger to themselves or others because of mental illness.¹ But taking this step can be tough. Deciding to hospitalize a patient against her will involves weighing her wants and freedom against your duty to look out for her long-term welfare and the community’s safety.^2,3 Often, psychiatrists make these decisions under pressure because the family wants something done immediately, other patients also need attention, the clinical picture is incomplete, or potential dispositions (eg, crisis care and inpatient beds) are limited.³ Given such constraints, you can’t always make perfect decisions.

Dr. R’s question has 2 parts:

• What liabilities can a clinician face if a patient is wrongfully committed?
• What liabilities could arise from relying on inaccurate information or making a false petition in order to hospitalize a patient?

We hope that as you and Dr. R read our answers, you’ll have a clearer understanding of:

• the rationale for civil commitment
• how patients, doctors, and courts view civil commitment
• the role of collateral information in decision-making
• relevant legal concepts and case law.

Rationale for civil commitment

For centuries, society has used civil commitment as one of its legal methods for intervening when persons pose a danger to themselves or others because of their mental illness.⁴ Because incapacitation or death could result from a “false-negative” decision to release a dangerous patient, psychiatrists err on the side of caution and tolerate many “false-positive” hospitalizations of persons who wouldn’t have hurt anyone.⁵

We can never know if a patient would have done harm had she not been hospitalized. Measures of suicidality and hostility tend to subside during involuntary hospital treatment.⁶ After hospitalization, many patients cite protection from harm as a reason they are thankful for their treatment.^7-9 Some involuntary inpatients want to be hospitalized but hide this for conscious or unconscious reasons,^10,11 and involuntary treatment sometimes is the only way to help persons whose illness-induced anosognosia¹² prevents them from understanding why they need treatment.¹³ Involuntary inpatient care leads to modest symptom reduction^14,15 and produces treatment outcomes no worse than those of non-coerced patients.¹⁰

Patients’ views

Patients often view commitment as unjustified.¹⁶ They and their advocates object to what some view as the ultimate infringement on civil liberty.^7,17 By its nature, involuntary commitment eliminates patients’ involvement in a major treatment decision,⁸ disempowers them,¹⁸ and influences their relationship with the treatment team.¹⁵

Some involuntary patients feel disrespected by staff members⁸ or experience inadvertent psychological harm, including “loss of self-esteem, identity, self-control, and self-efficacy, as well as diminished hope in the possibility of recovery.”¹⁵ Involuntary hospitalization also can have serious practical consequences. Commitment can lead to social stigma, loss of gun rights, increased risks of losing child custody, housing problems, and possible disqualification from some professions.¹⁹

Having seen many involuntary patients undergo a change of heart after treatment, psychiatrist Alan Stone proposed the “Thank You Theory” of civil commitment: involuntary hospitalization can be justified by showing that the patient is grateful after recovering.²⁰ Studies show, however, that gratitude is far from universal.¹

How coercion is experienced often depends on how it is communicated. The less coercion patients perceive, the better they feel about the treatment they received.²¹ Satisfaction is important because it leads to less compulsory readmission,²² and dissatisfaction makes malpractice lawsuits more likely.²³

Commitment decision-making

States’ laws, judges’ attitudes, and court decisions establish each jurisdiction’s legal methods for instituting emergency holds and willingness to tolerate “false-positive” involuntary hospitalization,^4,24 all of which create variation between and within states in how civil commitment laws are applied. As a result, clinicians’ decisions are influenced “by a range of social, political, and economic factors,”²⁵ including patients’ sex, race, age, homelessness, employment status, living situation, diagnoses, previous involuntary treatment, and dissatisfaction with mental health treatment.^22,26-32 Furthermore, the potential for coercion often blurs the line between an offer of voluntary admission and an involuntary hospitalization.¹⁸

Collateral information

Psychiatrists owe each patient a sound clinical assessment before deciding to initiate involuntarily hospitalization. During a psychiatric crisis, a patient might not be forthcoming or could have impaired memory or judgment. Information from friends or family can help fill in gaps in a patient’s self-report.³³ As Dr. R’s question illustrates, adequate assessment often includes seeking information from persons familiar with the patient.¹ A report on the Virginia Tech shootings by the Virginia Office of the Inspector General describes how collateral sources can provide otherwise missing evidence of dangerousness,³⁴ and it often leads clinicians toward favoring admission.³⁵

Yet clinicians should regard third-party reports with caution.³⁶ As one attorney warns, “Psychiatrists should be cautious of the underlying motives of well-meaning family members and relatives.”³⁷ If you make a decision to hospitalize a patient involuntarily based on collateral information that turns out to be flawed, are you at fault and potentially liable for harm to the patient?

False petitions and liability

If you’re in a situation similar to the one Dr. R describes, you can take solace in knowing that courts generally provide immunity to a psychiatrist who makes a reasonable, well-intentioned decision to commit someone. The degree of immunity offered varies by jurisdiction. Table 1 provides examples of immunity language from several states’ statutes.

Many states’ statutes also lay out the potential consequences if a psychiatrist takes action to involuntarily hospitalize someone in bad faith or with malicious intent. In some jurisdictions, such actions can lead to criminal sanctions against the doctor or against the party who made a false petition (eg, a devious family member) (Table 2). Commenting on Texas’s statute, attorney Jeffrey Anderson explains, “The touchstone for causes of action based upon a wrongful civil commitment require that the psychiatrist[’s] conduct be found to be unreasonable and negligent. [Immunity…] still requires that a psychiatrist[’s] diagnosis of a patient[’s] threat to harm himself or others be a reasonable and prudent one.”³⁷

Ways to reduce liability risk

Although an involuntary hospitalization could have an uncertain basis, psychiatrists can reduce the risk of legal liability for their decisions. Good documentation is important. Admitting psychiatrists usually make sound decisions, but the corresponding documentation frequently lacks clinical justification.^42-44 As the rate of appropriate documentation of admission decision-making improves, the rate of commitment falls,⁴⁴ and patients’ legal rights enjoy greater protection.⁴³ Poor communication can decrease the quality of care and increase the risk of a malpractice lawsuit.⁴⁵ This is just one of many reasons why you should explain your reasons for involuntary hospitalization and inform patients of the procedures for judicial review.^8,9 Table 3 summarizes other steps to reduce liability risk when committing patients to the hospital.^{1,8,15,21,33,35-37,42,45-47}

The primary symptoms of PTSD are recurrent and include intrusive memories and dreams of the traumatic events, flashbacks, hypervigilance, irritability, sleep disturbances, and persistent avoidance of stimuli associated with the traumatic event. According to the National Comorbidity Survey, the estimated lifetime prevalence of PTSD among adults is 6.8% and is more common in women (9.7%) than men (3.6%).² Among veterans, the prevalence of PTSD has been reported as:

• 31% among male Vietnam veterans (lifetime)
• 10% among Gulf War veterans
• 14% among Iraq and Afghanistan veterans.³

Why is PTSD overlooked in substance use?

Among individuals with SUD, 10% to 63% have comorbid PTSD.⁴ A recent report underscores the complexity and challenges of SUD–PTSD comorbidity.⁵ Most PTSD patients with comorbid SUD receive treatment only for SUD and the PTSD symptoms often are unaddressed.⁵ Those suffering from PTSD often abuse alcohol because they might consider it to be a coping strategy. Alcohol reduces hyperactivation of the dorsal anterior cingulate cortex caused by re-experiencing PTSD symptoms. Other substances of abuse, such as Cannabis, could suppress PTSD symptoms through alternate mechanisms (eg, endocannabinoid receptors). All of these could mask PTSD symptoms, which can delay diagnosis and treatment.

SUD is the tip of the “SUD-PTSD iceberg.” Some clinicians tend to focus on detoxification while completely ignoring the underlying psychopathology of SUD, which may be PTSD. Even during detoxification, PTSD should be aggressively treated.⁶ Lastly, practice guidelines for managing SUD–PTSD comorbidity are lacking.

Targeting mechanisms of action

Noradrenergic mechanisms have been strongly implicated in the pathophysiology of PTSD. However, selective serotonin reuptake inhibitors, such as sertraline and paroxetine, are the only FDA-approved pharmacotherapy options for PTSD, although their efficacy is limited, perhaps because they are serotonergic.

Prazosin, an alpha-1 (α-1) adrenergic antagonist that is FDA-approved for hypertension and benign prostatic hypertrophy, has been studied for treating nightmares in PTSD.⁷ Prazosin has shown efficacy for nightmares in PTSD and other daytime symptoms, such as flashbacks, hypervigilance, and irritability.⁸ Several studies support the efficacy of prazosin in persons suffering from PTSD.^9-11 Use of lower dosages in clinical trials might explain why prazosin did not separate from placebo in some studies. (See Table summarizing studies of prazosin dosing for PTSD.)

In a study of 12,844 veterans, the mean maximum prazosin dosage reached in the first year of treatment was 3.6 mg/d, and only 14% of patients reached the minimum Veterans Affairs recommended dosage of 6 mg/d.¹⁷ The most recent (March 2009) American Psychiatric Association practice guidelines recommend prazosin, 3 to 15 mg at bedtime.¹⁸

Prazosin has a short half-life of 2 to 3 hours and duration of action of 6 to 10 hours. Therefore, its use is limited to 2 or 3 times daily dosing. Higher (30 to 50 mg) and more frequent (2 to 3 times per day) dosages^8,12,13 might be needed because of the drug’s short half-life.

Doxazosin. Another α-1 adrenergic drug, doxazosin, 8 to 16 mg/d, has shown benefit for PTSD as well.^14,15 Doxazosin, which has a longer half-life (16 to 30 hours), requires only once-daily dosing.¹⁶ The most common side effects of prazosin and doxazosin are dizziness, headache, and drowsiness; syncope has been reported but is rare.

Prazosin and doxazosin also are used to treat substance abuse, such as alcohol use disorder^19-21 and cocaine use disorder.^22,23 This “two birds with one stone” approach could become more common in clinical practice.

Until a major breakthrough in PTSD treatment emerges, prazosin and doxazosin, although off-label, are reasonable treatment approaches.

The primary symptoms of PTSD are recurrent and include intrusive memories and dreams of the traumatic events, flashbacks, hypervigilance, irritability, sleep disturbances, and persistent avoidance of stimuli associated with the traumatic event. According to the National Comorbidity Survey, the estimated lifetime prevalence of PTSD among adults is 6.8% and is more common in women (9.7%) than men (3.6%).² Among veterans, the prevalence of PTSD has been reported as:

• 31% among male Vietnam veterans (lifetime)
• 10% among Gulf War veterans
• 14% among Iraq and Afghanistan veterans.³

Why is PTSD overlooked in substance use?

Among individuals with SUD, 10% to 63% have comorbid PTSD.⁴ A recent report underscores the complexity and challenges of SUD–PTSD comorbidity.⁵ Most PTSD patients with comorbid SUD receive treatment only for SUD and the PTSD symptoms often are unaddressed.⁵ Those suffering from PTSD often abuse alcohol because they might consider it to be a coping strategy. Alcohol reduces hyperactivation of the dorsal anterior cingulate cortex caused by re-experiencing PTSD symptoms. Other substances of abuse, such as Cannabis, could suppress PTSD symptoms through alternate mechanisms (eg, endocannabinoid receptors). All of these could mask PTSD symptoms, which can delay diagnosis and treatment.

SUD is the tip of the “SUD-PTSD iceberg.” Some clinicians tend to focus on detoxification while completely ignoring the underlying psychopathology of SUD, which may be PTSD. Even during detoxification, PTSD should be aggressively treated.⁶ Lastly, practice guidelines for managing SUD–PTSD comorbidity are lacking.

Targeting mechanisms of action

Noradrenergic mechanisms have been strongly implicated in the pathophysiology of PTSD. However, selective serotonin reuptake inhibitors, such as sertraline and paroxetine, are the only FDA-approved pharmacotherapy options for PTSD, although their efficacy is limited, perhaps because they are serotonergic.

Prazosin, an alpha-1 (α-1) adrenergic antagonist that is FDA-approved for hypertension and benign prostatic hypertrophy, has been studied for treating nightmares in PTSD.⁷ Prazosin has shown efficacy for nightmares in PTSD and other daytime symptoms, such as flashbacks, hypervigilance, and irritability.⁸ Several studies support the efficacy of prazosin in persons suffering from PTSD.^9-11 Use of lower dosages in clinical trials might explain why prazosin did not separate from placebo in some studies. (See Table summarizing studies of prazosin dosing for PTSD.)

In a study of 12,844 veterans, the mean maximum prazosin dosage reached in the first year of treatment was 3.6 mg/d, and only 14% of patients reached the minimum Veterans Affairs recommended dosage of 6 mg/d.¹⁷ The most recent (March 2009) American Psychiatric Association practice guidelines recommend prazosin, 3 to 15 mg at bedtime.¹⁸

Prazosin has a short half-life of 2 to 3 hours and duration of action of 6 to 10 hours. Therefore, its use is limited to 2 or 3 times daily dosing. Higher (30 to 50 mg) and more frequent (2 to 3 times per day) dosages^8,12,13 might be needed because of the drug’s short half-life.

Doxazosin. Another α-1 adrenergic drug, doxazosin, 8 to 16 mg/d, has shown benefit for PTSD as well.^14,15 Doxazosin, which has a longer half-life (16 to 30 hours), requires only once-daily dosing.¹⁶ The most common side effects of prazosin and doxazosin are dizziness, headache, and drowsiness; syncope has been reported but is rare.

Prazosin and doxazosin also are used to treat substance abuse, such as alcohol use disorder^19-21 and cocaine use disorder.^22,23 This “two birds with one stone” approach could become more common in clinical practice.

Until a major breakthrough in PTSD treatment emerges, prazosin and doxazosin, although off-label, are reasonable treatment approaches.

The primary symptoms of PTSD are recurrent and include intrusive memories and dreams of the traumatic events, flashbacks, hypervigilance, irritability, sleep disturbances, and persistent avoidance of stimuli associated with the traumatic event. According to the National Comorbidity Survey, the estimated lifetime prevalence of PTSD among adults is 6.8% and is more common in women (9.7%) than men (3.6%).² Among veterans, the prevalence of PTSD has been reported as:

• 31% among male Vietnam veterans (lifetime)
• 10% among Gulf War veterans
• 14% among Iraq and Afghanistan veterans.³

Why is PTSD overlooked in substance use?

Among individuals with SUD, 10% to 63% have comorbid PTSD.⁴ A recent report underscores the complexity and challenges of SUD–PTSD comorbidity.⁵ Most PTSD patients with comorbid SUD receive treatment only for SUD and the PTSD symptoms often are unaddressed.⁵ Those suffering from PTSD often abuse alcohol because they might consider it to be a coping strategy. Alcohol reduces hyperactivation of the dorsal anterior cingulate cortex caused by re-experiencing PTSD symptoms. Other substances of abuse, such as Cannabis, could suppress PTSD symptoms through alternate mechanisms (eg, endocannabinoid receptors). All of these could mask PTSD symptoms, which can delay diagnosis and treatment.

SUD is the tip of the “SUD-PTSD iceberg.” Some clinicians tend to focus on detoxification while completely ignoring the underlying psychopathology of SUD, which may be PTSD. Even during detoxification, PTSD should be aggressively treated.⁶ Lastly, practice guidelines for managing SUD–PTSD comorbidity are lacking.

Targeting mechanisms of action

Noradrenergic mechanisms have been strongly implicated in the pathophysiology of PTSD. However, selective serotonin reuptake inhibitors, such as sertraline and paroxetine, are the only FDA-approved pharmacotherapy options for PTSD, although their efficacy is limited, perhaps because they are serotonergic.

Prazosin, an alpha-1 (α-1) adrenergic antagonist that is FDA-approved for hypertension and benign prostatic hypertrophy, has been studied for treating nightmares in PTSD.⁷ Prazosin has shown efficacy for nightmares in PTSD and other daytime symptoms, such as flashbacks, hypervigilance, and irritability.⁸ Several studies support the efficacy of prazosin in persons suffering from PTSD.^9-11 Use of lower dosages in clinical trials might explain why prazosin did not separate from placebo in some studies. (See Table summarizing studies of prazosin dosing for PTSD.)

In a study of 12,844 veterans, the mean maximum prazosin dosage reached in the first year of treatment was 3.6 mg/d, and only 14% of patients reached the minimum Veterans Affairs recommended dosage of 6 mg/d.¹⁷ The most recent (March 2009) American Psychiatric Association practice guidelines recommend prazosin, 3 to 15 mg at bedtime.¹⁸

Prazosin has a short half-life of 2 to 3 hours and duration of action of 6 to 10 hours. Therefore, its use is limited to 2 or 3 times daily dosing. Higher (30 to 50 mg) and more frequent (2 to 3 times per day) dosages^8,12,13 might be needed because of the drug’s short half-life.

Doxazosin. Another α-1 adrenergic drug, doxazosin, 8 to 16 mg/d, has shown benefit for PTSD as well.^14,15 Doxazosin, which has a longer half-life (16 to 30 hours), requires only once-daily dosing.¹⁶ The most common side effects of prazosin and doxazosin are dizziness, headache, and drowsiness; syncope has been reported but is rare.

Prazosin and doxazosin also are used to treat substance abuse, such as alcohol use disorder^19-21 and cocaine use disorder.^22,23 This “two birds with one stone” approach could become more common in clinical practice.

Until a major breakthrough in PTSD treatment emerges, prazosin and doxazosin, although off-label, are reasonable treatment approaches.

Several recent developments have prompted a renewed focus on the way we screen for, and manage the treatment of, hepatitis C virus (HCV) infection. In 2013, the United States Preventive Services Task Force expanded its HCV screening guidelines to include baby boomers born between 1945 and 1965, regardless of apparent risk factors (TABLE 1¹).² The recommendation is based on the high prevalence of chronic HCV in this cohort, estimated to be 4.3%, which is about 4 times higher than that of the general US population.³ It is believed that 75% of chronic HCV infections in the United States are in this cohort. After decades of infection, many in this age group are now presenting with advanced disease, leading to 19,659 HCV-related deaths in America in 2014.⁴

In addition, while HCV incidence in America had been steadily declining, it is now once again on the rise among young, non-urban whites, mainly because of increasing intravenous drug use in this population.⁵ On a positive note, new highly-effective and better-tolerated treatments are greatly improving the care we can provide.

In light of these factors, family physicians (FPs) are likely to be screening for HCV more than ever before and must be prepared to provide appropriate counseling and initial clinical management for those with positive test results. This article reviews the evaluation and primary care management of HCV-infected patients, as well as approaches to treatment with the newest direct-acting antivirals (DAAs).

IMAGE: © JOE GORMAN

The natural history of hepatitis C (and what we’re seeing as boomers age)

Acute HCV infection is rarely symptomatic, but results in chronic infection approximately 75% of the time.⁶ While some chronically infected individuals remain unaffected, most develop some degree of hepatic fibrosis, and 20% will develop cirrhosis within 20 years of diagnosis.^7-9

The rate of progression is variable; factors that result in more rapid progression of liver disease include coinfection with HIV or HBV, overweight or obesity, insulin resistance, male gender, and use of alcohol.⁷ As the baby boomer cohort has aged, patients infected in their youth are now presenting with the sequelae of decompensated cirrhosis, including ascites, portal vein thrombosis, and thrombocytopenia.

Extrahepatic manifestations of chronic hepatitis C can include fatigue, membrano­proliferative glomerulonephritis, porphyria cutanea tarda, cryoglobulinemia, a higher likelihood of insulin resistance, and possibly lymphoma.^10-12

Chronic HCV is also the major contributor to the increased incidence of hepatocellular carcinoma (HCC), which has tripled in the past 2 decades in the United States.¹³

Although results are inconsistent, studies suggest 5% to 10% of HCV-infected patients will succumb to liver-related death.⁷

Who you’ll screen

If your patient is at heightened risk of contracting HCV infection (TABLE 1¹) or was born between 1945 and 1965, you’ll want to screen for infection with an HCV antibody test. A positive antibody test must be followed by testing for hepatitis C viral RNA to confirm whether the patient is chronically infected or is among the approximately 25% of patients who spontaneously clear the virus.⁶

The prevalence of  chronic HCV infection among baby boomers is about 4 times higher than that of the general US population.For the patient with no detectable HCV RNA, no further evaluation or treatment is necessary. HCV viral load itself provides little insight into the rate of progression of the illness, but does correlate with risk of transmission.¹⁴ Counseling patients about the full testing protocol before screening can help to reduce anxiety and confusion.

At present, 6 genotypes and multiple subtypes of HCV have been identified; these have important implications for prognosis and treatment.¹⁵ HCV genotyping is frequently ordered along with a test for HCV viral load, but may be deferred until after fibrosis staging is performed (more on that in a bit). It may also be deferred if treatment is not planned within the next 12 weeks, as its main clinical use is to guide choice of treatment. Once chronic infection has been confirmed by the presence of HCV viremia, further work-up focuses on evaluating the effects on the host, which, in turn, helps the provider finalize a treatment plan (FIGURE 1¹⁶).

Follow initial screening with an evaluation including liver disease staging

Following a screen that comes back positive for HCV, you’ll conduct a more thorough history including questioning about previous or ongoing risk factors for HCV, perform a physical examination that includes looking for signs of liver failure or extrahepatic disease, and order more lab work. Laboratory investigations include a complete blood count; renal and hepatic panels; and testing for human immunodeficiency virus (HIV) antibody, hepatitis B virus (HBV) surface antigen, HBV surface antibody, and HBV core antibody.^1,17 Finally, the patient must be evaluated for hepatic fibrosis and cirrhosis to quantify the likelihood of developing liver failure and HCC.

Staging liver disease is a prerequisite to treating HCV infection because the extent of liver fibrosis impacts not only prognosis, but also the choice of the treatment regimen and the duration of therapy. The traditional gold standard for diagnosing hepatic fibrosis and cirrhosis has been a liver biopsy; however, a single 1.6-mm biopsy evaluates only a small portion of the liver and can miss affected liver parenchyma. In addition, a liver biopsy carries a small, but not inconsequential, risk of morbidity, and can be costly and complex to arrange.

Several noninvasive options are now available and are typically the preferred methods for staging liver disease. FibroSURE (LabCorp), for example, uses a peripheral venous blood sample and combines the patient’s age, gender, and 6 biochemical markers to generate a range of scores that correspond to the fibrosis component of the well-known METAVIR scoring system and correlate with results of liver biopsies.^18,19 (The METAVIR system is a histology-based scoring system that grades fibrosis from F0 [no fibrosis] to F4 [cirrhosis].)

Chronic HCV infection is a major contributor to the increased incidence of hepatocellular carcinoma, which has tripled in the past 2 decades in the United States.Noninvasive imaging studies assess for fibrosis more directly by assessing liver elasticity, either by ultrasound or magnetic resonance (MR) technology. The ultrasound modality FibroScan (Echosens) is currently the most widely available, although some data suggest the more expensive MR elastography has higher sensitivity (94% sensitive for METAVIR F2 or higher compared to 79% by FibroScan).^20,21 While each of these modalities has limitations (eg, body habitus, availability), these tests allow stratification of patients into categories of low, moderate, and high risk for cirrhosis without the risks of biopsy.

A curable viral infection

HCV is one of the few curable chronic viral infections; unlike HBV and HIV, HCV does not create a long-term intra-nuclear reservoir. DAAs have cure rates of more than 95% for many HCV genotypes,^22-24 allowing the possibility for dramatic reductions in prevalence in the decades to come.

Cure is defined by reaching a sustained virologic response (SVR), or absence of detectable viral load, 12 weeks after completion of therapy. Patients with HCV infection with advanced fibrosis who achieve SVR have shown benefits beyond improvement in liver function and histology. One large, multicenter, prospective study of 530 patients with chronic HCV, for example, found that those who achieved SVR experienced a 76% reduction in the risk of HCC and a 66% reduction in all-cause mortality (number needed to treat [NNT] was 5.8 to prevent one death or 6 to prevent one case of HCC in 10 years) compared to those without SVR.²⁵ Other extrahepatic manifestations that impair quality of life, such as renal disease, autoimmune disease, and circulatory problems, are likewise reduced.²⁵

Guidelines now recommend treating most patients with HCV infection

Until 2011, HCV treatment included the injectable immune-activating agent interferon and the non–HCV-specific antiviral ribavirin. This regimen had low SVR rates of 40% to 60% and adverse effects that were often intolerable.²⁶ The advent of the first-generation HCV protease inhibitors in 2011 improved SVR rates, which have continued to improve exponentially with the development of combination therapy using DAAs (TABLE 2^27-29). (In order to stay up to date with the latest options for the treatment of HCV, see The American Association for the Study of Liver Diseases treatment guidelines at: http://hcvguidelines.org.)

What the guidelines say. Due to the tolerability and efficacy of the new DAAs, current guidelines state that HCV treatment should be recommended to most patients with HCV infection—not just those with advanced disease.³⁰ This is a major change from prior guidelines, which were based on more toxic and less effective regimens. Limited data from long-term cohort studies of patients using interferon-based regimens suggest that the benefits of SVR are greatest for those treated at early stages before significant fibrosis develops. At least one analysis involving over 4000 patients found, however, that this approach may be less cost-effective, with an NNT of 20 to prevent one death in 20 years.³¹

Current guidelines state that HCV treatment should be recommended to most patients with HCV infection—not just those with advanced disease.In practice, the decision to treat requires a discussion between the patient and provider, weighing the risks and benefits of treatment in the context of the patients’ comorbidities and overall life expectancy. Such a discussion must also include cost. Many insurance companies will still only cover antiviral therapy for patients with advanced fibrosis, but these restrictions are slowly lifting and are having significant implications for our health care system. By one estimate, treating all patients with HCV at current drug prices would cost approximately $250 billion—about one-tenth of the total annual health care costs in this country.³² As policies change and the cost of drug regimens decreases from increasing competition, access is likely to improve for the majority of Americans.

Which regimen is most likely to be successful?

Many factors influence the choice of regimen and likelihood for SVR. These factors include whether the patient has cirrhosis and any comorbidities, the hepatitis C genotype involved, and any prior treatment the patient may have received. (See TABLE 3^{7,12,18,28,30,33} for a comprehensive list.)

The easiest patients to treat are treatment-naive, with minimal liver disease and a favorable genotype. For example, combination therapy with the NS5B inhibitor sofosbuvir and an NS5A inhibitor (ledipasvir, daclatasvir, or velpatasvir) administered for 12 weeks has an SVR rate of >95% in genotype-1, treatment-naive, non-cirrhotic patients.^22-24 Patients with prior treatment failure, especially failure on DAA therapy, or who have genotype 3, may be less responsive to standard therapies and may require more complex regimens or a longer duration of therapy.

Patients requiring special attention. It’s preferable to manage patients with decompensated liver disease in a specialized hepatology center due to the possibility of further decline and need for transplant prior to completion of therapy. Patients with HIV are another population that requires special attention. As many as 25% of HIV-infected patients are co-infected with HCV; their treatment follows the same principles as that in non-HIV patients, with extra attention paid to avoiding drug-drug interactions. Elbasvir/­grazoprevir, for example, should not be used with any protease inhibitors, with nevirapine, or with efavirenz, and sofosbuvir should not be used with efavirenz, nevirapine, or tipranavir.³⁴

Beyond medication regimens: The advice you’ll offer

In addition to counseling about antiviral therapy, patients with HCV infection require other types of advice and care that are often best administered by a primary care physician who is familiar with the patient and his or her family and community.

Prevention of transmission

Many patients have concerns about transmission of the virus to family members, co-workers, and sexual partners. You can assure patients that they are not likely to spread the virus in the workplace, even in health care environments.

Consider screening all HCV patients for diabetes mellitus because patients with chronic HCV infection have a higher prevalence of insulin resistance than those in the general population.Close contacts are also not at risk as long as basic prevention measures, such as not sharing toothbrushes or razors, are established to avoid transmission of blood and bodily fluids. Patient handouts can be found at the Centers for Disease Control and Prevention Web site (http://www.cdc.gov/hepatitis/hcv/patienteduhcv.htm#cdc).³⁵

Patients and their sexual partners, however, must be counseled about the risk of sexual transmission. In monogamous relationships between serodiscordant partners who practice vaginal intercourse, there is a low, but clinically important, risk of transmission of HCV—up to 0.6% per year.³⁶ Anal intercourse and co-infection with HIV increase this risk significantly.³⁷ Pregnant women must be advised on the currently non-modifiable risk of transmission to newborns, which is approximately 6% in mono-infected women, but may be at least twice as likely in HIV/HCV co-infected women.^38,39

Staying healthy. In addition to pneumococcal and standard age-appropriate vaccines, vaccination against hepatitis A and HBV is recommended for all HCV-infected patients to reduce the risk of a severe acute hepatitis.^40,41 Advise patients to avoid alcohol, to consume a healthy diet, and to participate in regular activity and exercise. Review the patient’s medication list for hepatotoxic drugs and counsel the patient on the risks of excessive use of acetaminophen, non-steroidal anti-inflammatory drugs, and herbal medicines such as kava kava. Because obesity and metabolic syndrome are known risk factors for hepatic steatosis, which hastens the progression to cirrhosis and liver failure, counsel overweight and obese patients on the importance of healthy weight loss.^42,43

Disease-related screenings. Consider screening all HCV patients for diabetes mellitus (DM) because people with chronic HCV infection have a higher prevalence of insulin resistance than those who are HCV-negative, and patients with type 2 DM are at higher risk for worse outcomes of their HCV infection.⁴⁴ In addition, screen all patients with a METAVIR score of F3 or higher every 6 months for HCC using liver ultrasound, and recommend upper endoscopy to patients with cirrhosis to screen for esophageal varices.^45,46

Health maintenance after treatment

Once patients have achieved SVR 12 weeks after completion of therapy, they are deemed cured. However, those patients who were already METAVIR F3 or higher maintain sufficient risk of HCC to recommend ongoing screening with ultrasound.^47,48

CORRESPONDENCE
Mark Shaffer, MD, 3209 Colonial Drive, Columbia, SC 29206; [email protected].

Several recent developments have prompted a renewed focus on the way we screen for, and manage the treatment of, hepatitis C virus (HCV) infection. In 2013, the United States Preventive Services Task Force expanded its HCV screening guidelines to include baby boomers born between 1945 and 1965, regardless of apparent risk factors (TABLE 1¹).² The recommendation is based on the high prevalence of chronic HCV in this cohort, estimated to be 4.3%, which is about 4 times higher than that of the general US population.³ It is believed that 75% of chronic HCV infections in the United States are in this cohort. After decades of infection, many in this age group are now presenting with advanced disease, leading to 19,659 HCV-related deaths in America in 2014.⁴

In addition, while HCV incidence in America had been steadily declining, it is now once again on the rise among young, non-urban whites, mainly because of increasing intravenous drug use in this population.⁵ On a positive note, new highly-effective and better-tolerated treatments are greatly improving the care we can provide.

In light of these factors, family physicians (FPs) are likely to be screening for HCV more than ever before and must be prepared to provide appropriate counseling and initial clinical management for those with positive test results. This article reviews the evaluation and primary care management of HCV-infected patients, as well as approaches to treatment with the newest direct-acting antivirals (DAAs).

IMAGE: © JOE GORMAN

The natural history of hepatitis C (and what we’re seeing as boomers age)

Acute HCV infection is rarely symptomatic, but results in chronic infection approximately 75% of the time.⁶ While some chronically infected individuals remain unaffected, most develop some degree of hepatic fibrosis, and 20% will develop cirrhosis within 20 years of diagnosis.^7-9

The rate of progression is variable; factors that result in more rapid progression of liver disease include coinfection with HIV or HBV, overweight or obesity, insulin resistance, male gender, and use of alcohol.⁷ As the baby boomer cohort has aged, patients infected in their youth are now presenting with the sequelae of decompensated cirrhosis, including ascites, portal vein thrombosis, and thrombocytopenia.

Extrahepatic manifestations of chronic hepatitis C can include fatigue, membrano­proliferative glomerulonephritis, porphyria cutanea tarda, cryoglobulinemia, a higher likelihood of insulin resistance, and possibly lymphoma.^10-12

Chronic HCV is also the major contributor to the increased incidence of hepatocellular carcinoma (HCC), which has tripled in the past 2 decades in the United States.¹³

Although results are inconsistent, studies suggest 5% to 10% of HCV-infected patients will succumb to liver-related death.⁷

Who you’ll screen

If your patient is at heightened risk of contracting HCV infection (TABLE 1¹) or was born between 1945 and 1965, you’ll want to screen for infection with an HCV antibody test. A positive antibody test must be followed by testing for hepatitis C viral RNA to confirm whether the patient is chronically infected or is among the approximately 25% of patients who spontaneously clear the virus.⁶

The prevalence of  chronic HCV infection among baby boomers is about 4 times higher than that of the general US population.For the patient with no detectable HCV RNA, no further evaluation or treatment is necessary. HCV viral load itself provides little insight into the rate of progression of the illness, but does correlate with risk of transmission.¹⁴ Counseling patients about the full testing protocol before screening can help to reduce anxiety and confusion.

At present, 6 genotypes and multiple subtypes of HCV have been identified; these have important implications for prognosis and treatment.¹⁵ HCV genotyping is frequently ordered along with a test for HCV viral load, but may be deferred until after fibrosis staging is performed (more on that in a bit). It may also be deferred if treatment is not planned within the next 12 weeks, as its main clinical use is to guide choice of treatment. Once chronic infection has been confirmed by the presence of HCV viremia, further work-up focuses on evaluating the effects on the host, which, in turn, helps the provider finalize a treatment plan (FIGURE 1¹⁶).

Follow initial screening with an evaluation including liver disease staging

Following a screen that comes back positive for HCV, you’ll conduct a more thorough history including questioning about previous or ongoing risk factors for HCV, perform a physical examination that includes looking for signs of liver failure or extrahepatic disease, and order more lab work. Laboratory investigations include a complete blood count; renal and hepatic panels; and testing for human immunodeficiency virus (HIV) antibody, hepatitis B virus (HBV) surface antigen, HBV surface antibody, and HBV core antibody.^1,17 Finally, the patient must be evaluated for hepatic fibrosis and cirrhosis to quantify the likelihood of developing liver failure and HCC.

Staging liver disease is a prerequisite to treating HCV infection because the extent of liver fibrosis impacts not only prognosis, but also the choice of the treatment regimen and the duration of therapy. The traditional gold standard for diagnosing hepatic fibrosis and cirrhosis has been a liver biopsy; however, a single 1.6-mm biopsy evaluates only a small portion of the liver and can miss affected liver parenchyma. In addition, a liver biopsy carries a small, but not inconsequential, risk of morbidity, and can be costly and complex to arrange.

Several noninvasive options are now available and are typically the preferred methods for staging liver disease. FibroSURE (LabCorp), for example, uses a peripheral venous blood sample and combines the patient’s age, gender, and 6 biochemical markers to generate a range of scores that correspond to the fibrosis component of the well-known METAVIR scoring system and correlate with results of liver biopsies.^18,19 (The METAVIR system is a histology-based scoring system that grades fibrosis from F0 [no fibrosis] to F4 [cirrhosis].)

Chronic HCV infection is a major contributor to the increased incidence of hepatocellular carcinoma, which has tripled in the past 2 decades in the United States.Noninvasive imaging studies assess for fibrosis more directly by assessing liver elasticity, either by ultrasound or magnetic resonance (MR) technology. The ultrasound modality FibroScan (Echosens) is currently the most widely available, although some data suggest the more expensive MR elastography has higher sensitivity (94% sensitive for METAVIR F2 or higher compared to 79% by FibroScan).^20,21 While each of these modalities has limitations (eg, body habitus, availability), these tests allow stratification of patients into categories of low, moderate, and high risk for cirrhosis without the risks of biopsy.

A curable viral infection

HCV is one of the few curable chronic viral infections; unlike HBV and HIV, HCV does not create a long-term intra-nuclear reservoir. DAAs have cure rates of more than 95% for many HCV genotypes,^22-24 allowing the possibility for dramatic reductions in prevalence in the decades to come.

Cure is defined by reaching a sustained virologic response (SVR), or absence of detectable viral load, 12 weeks after completion of therapy. Patients with HCV infection with advanced fibrosis who achieve SVR have shown benefits beyond improvement in liver function and histology. One large, multicenter, prospective study of 530 patients with chronic HCV, for example, found that those who achieved SVR experienced a 76% reduction in the risk of HCC and a 66% reduction in all-cause mortality (number needed to treat [NNT] was 5.8 to prevent one death or 6 to prevent one case of HCC in 10 years) compared to those without SVR.²⁵ Other extrahepatic manifestations that impair quality of life, such as renal disease, autoimmune disease, and circulatory problems, are likewise reduced.²⁵

Guidelines now recommend treating most patients with HCV infection

Until 2011, HCV treatment included the injectable immune-activating agent interferon and the non–HCV-specific antiviral ribavirin. This regimen had low SVR rates of 40% to 60% and adverse effects that were often intolerable.²⁶ The advent of the first-generation HCV protease inhibitors in 2011 improved SVR rates, which have continued to improve exponentially with the development of combination therapy using DAAs (TABLE 2^27-29). (In order to stay up to date with the latest options for the treatment of HCV, see The American Association for the Study of Liver Diseases treatment guidelines at: http://hcvguidelines.org.)

What the guidelines say. Due to the tolerability and efficacy of the new DAAs, current guidelines state that HCV treatment should be recommended to most patients with HCV infection—not just those with advanced disease.³⁰ This is a major change from prior guidelines, which were based on more toxic and less effective regimens. Limited data from long-term cohort studies of patients using interferon-based regimens suggest that the benefits of SVR are greatest for those treated at early stages before significant fibrosis develops. At least one analysis involving over 4000 patients found, however, that this approach may be less cost-effective, with an NNT of 20 to prevent one death in 20 years.³¹

Current guidelines state that HCV treatment should be recommended to most patients with HCV infection—not just those with advanced disease.In practice, the decision to treat requires a discussion between the patient and provider, weighing the risks and benefits of treatment in the context of the patients’ comorbidities and overall life expectancy. Such a discussion must also include cost. Many insurance companies will still only cover antiviral therapy for patients with advanced fibrosis, but these restrictions are slowly lifting and are having significant implications for our health care system. By one estimate, treating all patients with HCV at current drug prices would cost approximately $250 billion—about one-tenth of the total annual health care costs in this country.³² As policies change and the cost of drug regimens decreases from increasing competition, access is likely to improve for the majority of Americans.

Which regimen is most likely to be successful?

Many factors influence the choice of regimen and likelihood for SVR. These factors include whether the patient has cirrhosis and any comorbidities, the hepatitis C genotype involved, and any prior treatment the patient may have received. (See TABLE 3^{7,12,18,28,30,33} for a comprehensive list.)

The easiest patients to treat are treatment-naive, with minimal liver disease and a favorable genotype. For example, combination therapy with the NS5B inhibitor sofosbuvir and an NS5A inhibitor (ledipasvir, daclatasvir, or velpatasvir) administered for 12 weeks has an SVR rate of >95% in genotype-1, treatment-naive, non-cirrhotic patients.^22-24 Patients with prior treatment failure, especially failure on DAA therapy, or who have genotype 3, may be less responsive to standard therapies and may require more complex regimens or a longer duration of therapy.

Patients requiring special attention. It’s preferable to manage patients with decompensated liver disease in a specialized hepatology center due to the possibility of further decline and need for transplant prior to completion of therapy. Patients with HIV are another population that requires special attention. As many as 25% of HIV-infected patients are co-infected with HCV; their treatment follows the same principles as that in non-HIV patients, with extra attention paid to avoiding drug-drug interactions. Elbasvir/­grazoprevir, for example, should not be used with any protease inhibitors, with nevirapine, or with efavirenz, and sofosbuvir should not be used with efavirenz, nevirapine, or tipranavir.³⁴

Beyond medication regimens: The advice you’ll offer

In addition to counseling about antiviral therapy, patients with HCV infection require other types of advice and care that are often best administered by a primary care physician who is familiar with the patient and his or her family and community.

Prevention of transmission

Many patients have concerns about transmission of the virus to family members, co-workers, and sexual partners. You can assure patients that they are not likely to spread the virus in the workplace, even in health care environments.

Consider screening all HCV patients for diabetes mellitus because patients with chronic HCV infection have a higher prevalence of insulin resistance than those in the general population.Close contacts are also not at risk as long as basic prevention measures, such as not sharing toothbrushes or razors, are established to avoid transmission of blood and bodily fluids. Patient handouts can be found at the Centers for Disease Control and Prevention Web site (http://www.cdc.gov/hepatitis/hcv/patienteduhcv.htm#cdc).³⁵

Patients and their sexual partners, however, must be counseled about the risk of sexual transmission. In monogamous relationships between serodiscordant partners who practice vaginal intercourse, there is a low, but clinically important, risk of transmission of HCV—up to 0.6% per year.³⁶ Anal intercourse and co-infection with HIV increase this risk significantly.³⁷ Pregnant women must be advised on the currently non-modifiable risk of transmission to newborns, which is approximately 6% in mono-infected women, but may be at least twice as likely in HIV/HCV co-infected women.^38,39

Staying healthy. In addition to pneumococcal and standard age-appropriate vaccines, vaccination against hepatitis A and HBV is recommended for all HCV-infected patients to reduce the risk of a severe acute hepatitis.^40,41 Advise patients to avoid alcohol, to consume a healthy diet, and to participate in regular activity and exercise. Review the patient’s medication list for hepatotoxic drugs and counsel the patient on the risks of excessive use of acetaminophen, non-steroidal anti-inflammatory drugs, and herbal medicines such as kava kava. Because obesity and metabolic syndrome are known risk factors for hepatic steatosis, which hastens the progression to cirrhosis and liver failure, counsel overweight and obese patients on the importance of healthy weight loss.^42,43

Disease-related screenings. Consider screening all HCV patients for diabetes mellitus (DM) because people with chronic HCV infection have a higher prevalence of insulin resistance than those who are HCV-negative, and patients with type 2 DM are at higher risk for worse outcomes of their HCV infection.⁴⁴ In addition, screen all patients with a METAVIR score of F3 or higher every 6 months for HCC using liver ultrasound, and recommend upper endoscopy to patients with cirrhosis to screen for esophageal varices.^45,46

Health maintenance after treatment

Once patients have achieved SVR 12 weeks after completion of therapy, they are deemed cured. However, those patients who were already METAVIR F3 or higher maintain sufficient risk of HCC to recommend ongoing screening with ultrasound.^47,48

CORRESPONDENCE
Mark Shaffer, MD, 3209 Colonial Drive, Columbia, SC 29206; [email protected].

Several recent developments have prompted a renewed focus on the way we screen for, and manage the treatment of, hepatitis C virus (HCV) infection. In 2013, the United States Preventive Services Task Force expanded its HCV screening guidelines to include baby boomers born between 1945 and 1965, regardless of apparent risk factors (TABLE 1¹).² The recommendation is based on the high prevalence of chronic HCV in this cohort, estimated to be 4.3%, which is about 4 times higher than that of the general US population.³ It is believed that 75% of chronic HCV infections in the United States are in this cohort. After decades of infection, many in this age group are now presenting with advanced disease, leading to 19,659 HCV-related deaths in America in 2014.⁴

In addition, while HCV incidence in America had been steadily declining, it is now once again on the rise among young, non-urban whites, mainly because of increasing intravenous drug use in this population.⁵ On a positive note, new highly-effective and better-tolerated treatments are greatly improving the care we can provide.

In light of these factors, family physicians (FPs) are likely to be screening for HCV more than ever before and must be prepared to provide appropriate counseling and initial clinical management for those with positive test results. This article reviews the evaluation and primary care management of HCV-infected patients, as well as approaches to treatment with the newest direct-acting antivirals (DAAs).

IMAGE: © JOE GORMAN

The natural history of hepatitis C (and what we’re seeing as boomers age)

Acute HCV infection is rarely symptomatic, but results in chronic infection approximately 75% of the time.⁶ While some chronically infected individuals remain unaffected, most develop some degree of hepatic fibrosis, and 20% will develop cirrhosis within 20 years of diagnosis.^7-9

The rate of progression is variable; factors that result in more rapid progression of liver disease include coinfection with HIV or HBV, overweight or obesity, insulin resistance, male gender, and use of alcohol.⁷ As the baby boomer cohort has aged, patients infected in their youth are now presenting with the sequelae of decompensated cirrhosis, including ascites, portal vein thrombosis, and thrombocytopenia.

Extrahepatic manifestations of chronic hepatitis C can include fatigue, membrano­proliferative glomerulonephritis, porphyria cutanea tarda, cryoglobulinemia, a higher likelihood of insulin resistance, and possibly lymphoma.^10-12

Chronic HCV is also the major contributor to the increased incidence of hepatocellular carcinoma (HCC), which has tripled in the past 2 decades in the United States.¹³

Although results are inconsistent, studies suggest 5% to 10% of HCV-infected patients will succumb to liver-related death.⁷

Who you’ll screen

If your patient is at heightened risk of contracting HCV infection (TABLE 1¹) or was born between 1945 and 1965, you’ll want to screen for infection with an HCV antibody test. A positive antibody test must be followed by testing for hepatitis C viral RNA to confirm whether the patient is chronically infected or is among the approximately 25% of patients who spontaneously clear the virus.⁶

The prevalence of  chronic HCV infection among baby boomers is about 4 times higher than that of the general US population.For the patient with no detectable HCV RNA, no further evaluation or treatment is necessary. HCV viral load itself provides little insight into the rate of progression of the illness, but does correlate with risk of transmission.¹⁴ Counseling patients about the full testing protocol before screening can help to reduce anxiety and confusion.

At present, 6 genotypes and multiple subtypes of HCV have been identified; these have important implications for prognosis and treatment.¹⁵ HCV genotyping is frequently ordered along with a test for HCV viral load, but may be deferred until after fibrosis staging is performed (more on that in a bit). It may also be deferred if treatment is not planned within the next 12 weeks, as its main clinical use is to guide choice of treatment. Once chronic infection has been confirmed by the presence of HCV viremia, further work-up focuses on evaluating the effects on the host, which, in turn, helps the provider finalize a treatment plan (FIGURE 1¹⁶).

Follow initial screening with an evaluation including liver disease staging

Following a screen that comes back positive for HCV, you’ll conduct a more thorough history including questioning about previous or ongoing risk factors for HCV, perform a physical examination that includes looking for signs of liver failure or extrahepatic disease, and order more lab work. Laboratory investigations include a complete blood count; renal and hepatic panels; and testing for human immunodeficiency virus (HIV) antibody, hepatitis B virus (HBV) surface antigen, HBV surface antibody, and HBV core antibody.^1,17 Finally, the patient must be evaluated for hepatic fibrosis and cirrhosis to quantify the likelihood of developing liver failure and HCC.

Staging liver disease is a prerequisite to treating HCV infection because the extent of liver fibrosis impacts not only prognosis, but also the choice of the treatment regimen and the duration of therapy. The traditional gold standard for diagnosing hepatic fibrosis and cirrhosis has been a liver biopsy; however, a single 1.6-mm biopsy evaluates only a small portion of the liver and can miss affected liver parenchyma. In addition, a liver biopsy carries a small, but not inconsequential, risk of morbidity, and can be costly and complex to arrange.

Several noninvasive options are now available and are typically the preferred methods for staging liver disease. FibroSURE (LabCorp), for example, uses a peripheral venous blood sample and combines the patient’s age, gender, and 6 biochemical markers to generate a range of scores that correspond to the fibrosis component of the well-known METAVIR scoring system and correlate with results of liver biopsies.^18,19 (The METAVIR system is a histology-based scoring system that grades fibrosis from F0 [no fibrosis] to F4 [cirrhosis].)

Chronic HCV infection is a major contributor to the increased incidence of hepatocellular carcinoma, which has tripled in the past 2 decades in the United States.Noninvasive imaging studies assess for fibrosis more directly by assessing liver elasticity, either by ultrasound or magnetic resonance (MR) technology. The ultrasound modality FibroScan (Echosens) is currently the most widely available, although some data suggest the more expensive MR elastography has higher sensitivity (94% sensitive for METAVIR F2 or higher compared to 79% by FibroScan).^20,21 While each of these modalities has limitations (eg, body habitus, availability), these tests allow stratification of patients into categories of low, moderate, and high risk for cirrhosis without the risks of biopsy.

A curable viral infection

HCV is one of the few curable chronic viral infections; unlike HBV and HIV, HCV does not create a long-term intra-nuclear reservoir. DAAs have cure rates of more than 95% for many HCV genotypes,^22-24 allowing the possibility for dramatic reductions in prevalence in the decades to come.

Cure is defined by reaching a sustained virologic response (SVR), or absence of detectable viral load, 12 weeks after completion of therapy. Patients with HCV infection with advanced fibrosis who achieve SVR have shown benefits beyond improvement in liver function and histology. One large, multicenter, prospective study of 530 patients with chronic HCV, for example, found that those who achieved SVR experienced a 76% reduction in the risk of HCC and a 66% reduction in all-cause mortality (number needed to treat [NNT] was 5.8 to prevent one death or 6 to prevent one case of HCC in 10 years) compared to those without SVR.²⁵ Other extrahepatic manifestations that impair quality of life, such as renal disease, autoimmune disease, and circulatory problems, are likewise reduced.²⁵

Guidelines now recommend treating most patients with HCV infection

Until 2011, HCV treatment included the injectable immune-activating agent interferon and the non–HCV-specific antiviral ribavirin. This regimen had low SVR rates of 40% to 60% and adverse effects that were often intolerable.²⁶ The advent of the first-generation HCV protease inhibitors in 2011 improved SVR rates, which have continued to improve exponentially with the development of combination therapy using DAAs (TABLE 2^27-29). (In order to stay up to date with the latest options for the treatment of HCV, see The American Association for the Study of Liver Diseases treatment guidelines at: http://hcvguidelines.org.)

What the guidelines say. Due to the tolerability and efficacy of the new DAAs, current guidelines state that HCV treatment should be recommended to most patients with HCV infection—not just those with advanced disease.³⁰ This is a major change from prior guidelines, which were based on more toxic and less effective regimens. Limited data from long-term cohort studies of patients using interferon-based regimens suggest that the benefits of SVR are greatest for those treated at early stages before significant fibrosis develops. At least one analysis involving over 4000 patients found, however, that this approach may be less cost-effective, with an NNT of 20 to prevent one death in 20 years.³¹

Current guidelines state that HCV treatment should be recommended to most patients with HCV infection—not just those with advanced disease.In practice, the decision to treat requires a discussion between the patient and provider, weighing the risks and benefits of treatment in the context of the patients’ comorbidities and overall life expectancy. Such a discussion must also include cost. Many insurance companies will still only cover antiviral therapy for patients with advanced fibrosis, but these restrictions are slowly lifting and are having significant implications for our health care system. By one estimate, treating all patients with HCV at current drug prices would cost approximately $250 billion—about one-tenth of the total annual health care costs in this country.³² As policies change and the cost of drug regimens decreases from increasing competition, access is likely to improve for the majority of Americans.

Which regimen is most likely to be successful?

Many factors influence the choice of regimen and likelihood for SVR. These factors include whether the patient has cirrhosis and any comorbidities, the hepatitis C genotype involved, and any prior treatment the patient may have received. (See TABLE 3^{7,12,18,28,30,33} for a comprehensive list.)

The easiest patients to treat are treatment-naive, with minimal liver disease and a favorable genotype. For example, combination therapy with the NS5B inhibitor sofosbuvir and an NS5A inhibitor (ledipasvir, daclatasvir, or velpatasvir) administered for 12 weeks has an SVR rate of >95% in genotype-1, treatment-naive, non-cirrhotic patients.^22-24 Patients with prior treatment failure, especially failure on DAA therapy, or who have genotype 3, may be less responsive to standard therapies and may require more complex regimens or a longer duration of therapy.

Patients requiring special attention. It’s preferable to manage patients with decompensated liver disease in a specialized hepatology center due to the possibility of further decline and need for transplant prior to completion of therapy. Patients with HIV are another population that requires special attention. As many as 25% of HIV-infected patients are co-infected with HCV; their treatment follows the same principles as that in non-HIV patients, with extra attention paid to avoiding drug-drug interactions. Elbasvir/­grazoprevir, for example, should not be used with any protease inhibitors, with nevirapine, or with efavirenz, and sofosbuvir should not be used with efavirenz, nevirapine, or tipranavir.³⁴

Beyond medication regimens: The advice you’ll offer

In addition to counseling about antiviral therapy, patients with HCV infection require other types of advice and care that are often best administered by a primary care physician who is familiar with the patient and his or her family and community.

Prevention of transmission

Many patients have concerns about transmission of the virus to family members, co-workers, and sexual partners. You can assure patients that they are not likely to spread the virus in the workplace, even in health care environments.

Consider screening all HCV patients for diabetes mellitus because patients with chronic HCV infection have a higher prevalence of insulin resistance than those in the general population.Close contacts are also not at risk as long as basic prevention measures, such as not sharing toothbrushes or razors, are established to avoid transmission of blood and bodily fluids. Patient handouts can be found at the Centers for Disease Control and Prevention Web site (http://www.cdc.gov/hepatitis/hcv/patienteduhcv.htm#cdc).³⁵

Patients and their sexual partners, however, must be counseled about the risk of sexual transmission. In monogamous relationships between serodiscordant partners who practice vaginal intercourse, there is a low, but clinically important, risk of transmission of HCV—up to 0.6% per year.³⁶ Anal intercourse and co-infection with HIV increase this risk significantly.³⁷ Pregnant women must be advised on the currently non-modifiable risk of transmission to newborns, which is approximately 6% in mono-infected women, but may be at least twice as likely in HIV/HCV co-infected women.^38,39

Staying healthy. In addition to pneumococcal and standard age-appropriate vaccines, vaccination against hepatitis A and HBV is recommended for all HCV-infected patients to reduce the risk of a severe acute hepatitis.^40,41 Advise patients to avoid alcohol, to consume a healthy diet, and to participate in regular activity and exercise. Review the patient’s medication list for hepatotoxic drugs and counsel the patient on the risks of excessive use of acetaminophen, non-steroidal anti-inflammatory drugs, and herbal medicines such as kava kava. Because obesity and metabolic syndrome are known risk factors for hepatic steatosis, which hastens the progression to cirrhosis and liver failure, counsel overweight and obese patients on the importance of healthy weight loss.^42,43

Disease-related screenings. Consider screening all HCV patients for diabetes mellitus (DM) because people with chronic HCV infection have a higher prevalence of insulin resistance than those who are HCV-negative, and patients with type 2 DM are at higher risk for worse outcomes of their HCV infection.⁴⁴ In addition, screen all patients with a METAVIR score of F3 or higher every 6 months for HCC using liver ultrasound, and recommend upper endoscopy to patients with cirrhosis to screen for esophageal varices.^45,46

Health maintenance after treatment

Once patients have achieved SVR 12 weeks after completion of therapy, they are deemed cured. However, those patients who were already METAVIR F3 or higher maintain sufficient risk of HCC to recommend ongoing screening with ultrasound.^47,48

CORRESPONDENCE
Mark Shaffer, MD, 3209 Colonial Drive, Columbia, SC 29206; [email protected].

You are probably one of the million+ physicians who received a letter from the Surgeon General urging us to use opioids judiciously,¹ and you are likely familiar with the 2016 CDC Guideline for Prescribing Opioids for Chronic Pain.² (See JFP’s “Opioids for chronic pain: The CDC’s 12 recommendations,” 2016;65:906-909.) Most of these recommendations are common-sense practices, such as reducing doses, using alternative medications and treatments, monitoring prescribing through state databases, conducting random drug tests, consulting pain and addiction specialists, and establishing clear treatment goals.

But the guidelines only go so far. They don’t address the empathy, perseverance, and insight needed to stick with these patients and oversee their care. And they don’t directly address the patients who are already taking opioids for chronic pain when they arrive at our offices. Despite nearly 40 years of practicing family medicine, I can count on one hand the number of patients for whom I initiated opioid medication. Yet I have managed many patients with chronic pain who were already on hefty doses of narcotics when they became my patients. Rather than refuse to care for them, we should seek to understand their story, continuously try other medications and therapies, repeatedly attempt to reduce dosages, and frequently check substance databases.

It's no wonder some of us just say "No" to caring for patients with chronic pain.Following the guidelines is no guarantee that our prescribing practices won’t be called into question. I have seen excellent family physicians censured by state licensing boards unjustifiably. One colleague was accused by a patient of “getting him addicted,” only after the physician refused to continue prescribing narcotics. Based on this single complaint, the physician had his license temporarily revoked with no due process whatsoever. He got his license back after an appeals process that took several months, cost many dollars, and inflicted significant emotional trauma. No wonder some of us just say “No” to caring for patients with chronic pain.

Perseverance and motivation. I remind myself that good, well-intentioned, and careful primary care physicians are NOT the cause of this epidemic. I encourage you to stick with these patients (lest they turn to the streets to obtain heroin laced with fen­tanyl), and look for sources of motivation. You may be motivated, as I was, by a physician’s story in JAMA about his 49-year-old younger sister, a vibrant, accomplished, caring woman whose chronic pain led to her death in a jail cell after she became combative in the ED.³ Had she been treated as a patient with a chronic illness, rather than a criminal with a character flaw, I suspect she would be alive today.

You are probably one of the million+ physicians who received a letter from the Surgeon General urging us to use opioids judiciously,¹ and you are likely familiar with the 2016 CDC Guideline for Prescribing Opioids for Chronic Pain.² (See JFP’s “Opioids for chronic pain: The CDC’s 12 recommendations,” 2016;65:906-909.) Most of these recommendations are common-sense practices, such as reducing doses, using alternative medications and treatments, monitoring prescribing through state databases, conducting random drug tests, consulting pain and addiction specialists, and establishing clear treatment goals.

But the guidelines only go so far. They don’t address the empathy, perseverance, and insight needed to stick with these patients and oversee their care. And they don’t directly address the patients who are already taking opioids for chronic pain when they arrive at our offices. Despite nearly 40 years of practicing family medicine, I can count on one hand the number of patients for whom I initiated opioid medication. Yet I have managed many patients with chronic pain who were already on hefty doses of narcotics when they became my patients. Rather than refuse to care for them, we should seek to understand their story, continuously try other medications and therapies, repeatedly attempt to reduce dosages, and frequently check substance databases.

It's no wonder some of us just say "No" to caring for patients with chronic pain.Following the guidelines is no guarantee that our prescribing practices won’t be called into question. I have seen excellent family physicians censured by state licensing boards unjustifiably. One colleague was accused by a patient of “getting him addicted,” only after the physician refused to continue prescribing narcotics. Based on this single complaint, the physician had his license temporarily revoked with no due process whatsoever. He got his license back after an appeals process that took several months, cost many dollars, and inflicted significant emotional trauma. No wonder some of us just say “No” to caring for patients with chronic pain.

Perseverance and motivation. I remind myself that good, well-intentioned, and careful primary care physicians are NOT the cause of this epidemic. I encourage you to stick with these patients (lest they turn to the streets to obtain heroin laced with fen­tanyl), and look for sources of motivation. You may be motivated, as I was, by a physician’s story in JAMA about his 49-year-old younger sister, a vibrant, accomplished, caring woman whose chronic pain led to her death in a jail cell after she became combative in the ED.³ Had she been treated as a patient with a chronic illness, rather than a criminal with a character flaw, I suspect she would be alive today.

You are probably one of the million+ physicians who received a letter from the Surgeon General urging us to use opioids judiciously,¹ and you are likely familiar with the 2016 CDC Guideline for Prescribing Opioids for Chronic Pain.² (See JFP’s “Opioids for chronic pain: The CDC’s 12 recommendations,” 2016;65:906-909.) Most of these recommendations are common-sense practices, such as reducing doses, using alternative medications and treatments, monitoring prescribing through state databases, conducting random drug tests, consulting pain and addiction specialists, and establishing clear treatment goals.

But the guidelines only go so far. They don’t address the empathy, perseverance, and insight needed to stick with these patients and oversee their care. And they don’t directly address the patients who are already taking opioids for chronic pain when they arrive at our offices. Despite nearly 40 years of practicing family medicine, I can count on one hand the number of patients for whom I initiated opioid medication. Yet I have managed many patients with chronic pain who were already on hefty doses of narcotics when they became my patients. Rather than refuse to care for them, we should seek to understand their story, continuously try other medications and therapies, repeatedly attempt to reduce dosages, and frequently check substance databases.

It's no wonder some of us just say "No" to caring for patients with chronic pain.Following the guidelines is no guarantee that our prescribing practices won’t be called into question. I have seen excellent family physicians censured by state licensing boards unjustifiably. One colleague was accused by a patient of “getting him addicted,” only after the physician refused to continue prescribing narcotics. Based on this single complaint, the physician had his license temporarily revoked with no due process whatsoever. He got his license back after an appeals process that took several months, cost many dollars, and inflicted significant emotional trauma. No wonder some of us just say “No” to caring for patients with chronic pain.

Perseverance and motivation. I remind myself that good, well-intentioned, and careful primary care physicians are NOT the cause of this epidemic. I encourage you to stick with these patients (lest they turn to the streets to obtain heroin laced with fen­tanyl), and look for sources of motivation. You may be motivated, as I was, by a physician’s story in JAMA about his 49-year-old younger sister, a vibrant, accomplished, caring woman whose chronic pain led to her death in a jail cell after she became combative in the ED.³ Had she been treated as a patient with a chronic illness, rather than a criminal with a character flaw, I suspect she would be alive today.

EVIDENCE SUMMARY

A 2010 meta-analysis evaluated 14 RCTs investigating the effectiveness of giving sweet solutions before immunization in 1707 healthy term infants from beyond the neonatal period to 12 months of age.¹ Intervention groups received 0.25 to 10 mL (median, 2 mL) of 12% to 75% sucrose or 30% to 40% glucose orally 2 minutes before one to 4 injections (one study used 3 oral doses every 30 seconds, and one study added topical EMLA cream). Control groups received water or nothing (plus topical placebo in one study).

Pooled outcome data for crying duration from 6 studies (5 sucrose, one glucose; 716 injections) showed no significant difference between groups. When 2 studies with widely differing results using 12% sucrose were removed, however, a statistically significant weighted mean difference of 12 seconds less crying favored sweet solutions (3 sucrose, one glucose; 568 injections; 95% confidence interval, −23 to −0.78).

Differences among studies in volumes and concentrations of sweet solutions used prevented investigators from ascertaining optimal dosing.

Sucrose solution significantly reduces crying time compared with placebo

A 2014 double-blind RCT evaluated sucrose solutions compared with sterile water in older infants.² One nurse gave 2 mL of a 75% sucrose solution, a 25% sucrose solution, or sterile water orally over 15 seconds immediately before administering diphtheria, tetanus, acellular pertussis/Haemophilus influenzae type b/inactivated poliovirus (DTaP/Hib/IPV), pneumococcal, and hepatitis A vaccines to 537 healthy 16- to 19-month-old infants simultaneously in the right and left deltoids. Parents cuddled the infant over one shoulder while a distracting noise was made. Pacifiers (5 infants) and pretreatment paracetamol (8 infants) were permitted.

Infants receiving sucrose solutions showed significantly reduced total crying times compared with controls (75% sucrose, 43 seconds; 25% sucrose, 62 seconds; placebo, 120 seconds; P<.001 for 75% sucrose compared with other solutions; P<.001 for 25% sucrose compared with placebo).

Glucose also shortens crying

A 2012 double-blind RCT compared glucose solution with sterile water before vaccination in 120 healthy infants 2 months of age.³ Parents used a syringe to apply 2 mL of a 25% glucose solution or sterile water over 30 seconds to the lateral side of the infant’s tongue immediately before injection of DTaP/Hib/IPV vaccine into the right thigh followed by injection of hepatitis B vaccine into the left thigh.

Infants lay on the examination table in the supine position with the head elevated. Parents weren’t permitted to use a pacifier or bottle, or swaddle, cuddle, or restrain the infant during the procedure, but they were allowed to lift and calm the infant 15 seconds after the injections. Mean full-lung crying time and mean total crying time were significantly shorter in the treatment group (TABLE³).

EVIDENCE SUMMARY

A 2010 meta-analysis evaluated 14 RCTs investigating the effectiveness of giving sweet solutions before immunization in 1707 healthy term infants from beyond the neonatal period to 12 months of age.¹ Intervention groups received 0.25 to 10 mL (median, 2 mL) of 12% to 75% sucrose or 30% to 40% glucose orally 2 minutes before one to 4 injections (one study used 3 oral doses every 30 seconds, and one study added topical EMLA cream). Control groups received water or nothing (plus topical placebo in one study).

Pooled outcome data for crying duration from 6 studies (5 sucrose, one glucose; 716 injections) showed no significant difference between groups. When 2 studies with widely differing results using 12% sucrose were removed, however, a statistically significant weighted mean difference of 12 seconds less crying favored sweet solutions (3 sucrose, one glucose; 568 injections; 95% confidence interval, −23 to −0.78).

Differences among studies in volumes and concentrations of sweet solutions used prevented investigators from ascertaining optimal dosing.

Sucrose solution significantly reduces crying time compared with placebo

A 2014 double-blind RCT evaluated sucrose solutions compared with sterile water in older infants.² One nurse gave 2 mL of a 75% sucrose solution, a 25% sucrose solution, or sterile water orally over 15 seconds immediately before administering diphtheria, tetanus, acellular pertussis/Haemophilus influenzae type b/inactivated poliovirus (DTaP/Hib/IPV), pneumococcal, and hepatitis A vaccines to 537 healthy 16- to 19-month-old infants simultaneously in the right and left deltoids. Parents cuddled the infant over one shoulder while a distracting noise was made. Pacifiers (5 infants) and pretreatment paracetamol (8 infants) were permitted.

Infants receiving sucrose solutions showed significantly reduced total crying times compared with controls (75% sucrose, 43 seconds; 25% sucrose, 62 seconds; placebo, 120 seconds; P<.001 for 75% sucrose compared with other solutions; P<.001 for 25% sucrose compared with placebo).

Glucose also shortens crying

A 2012 double-blind RCT compared glucose solution with sterile water before vaccination in 120 healthy infants 2 months of age.³ Parents used a syringe to apply 2 mL of a 25% glucose solution or sterile water over 30 seconds to the lateral side of the infant’s tongue immediately before injection of DTaP/Hib/IPV vaccine into the right thigh followed by injection of hepatitis B vaccine into the left thigh.

Infants lay on the examination table in the supine position with the head elevated. Parents weren’t permitted to use a pacifier or bottle, or swaddle, cuddle, or restrain the infant during the procedure, but they were allowed to lift and calm the infant 15 seconds after the injections. Mean full-lung crying time and mean total crying time were significantly shorter in the treatment group (TABLE³).

EVIDENCE SUMMARY

A 2010 meta-analysis evaluated 14 RCTs investigating the effectiveness of giving sweet solutions before immunization in 1707 healthy term infants from beyond the neonatal period to 12 months of age.¹ Intervention groups received 0.25 to 10 mL (median, 2 mL) of 12% to 75% sucrose or 30% to 40% glucose orally 2 minutes before one to 4 injections (one study used 3 oral doses every 30 seconds, and one study added topical EMLA cream). Control groups received water or nothing (plus topical placebo in one study).

Pooled outcome data for crying duration from 6 studies (5 sucrose, one glucose; 716 injections) showed no significant difference between groups. When 2 studies with widely differing results using 12% sucrose were removed, however, a statistically significant weighted mean difference of 12 seconds less crying favored sweet solutions (3 sucrose, one glucose; 568 injections; 95% confidence interval, −23 to −0.78).

Differences among studies in volumes and concentrations of sweet solutions used prevented investigators from ascertaining optimal dosing.

Sucrose solution significantly reduces crying time compared with placebo

A 2014 double-blind RCT evaluated sucrose solutions compared with sterile water in older infants.² One nurse gave 2 mL of a 75% sucrose solution, a 25% sucrose solution, or sterile water orally over 15 seconds immediately before administering diphtheria, tetanus, acellular pertussis/Haemophilus influenzae type b/inactivated poliovirus (DTaP/Hib/IPV), pneumococcal, and hepatitis A vaccines to 537 healthy 16- to 19-month-old infants simultaneously in the right and left deltoids. Parents cuddled the infant over one shoulder while a distracting noise was made. Pacifiers (5 infants) and pretreatment paracetamol (8 infants) were permitted.

Infants receiving sucrose solutions showed significantly reduced total crying times compared with controls (75% sucrose, 43 seconds; 25% sucrose, 62 seconds; placebo, 120 seconds; P<.001 for 75% sucrose compared with other solutions; P<.001 for 25% sucrose compared with placebo).

Glucose also shortens crying

A 2012 double-blind RCT compared glucose solution with sterile water before vaccination in 120 healthy infants 2 months of age.³ Parents used a syringe to apply 2 mL of a 25% glucose solution or sterile water over 30 seconds to the lateral side of the infant’s tongue immediately before injection of DTaP/Hib/IPV vaccine into the right thigh followed by injection of hepatitis B vaccine into the left thigh.

Infants lay on the examination table in the supine position with the head elevated. Parents weren’t permitted to use a pacifier or bottle, or swaddle, cuddle, or restrain the infant during the procedure, but they were allowed to lift and calm the infant 15 seconds after the injections. Mean full-lung crying time and mean total crying time were significantly shorter in the treatment group (TABLE³).

ILLUSTRATIVE CASE

A 43-year-old man has a 35-pack-year smoking history and currently smokes a pack of cigarettes a day. He is eager to quit smoking after recently learning that a close friend of his has been diagnosed with lung cancer. He asks you whether he should quit “cold turkey” or gradually. What would you recommend?

Between 2013 and 2014, one in 5 American adults reported using tobacco products some days or every day, and 66% of smokers in 2013 made at least one attempt to quit.^2,3 The risks of tobacco use and the benefits of cessation are well established, and behavioral and pharmacologic interventions both alone and in combination increase smoking cessation rates.⁴ The US Preventive Services Task Force recommends that health care providers address tobacco use and cessation with patients at regular office visits and offer behavioral and pharmacologic interventions.⁵ Current guidelines, however, make no specific recommendations regarding gradual vs abrupt smoking cessation methods.⁵

A previous Cochrane review of 10 randomized controlled trials demonstrated no significant difference in quit rates between gradual cigarette reduction leading up to a designated quit day and abrupt cessation. The meta-analysis was limited, however, by differences in patient populations, outcome definitions, and types of interventions (both pharmacologic and behavioral).⁶

In a retrospective cohort study, French investigators reviewed an online database of 62,508 smokers who presented to nationwide cessation services. The researchers found that older participants (≥45 years of age) and heavy smokers (≥21 cigarettes/d) were more likely to quit gradually than abruptly.⁷

STUDY SUMMARY

Quitting “cold turkey” is better than gradual cessation at 6 months

Lindson-Hawley, et al, conducted a randomized, controlled, non-inferiority trial in England to assess if gradual cessation is as successful as abrupt cessation as a means of quitting smoking.¹ The primary outcome was abstinence from smoking at 4 weeks, assessed using the Russell Standard, a set of 6 standard criteria (including validation by exhaled carbon monoxide concentrations of <10 ppm) used by the National Centre for Smoking Cessation and Training to decrease variability of reported smoking cessation rates in English studies.⁸

Study participants were recruited via letters from their primary care practice inviting them to call the researchers if they were interested in participating in a smoking cessation study. Almost 1100 people inquired about the study. In the end, 697 were randomized to either the abrupt-cessation group (n=355) or the gradual-cessation group (n=342). Baseline characteristics between the 2 groups were similar.

All participants were asked to schedule a quit date for 2 weeks after their enrollment. Patients randomized to the gradual-cessation group were provided nicotine replacement patches (21 mg/d) and their choice of short-acting nicotine replacement therapy (NRT) (gum, lozenges, nasal spray, sublingual tablets, inhalator, or mouth spray) to use in the 2 weeks leading up to the quit date, along with instructions to reduce smoking by half of the baseline amount by the end of the first week, and to a quarter of baseline by the end of the second week.

Patients randomized to the abrupt-cessation group were instructed to continue their current smoking habits until the cessation date; during those 2 weeks they were given nicotine patches (because the other group received them and some evidence suggests that precessation NRT increases quit rates), but no short-acting NRT.

Following the cessation date, treatment in both groups was identical, including behavioral support, 21 mg/d nicotine patches, and the participant’s choice of short-acting NRT. Behavioral support consisted of visits with a research nurse at the patient’s primary care practice weekly for 2 weeks before the quit date, the day before the quit date, weekly for 4 weeks after the quit date, and 8 weeks after the quit date.

The chosen non-inferiority margin was equal to a relative risk (RR) of 0.81 (19% reduction in effectiveness) of quitting gradually compared with abrupt cessation of smoking. Quit rates in the gradual-reduction group did not reach the threshold for non-inferiority; in fact, 4-week abstinence was significantly more likely in the abrupt-cessation group (49%) than in the gradual-cessation group (39.2%) (RR=0.80; 95% confidence interval [CI], 0.66-0.93; number needed to treat [NNT]=10). Similarly, secondary outcomes of 8-week and 6-month abstinence rates showed superiority of abrupt over gradual cessation. At 6 months after the quit date, 15.5% of the gradual-cessation group and 22% of the abrupt-cessation group remained abstinent (RR=0.71; 95% CI, 0.46-0.91; NNT=15).

Patients’ preferred method of cessation plays a role

The investigators also found a difference in successful cessation based on the participants preferred method of cessation. Participants who preferred abrupt cessation were more likely to be abstinent at 4 weeks than participants who preferred gradual cessation (52.2% vs 38.3%; P=.007).

People who prefer gradual cessation are less likely to be successful at quitting—regardless of whether they try to quit abruptly or gradually.Patients with a baseline preference for gradual cessation were equally as likely to successfully quit when allocated to abrupt cessation against their preference as when they were allocated to gradual cessation: 4-week abstinence was seen in 34.6% of patients who preferred gradual cessation and were allocated to gradual cessation and in 42% of patients who preferred gradual cessation but were allocated to abrupt cessation (P=.152).

WHAT'S NEW

Higher quality than previous studies and added element of preference

This large, well-designed, non-inferiority study showed that abrupt cessation is superior to gradual cessation. The size and design of the study, including a standardized method of assessing cessation and a standardized intervention, make this a higher quality study than those in the Cochrane meta-analysis.⁶ This study also showed that participants who preferred gradual cessation were less likely to be successful—regardless of the method to which they were ultimately randomized.

CAVEATS

Generalizability limited by race and number of cigarettes smoked

Patients lost to follow-up at 4 weeks (35 in the abrupt-cessation group and 48 in the gradual-cessation group) were assumed to have continued smoking, which may have biased the results toward abrupt cessation. That said, the large number of participants included in the study, along with the relatively small number of patients lost to follow-up, minimizes this weakness.

The participants were largely white, which may limit generalizability to non-white populations. In addition, participants smoked an average of 20 cigarettes per day and, as noted previously, an observational study of tobacco users in France found that heavy smokers (≥21 cigarettes/d) were more likely to quit gradually than abruptly, so results may not be generalizable to heavy smokers.⁷

CHALLENGES TO IMPLEMENTATION

Finding the time and staff for considerable behavioral support

One important challenge is the implementation of such a structured tobacco cessation program in primary care. Both abrupt- and gradual-cessation groups were given considerable behavioral support from research nurses. Participants in this study were seen by a nurse 7 times in the first 6 weeks of the study, and the intervention included nurse-created reduction schedules.

Even if patients in the study preferred one method of cessation to another, they were receptive to quitting either gradually or abruptly. In clinical practice, patients are often set in their desired method of cessation. In that setting, our role is then to inform them of the data and support them in whatever method they choose.

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

A 43-year-old man has a 35-pack-year smoking history and currently smokes a pack of cigarettes a day. He is eager to quit smoking after recently learning that a close friend of his has been diagnosed with lung cancer. He asks you whether he should quit “cold turkey” or gradually. What would you recommend?

Between 2013 and 2014, one in 5 American adults reported using tobacco products some days or every day, and 66% of smokers in 2013 made at least one attempt to quit.^2,3 The risks of tobacco use and the benefits of cessation are well established, and behavioral and pharmacologic interventions both alone and in combination increase smoking cessation rates.⁴ The US Preventive Services Task Force recommends that health care providers address tobacco use and cessation with patients at regular office visits and offer behavioral and pharmacologic interventions.⁵ Current guidelines, however, make no specific recommendations regarding gradual vs abrupt smoking cessation methods.⁵

A previous Cochrane review of 10 randomized controlled trials demonstrated no significant difference in quit rates between gradual cigarette reduction leading up to a designated quit day and abrupt cessation. The meta-analysis was limited, however, by differences in patient populations, outcome definitions, and types of interventions (both pharmacologic and behavioral).⁶

In a retrospective cohort study, French investigators reviewed an online database of 62,508 smokers who presented to nationwide cessation services. The researchers found that older participants (≥45 years of age) and heavy smokers (≥21 cigarettes/d) were more likely to quit gradually than abruptly.⁷

STUDY SUMMARY

Quitting “cold turkey” is better than gradual cessation at 6 months

Lindson-Hawley, et al, conducted a randomized, controlled, non-inferiority trial in England to assess if gradual cessation is as successful as abrupt cessation as a means of quitting smoking.¹ The primary outcome was abstinence from smoking at 4 weeks, assessed using the Russell Standard, a set of 6 standard criteria (including validation by exhaled carbon monoxide concentrations of <10 ppm) used by the National Centre for Smoking Cessation and Training to decrease variability of reported smoking cessation rates in English studies.⁸

Study participants were recruited via letters from their primary care practice inviting them to call the researchers if they were interested in participating in a smoking cessation study. Almost 1100 people inquired about the study. In the end, 697 were randomized to either the abrupt-cessation group (n=355) or the gradual-cessation group (n=342). Baseline characteristics between the 2 groups were similar.

All participants were asked to schedule a quit date for 2 weeks after their enrollment. Patients randomized to the gradual-cessation group were provided nicotine replacement patches (21 mg/d) and their choice of short-acting nicotine replacement therapy (NRT) (gum, lozenges, nasal spray, sublingual tablets, inhalator, or mouth spray) to use in the 2 weeks leading up to the quit date, along with instructions to reduce smoking by half of the baseline amount by the end of the first week, and to a quarter of baseline by the end of the second week.

Patients randomized to the abrupt-cessation group were instructed to continue their current smoking habits until the cessation date; during those 2 weeks they were given nicotine patches (because the other group received them and some evidence suggests that precessation NRT increases quit rates), but no short-acting NRT.

Following the cessation date, treatment in both groups was identical, including behavioral support, 21 mg/d nicotine patches, and the participant’s choice of short-acting NRT. Behavioral support consisted of visits with a research nurse at the patient’s primary care practice weekly for 2 weeks before the quit date, the day before the quit date, weekly for 4 weeks after the quit date, and 8 weeks after the quit date.

The chosen non-inferiority margin was equal to a relative risk (RR) of 0.81 (19% reduction in effectiveness) of quitting gradually compared with abrupt cessation of smoking. Quit rates in the gradual-reduction group did not reach the threshold for non-inferiority; in fact, 4-week abstinence was significantly more likely in the abrupt-cessation group (49%) than in the gradual-cessation group (39.2%) (RR=0.80; 95% confidence interval [CI], 0.66-0.93; number needed to treat [NNT]=10). Similarly, secondary outcomes of 8-week and 6-month abstinence rates showed superiority of abrupt over gradual cessation. At 6 months after the quit date, 15.5% of the gradual-cessation group and 22% of the abrupt-cessation group remained abstinent (RR=0.71; 95% CI, 0.46-0.91; NNT=15).

Patients’ preferred method of cessation plays a role

The investigators also found a difference in successful cessation based on the participants preferred method of cessation. Participants who preferred abrupt cessation were more likely to be abstinent at 4 weeks than participants who preferred gradual cessation (52.2% vs 38.3%; P=.007).

People who prefer gradual cessation are less likely to be successful at quitting—regardless of whether they try to quit abruptly or gradually.Patients with a baseline preference for gradual cessation were equally as likely to successfully quit when allocated to abrupt cessation against their preference as when they were allocated to gradual cessation: 4-week abstinence was seen in 34.6% of patients who preferred gradual cessation and were allocated to gradual cessation and in 42% of patients who preferred gradual cessation but were allocated to abrupt cessation (P=.152).

WHAT'S NEW

Higher quality than previous studies and added element of preference

This large, well-designed, non-inferiority study showed that abrupt cessation is superior to gradual cessation. The size and design of the study, including a standardized method of assessing cessation and a standardized intervention, make this a higher quality study than those in the Cochrane meta-analysis.⁶ This study also showed that participants who preferred gradual cessation were less likely to be successful—regardless of the method to which they were ultimately randomized.

CAVEATS

Generalizability limited by race and number of cigarettes smoked

Patients lost to follow-up at 4 weeks (35 in the abrupt-cessation group and 48 in the gradual-cessation group) were assumed to have continued smoking, which may have biased the results toward abrupt cessation. That said, the large number of participants included in the study, along with the relatively small number of patients lost to follow-up, minimizes this weakness.

The participants were largely white, which may limit generalizability to non-white populations. In addition, participants smoked an average of 20 cigarettes per day and, as noted previously, an observational study of tobacco users in France found that heavy smokers (≥21 cigarettes/d) were more likely to quit gradually than abruptly, so results may not be generalizable to heavy smokers.⁷

CHALLENGES TO IMPLEMENTATION

Finding the time and staff for considerable behavioral support

One important challenge is the implementation of such a structured tobacco cessation program in primary care. Both abrupt- and gradual-cessation groups were given considerable behavioral support from research nurses. Participants in this study were seen by a nurse 7 times in the first 6 weeks of the study, and the intervention included nurse-created reduction schedules.

Even if patients in the study preferred one method of cessation to another, they were receptive to quitting either gradually or abruptly. In clinical practice, patients are often set in their desired method of cessation. In that setting, our role is then to inform them of the data and support them in whatever method they choose.

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

A 43-year-old man has a 35-pack-year smoking history and currently smokes a pack of cigarettes a day. He is eager to quit smoking after recently learning that a close friend of his has been diagnosed with lung cancer. He asks you whether he should quit “cold turkey” or gradually. What would you recommend?

Between 2013 and 2014, one in 5 American adults reported using tobacco products some days or every day, and 66% of smokers in 2013 made at least one attempt to quit.^2,3 The risks of tobacco use and the benefits of cessation are well established, and behavioral and pharmacologic interventions both alone and in combination increase smoking cessation rates.⁴ The US Preventive Services Task Force recommends that health care providers address tobacco use and cessation with patients at regular office visits and offer behavioral and pharmacologic interventions.⁵ Current guidelines, however, make no specific recommendations regarding gradual vs abrupt smoking cessation methods.⁵

A previous Cochrane review of 10 randomized controlled trials demonstrated no significant difference in quit rates between gradual cigarette reduction leading up to a designated quit day and abrupt cessation. The meta-analysis was limited, however, by differences in patient populations, outcome definitions, and types of interventions (both pharmacologic and behavioral).⁶

In a retrospective cohort study, French investigators reviewed an online database of 62,508 smokers who presented to nationwide cessation services. The researchers found that older participants (≥45 years of age) and heavy smokers (≥21 cigarettes/d) were more likely to quit gradually than abruptly.⁷

STUDY SUMMARY

Quitting “cold turkey” is better than gradual cessation at 6 months

Lindson-Hawley, et al, conducted a randomized, controlled, non-inferiority trial in England to assess if gradual cessation is as successful as abrupt cessation as a means of quitting smoking.¹ The primary outcome was abstinence from smoking at 4 weeks, assessed using the Russell Standard, a set of 6 standard criteria (including validation by exhaled carbon monoxide concentrations of <10 ppm) used by the National Centre for Smoking Cessation and Training to decrease variability of reported smoking cessation rates in English studies.⁸

Study participants were recruited via letters from their primary care practice inviting them to call the researchers if they were interested in participating in a smoking cessation study. Almost 1100 people inquired about the study. In the end, 697 were randomized to either the abrupt-cessation group (n=355) or the gradual-cessation group (n=342). Baseline characteristics between the 2 groups were similar.

All participants were asked to schedule a quit date for 2 weeks after their enrollment. Patients randomized to the gradual-cessation group were provided nicotine replacement patches (21 mg/d) and their choice of short-acting nicotine replacement therapy (NRT) (gum, lozenges, nasal spray, sublingual tablets, inhalator, or mouth spray) to use in the 2 weeks leading up to the quit date, along with instructions to reduce smoking by half of the baseline amount by the end of the first week, and to a quarter of baseline by the end of the second week.

Patients randomized to the abrupt-cessation group were instructed to continue their current smoking habits until the cessation date; during those 2 weeks they were given nicotine patches (because the other group received them and some evidence suggests that precessation NRT increases quit rates), but no short-acting NRT.

Following the cessation date, treatment in both groups was identical, including behavioral support, 21 mg/d nicotine patches, and the participant’s choice of short-acting NRT. Behavioral support consisted of visits with a research nurse at the patient’s primary care practice weekly for 2 weeks before the quit date, the day before the quit date, weekly for 4 weeks after the quit date, and 8 weeks after the quit date.

The chosen non-inferiority margin was equal to a relative risk (RR) of 0.81 (19% reduction in effectiveness) of quitting gradually compared with abrupt cessation of smoking. Quit rates in the gradual-reduction group did not reach the threshold for non-inferiority; in fact, 4-week abstinence was significantly more likely in the abrupt-cessation group (49%) than in the gradual-cessation group (39.2%) (RR=0.80; 95% confidence interval [CI], 0.66-0.93; number needed to treat [NNT]=10). Similarly, secondary outcomes of 8-week and 6-month abstinence rates showed superiority of abrupt over gradual cessation. At 6 months after the quit date, 15.5% of the gradual-cessation group and 22% of the abrupt-cessation group remained abstinent (RR=0.71; 95% CI, 0.46-0.91; NNT=15).

Patients’ preferred method of cessation plays a role

The investigators also found a difference in successful cessation based on the participants preferred method of cessation. Participants who preferred abrupt cessation were more likely to be abstinent at 4 weeks than participants who preferred gradual cessation (52.2% vs 38.3%; P=.007).

People who prefer gradual cessation are less likely to be successful at quitting—regardless of whether they try to quit abruptly or gradually.Patients with a baseline preference for gradual cessation were equally as likely to successfully quit when allocated to abrupt cessation against their preference as when they were allocated to gradual cessation: 4-week abstinence was seen in 34.6% of patients who preferred gradual cessation and were allocated to gradual cessation and in 42% of patients who preferred gradual cessation but were allocated to abrupt cessation (P=.152).

WHAT'S NEW

Higher quality than previous studies and added element of preference

This large, well-designed, non-inferiority study showed that abrupt cessation is superior to gradual cessation. The size and design of the study, including a standardized method of assessing cessation and a standardized intervention, make this a higher quality study than those in the Cochrane meta-analysis.⁶ This study also showed that participants who preferred gradual cessation were less likely to be successful—regardless of the method to which they were ultimately randomized.

CAVEATS

Generalizability limited by race and number of cigarettes smoked

Patients lost to follow-up at 4 weeks (35 in the abrupt-cessation group and 48 in the gradual-cessation group) were assumed to have continued smoking, which may have biased the results toward abrupt cessation. That said, the large number of participants included in the study, along with the relatively small number of patients lost to follow-up, minimizes this weakness.

The participants were largely white, which may limit generalizability to non-white populations. In addition, participants smoked an average of 20 cigarettes per day and, as noted previously, an observational study of tobacco users in France found that heavy smokers (≥21 cigarettes/d) were more likely to quit gradually than abruptly, so results may not be generalizable to heavy smokers.⁷

CHALLENGES TO IMPLEMENTATION

Finding the time and staff for considerable behavioral support

One important challenge is the implementation of such a structured tobacco cessation program in primary care. Both abrupt- and gradual-cessation groups were given considerable behavioral support from research nurses. Participants in this study were seen by a nurse 7 times in the first 6 weeks of the study, and the intervention included nurse-created reduction schedules.

Even if patients in the study preferred one method of cessation to another, they were receptive to quitting either gradually or abruptly. In clinical practice, patients are often set in their desired method of cessation. In that setting, our role is then to inform them of the data and support them in whatever method they choose.

ACKNOWLEDGEMENT

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

I read Dr. Unger’s guest editorial, “Staring down the opioid epidemic” (J Fam Pract. 2017;66:8) and thought that he made some good points, but as an internist for 38 years and a detox addiction specialist for the past 7 years, I have seen too much “pendulum swinging” with regard to opioids.

The state of Pennsylvania is enforcing opioid prescription laws so intensely that I now see underprescribing of needed medications by physicians and dentists. For example, I recently had dental surgery and wasn’t prescribed a narcotic. I suffered for 24 hours with ineffective nonsteroidal anti-inflammatory drugs. And a relative of mine experienced excessive pain following gynecologic cancer surgery because the surgeon wouldn’t prescribe opioids for fear of reprisal.

I would like to see someone conduct a nationwide survey of primary care physicians regarding their views on narcotics for pain so that I can better understand my colleagues’ perspectives on this issue.

Don Sesso, DO, FCCP
Gwynedd Valley, PA

In his guest editorial, Dr. Unger urged family physicians to treat patients who are addicted to opioids with buprenorphine. It’s a shame that so few of us do so.

Patients who are addicted to opioids are no more difficult to treat than patients with diabetes, yet we, as family physicians, often fail to fulfill our basic duty to respond to their illness. Using buprenorphine to help a patient who is addicted to opioids achieve sobriety is highly effective. And treating these patients is amazingly satisfying, as you’ll never have more grateful patients than these.

I began integrating buprenorphine treatment into my family practice 10 years ago. It has made me much more effective in treating my patients who are addicted to alcohol, and it has provided me with a great deal of personal satisfaction in the latter part of my career.

I challenge all family physicians to step up and do their duty to help combat the opioid epidemic.

David A. Moore, MD
Salt Lake City, Utah

I read Dr. Unger’s guest editorial, “Staring down the opioid epidemic” (J Fam Pract. 2017;66:8) and thought that he made some good points, but as an internist for 38 years and a detox addiction specialist for the past 7 years, I have seen too much “pendulum swinging” with regard to opioids.

The state of Pennsylvania is enforcing opioid prescription laws so intensely that I now see underprescribing of needed medications by physicians and dentists. For example, I recently had dental surgery and wasn’t prescribed a narcotic. I suffered for 24 hours with ineffective nonsteroidal anti-inflammatory drugs. And a relative of mine experienced excessive pain following gynecologic cancer surgery because the surgeon wouldn’t prescribe opioids for fear of reprisal.

I would like to see someone conduct a nationwide survey of primary care physicians regarding their views on narcotics for pain so that I can better understand my colleagues’ perspectives on this issue.

Don Sesso, DO, FCCP
Gwynedd Valley, PA

In his guest editorial, Dr. Unger urged family physicians to treat patients who are addicted to opioids with buprenorphine. It’s a shame that so few of us do so.

Patients who are addicted to opioids are no more difficult to treat than patients with diabetes, yet we, as family physicians, often fail to fulfill our basic duty to respond to their illness. Using buprenorphine to help a patient who is addicted to opioids achieve sobriety is highly effective. And treating these patients is amazingly satisfying, as you’ll never have more grateful patients than these.

I began integrating buprenorphine treatment into my family practice 10 years ago. It has made me much more effective in treating my patients who are addicted to alcohol, and it has provided me with a great deal of personal satisfaction in the latter part of my career.

I challenge all family physicians to step up and do their duty to help combat the opioid epidemic.

David A. Moore, MD
Salt Lake City, Utah

I read Dr. Unger’s guest editorial, “Staring down the opioid epidemic” (J Fam Pract. 2017;66:8) and thought that he made some good points, but as an internist for 38 years and a detox addiction specialist for the past 7 years, I have seen too much “pendulum swinging” with regard to opioids.

The state of Pennsylvania is enforcing opioid prescription laws so intensely that I now see underprescribing of needed medications by physicians and dentists. For example, I recently had dental surgery and wasn’t prescribed a narcotic. I suffered for 24 hours with ineffective nonsteroidal anti-inflammatory drugs. And a relative of mine experienced excessive pain following gynecologic cancer surgery because the surgeon wouldn’t prescribe opioids for fear of reprisal.

I would like to see someone conduct a nationwide survey of primary care physicians regarding their views on narcotics for pain so that I can better understand my colleagues’ perspectives on this issue.

Don Sesso, DO, FCCP
Gwynedd Valley, PA

In his guest editorial, Dr. Unger urged family physicians to treat patients who are addicted to opioids with buprenorphine. It’s a shame that so few of us do so.

Patients who are addicted to opioids are no more difficult to treat than patients with diabetes, yet we, as family physicians, often fail to fulfill our basic duty to respond to their illness. Using buprenorphine to help a patient who is addicted to opioids achieve sobriety is highly effective. And treating these patients is amazingly satisfying, as you’ll never have more grateful patients than these.

I began integrating buprenorphine treatment into my family practice 10 years ago. It has made me much more effective in treating my patients who are addicted to alcohol, and it has provided me with a great deal of personal satisfaction in the latter part of my career.

I challenge all family physicians to step up and do their duty to help combat the opioid epidemic.

David A. Moore, MD
Salt Lake City, Utah

In the article, “Improving your approach to nasal obstruction” (J Fam Pract. 2016;65:889-893,898-899), I noticed that ipratropium nasal spray was not mentioned in Table 2, which listed commonly used medications for nasal obstruction.

We frequently recommend iprat­ropium nasal spray in our office, as it is an effective, non-addictive nasal decongestant. It is available in 2 strengths, .03% and .06%, and we usually prescribe 2 sprays in each nostril, 2 to 3 times a day, as needed.

We have found this to be very effective for short-term use. Its value, of course, is that it acts rapidly and there is no limit on how long it may be used.

Walter D. Leventhal, MD
Summerville, SC

In the article, “Improving your approach to nasal obstruction” (J Fam Pract. 2016;65:889-893,898-899), I noticed that ipratropium nasal spray was not mentioned in Table 2, which listed commonly used medications for nasal obstruction.

We frequently recommend iprat­ropium nasal spray in our office, as it is an effective, non-addictive nasal decongestant. It is available in 2 strengths, .03% and .06%, and we usually prescribe 2 sprays in each nostril, 2 to 3 times a day, as needed.

We have found this to be very effective for short-term use. Its value, of course, is that it acts rapidly and there is no limit on how long it may be used.

Walter D. Leventhal, MD
Summerville, SC

In the article, “Improving your approach to nasal obstruction” (J Fam Pract. 2016;65:889-893,898-899), I noticed that ipratropium nasal spray was not mentioned in Table 2, which listed commonly used medications for nasal obstruction.

We frequently recommend iprat­ropium nasal spray in our office, as it is an effective, non-addictive nasal decongestant. It is available in 2 strengths, .03% and .06%, and we usually prescribe 2 sprays in each nostril, 2 to 3 times a day, as needed.

We have found this to be very effective for short-term use. Its value, of course, is that it acts rapidly and there is no limit on how long it may be used.

Walter D. Leventhal, MD
Summerville, SC

As we know, the active ingredient of marijuana, delta-9 tetrahydrocannabinol (THC), has been available by prescription since 1985.¹ The Food and Drug Administration (FDA) has allowed a pill form to be prescribed for wasting related to acquired immunodeficiency syndrome and for patients with terminal cancer.

And while the FDA can extend use of the pills to other conditions when scientific, evidence-based studies prove that they are effective, it has not done so. The reason? The evidence is lacking.

According to The Medical Letter on Drugs and Therapeutics (August 1, 2016), no adequate studies of cannabis (botanical marijuana) are available for such indications as cancer pain, multiple sclerosis, epilepsy, and neuropathic pain.¹ Thus, I feel that there isn’t a need for “medical marijuana clinics,” which sell a product that isn’t regulated, is of unknown quality and strength, and may be dangerous or ineffective.

Illness should continue to be treated by health professionals employing scientific evidence. This is responsible policy. It is not appropriate or medically justified for family physicians to refer patients to medical marijuana clinics; instead, they should inform their patients that medical treatment must be based on scientific evidence.

Nayvin Gordon, MD
Oakland, Calif

As we know, the active ingredient of marijuana, delta-9 tetrahydrocannabinol (THC), has been available by prescription since 1985.¹ The Food and Drug Administration (FDA) has allowed a pill form to be prescribed for wasting related to acquired immunodeficiency syndrome and for patients with terminal cancer.

And while the FDA can extend use of the pills to other conditions when scientific, evidence-based studies prove that they are effective, it has not done so. The reason? The evidence is lacking.

According to The Medical Letter on Drugs and Therapeutics (August 1, 2016), no adequate studies of cannabis (botanical marijuana) are available for such indications as cancer pain, multiple sclerosis, epilepsy, and neuropathic pain.¹ Thus, I feel that there isn’t a need for “medical marijuana clinics,” which sell a product that isn’t regulated, is of unknown quality and strength, and may be dangerous or ineffective.

Illness should continue to be treated by health professionals employing scientific evidence. This is responsible policy. It is not appropriate or medically justified for family physicians to refer patients to medical marijuana clinics; instead, they should inform their patients that medical treatment must be based on scientific evidence.

Nayvin Gordon, MD
Oakland, Calif

As we know, the active ingredient of marijuana, delta-9 tetrahydrocannabinol (THC), has been available by prescription since 1985.¹ The Food and Drug Administration (FDA) has allowed a pill form to be prescribed for wasting related to acquired immunodeficiency syndrome and for patients with terminal cancer.

And while the FDA can extend use of the pills to other conditions when scientific, evidence-based studies prove that they are effective, it has not done so. The reason? The evidence is lacking.

According to The Medical Letter on Drugs and Therapeutics (August 1, 2016), no adequate studies of cannabis (botanical marijuana) are available for such indications as cancer pain, multiple sclerosis, epilepsy, and neuropathic pain.¹ Thus, I feel that there isn’t a need for “medical marijuana clinics,” which sell a product that isn’t regulated, is of unknown quality and strength, and may be dangerous or ineffective.

Illness should continue to be treated by health professionals employing scientific evidence. This is responsible policy. It is not appropriate or medically justified for family physicians to refer patients to medical marijuana clinics; instead, they should inform their patients that medical treatment must be based on scientific evidence.

Nayvin Gordon, MD
Oakland, Calif