Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are each rare psychiatric emergencies that can lead to fatal outcomes. Their clinical presentations can overlap, which can make it difficult to differentiate between the 2 syndromes; however, their treatments are distinct, and it is imperative to know how to identify symptoms and accurately diagnose each of them to provide appropriate intervention. This article summarizes the 2 syndromes and their treatments, with a focus on how clinicians can distinguish them, provide prompt intervention, and prevent occurrence.

Serotonin syndrome

Mechanism. The decarboxylation and hydroxylation of tryptophan forms serotonin, also known as 5-hydroxytryptamine (5-HT), which can then be metabolized by monoamine oxidase-A (MAO-A) into 5-hydroxyindoleacetic acid (5-HIAA).¹Medications can disrupt this pathway of serotonin production or its metabolism, and result in excessive levels of serotonin, which subsequently leads to an overactivation of central and peripheral serotonin receptors.¹ Increased receptor activation leads to further upregulation, and ultimately more serotonin transmission. This can be caused by monotherapy or use of multiple serotonergic agents, polypharmacy with a combination of medication classes, drug interactions, or overdose. The wide variety of medications often prescribed by different clinicians can make identification of excessive serotonergic activity difficult, especially because mood stabilizers such as lithium,² and non-psychiatric medications such as ciprofloxacin and fluconazole, can also contribute. Table 1³ lists medications that can cause SS. The pathways that increase serotonin transmission, potentially causing SS, include:

• inhibition of serotonin uptake (seen with selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], and tricyclic antidepressants [TCAs])
• inhibition of serotonin metabolism (seen with monoamine oxidase inhibitors [MAOIs])
• increased serotonin synthesis (seen with stimulants)
• increased serotonin release (seen with stimulants and opiates)
• activation of serotonin receptors (seen with lithium)
• inhibition of certain cytochrome P450 (CYP450) enzymes (seen with ciprofloxacin, fluconazole, etc.).

It is important to recognize that various serotonergic agents are involved in the CYP450 system. Inhibition of the CYP450 pathway by common antibiotics such as ciprofloxacin, or antifungals such as fluconazole, may result in an accumulation of serotonergic agents and place patients at increased risk for developing SS.

Clinical presentation. The clinical presentation of SS can range from mild to fatal. There is no specific laboratory test for diagnosis, although an elevation of the total creatine kinase (CK) and leukocyte count, as well as increased transaminase levels or lower bicarbonate levels, have been reported in the literature.⁴

Symptoms of SS generally present within 24 hours of starting/changing therapy and include a triad of mental status changes (altered mental status [AMS]), autonomic instability, and abnormalities of neuromuscular tone. Examples of AMS include agitation, anxiety, disorientation, and restlessness. Symptoms of autonomic instability include hypertension, tachycardia, tachypnea, hyperthermia, diaphoresis, flushed skin, vomiting, diarrhea, and arrhythmias. Symptoms stemming from changes in neuro­muscular tone include tremors, clonus, hyperreflexia, and muscle rigidity.¹ The multiple possible clinical presentations, as well as symptoms that overlap with those of other syndromes, can make SS difficult to recognize quickly in a clinical setting.

Diagnostic criteria. Sternbach’s diagnostic criteria for SS are defined as the presence of 3 or more of the 10 most common clinical features (Table 2⁵). Due to concerns that Sternbach’s diagnostic criteria overemphasized an abnormal mental state (leading to possible confusion of SS with other AMS syndromes), the Hunter serotonin toxicity criteria⁶ (Figure⁶) were developed in 2003, and were found to be more sensitive and specific than Sternbach’s criteria. Both tools are often used in clinical practice.

Treatment. Treatment of SS begins with prompt discontinuation of all sero­tonergic agents. The intensity of treatment depends on the severity of the symptoms. Mild symptoms can be managed with supportive care,³ and in such cases, the syndrome generally resolves within 24 hours.⁷ Clinicians may use supportive care to normalize vital signs (oxygenation to maintain SpO2 >94%, IV fluids for volume depletion, cooling agents, antihypertensives, benzodiazepines for sedation or control of agitation, etc.). Patients who are more ill may require more aggressive treatment, such as the use of a serotonergic antagonist (ie, cyproheptadine) and those who are severely hyperthermic (temperature >41.1ºC) may require neuromuscular sedation, paralysis, and possibly endotracheal intubation.³

Continue to: Management pitfalls include...

Management pitfalls include misdiagnosis of SS, failure to recognize its rapid rate of progression, and adverse effects of pharmacologic therapy.³ The most effective treatment for SS is prevention. SS can be prevented by astute pharmacologic understanding, avoidance of polypharmacy, and physician education.³

Neuroleptic malignant syndrome

Possible mechanisms. Neuromuscular malignant syndrome is thought to result from dopamine receptor antagonism leading to a hypodopaminergic state in the striatum and hypothalamus.⁸ The pathophysiology behind NMS has not fully been elucidated; however, several hypotheses attempt to explain this life-threatening reaction. The first focuses on dopamine D2 receptor antagonism, because many of the neuroleptic (antipsychotic) medications that can precipitate NMS are involved in dopamine blockade. In this theory, blocking dopamine D2 receptors in the anterior hypothalamus explains the hyperthermia seen in NMS, while blockade in the corpus striatum is believed to lead to muscle rigidity.⁹

The second hypothesis suggests that neuroleptics may have a direct toxic effect to muscle cells. Neuroleptics influence calcium transport across the sarcoplasmic reticulum and can lead to increased calcium release, which may contribute to the muscle rigidity and hyperthermia seen in NMS.⁹

The third hypothesis involves hyperactivity of the sympathetic nervous system; it is thought that psychologic stressors alter frontal lobe function, with neuroleptics disrupting the inhibitory pathways of the sympathetic nervous system. The autonomic nervous system innervates multiple organ systems, so this excessively dysregulated sympathetic nervous system may be responsible for multiple NMS symptoms (hyperthermia, muscle rigidity, hypertension, diaphoresis, tachycardia, elevated CK.¹⁰

NMS can be caused by neuroleptic agents (both first- and second-generation anti­psychotics) as well as antiemetics (Table 3¹). The time between use of these medications and onset of symptoms is highly variable. NMS can occur after a single dose, after a dose adjustment, or possibly after years of treatment with the same medication. It is not dose-dependent.¹¹ In certain individuals, NMS may occur at therapeutic doses.

Continue to: Clinical presentation

Clinical presentation. Patients with NMS typically present with a tetrad of symptoms: mental status changes, muscular rigidity, hyperthermia, and autonomic instability.¹² Mental status changes can include confusion and agitation, as well as catatonic signs and mutism. The muscular rigidity of NMS is characterized by “lead pipe rigidity” and may be accompanied by tremor, dystonia, or dyskinesias. Laboratory findings include elevated serum CK (from severe rigidity), often >1,000 U/L, although normal levels can be observed if rigidity has not yet developed.¹³

Treatment. The first step for treatment is to discontinue the causative medication.¹⁴ Initiate supportive therapy immediately to restrict the progression of symptoms. Interventions include cooling blankets, fluid resuscitation, and antihypertensives to maintain autonomic stability¹⁵ or benzodiazepines to control agitation. In severe cases, muscular rigidity may extend to the airways and intubation may be required. The severity of these symptoms may warrant admission to the ICU for close monitoring. Pharmacologic treatment with dantrolene (a muscle relaxant that blocks calcium efflux from the sarcoplasmic reticulum) and bromocriptine (a dopamine agonist) have been utilized.¹⁴ In case reports, electroconvulsive therapy (ECT) has been used to treat NMS^15,16; however, prospective research comparing ECT with traditional treatment has not been conducted. It is also worth mentioning that if a clinician wishes to restart the neuroleptic medication, a 2-week washout period will minimize the risk of NMS recurrence.¹⁷

Differentiating between SS and NMS

Differentiating between these 2 syndromes (Table 4¹⁷) is critical to direct appropriate intervention. Table 5¹⁷ outlines the treatment overview for SS and NMS.

Detailed history. A detailed history is imperative in making accurate diagnoses. Useful components of the history include a patient’s duration of symptoms and medication history (prescription medications as well as over-the-counter medications, supplements, and illicit drugs). Also assess for medical comorbidities, because certain medical diagnoses may alert the clinician that it is likely the patient had been prescribed serotonergic agents or neuroleptics, and renal or liver impairment may alert the clinician of decreased metabolism rates. Medication history is arguably the most useful piece of the interview, because serotonergic agents can cause SS, whereas dopamine blockers cause NMS. It should be noted that excess serotonin acts as a true toxidrome and is concentration-dependent in causing SS, whereas NMS is an idiosyncratic reaction to a drug.

Physical exam. Although there are many overlapping clinical manifestations, SS produces neuromuscular hyperactivity (ie, clonus, hyperreflexia), whereas NMS is characterized by more sluggish responses (ie, rigidity, bradyreflexia).¹⁸

Continue to: Laboratory findings

Laboratory findings. Overlap between NMS and SS also occurs with lab findings; both syndromes can result in leukocytosis, elevated CK from muscle damage, and low serum iron levels. However, these findings are more commonly associated with NMS and are seen in 75% of cases.^17,19

Course of illness. Duration of symptoms can also help differentiate the 2 syndromes. SS typically develops within 24 hours of starting/changing therapy, whereas NMS symptoms can be present for days to weeks. Resolution of symptoms may also be helpful in differentiation because SS typically resolves within a few days of initiating treatment, whereas NMS resolves within 9 to 14 days of starting treatment.¹⁹

Bottom Line

The clinical presentations of serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) overlap, which can make them difficult to differentiate; however, they each have distinct approaches to treatment. Features in SS that are distinct from NMS include a history of serotonergic agents, rapid onset of symptoms, hyperreflexia, and clonus. NMS is slower in onset and can be found in patients who are prescribed dopamine antagonists, with distinct symptoms of rigidity and hyporeflexia.

Related Resources

• Kimmel R. Serotonin syndrome or NMS? Clues to diagnosis. Current Psychiatry. 2010;9(2):92.
• Strawn JR, Keck Jr PE, Caroff SN. Neuroleptic malignant syndrome: Answers to 6 tough questions. Current Psychiatry. 2008;7(1):95-101.

Drug Brand Names

Amantadine • Symmetrel
Amitriptyline • Elavil, Endep
Aripiprazole • Abilify
Bromocriptine • Cycloset, Parlodel
Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Ciprofloxacin • Cipro
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Cyclobenzaprine • Amrix, Flexeril
Cyproheptadine • Periactin
Dantrolene • Dantrium
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dextromethorphan • Benylin, Dexalone
Dolasetron • Anzemet
Doxepin • Silenor
Droperidol • Inapsine
Duloxetine • Cymbalt
Escitalopram • Lexapro
Fentanyl • Actiq, Duragesic
Fluconazole • Diflucan
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Granisetron • Kytril
Haloperidol • Haldol
Isocarboxazid • Marplan
Levomilnacipran • Fetzima
Linezolid • Zyvox
Lithium • Eskalith, Lithobid
Meperidone • Demerol
Metoclopramide • Reglan
Milnacipran • Savella
Nefazodone • Serzone
Olanzapine • Zyprexa
Ondansetron • Zofran
Paliperidone • Invega
Palonosetron • Aloxi
Paroxetine • Paxil
Pentazocine • Talwin, Talacen
Perphenazine • Trilafon
Phenelzine • Nardil
Procarbazine • Matulane
Prochlorperazine • Compazine
Promethazine • Phenergan
Quetiapine • Seroquel
Rasagiline • Azilect
Risperidone • Risperdal
Safinamide • Xadago
Selegiline • Eldepryl, Zelapar
Sertraline • Zoloft
Sibutramine • Meridia
Tedizolid • Sivextro
Thioridazine • Mellaril
Tranylcypromine • Parnate
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Vilazodone • Viibryd
Vortioxetine • Trintellix
Valproate • Depacon
Ziprasidone • Geodon

Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are each rare psychiatric emergencies that can lead to fatal outcomes. Their clinical presentations can overlap, which can make it difficult to differentiate between the 2 syndromes; however, their treatments are distinct, and it is imperative to know how to identify symptoms and accurately diagnose each of them to provide appropriate intervention. This article summarizes the 2 syndromes and their treatments, with a focus on how clinicians can distinguish them, provide prompt intervention, and prevent occurrence.

Serotonin syndrome

Mechanism. The decarboxylation and hydroxylation of tryptophan forms serotonin, also known as 5-hydroxytryptamine (5-HT), which can then be metabolized by monoamine oxidase-A (MAO-A) into 5-hydroxyindoleacetic acid (5-HIAA).¹Medications can disrupt this pathway of serotonin production or its metabolism, and result in excessive levels of serotonin, which subsequently leads to an overactivation of central and peripheral serotonin receptors.¹ Increased receptor activation leads to further upregulation, and ultimately more serotonin transmission. This can be caused by monotherapy or use of multiple serotonergic agents, polypharmacy with a combination of medication classes, drug interactions, or overdose. The wide variety of medications often prescribed by different clinicians can make identification of excessive serotonergic activity difficult, especially because mood stabilizers such as lithium,² and non-psychiatric medications such as ciprofloxacin and fluconazole, can also contribute. Table 1³ lists medications that can cause SS. The pathways that increase serotonin transmission, potentially causing SS, include:

• inhibition of serotonin uptake (seen with selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], and tricyclic antidepressants [TCAs])
• inhibition of serotonin metabolism (seen with monoamine oxidase inhibitors [MAOIs])
• increased serotonin synthesis (seen with stimulants)
• increased serotonin release (seen with stimulants and opiates)
• activation of serotonin receptors (seen with lithium)
• inhibition of certain cytochrome P450 (CYP450) enzymes (seen with ciprofloxacin, fluconazole, etc.).

It is important to recognize that various serotonergic agents are involved in the CYP450 system. Inhibition of the CYP450 pathway by common antibiotics such as ciprofloxacin, or antifungals such as fluconazole, may result in an accumulation of serotonergic agents and place patients at increased risk for developing SS.

Clinical presentation. The clinical presentation of SS can range from mild to fatal. There is no specific laboratory test for diagnosis, although an elevation of the total creatine kinase (CK) and leukocyte count, as well as increased transaminase levels or lower bicarbonate levels, have been reported in the literature.⁴

Symptoms of SS generally present within 24 hours of starting/changing therapy and include a triad of mental status changes (altered mental status [AMS]), autonomic instability, and abnormalities of neuromuscular tone. Examples of AMS include agitation, anxiety, disorientation, and restlessness. Symptoms of autonomic instability include hypertension, tachycardia, tachypnea, hyperthermia, diaphoresis, flushed skin, vomiting, diarrhea, and arrhythmias. Symptoms stemming from changes in neuro­muscular tone include tremors, clonus, hyperreflexia, and muscle rigidity.¹ The multiple possible clinical presentations, as well as symptoms that overlap with those of other syndromes, can make SS difficult to recognize quickly in a clinical setting.

Diagnostic criteria. Sternbach’s diagnostic criteria for SS are defined as the presence of 3 or more of the 10 most common clinical features (Table 2⁵). Due to concerns that Sternbach’s diagnostic criteria overemphasized an abnormal mental state (leading to possible confusion of SS with other AMS syndromes), the Hunter serotonin toxicity criteria⁶ (Figure⁶) were developed in 2003, and were found to be more sensitive and specific than Sternbach’s criteria. Both tools are often used in clinical practice.

Treatment. Treatment of SS begins with prompt discontinuation of all sero­tonergic agents. The intensity of treatment depends on the severity of the symptoms. Mild symptoms can be managed with supportive care,³ and in such cases, the syndrome generally resolves within 24 hours.⁷ Clinicians may use supportive care to normalize vital signs (oxygenation to maintain SpO2 >94%, IV fluids for volume depletion, cooling agents, antihypertensives, benzodiazepines for sedation or control of agitation, etc.). Patients who are more ill may require more aggressive treatment, such as the use of a serotonergic antagonist (ie, cyproheptadine) and those who are severely hyperthermic (temperature >41.1ºC) may require neuromuscular sedation, paralysis, and possibly endotracheal intubation.³

Continue to: Management pitfalls include...

Management pitfalls include misdiagnosis of SS, failure to recognize its rapid rate of progression, and adverse effects of pharmacologic therapy.³ The most effective treatment for SS is prevention. SS can be prevented by astute pharmacologic understanding, avoidance of polypharmacy, and physician education.³

Neuroleptic malignant syndrome

Possible mechanisms. Neuromuscular malignant syndrome is thought to result from dopamine receptor antagonism leading to a hypodopaminergic state in the striatum and hypothalamus.⁸ The pathophysiology behind NMS has not fully been elucidated; however, several hypotheses attempt to explain this life-threatening reaction. The first focuses on dopamine D2 receptor antagonism, because many of the neuroleptic (antipsychotic) medications that can precipitate NMS are involved in dopamine blockade. In this theory, blocking dopamine D2 receptors in the anterior hypothalamus explains the hyperthermia seen in NMS, while blockade in the corpus striatum is believed to lead to muscle rigidity.⁹

The second hypothesis suggests that neuroleptics may have a direct toxic effect to muscle cells. Neuroleptics influence calcium transport across the sarcoplasmic reticulum and can lead to increased calcium release, which may contribute to the muscle rigidity and hyperthermia seen in NMS.⁹

The third hypothesis involves hyperactivity of the sympathetic nervous system; it is thought that psychologic stressors alter frontal lobe function, with neuroleptics disrupting the inhibitory pathways of the sympathetic nervous system. The autonomic nervous system innervates multiple organ systems, so this excessively dysregulated sympathetic nervous system may be responsible for multiple NMS symptoms (hyperthermia, muscle rigidity, hypertension, diaphoresis, tachycardia, elevated CK.¹⁰

NMS can be caused by neuroleptic agents (both first- and second-generation anti­psychotics) as well as antiemetics (Table 3¹). The time between use of these medications and onset of symptoms is highly variable. NMS can occur after a single dose, after a dose adjustment, or possibly after years of treatment with the same medication. It is not dose-dependent.¹¹ In certain individuals, NMS may occur at therapeutic doses.

Continue to: Clinical presentation

Clinical presentation. Patients with NMS typically present with a tetrad of symptoms: mental status changes, muscular rigidity, hyperthermia, and autonomic instability.¹² Mental status changes can include confusion and agitation, as well as catatonic signs and mutism. The muscular rigidity of NMS is characterized by “lead pipe rigidity” and may be accompanied by tremor, dystonia, or dyskinesias. Laboratory findings include elevated serum CK (from severe rigidity), often >1,000 U/L, although normal levels can be observed if rigidity has not yet developed.¹³

Treatment. The first step for treatment is to discontinue the causative medication.¹⁴ Initiate supportive therapy immediately to restrict the progression of symptoms. Interventions include cooling blankets, fluid resuscitation, and antihypertensives to maintain autonomic stability¹⁵ or benzodiazepines to control agitation. In severe cases, muscular rigidity may extend to the airways and intubation may be required. The severity of these symptoms may warrant admission to the ICU for close monitoring. Pharmacologic treatment with dantrolene (a muscle relaxant that blocks calcium efflux from the sarcoplasmic reticulum) and bromocriptine (a dopamine agonist) have been utilized.¹⁴ In case reports, electroconvulsive therapy (ECT) has been used to treat NMS^15,16; however, prospective research comparing ECT with traditional treatment has not been conducted. It is also worth mentioning that if a clinician wishes to restart the neuroleptic medication, a 2-week washout period will minimize the risk of NMS recurrence.¹⁷

Differentiating between SS and NMS

Differentiating between these 2 syndromes (Table 4¹⁷) is critical to direct appropriate intervention. Table 5¹⁷ outlines the treatment overview for SS and NMS.

Detailed history. A detailed history is imperative in making accurate diagnoses. Useful components of the history include a patient’s duration of symptoms and medication history (prescription medications as well as over-the-counter medications, supplements, and illicit drugs). Also assess for medical comorbidities, because certain medical diagnoses may alert the clinician that it is likely the patient had been prescribed serotonergic agents or neuroleptics, and renal or liver impairment may alert the clinician of decreased metabolism rates. Medication history is arguably the most useful piece of the interview, because serotonergic agents can cause SS, whereas dopamine blockers cause NMS. It should be noted that excess serotonin acts as a true toxidrome and is concentration-dependent in causing SS, whereas NMS is an idiosyncratic reaction to a drug.

Physical exam. Although there are many overlapping clinical manifestations, SS produces neuromuscular hyperactivity (ie, clonus, hyperreflexia), whereas NMS is characterized by more sluggish responses (ie, rigidity, bradyreflexia).¹⁸

Continue to: Laboratory findings

Laboratory findings. Overlap between NMS and SS also occurs with lab findings; both syndromes can result in leukocytosis, elevated CK from muscle damage, and low serum iron levels. However, these findings are more commonly associated with NMS and are seen in 75% of cases.^17,19

Course of illness. Duration of symptoms can also help differentiate the 2 syndromes. SS typically develops within 24 hours of starting/changing therapy, whereas NMS symptoms can be present for days to weeks. Resolution of symptoms may also be helpful in differentiation because SS typically resolves within a few days of initiating treatment, whereas NMS resolves within 9 to 14 days of starting treatment.¹⁹

Bottom Line

The clinical presentations of serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) overlap, which can make them difficult to differentiate; however, they each have distinct approaches to treatment. Features in SS that are distinct from NMS include a history of serotonergic agents, rapid onset of symptoms, hyperreflexia, and clonus. NMS is slower in onset and can be found in patients who are prescribed dopamine antagonists, with distinct symptoms of rigidity and hyporeflexia.

Related Resources

• Kimmel R. Serotonin syndrome or NMS? Clues to diagnosis. Current Psychiatry. 2010;9(2):92.
• Strawn JR, Keck Jr PE, Caroff SN. Neuroleptic malignant syndrome: Answers to 6 tough questions. Current Psychiatry. 2008;7(1):95-101.

Drug Brand Names

Amantadine • Symmetrel
Amitriptyline • Elavil, Endep
Aripiprazole • Abilify
Bromocriptine • Cycloset, Parlodel
Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Ciprofloxacin • Cipro
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Cyclobenzaprine • Amrix, Flexeril
Cyproheptadine • Periactin
Dantrolene • Dantrium
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dextromethorphan • Benylin, Dexalone
Dolasetron • Anzemet
Doxepin • Silenor
Droperidol • Inapsine
Duloxetine • Cymbalt
Escitalopram • Lexapro
Fentanyl • Actiq, Duragesic
Fluconazole • Diflucan
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Granisetron • Kytril
Haloperidol • Haldol
Isocarboxazid • Marplan
Levomilnacipran • Fetzima
Linezolid • Zyvox
Lithium • Eskalith, Lithobid
Meperidone • Demerol
Metoclopramide • Reglan
Milnacipran • Savella
Nefazodone • Serzone
Olanzapine • Zyprexa
Ondansetron • Zofran
Paliperidone • Invega
Palonosetron • Aloxi
Paroxetine • Paxil
Pentazocine • Talwin, Talacen
Perphenazine • Trilafon
Phenelzine • Nardil
Procarbazine • Matulane
Prochlorperazine • Compazine
Promethazine • Phenergan
Quetiapine • Seroquel
Rasagiline • Azilect
Risperidone • Risperdal
Safinamide • Xadago
Selegiline • Eldepryl, Zelapar
Sertraline • Zoloft
Sibutramine • Meridia
Tedizolid • Sivextro
Thioridazine • Mellaril
Tranylcypromine • Parnate
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Vilazodone • Viibryd
Vortioxetine • Trintellix
Valproate • Depacon
Ziprasidone • Geodon

Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are each rare psychiatric emergencies that can lead to fatal outcomes. Their clinical presentations can overlap, which can make it difficult to differentiate between the 2 syndromes; however, their treatments are distinct, and it is imperative to know how to identify symptoms and accurately diagnose each of them to provide appropriate intervention. This article summarizes the 2 syndromes and their treatments, with a focus on how clinicians can distinguish them, provide prompt intervention, and prevent occurrence.

Serotonin syndrome

Mechanism. The decarboxylation and hydroxylation of tryptophan forms serotonin, also known as 5-hydroxytryptamine (5-HT), which can then be metabolized by monoamine oxidase-A (MAO-A) into 5-hydroxyindoleacetic acid (5-HIAA).¹Medications can disrupt this pathway of serotonin production or its metabolism, and result in excessive levels of serotonin, which subsequently leads to an overactivation of central and peripheral serotonin receptors.¹ Increased receptor activation leads to further upregulation, and ultimately more serotonin transmission. This can be caused by monotherapy or use of multiple serotonergic agents, polypharmacy with a combination of medication classes, drug interactions, or overdose. The wide variety of medications often prescribed by different clinicians can make identification of excessive serotonergic activity difficult, especially because mood stabilizers such as lithium,² and non-psychiatric medications such as ciprofloxacin and fluconazole, can also contribute. Table 1³ lists medications that can cause SS. The pathways that increase serotonin transmission, potentially causing SS, include:

• inhibition of serotonin uptake (seen with selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], and tricyclic antidepressants [TCAs])
• inhibition of serotonin metabolism (seen with monoamine oxidase inhibitors [MAOIs])
• increased serotonin synthesis (seen with stimulants)
• increased serotonin release (seen with stimulants and opiates)
• activation of serotonin receptors (seen with lithium)
• inhibition of certain cytochrome P450 (CYP450) enzymes (seen with ciprofloxacin, fluconazole, etc.).

It is important to recognize that various serotonergic agents are involved in the CYP450 system. Inhibition of the CYP450 pathway by common antibiotics such as ciprofloxacin, or antifungals such as fluconazole, may result in an accumulation of serotonergic agents and place patients at increased risk for developing SS.

Clinical presentation. The clinical presentation of SS can range from mild to fatal. There is no specific laboratory test for diagnosis, although an elevation of the total creatine kinase (CK) and leukocyte count, as well as increased transaminase levels or lower bicarbonate levels, have been reported in the literature.⁴

Symptoms of SS generally present within 24 hours of starting/changing therapy and include a triad of mental status changes (altered mental status [AMS]), autonomic instability, and abnormalities of neuromuscular tone. Examples of AMS include agitation, anxiety, disorientation, and restlessness. Symptoms of autonomic instability include hypertension, tachycardia, tachypnea, hyperthermia, diaphoresis, flushed skin, vomiting, diarrhea, and arrhythmias. Symptoms stemming from changes in neuro­muscular tone include tremors, clonus, hyperreflexia, and muscle rigidity.¹ The multiple possible clinical presentations, as well as symptoms that overlap with those of other syndromes, can make SS difficult to recognize quickly in a clinical setting.

Diagnostic criteria. Sternbach’s diagnostic criteria for SS are defined as the presence of 3 or more of the 10 most common clinical features (Table 2⁵). Due to concerns that Sternbach’s diagnostic criteria overemphasized an abnormal mental state (leading to possible confusion of SS with other AMS syndromes), the Hunter serotonin toxicity criteria⁶ (Figure⁶) were developed in 2003, and were found to be more sensitive and specific than Sternbach’s criteria. Both tools are often used in clinical practice.

Treatment. Treatment of SS begins with prompt discontinuation of all sero­tonergic agents. The intensity of treatment depends on the severity of the symptoms. Mild symptoms can be managed with supportive care,³ and in such cases, the syndrome generally resolves within 24 hours.⁷ Clinicians may use supportive care to normalize vital signs (oxygenation to maintain SpO2 >94%, IV fluids for volume depletion, cooling agents, antihypertensives, benzodiazepines for sedation or control of agitation, etc.). Patients who are more ill may require more aggressive treatment, such as the use of a serotonergic antagonist (ie, cyproheptadine) and those who are severely hyperthermic (temperature >41.1ºC) may require neuromuscular sedation, paralysis, and possibly endotracheal intubation.³

Continue to: Management pitfalls include...

Management pitfalls include misdiagnosis of SS, failure to recognize its rapid rate of progression, and adverse effects of pharmacologic therapy.³ The most effective treatment for SS is prevention. SS can be prevented by astute pharmacologic understanding, avoidance of polypharmacy, and physician education.³

Neuroleptic malignant syndrome

Possible mechanisms. Neuromuscular malignant syndrome is thought to result from dopamine receptor antagonism leading to a hypodopaminergic state in the striatum and hypothalamus.⁸ The pathophysiology behind NMS has not fully been elucidated; however, several hypotheses attempt to explain this life-threatening reaction. The first focuses on dopamine D2 receptor antagonism, because many of the neuroleptic (antipsychotic) medications that can precipitate NMS are involved in dopamine blockade. In this theory, blocking dopamine D2 receptors in the anterior hypothalamus explains the hyperthermia seen in NMS, while blockade in the corpus striatum is believed to lead to muscle rigidity.⁹

The second hypothesis suggests that neuroleptics may have a direct toxic effect to muscle cells. Neuroleptics influence calcium transport across the sarcoplasmic reticulum and can lead to increased calcium release, which may contribute to the muscle rigidity and hyperthermia seen in NMS.⁹

The third hypothesis involves hyperactivity of the sympathetic nervous system; it is thought that psychologic stressors alter frontal lobe function, with neuroleptics disrupting the inhibitory pathways of the sympathetic nervous system. The autonomic nervous system innervates multiple organ systems, so this excessively dysregulated sympathetic nervous system may be responsible for multiple NMS symptoms (hyperthermia, muscle rigidity, hypertension, diaphoresis, tachycardia, elevated CK.¹⁰

NMS can be caused by neuroleptic agents (both first- and second-generation anti­psychotics) as well as antiemetics (Table 3¹). The time between use of these medications and onset of symptoms is highly variable. NMS can occur after a single dose, after a dose adjustment, or possibly after years of treatment with the same medication. It is not dose-dependent.¹¹ In certain individuals, NMS may occur at therapeutic doses.

Continue to: Clinical presentation

Clinical presentation. Patients with NMS typically present with a tetrad of symptoms: mental status changes, muscular rigidity, hyperthermia, and autonomic instability.¹² Mental status changes can include confusion and agitation, as well as catatonic signs and mutism. The muscular rigidity of NMS is characterized by “lead pipe rigidity” and may be accompanied by tremor, dystonia, or dyskinesias. Laboratory findings include elevated serum CK (from severe rigidity), often >1,000 U/L, although normal levels can be observed if rigidity has not yet developed.¹³

Treatment. The first step for treatment is to discontinue the causative medication.¹⁴ Initiate supportive therapy immediately to restrict the progression of symptoms. Interventions include cooling blankets, fluid resuscitation, and antihypertensives to maintain autonomic stability¹⁵ or benzodiazepines to control agitation. In severe cases, muscular rigidity may extend to the airways and intubation may be required. The severity of these symptoms may warrant admission to the ICU for close monitoring. Pharmacologic treatment with dantrolene (a muscle relaxant that blocks calcium efflux from the sarcoplasmic reticulum) and bromocriptine (a dopamine agonist) have been utilized.¹⁴ In case reports, electroconvulsive therapy (ECT) has been used to treat NMS^15,16; however, prospective research comparing ECT with traditional treatment has not been conducted. It is also worth mentioning that if a clinician wishes to restart the neuroleptic medication, a 2-week washout period will minimize the risk of NMS recurrence.¹⁷

Differentiating between SS and NMS

Differentiating between these 2 syndromes (Table 4¹⁷) is critical to direct appropriate intervention. Table 5¹⁷ outlines the treatment overview for SS and NMS.

Detailed history. A detailed history is imperative in making accurate diagnoses. Useful components of the history include a patient’s duration of symptoms and medication history (prescription medications as well as over-the-counter medications, supplements, and illicit drugs). Also assess for medical comorbidities, because certain medical diagnoses may alert the clinician that it is likely the patient had been prescribed serotonergic agents or neuroleptics, and renal or liver impairment may alert the clinician of decreased metabolism rates. Medication history is arguably the most useful piece of the interview, because serotonergic agents can cause SS, whereas dopamine blockers cause NMS. It should be noted that excess serotonin acts as a true toxidrome and is concentration-dependent in causing SS, whereas NMS is an idiosyncratic reaction to a drug.

Physical exam. Although there are many overlapping clinical manifestations, SS produces neuromuscular hyperactivity (ie, clonus, hyperreflexia), whereas NMS is characterized by more sluggish responses (ie, rigidity, bradyreflexia).¹⁸

Continue to: Laboratory findings

Laboratory findings. Overlap between NMS and SS also occurs with lab findings; both syndromes can result in leukocytosis, elevated CK from muscle damage, and low serum iron levels. However, these findings are more commonly associated with NMS and are seen in 75% of cases.^17,19

Course of illness. Duration of symptoms can also help differentiate the 2 syndromes. SS typically develops within 24 hours of starting/changing therapy, whereas NMS symptoms can be present for days to weeks. Resolution of symptoms may also be helpful in differentiation because SS typically resolves within a few days of initiating treatment, whereas NMS resolves within 9 to 14 days of starting treatment.¹⁹

Bottom Line

The clinical presentations of serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) overlap, which can make them difficult to differentiate; however, they each have distinct approaches to treatment. Features in SS that are distinct from NMS include a history of serotonergic agents, rapid onset of symptoms, hyperreflexia, and clonus. NMS is slower in onset and can be found in patients who are prescribed dopamine antagonists, with distinct symptoms of rigidity and hyporeflexia.

Related Resources

• Kimmel R. Serotonin syndrome or NMS? Clues to diagnosis. Current Psychiatry. 2010;9(2):92.
• Strawn JR, Keck Jr PE, Caroff SN. Neuroleptic malignant syndrome: Answers to 6 tough questions. Current Psychiatry. 2008;7(1):95-101.

Drug Brand Names

Amantadine • Symmetrel
Amitriptyline • Elavil, Endep
Aripiprazole • Abilify
Bromocriptine • Cycloset, Parlodel
Bupropion • Wellbutrin, Zyban
Buspirone • BuSpar
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Ciprofloxacin • Cipro
Citalopram • Celexa
Clomipramine • Anafranil
Clozapine • Clozaril
Cyclobenzaprine • Amrix, Flexeril
Cyproheptadine • Periactin
Dantrolene • Dantrium
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Dextromethorphan • Benylin, Dexalone
Dolasetron • Anzemet
Doxepin • Silenor
Droperidol • Inapsine
Duloxetine • Cymbalt
Escitalopram • Lexapro
Fentanyl • Actiq, Duragesic
Fluconazole • Diflucan
Fluoxetine • Prozac
Fluphenazine • Prolixin
Fluvoxamine • Luvox
Granisetron • Kytril
Haloperidol • Haldol
Isocarboxazid • Marplan
Levomilnacipran • Fetzima
Linezolid • Zyvox
Lithium • Eskalith, Lithobid
Meperidone • Demerol
Metoclopramide • Reglan
Milnacipran • Savella
Nefazodone • Serzone
Olanzapine • Zyprexa
Ondansetron • Zofran
Paliperidone • Invega
Palonosetron • Aloxi
Paroxetine • Paxil
Pentazocine • Talwin, Talacen
Perphenazine • Trilafon
Phenelzine • Nardil
Procarbazine • Matulane
Prochlorperazine • Compazine
Promethazine • Phenergan
Quetiapine • Seroquel
Rasagiline • Azilect
Risperidone • Risperdal
Safinamide • Xadago
Selegiline • Eldepryl, Zelapar
Sertraline • Zoloft
Sibutramine • Meridia
Tedizolid • Sivextro
Thioridazine • Mellaril
Tranylcypromine • Parnate
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Vilazodone • Viibryd
Vortioxetine • Trintellix
Valproate • Depacon
Ziprasidone • Geodon

Although the peak age of onset of bipolar disorder (BD) is between 20 and 40 years,¹ some patients develop BD later in life. The International Society for Bipolar Disorders Task Force has classified the illness into 3 categories:

• early-onset bipolar disorder (EOBD), in which the first manic episode occurs before age 40
• late-onset bipolar disorder (LOBD), in which the initial manic/hypomanic episode occurs after age 50
• older-age bipolar disorder (OABD), in which the first manic/hypomanic episode occurs after age 60.²

OABD represents 25% of the population with BD.³ OABD differs from EOBD in its clinical presentation, biological factors, and psychiatric and somatic comorbidities.⁴ Studies suggest OABD warrants a more extensive workup to rule out organic causes because symptoms are often attributable to a variety of organic etiologies.

This article describes 3 cases of OABD, including treatments and outcomes. We discuss general treatment recommendations for patients with OABD as cited in the literature. Further research is needed to expand our ability to better care for this unique population.

CASE 1

Mr. D was a 66-year-old African American male with no psychiatric history. His medical history was significant for hypertension, poorly controlled diabetes mellitus, and chronic kidney disease. One year ago, he was diagnosed with cholangiocarcinoma, and underwent uncomplicated right trisegmentectomy, resection of extrahepatic biliary tree, and complete portal lymphadenectomy, with Roux-en-Y hepaticojejunostomy to 2 intrahepatic ducts. He presented to the emergency department (ED) with disorganized behavior for 3 weeks. During that time, Mr. D reported increased distractibility, irritability, hyper-religiosity, racing thoughts, decreased appetite, and decreased need for sleep. There was no pertinent family history.

On mental status examination, Mr. D was agitated, noncooperative, and guarded. His speech was loud and pressured. Mr. D was distractible, tangential, and goal-directed. His Young Mania Rating Scale (YMRS) score was 31, which is highly indicative of mania.⁵ Computed tomography (CT) scan of the head (Figure 1) showed age-related changes but no acute findings. Mr. D was diagnosed with unspecified bipolar disorder and admitted. He was started on divalproex sodium extended release, which was titrated to 1,500 mg/d, and olanzapine, 15 mg nightly, with subsequent improvement. At discharge, his YMRS score was 9.

CASE 2

Mr. M was a 63-year-old African American male with no psychiatric history and a medical history significant for hypertension and hypercholesterolemia. He presented to the ED with behavioral changes for 2 weeks. During this time, he experienced decreased need for sleep, agitation, excessive spending, self-conversing, hypersexuality, and paranoia. His family history was significant for schizoaffective disorder, bipolar type.

A mental status examination revealed pressured speech, grandiose delusions, hyper-religiosity, flight of ideas, looseness of association, auditory hallucinations, and tangential thought processes. Mr. M’s initial YMRS score was 56. A CT scan of the head revealed no acute abnormality, but MRI of the brain (Figure 2) showed chronic microvascular ischemic change. Mr. M was diagnosed with bipolar I disorder and admitted. He was started on quetiapine extended release, which was titrated to 600 mg nightly. Divalproex sodium extended release was titrated to 1,500 mg nightly, with subsequent improvement. At discharge, his YMRS score was 15.

Continue to: CASE 3

CASE 3

Ms. F was a 69-year-old White female with no psychiatric history. Her medical history was significant for hypertension, osteoarthritis, and stage III-C ovarian adenocarcinoma with a debulking surgical procedure 5 years earlier. After that, she received adjuvant therapy with paclitaxel and carboplatin, which resulted in a 10-month disease-free interval. Subsequent progression led to cycles of doxorubicin liposomal and gemcitabine. She was in remission until 1 week earlier, when a CT scan of the abdomen/pelvis showed recurrence. She presented to the hospital after disrobing in the street due to hyper-religiosity and divine instruction. She endorsed elevated mood and increased energy despite sleeping only 2 hours daily. Her family psychiatric history was significant for her daughter’s suicide attempt.

A mental status examination revealed disorganized behavior and agitation. Her speech was loud and pressured. She described a “great” mood with congruent affect. Her thought process was circumstantial and illogical. She displayed flight of ideas, grandiose delusions, and paranoia. Ms. F’s initial YMRS score was 38. Vital signs were significant for an elevated blood pressure of 153/113 mm Hg. A CT scan of the head (Figure 3) showed age-related change with no acute findings. Ms. F was admitted with a diagnosis of bipolar I disorder and prescribed olanzapine, 2.5 mg nightly. Due to continued manic symptoms, olanzapine was discontinued, and Ms. F was started on quetiapine, 300 mg nightly, with subsequent improvement. At discharge, her YMRS score was 10.

Differences between EOBD and OABD

BD has always been considered a multi-system illness; however, comorbidity is much more common in OABD than in EOBD. Comorbid conditions are 3 to 4 times more common in patients with OABD.² Common comorbidities include metabolic syndrome, allergic rhinitis, arthritis, asthma, and cardiovascular disease.

Compared with younger individuals, older patients with BD score lower on the YMRS in the areas of increased activity-energy, language-thought disorder, and sexual interest.⁶ Psychotic symptoms are less common or less severe in OABD. Although symptom severity is lower, the prevalence of rapid cycling illness is 20% higher in patients with OABD.⁶ OABD is less commonly associated with a family history.⁷ This may suggest a difference from the popular genetic component typically found in patients with EOBD.

Cognitive impairment is more commonly found in OABD. Patients with OABD suffer from neuropsychological deficits even during euthymic phases.⁸ While these deficits may also be found in patients with EOBD, compared with younger patients, older adults are more susceptible to accelerated decline in cognition. OABD can first present within the context of cardiovascular or neuropsychological impairment. It has also been linked to a greater prevalence of white matter hyperintensities compared with EOBD.^9,10

Continue to: Treatment is not specific to OABD

No established treatment guidelines specifically address OABD. It has been treated similarly to EOBD, with antipsychotics, mood stabilizers, antidepressants, and electroconvulsive therapy (ECT). Although lithium is effective, special precautions should be taken when prescribing it to older adults because these patients may be more sensitive to adverse events.¹¹ Drug–drug interactions may also be more likely due to concomitant use of medications for common medical issues such as hypertension.

Treatment with antipsychotics in older patients carries risks. Use of antipsychotics may result in higher rates of morbidity and mortality related to cardiovascular, metabolic, and infectious etiologies. Some literature recommends the use of antipsychotics for OABD; however, the potential benefits must outweigh the risks.⁶ Monotherapy followed by combination therapy has demonstrated effectiveness in OABD.¹¹ Because symptoms of OABD are often less severe, it may be best to avoid maintenance antipsychotic therapy when possible. With a higher prevalence of depressed mood following manic episodes, use of antidepressant therapy is common in OABD.⁶ ECT should be considered for patients with treatment-refractory BD.¹¹

Lessons from our case series

Our case series included 3 patients with OABD. These patients’ comorbid conditions included hypertension, hypercholesteremia, and diabetes mellitus. Two patients had a history of cancer, but there was no metastasis to the brain in either case. However, we considered the possibility of structural changes in the brain or cognitive impairment secondary to cancer or its treatment. A literature review confirmed that adult patients treated for noncentral nervous system cancer experienced cancer-related cognitive impairment (CRCI).¹² New research suggests that CRCI could be related to altered neuronal integrity along with a disturbance of brain structure networks that process and integrate information.¹³

We used the YMRS to compare symptom severity and treatment response (Figure 4). Two patients were treated with atypical antipsychotics with a mood stabilizer, and the third patient was prescribed an antipsychotic only. We avoided lithium and carbamazepine as mood stabilizers due to their adverse effect profiles and potential for drug–drug interactions. Each patient responded well to treatment without adverse events.

Continue to: Etiology of OABD may be different

OABD may be associated with manic presentations and vascular risk factors. MRI imaging that found more white matter hyperintensities and cerebrovascular lesions in patients with OABD compared with younger patients provides evidence of possible differing etiologies.¹⁴ Cassidy and Carroll¹⁵ found a higher incidence of smoking, hypertension, diabetes mellitus, coronary heart disease, and atrial fibrillation in patients in the older onset group. Bellivier et al¹⁶ proposed 3 subgroups of bipolar I disorder; the late-onset subgroup’s etiology was multifactorial. EOBD and OABD subgroups have similar gender ratios,¹⁷ first-episode descriptions, and alcohol use rates; however, OABD subgroups have more neuro­logical comorbidity, lesser severe psychosis, and less genetic predisposition.

Although 25% of BD cases are late onset,³ there is still little consensus regarding subgroups and etiological causes. Therefore, additional research specifically focusing on vascular risks may provide much-needed information. Controlling and mitigating vascular risks in OABD may affect its development and course. Despite debated etiologies, the treatment of BD remains consistent, with anticonvulsants preferred over lithium in older individuals.¹⁸

Bottom Line

Compared with younger patients with bipolar disorder (BD), those who develop BD later in life may be more likely to have rapid cycling, medical comorbidities, and cognitive impairment. Older patients with BD also may be more likely to experience adverse effects of the medications commonly used to treat BD, including antipsychotics, lithium, and carbamazepine.

Related Resources

• Carlino AR, Stinnett JL, Kim DR. New onset of bipolar disorder in late life. Psychosomatics. 2013;54(1):94-97.
• Sajatovic M, Kales HC, Mulsant BH. Prescribing antipsychotics in geriatric patients: Focus on schizophrenia and bipolar disorder. Current Psychiatry. 2017;16(10):20-26,28.

Drug Brand Names

Carbamazepine • Carbatrol, Tegretol
Carboplatin • Paraplatin
Divalproex sodium • Depakote
Doxorubicin liposome injection • Doxil
Gemcitabine injection • Gemzar
Lithium • Eskalith, Lithobid
Olanzapine • Zyprexa
Paclitaxel injection • Abraxane
Quetiapine • Seroquel

Although the peak age of onset of bipolar disorder (BD) is between 20 and 40 years,¹ some patients develop BD later in life. The International Society for Bipolar Disorders Task Force has classified the illness into 3 categories:

• early-onset bipolar disorder (EOBD), in which the first manic episode occurs before age 40
• late-onset bipolar disorder (LOBD), in which the initial manic/hypomanic episode occurs after age 50
• older-age bipolar disorder (OABD), in which the first manic/hypomanic episode occurs after age 60.²

OABD represents 25% of the population with BD.³ OABD differs from EOBD in its clinical presentation, biological factors, and psychiatric and somatic comorbidities.⁴ Studies suggest OABD warrants a more extensive workup to rule out organic causes because symptoms are often attributable to a variety of organic etiologies.

This article describes 3 cases of OABD, including treatments and outcomes. We discuss general treatment recommendations for patients with OABD as cited in the literature. Further research is needed to expand our ability to better care for this unique population.

CASE 1

Mr. D was a 66-year-old African American male with no psychiatric history. His medical history was significant for hypertension, poorly controlled diabetes mellitus, and chronic kidney disease. One year ago, he was diagnosed with cholangiocarcinoma, and underwent uncomplicated right trisegmentectomy, resection of extrahepatic biliary tree, and complete portal lymphadenectomy, with Roux-en-Y hepaticojejunostomy to 2 intrahepatic ducts. He presented to the emergency department (ED) with disorganized behavior for 3 weeks. During that time, Mr. D reported increased distractibility, irritability, hyper-religiosity, racing thoughts, decreased appetite, and decreased need for sleep. There was no pertinent family history.

On mental status examination, Mr. D was agitated, noncooperative, and guarded. His speech was loud and pressured. Mr. D was distractible, tangential, and goal-directed. His Young Mania Rating Scale (YMRS) score was 31, which is highly indicative of mania.⁵ Computed tomography (CT) scan of the head (Figure 1) showed age-related changes but no acute findings. Mr. D was diagnosed with unspecified bipolar disorder and admitted. He was started on divalproex sodium extended release, which was titrated to 1,500 mg/d, and olanzapine, 15 mg nightly, with subsequent improvement. At discharge, his YMRS score was 9.

CASE 2

Mr. M was a 63-year-old African American male with no psychiatric history and a medical history significant for hypertension and hypercholesterolemia. He presented to the ED with behavioral changes for 2 weeks. During this time, he experienced decreased need for sleep, agitation, excessive spending, self-conversing, hypersexuality, and paranoia. His family history was significant for schizoaffective disorder, bipolar type.

A mental status examination revealed pressured speech, grandiose delusions, hyper-religiosity, flight of ideas, looseness of association, auditory hallucinations, and tangential thought processes. Mr. M’s initial YMRS score was 56. A CT scan of the head revealed no acute abnormality, but MRI of the brain (Figure 2) showed chronic microvascular ischemic change. Mr. M was diagnosed with bipolar I disorder and admitted. He was started on quetiapine extended release, which was titrated to 600 mg nightly. Divalproex sodium extended release was titrated to 1,500 mg nightly, with subsequent improvement. At discharge, his YMRS score was 15.

Continue to: CASE 3

CASE 3

Ms. F was a 69-year-old White female with no psychiatric history. Her medical history was significant for hypertension, osteoarthritis, and stage III-C ovarian adenocarcinoma with a debulking surgical procedure 5 years earlier. After that, she received adjuvant therapy with paclitaxel and carboplatin, which resulted in a 10-month disease-free interval. Subsequent progression led to cycles of doxorubicin liposomal and gemcitabine. She was in remission until 1 week earlier, when a CT scan of the abdomen/pelvis showed recurrence. She presented to the hospital after disrobing in the street due to hyper-religiosity and divine instruction. She endorsed elevated mood and increased energy despite sleeping only 2 hours daily. Her family psychiatric history was significant for her daughter’s suicide attempt.

A mental status examination revealed disorganized behavior and agitation. Her speech was loud and pressured. She described a “great” mood with congruent affect. Her thought process was circumstantial and illogical. She displayed flight of ideas, grandiose delusions, and paranoia. Ms. F’s initial YMRS score was 38. Vital signs were significant for an elevated blood pressure of 153/113 mm Hg. A CT scan of the head (Figure 3) showed age-related change with no acute findings. Ms. F was admitted with a diagnosis of bipolar I disorder and prescribed olanzapine, 2.5 mg nightly. Due to continued manic symptoms, olanzapine was discontinued, and Ms. F was started on quetiapine, 300 mg nightly, with subsequent improvement. At discharge, her YMRS score was 10.

Differences between EOBD and OABD

BD has always been considered a multi-system illness; however, comorbidity is much more common in OABD than in EOBD. Comorbid conditions are 3 to 4 times more common in patients with OABD.² Common comorbidities include metabolic syndrome, allergic rhinitis, arthritis, asthma, and cardiovascular disease.

Compared with younger individuals, older patients with BD score lower on the YMRS in the areas of increased activity-energy, language-thought disorder, and sexual interest.⁶ Psychotic symptoms are less common or less severe in OABD. Although symptom severity is lower, the prevalence of rapid cycling illness is 20% higher in patients with OABD.⁶ OABD is less commonly associated with a family history.⁷ This may suggest a difference from the popular genetic component typically found in patients with EOBD.

Cognitive impairment is more commonly found in OABD. Patients with OABD suffer from neuropsychological deficits even during euthymic phases.⁸ While these deficits may also be found in patients with EOBD, compared with younger patients, older adults are more susceptible to accelerated decline in cognition. OABD can first present within the context of cardiovascular or neuropsychological impairment. It has also been linked to a greater prevalence of white matter hyperintensities compared with EOBD.^9,10

Continue to: Treatment is not specific to OABD

No established treatment guidelines specifically address OABD. It has been treated similarly to EOBD, with antipsychotics, mood stabilizers, antidepressants, and electroconvulsive therapy (ECT). Although lithium is effective, special precautions should be taken when prescribing it to older adults because these patients may be more sensitive to adverse events.¹¹ Drug–drug interactions may also be more likely due to concomitant use of medications for common medical issues such as hypertension.

Treatment with antipsychotics in older patients carries risks. Use of antipsychotics may result in higher rates of morbidity and mortality related to cardiovascular, metabolic, and infectious etiologies. Some literature recommends the use of antipsychotics for OABD; however, the potential benefits must outweigh the risks.⁶ Monotherapy followed by combination therapy has demonstrated effectiveness in OABD.¹¹ Because symptoms of OABD are often less severe, it may be best to avoid maintenance antipsychotic therapy when possible. With a higher prevalence of depressed mood following manic episodes, use of antidepressant therapy is common in OABD.⁶ ECT should be considered for patients with treatment-refractory BD.¹¹

Lessons from our case series

Our case series included 3 patients with OABD. These patients’ comorbid conditions included hypertension, hypercholesteremia, and diabetes mellitus. Two patients had a history of cancer, but there was no metastasis to the brain in either case. However, we considered the possibility of structural changes in the brain or cognitive impairment secondary to cancer or its treatment. A literature review confirmed that adult patients treated for noncentral nervous system cancer experienced cancer-related cognitive impairment (CRCI).¹² New research suggests that CRCI could be related to altered neuronal integrity along with a disturbance of brain structure networks that process and integrate information.¹³

We used the YMRS to compare symptom severity and treatment response (Figure 4). Two patients were treated with atypical antipsychotics with a mood stabilizer, and the third patient was prescribed an antipsychotic only. We avoided lithium and carbamazepine as mood stabilizers due to their adverse effect profiles and potential for drug–drug interactions. Each patient responded well to treatment without adverse events.

Continue to: Etiology of OABD may be different

OABD may be associated with manic presentations and vascular risk factors. MRI imaging that found more white matter hyperintensities and cerebrovascular lesions in patients with OABD compared with younger patients provides evidence of possible differing etiologies.¹⁴ Cassidy and Carroll¹⁵ found a higher incidence of smoking, hypertension, diabetes mellitus, coronary heart disease, and atrial fibrillation in patients in the older onset group. Bellivier et al¹⁶ proposed 3 subgroups of bipolar I disorder; the late-onset subgroup’s etiology was multifactorial. EOBD and OABD subgroups have similar gender ratios,¹⁷ first-episode descriptions, and alcohol use rates; however, OABD subgroups have more neuro­logical comorbidity, lesser severe psychosis, and less genetic predisposition.

Although 25% of BD cases are late onset,³ there is still little consensus regarding subgroups and etiological causes. Therefore, additional research specifically focusing on vascular risks may provide much-needed information. Controlling and mitigating vascular risks in OABD may affect its development and course. Despite debated etiologies, the treatment of BD remains consistent, with anticonvulsants preferred over lithium in older individuals.¹⁸

Bottom Line

Compared with younger patients with bipolar disorder (BD), those who develop BD later in life may be more likely to have rapid cycling, medical comorbidities, and cognitive impairment. Older patients with BD also may be more likely to experience adverse effects of the medications commonly used to treat BD, including antipsychotics, lithium, and carbamazepine.

Related Resources

• Carlino AR, Stinnett JL, Kim DR. New onset of bipolar disorder in late life. Psychosomatics. 2013;54(1):94-97.
• Sajatovic M, Kales HC, Mulsant BH. Prescribing antipsychotics in geriatric patients: Focus on schizophrenia and bipolar disorder. Current Psychiatry. 2017;16(10):20-26,28.

Drug Brand Names

Carbamazepine • Carbatrol, Tegretol
Carboplatin • Paraplatin
Divalproex sodium • Depakote
Doxorubicin liposome injection • Doxil
Gemcitabine injection • Gemzar
Lithium • Eskalith, Lithobid
Olanzapine • Zyprexa
Paclitaxel injection • Abraxane
Quetiapine • Seroquel

Although the peak age of onset of bipolar disorder (BD) is between 20 and 40 years,¹ some patients develop BD later in life. The International Society for Bipolar Disorders Task Force has classified the illness into 3 categories:

• early-onset bipolar disorder (EOBD), in which the first manic episode occurs before age 40
• late-onset bipolar disorder (LOBD), in which the initial manic/hypomanic episode occurs after age 50
• older-age bipolar disorder (OABD), in which the first manic/hypomanic episode occurs after age 60.²

OABD represents 25% of the population with BD.³ OABD differs from EOBD in its clinical presentation, biological factors, and psychiatric and somatic comorbidities.⁴ Studies suggest OABD warrants a more extensive workup to rule out organic causes because symptoms are often attributable to a variety of organic etiologies.

This article describes 3 cases of OABD, including treatments and outcomes. We discuss general treatment recommendations for patients with OABD as cited in the literature. Further research is needed to expand our ability to better care for this unique population.

CASE 1

Mr. D was a 66-year-old African American male with no psychiatric history. His medical history was significant for hypertension, poorly controlled diabetes mellitus, and chronic kidney disease. One year ago, he was diagnosed with cholangiocarcinoma, and underwent uncomplicated right trisegmentectomy, resection of extrahepatic biliary tree, and complete portal lymphadenectomy, with Roux-en-Y hepaticojejunostomy to 2 intrahepatic ducts. He presented to the emergency department (ED) with disorganized behavior for 3 weeks. During that time, Mr. D reported increased distractibility, irritability, hyper-religiosity, racing thoughts, decreased appetite, and decreased need for sleep. There was no pertinent family history.

On mental status examination, Mr. D was agitated, noncooperative, and guarded. His speech was loud and pressured. Mr. D was distractible, tangential, and goal-directed. His Young Mania Rating Scale (YMRS) score was 31, which is highly indicative of mania.⁵ Computed tomography (CT) scan of the head (Figure 1) showed age-related changes but no acute findings. Mr. D was diagnosed with unspecified bipolar disorder and admitted. He was started on divalproex sodium extended release, which was titrated to 1,500 mg/d, and olanzapine, 15 mg nightly, with subsequent improvement. At discharge, his YMRS score was 9.

CASE 2

Mr. M was a 63-year-old African American male with no psychiatric history and a medical history significant for hypertension and hypercholesterolemia. He presented to the ED with behavioral changes for 2 weeks. During this time, he experienced decreased need for sleep, agitation, excessive spending, self-conversing, hypersexuality, and paranoia. His family history was significant for schizoaffective disorder, bipolar type.

A mental status examination revealed pressured speech, grandiose delusions, hyper-religiosity, flight of ideas, looseness of association, auditory hallucinations, and tangential thought processes. Mr. M’s initial YMRS score was 56. A CT scan of the head revealed no acute abnormality, but MRI of the brain (Figure 2) showed chronic microvascular ischemic change. Mr. M was diagnosed with bipolar I disorder and admitted. He was started on quetiapine extended release, which was titrated to 600 mg nightly. Divalproex sodium extended release was titrated to 1,500 mg nightly, with subsequent improvement. At discharge, his YMRS score was 15.

Continue to: CASE 3

CASE 3

Ms. F was a 69-year-old White female with no psychiatric history. Her medical history was significant for hypertension, osteoarthritis, and stage III-C ovarian adenocarcinoma with a debulking surgical procedure 5 years earlier. After that, she received adjuvant therapy with paclitaxel and carboplatin, which resulted in a 10-month disease-free interval. Subsequent progression led to cycles of doxorubicin liposomal and gemcitabine. She was in remission until 1 week earlier, when a CT scan of the abdomen/pelvis showed recurrence. She presented to the hospital after disrobing in the street due to hyper-religiosity and divine instruction. She endorsed elevated mood and increased energy despite sleeping only 2 hours daily. Her family psychiatric history was significant for her daughter’s suicide attempt.

A mental status examination revealed disorganized behavior and agitation. Her speech was loud and pressured. She described a “great” mood with congruent affect. Her thought process was circumstantial and illogical. She displayed flight of ideas, grandiose delusions, and paranoia. Ms. F’s initial YMRS score was 38. Vital signs were significant for an elevated blood pressure of 153/113 mm Hg. A CT scan of the head (Figure 3) showed age-related change with no acute findings. Ms. F was admitted with a diagnosis of bipolar I disorder and prescribed olanzapine, 2.5 mg nightly. Due to continued manic symptoms, olanzapine was discontinued, and Ms. F was started on quetiapine, 300 mg nightly, with subsequent improvement. At discharge, her YMRS score was 10.

Differences between EOBD and OABD

BD has always been considered a multi-system illness; however, comorbidity is much more common in OABD than in EOBD. Comorbid conditions are 3 to 4 times more common in patients with OABD.² Common comorbidities include metabolic syndrome, allergic rhinitis, arthritis, asthma, and cardiovascular disease.

Compared with younger individuals, older patients with BD score lower on the YMRS in the areas of increased activity-energy, language-thought disorder, and sexual interest.⁶ Psychotic symptoms are less common or less severe in OABD. Although symptom severity is lower, the prevalence of rapid cycling illness is 20% higher in patients with OABD.⁶ OABD is less commonly associated with a family history.⁷ This may suggest a difference from the popular genetic component typically found in patients with EOBD.

Cognitive impairment is more commonly found in OABD. Patients with OABD suffer from neuropsychological deficits even during euthymic phases.⁸ While these deficits may also be found in patients with EOBD, compared with younger patients, older adults are more susceptible to accelerated decline in cognition. OABD can first present within the context of cardiovascular or neuropsychological impairment. It has also been linked to a greater prevalence of white matter hyperintensities compared with EOBD.^9,10

Continue to: Treatment is not specific to OABD

No established treatment guidelines specifically address OABD. It has been treated similarly to EOBD, with antipsychotics, mood stabilizers, antidepressants, and electroconvulsive therapy (ECT). Although lithium is effective, special precautions should be taken when prescribing it to older adults because these patients may be more sensitive to adverse events.¹¹ Drug–drug interactions may also be more likely due to concomitant use of medications for common medical issues such as hypertension.

Treatment with antipsychotics in older patients carries risks. Use of antipsychotics may result in higher rates of morbidity and mortality related to cardiovascular, metabolic, and infectious etiologies. Some literature recommends the use of antipsychotics for OABD; however, the potential benefits must outweigh the risks.⁶ Monotherapy followed by combination therapy has demonstrated effectiveness in OABD.¹¹ Because symptoms of OABD are often less severe, it may be best to avoid maintenance antipsychotic therapy when possible. With a higher prevalence of depressed mood following manic episodes, use of antidepressant therapy is common in OABD.⁶ ECT should be considered for patients with treatment-refractory BD.¹¹

Lessons from our case series

Our case series included 3 patients with OABD. These patients’ comorbid conditions included hypertension, hypercholesteremia, and diabetes mellitus. Two patients had a history of cancer, but there was no metastasis to the brain in either case. However, we considered the possibility of structural changes in the brain or cognitive impairment secondary to cancer or its treatment. A literature review confirmed that adult patients treated for noncentral nervous system cancer experienced cancer-related cognitive impairment (CRCI).¹² New research suggests that CRCI could be related to altered neuronal integrity along with a disturbance of brain structure networks that process and integrate information.¹³

We used the YMRS to compare symptom severity and treatment response (Figure 4). Two patients were treated with atypical antipsychotics with a mood stabilizer, and the third patient was prescribed an antipsychotic only. We avoided lithium and carbamazepine as mood stabilizers due to their adverse effect profiles and potential for drug–drug interactions. Each patient responded well to treatment without adverse events.

Continue to: Etiology of OABD may be different

OABD may be associated with manic presentations and vascular risk factors. MRI imaging that found more white matter hyperintensities and cerebrovascular lesions in patients with OABD compared with younger patients provides evidence of possible differing etiologies.¹⁴ Cassidy and Carroll¹⁵ found a higher incidence of smoking, hypertension, diabetes mellitus, coronary heart disease, and atrial fibrillation in patients in the older onset group. Bellivier et al¹⁶ proposed 3 subgroups of bipolar I disorder; the late-onset subgroup’s etiology was multifactorial. EOBD and OABD subgroups have similar gender ratios,¹⁷ first-episode descriptions, and alcohol use rates; however, OABD subgroups have more neuro­logical comorbidity, lesser severe psychosis, and less genetic predisposition.

Although 25% of BD cases are late onset,³ there is still little consensus regarding subgroups and etiological causes. Therefore, additional research specifically focusing on vascular risks may provide much-needed information. Controlling and mitigating vascular risks in OABD may affect its development and course. Despite debated etiologies, the treatment of BD remains consistent, with anticonvulsants preferred over lithium in older individuals.¹⁸

Bottom Line

Compared with younger patients with bipolar disorder (BD), those who develop BD later in life may be more likely to have rapid cycling, medical comorbidities, and cognitive impairment. Older patients with BD also may be more likely to experience adverse effects of the medications commonly used to treat BD, including antipsychotics, lithium, and carbamazepine.

Related Resources

• Carlino AR, Stinnett JL, Kim DR. New onset of bipolar disorder in late life. Psychosomatics. 2013;54(1):94-97.
• Sajatovic M, Kales HC, Mulsant BH. Prescribing antipsychotics in geriatric patients: Focus on schizophrenia and bipolar disorder. Current Psychiatry. 2017;16(10):20-26,28.

Drug Brand Names

Carbamazepine • Carbatrol, Tegretol
Carboplatin • Paraplatin
Divalproex sodium • Depakote
Doxorubicin liposome injection • Doxil
Gemcitabine injection • Gemzar
Lithium • Eskalith, Lithobid
Olanzapine • Zyprexa
Paclitaxel injection • Abraxane
Quetiapine • Seroquel

Approximately 55 years ago, tricyclic antidepressants (TCAs) began to be used to treat neuropathic pain.¹ Eventually, clinical trials emerged suggesting the utility of TCAs for other chronic pain conditions, such as fibromyalgia (FM) and migraine prophylaxis. However, despite TCAs’ effectiveness in mitigating painful conditions, their adverse effects limited their use.

Pharmacologic advancements have led to the development of other antidepressant classes, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and the use of these agents has come to eclipse that of TCAs. In the realm of pain management, such developments have raised the hope of possible alternative co-analgesic agents that could avoid the adverse effects associated with TCAs. Some of these agents have demonstrated efficacy for managing chronic pain states, while others have demonstrated only limited utility.

This article provides a synopsis of systematic reviews and meta-analyses examining the role of antidepressant therapy for managing several chronic pain conditions, including pain associated with neuropathy, FM, headache, and irritable bowel syndrome (IBS). Because the literature base is rapidly evolving, it is necessary to revisit the information gleaned from clinical data with respect to treatment effectiveness, and to clarify how antidepressants might be positioned in the management of chronic pain.

The effectiveness of antidepressants for pain

The pathophysiologic processes that precipitate and maintain chronic pain conditions are complex (Box 1^2-10). The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects and indirect effects (Box 2^{2,3,8,10,11-33}).

Box 1

During the last several decades, anti­depressants have been used to address—and have demonstrated clinical utility for—a variety of chronic pain states. However, antidepressants are not a panacea; some chronic pain conditions are more responsive to antidepressants than are others. The chronic painful states most amenable to antidepressants are those that result primarily from a process of neural sensitization, as opposed to acute somatic or visceral nociception. Hence, several meta-analyses and evidence-based reviews have long suggested the usefulness of antidepressants for mitigating pain associated with neuropathy,^34,35 FM,^36,37 headache,³⁸ and IBS.^39,40

Box 2

Continue to: Neuropathic pain

Several treatment guidelines advocate for the use of antidepressants for neuropathic pain.^41-44 For decades, TCAs have been employed off-label to successfully treat many patients with neuropathic pain states. Early investigations suggested that TCAs were robustly efficacious in managing patients with neuropathy.^45-48 Calculated number-needed-to-treat (NNT) values for TCAs were quite low (ie, reflecting that few patients would need to be treated to yield a positive response in one patient compared with placebo), and were comparable to, if not slightly better than, the NNTs generated for anticonvulsants and α2-δ ligands, such as gabapentin or pregabalin.^45-48

Unfortunately, early studies involving TCAs conducted many years ago do not meet contemporary standards of methodological rigor; they featured relatively small samples of patients assessed for brief post-treatment intervals with variable outcome measures. Thus, the NNT values obtained in meta-analyses based on these studies may overestimate treatment benefits.⁴⁹ Further, NNT values derived from meta-analyses tended to combine all drugs within a particular antidepressant class (eg, amitriptyline, nortriptyline, desipramine, and imipramine among the TCAs) employed at diverse doses. Taken together, these limitations raise questions about the results of those meta-analyses.

Subsequent meta-analyses, which employed strict criteria to eliminate data from studies with potential sources of bias and used a primary outcome of frequencies of patients reporting at least 30% pain reduction compared with a placebo-controlled sample, suggest that the effectiveness of TCAs as a class for treating neuropathic pain is not as compelling as once was thought. Meta-analyses of studies employing specific TCAs revealed that there was little evidence to support the use of desipramine,⁵⁰ imipramine,⁵¹ or nortriptyline⁵² in managing diabetic neuropathy or postherpetic neuralgia. Studies evaluating amitriptyline (dose range 12.5 to 150 mg/d), found low-level evidence of effectiveness; the benefit was expected to be present for a small subset (approximately 25%) of patients with neuropathic pain.⁵³

There is moderate-quality evidence that duloxetine (60 to 120 mg/d) can produce a ≥50% improvement in pain severity ratings among patients with diabetic peripheral neuropathy.⁵⁴ Although head-to-head studies with other antidepressants are limited, it appears that duloxetine and amitriptyline have comparable efficacy, even though the NNTs for amitriptyline were derived from lower-quality studies than those for duloxetine. Duloxetine is the only antidepressant to receive FDA approval for managing diabetic neuropathy. By contrast, studies assessing the utility of venlafaxine in neuropathic pain comprised small samples for brief durations, which limits the ability to draw clear (unbiased) support for its usefulness.⁵⁵

Given the diversity of pathophysiologic processes underlying the disturbances that cause neuropathic pain disorders, it is unsurprising that the effectiveness of amitriptyline and duloxetine were not generalizable to all neuropathic pain states. Although amitriptyline produced pain-mitigating effects in patients with diabetic neuropathy and post-herpetic neuralgia, and duloxetine mitigated pain among patients with diabetic neuropathy, there was no evidence to suggest their effectiveness in phantom limb pain or human immunodeficiency virus-related and spinal cord-related neuropathies.^{35,53,54,56-58}

Continue to: Fibromyalgia

As with the issues encountered in interpreting the effectiveness of antidepressants in neuropathic pain, interpreting results gleaned from clinical trials of antidepressants for treating FM are fraught with similar difficulties. Although amitriptyline has been a first-line treatment for FM for many years, the evidence upon which such recommendations were based consisted of low-level studies that had a significant potential for bias.⁵⁹ Large randomized trials would offer more compelling data regarding the efficacy of amitriptyline, but the prohibitive costs of such studies makes it unlikely they will be conducted. Amitriptyline (25 to 50 mg/d) was effective in mitigating FM-related pain in a small percentage of patients studied, with an estimated NNT of 4.⁵⁹ Adverse effects, often contributing to treatment discontinuation, were encountered more frequently among patients who received amitriptyline compared with placebo.

Selective serotonin reuptake inhibitors failed to demonstrate significant pain relief (estimated NNT of 10), or improvement in fatigue or sleep problems, even though the studies upon which such conclusions were based were low-level studies with a high potential for bias.⁶⁰ Although SSRIs have limited utility for mitigating pain, they are still quite useful for reducing depression among patients with FM.⁶⁰

By contrast, the SNRIs duloxetine and milnacipran provided clinically relevant benefit over placebo in the frequency of patients reporting pain relief of ≥30%, as well as patients’ global impression of change.⁶¹ These agents, however, failed to provide clinically relevant benefit over placebo in improving health-related quality of life, reducing sleep problems, or improving fatigue. Nonetheless, duloxetine and milnacipran are FDA-approved for managing pain in FM. Studies assessing the efficacy of venlafaxine in the treatment of FM to date have been limited by small sample sizes, inconsistent dosing, lack of a placebo control, and lack of blinding, which limits the ability to clearly delineate the role of venlafaxine in managing FM.⁶²

Mirtazapine (15 to 45 mg/d) showed a clinically relevant benefit compared with placebo for participant-reported pain relief of ≥30% and sleep disturbances. There was no benefit in terms of participant-reported improvement of quality of life, fatigue, or negative mood.⁶³ The evidence was considered to be of low quality overall.

Headache

Amitriptyline has been employed off-label to address headache prophylaxis since 1964.⁶⁴ Compared with placebo, it is efficacious in ameliorating migraine frequency and intensity as well as the frequency of tension headache.^65,66 However, SSRIs and SNRIs (venlafaxine) failed to produce significant reductions in migraine frequency or severity or the frequencies of tension headache when compared with placebo.^67,68

Continue to: Irritable bowel syndrome

Early studies addressing antidepressant efficacy in IBS reveal inconsistencies. For example, whereas some suggest that TCAs are effective in mitigating chronic, severe abdominal pain,^39,40 others concluded that TCAs failed to demonstrate a significant analgesic benefit.⁶⁹ A recent meta-analysis that restricted analysis of efficacy to randomized controlled trials (RCTs) with more rigorous methodological adherence found that pain relief in IBS is possible with both TCAs as well as SSRIs. However, adverse effects were more commonly encountered with TCAs than with SSRIs. Some of the inconsistencies in treatment efficacy reported in early studies may be due to variations in responsiveness of subsets of IBS patients. Specifically, the utility of TCAs appears to be best among patients with diarrheal-type (as opposed to constipation-type) IBS, presumably due to TCAs’ anticholinergic effects, whereas SSRIs may provide more of a benefit for patients with predominantly constipation-type IBS.^40,70

Other chronic pain conditions

Antidepressants have been used to assist in the management of several other pain conditions, including oral-facial pain, interstitial cystitis, non-cardiac chest pain, and others. The role of antidepressants for such conditions remains unclear due to limitations in the prevailing empirical work, such as few trials, small sample sizes, variations in outcome measures, and insufficient randomization and blinding.^71-76 The interpretation of results from systematic reviews and meta-analyses is limited because of these shortcomings.⁷⁷ Hence, it has not always been possible to determine whether, and to what extent, patients with such conditions may benefit from antidepressants.

Neuromodulatory effects and efficacy for pain

The interplay of norepinephrine (NE) and serotonin (5-HT) neurotransmitter systems and cellular mechanisms involved in the descending modulation of pain pathways is complex. Experimental animal models of pain modulation suggest that 5-HT can both inhibit as well as promote pain perception by different physiological mechanisms, in contrast to NE, which is predominately inhibitory. While 5-HT in the descending modulating system can inhibit pain transmission ascending to the brain from the periphery, it appears that an intact noradrenergic system is necessary for the inhibitory influences of the serotonergic system to be appreciated.^16,78,79 Deficiencies in one or both of these neurotransmitter systems may contribute to hyperactive pain processing, and thereby precipitate or maintain chronic pain.

Pain mitigation may be achieved best by enhancing both neurotransmitters simultaneously, less so by enhancing NE alone, and least by enhancing 5-HT alone.⁶ The ability to impact pain modulation would, therefore, depend on the degree to which an antidepressant capitalizes on both noradrenergic and serotonergic neurotransmission. Antidepressants commonly employed to manage pain are presented in Table 1^{47,60,68,80-88} according to their primary neurotransmitter effects. Thus, the literature summarized above suggests that antidepressants that influence both NE and 5-HT transmission have greater analgesic effects than antidepressants with more specific effects, such as influencing 5-HT reuptake alone.^80-85 It is unsurprising, therefore, that the SSRIs have not been demonstrated to be as consistently analgesic.^{47,60,68,80,86-88}

Similarly, pharmacodynamic and pharmacokinetic differences within antidepressant classes may influence analgesic effectiveness. Simultaneous effects on NE and 5-HT are achieved at low doses with duloxetine and milnacipran. By contrast, 5-HT effects predominate at low doses for venlafaxine. To achieve pain-mitigating effects, higher doses of venlafaxine generally are required.⁸⁹ Therefore, inconsistencies across studies regarding the analgesic benefits of venlafaxine may be attributable to variability in dosing; patients treated with lower doses may not have experienced sufficient NE effects to garner positive results.

Continue to: The differences in analgesic efficacy...

The differences in analgesic efficacy among specific TCAs may be understood in a similar fashion. Specifically, tertiary TCAs (imipramine and amitriptyline) inhibit both 5-HT and NE reuptake.^6,90 Secondary amines (desipramine and nortriptyline) predominantly impact NE reuptake, possibly accounting for the lesser pain-mitigating benefit achieved with these agents, such as for treating neuro­pathic pain. Further, in vivo imipramine and amitriptyline are rapidly metabolized to secondary amines that are potent and selective NE reuptake inhibitors. In this way, the secondary amines may substantially lose the ability to modulate pain transmission because of the loss of concurrent 5-HT influences.⁹⁰

Clinical pearls

The following practical points can help guide clinicians regarding the usefulness of antidepressants for pain management:

• Antidepressants can alleviate symptoms of depression and pain. The pain-mitigating effects of antidepressants are possible even among chronic pain patients who are not depressed. Antidepressants may confer benefits for chronic pain patients with depression and other comorbid conditions, such as somatic symptom and related disorders.
• Antidepressants are useful for select chronic pain states. Although the noradrenergic and serotonergic antidepressants (SNRIs and, to some extent, amitriptyline) appear to have efficacy for neuropathic pain and FM, the benefits of SSRIs appear to be less robust. On the other hand, SSRIs and TCAs may have potential benefit for patients with IBS. However, the results of meta-analyses are limited in the ability to provide information about which patients will best respond to which specific antidepressant or how well. Future research directed at identifying characteristics that can predict which patients are likely to benefit from one antidepressant vs another would help inform how best to tailor treatment to individual needs.
• The pain-mitigating effects of antidepressants often emerge early in the course of treatment (often before mood-elevating effects are observed). For example, in the case of amitriptyline, pain relief may be possible for some patients at doses generally lower than those required for mood-elevating effects. To date, there is limited information in the literature to determine what constitutes a sufficient duration of treatment, or when treatment should be modified.
• Failure to reduce pain should raise questions about whether the dose should be increased, an alternative agent should be tried, or combinations with other analgesic agents should be considered. Failure to achieve pain-mitigating effects with one antidepressant does not mean failure with others. Hence, failure to achieve desired effects with one agent might warrant an empirical trial with another agent. Presently, too few double-blind RCTs have been conducted to assess the pain-mitigating effects of other antidepressants (eg, bupropion and newer SNRIs such as desvenlafaxine and levomilnacipran). Meta-analysis of the analgesic effectiveness of these agents or comparisons to the efficacy of other antidepressant classes is, therefore, impossible at this time.

Because many chronic pain states are complex, patients will seldom experience clinically relevant benefit from any one intervention.⁵³ The bigger implication for clinical research is to determine whether there is a sequence or combination of medication use that will provide overall better clinical effectiveness.⁵³ Only limited data are available exploring the utility of combining pharmacologic approaches to address pain.⁹¹ For example, preliminary evidence suggests that combinations of complementary strategies, such as duloxetine combined with pregabalin, may result in significantly greater numbers of FM patients achieving ≥30% pain reduction compared with monotherapy with either agent alone or placebo.⁹²

• Antidepressant selection may need to be based on medication-related adverse effect profiles and the potential for drug interactions. These factors are useful to consider in delineating multimodal treatment regimens for chronic pain in light of patients’ comorbidities and co-medication regimen. For example, the adverse effects of TCAs (anticholinergic and alpha-adrenergic influences) limit their utility for treating pain. Some of these effects can be more problematic in select populations, such as older adults or those with orthostatic difficulties, among others. TCAs are contraindicated in patients with closed-angle glaucoma, recent myocardial infarction, cardiac arrhythmias, poorly controlled seizures, or severe benign prostatic hypertrophy. Although the pain-mitigating effects of SNRIs have not been demonstrated to significantly exceed those of TCAs,^68,93,94 SNRIs would offer an advantage of greater tolerability of adverse effects and relative safety in patients with comorbid medical conditions that would otherwise preclude TCA use. The adverse effects and common drug interactions associated with antidepressants are summarized in Table 2⁹⁵.

Conclusion

Chronic, nonmalignant pain conditions afflict many patients and significantly impair their ability to function. Because of heightened concerns related to the appropriateness of, and restricting inordinate access to, long-term opioid analgesics, clinicians need to explore the usefulness of co-analgesic agents, such as antidepressants. Significant comorbidities exist between psychiatric disorders and chronic pain, and psychiatrists are uniquely positioned to diagnose and treat psychiatric comorbidities, as well as pain, among their patients, especially since they understand the kinetics and dynamics of antidepressants.

Bottom Line

Antidepressants can alleviate symptoms of depression and pain. Noradrenergic and serotonergic antidepressants appear to have efficacy for pain associated with neuropathy and fibromyalgia, while selective serotonin reuptake inhibitors and tricyclic antidepressants may have benefit for patients with irritable bowel syndrome. However, evidence regarding which patients will best respond to which specific antidepressant is limited.

Continue to: Related Resources

• Williams AM, Knox ED. When to prescribe antidepressants to treat comorbid depression and pain disorders. Current Psychiatry. 2017;16(1):55-58.
• Maletic V, Demuri B. Chronic pain and depression: treatment of 2 culprits in common. Current Psychiatry. 2016;15(3):41,47-50,52.

Drug Brand Names

Amitriptyline • Elavil, Endep
Bupropion • Wellbutrin, Zyban
Carisoprodol • Rela, Soma
Cyclobenzaprine • Amrix, Flexeril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Horizant, Neurontin
Imipramine • Tofranil
Levomilnacipran • Fetzima
Methadone • Dolophine, Methadose
Milnacipran • Savella
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Pregabalin • Lyrica, Lyrica CR
Tapentadol • Nucynta
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Warfarin • Coumadin, Jantoven

Approximately 55 years ago, tricyclic antidepressants (TCAs) began to be used to treat neuropathic pain.¹ Eventually, clinical trials emerged suggesting the utility of TCAs for other chronic pain conditions, such as fibromyalgia (FM) and migraine prophylaxis. However, despite TCAs’ effectiveness in mitigating painful conditions, their adverse effects limited their use.

Pharmacologic advancements have led to the development of other antidepressant classes, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and the use of these agents has come to eclipse that of TCAs. In the realm of pain management, such developments have raised the hope of possible alternative co-analgesic agents that could avoid the adverse effects associated with TCAs. Some of these agents have demonstrated efficacy for managing chronic pain states, while others have demonstrated only limited utility.

This article provides a synopsis of systematic reviews and meta-analyses examining the role of antidepressant therapy for managing several chronic pain conditions, including pain associated with neuropathy, FM, headache, and irritable bowel syndrome (IBS). Because the literature base is rapidly evolving, it is necessary to revisit the information gleaned from clinical data with respect to treatment effectiveness, and to clarify how antidepressants might be positioned in the management of chronic pain.

The effectiveness of antidepressants for pain

The pathophysiologic processes that precipitate and maintain chronic pain conditions are complex (Box 1^2-10). The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects and indirect effects (Box 2^{2,3,8,10,11-33}).

Box 1

During the last several decades, anti­depressants have been used to address—and have demonstrated clinical utility for—a variety of chronic pain states. However, antidepressants are not a panacea; some chronic pain conditions are more responsive to antidepressants than are others. The chronic painful states most amenable to antidepressants are those that result primarily from a process of neural sensitization, as opposed to acute somatic or visceral nociception. Hence, several meta-analyses and evidence-based reviews have long suggested the usefulness of antidepressants for mitigating pain associated with neuropathy,^34,35 FM,^36,37 headache,³⁸ and IBS.^39,40

Box 2

Continue to: Neuropathic pain

Several treatment guidelines advocate for the use of antidepressants for neuropathic pain.^41-44 For decades, TCAs have been employed off-label to successfully treat many patients with neuropathic pain states. Early investigations suggested that TCAs were robustly efficacious in managing patients with neuropathy.^45-48 Calculated number-needed-to-treat (NNT) values for TCAs were quite low (ie, reflecting that few patients would need to be treated to yield a positive response in one patient compared with placebo), and were comparable to, if not slightly better than, the NNTs generated for anticonvulsants and α2-δ ligands, such as gabapentin or pregabalin.^45-48

Unfortunately, early studies involving TCAs conducted many years ago do not meet contemporary standards of methodological rigor; they featured relatively small samples of patients assessed for brief post-treatment intervals with variable outcome measures. Thus, the NNT values obtained in meta-analyses based on these studies may overestimate treatment benefits.⁴⁹ Further, NNT values derived from meta-analyses tended to combine all drugs within a particular antidepressant class (eg, amitriptyline, nortriptyline, desipramine, and imipramine among the TCAs) employed at diverse doses. Taken together, these limitations raise questions about the results of those meta-analyses.

Subsequent meta-analyses, which employed strict criteria to eliminate data from studies with potential sources of bias and used a primary outcome of frequencies of patients reporting at least 30% pain reduction compared with a placebo-controlled sample, suggest that the effectiveness of TCAs as a class for treating neuropathic pain is not as compelling as once was thought. Meta-analyses of studies employing specific TCAs revealed that there was little evidence to support the use of desipramine,⁵⁰ imipramine,⁵¹ or nortriptyline⁵² in managing diabetic neuropathy or postherpetic neuralgia. Studies evaluating amitriptyline (dose range 12.5 to 150 mg/d), found low-level evidence of effectiveness; the benefit was expected to be present for a small subset (approximately 25%) of patients with neuropathic pain.⁵³

There is moderate-quality evidence that duloxetine (60 to 120 mg/d) can produce a ≥50% improvement in pain severity ratings among patients with diabetic peripheral neuropathy.⁵⁴ Although head-to-head studies with other antidepressants are limited, it appears that duloxetine and amitriptyline have comparable efficacy, even though the NNTs for amitriptyline were derived from lower-quality studies than those for duloxetine. Duloxetine is the only antidepressant to receive FDA approval for managing diabetic neuropathy. By contrast, studies assessing the utility of venlafaxine in neuropathic pain comprised small samples for brief durations, which limits the ability to draw clear (unbiased) support for its usefulness.⁵⁵

Given the diversity of pathophysiologic processes underlying the disturbances that cause neuropathic pain disorders, it is unsurprising that the effectiveness of amitriptyline and duloxetine were not generalizable to all neuropathic pain states. Although amitriptyline produced pain-mitigating effects in patients with diabetic neuropathy and post-herpetic neuralgia, and duloxetine mitigated pain among patients with diabetic neuropathy, there was no evidence to suggest their effectiveness in phantom limb pain or human immunodeficiency virus-related and spinal cord-related neuropathies.^{35,53,54,56-58}

Continue to: Fibromyalgia

As with the issues encountered in interpreting the effectiveness of antidepressants in neuropathic pain, interpreting results gleaned from clinical trials of antidepressants for treating FM are fraught with similar difficulties. Although amitriptyline has been a first-line treatment for FM for many years, the evidence upon which such recommendations were based consisted of low-level studies that had a significant potential for bias.⁵⁹ Large randomized trials would offer more compelling data regarding the efficacy of amitriptyline, but the prohibitive costs of such studies makes it unlikely they will be conducted. Amitriptyline (25 to 50 mg/d) was effective in mitigating FM-related pain in a small percentage of patients studied, with an estimated NNT of 4.⁵⁹ Adverse effects, often contributing to treatment discontinuation, were encountered more frequently among patients who received amitriptyline compared with placebo.

Selective serotonin reuptake inhibitors failed to demonstrate significant pain relief (estimated NNT of 10), or improvement in fatigue or sleep problems, even though the studies upon which such conclusions were based were low-level studies with a high potential for bias.⁶⁰ Although SSRIs have limited utility for mitigating pain, they are still quite useful for reducing depression among patients with FM.⁶⁰

By contrast, the SNRIs duloxetine and milnacipran provided clinically relevant benefit over placebo in the frequency of patients reporting pain relief of ≥30%, as well as patients’ global impression of change.⁶¹ These agents, however, failed to provide clinically relevant benefit over placebo in improving health-related quality of life, reducing sleep problems, or improving fatigue. Nonetheless, duloxetine and milnacipran are FDA-approved for managing pain in FM. Studies assessing the efficacy of venlafaxine in the treatment of FM to date have been limited by small sample sizes, inconsistent dosing, lack of a placebo control, and lack of blinding, which limits the ability to clearly delineate the role of venlafaxine in managing FM.⁶²

Mirtazapine (15 to 45 mg/d) showed a clinically relevant benefit compared with placebo for participant-reported pain relief of ≥30% and sleep disturbances. There was no benefit in terms of participant-reported improvement of quality of life, fatigue, or negative mood.⁶³ The evidence was considered to be of low quality overall.

Headache

Amitriptyline has been employed off-label to address headache prophylaxis since 1964.⁶⁴ Compared with placebo, it is efficacious in ameliorating migraine frequency and intensity as well as the frequency of tension headache.^65,66 However, SSRIs and SNRIs (venlafaxine) failed to produce significant reductions in migraine frequency or severity or the frequencies of tension headache when compared with placebo.^67,68

Continue to: Irritable bowel syndrome

Early studies addressing antidepressant efficacy in IBS reveal inconsistencies. For example, whereas some suggest that TCAs are effective in mitigating chronic, severe abdominal pain,^39,40 others concluded that TCAs failed to demonstrate a significant analgesic benefit.⁶⁹ A recent meta-analysis that restricted analysis of efficacy to randomized controlled trials (RCTs) with more rigorous methodological adherence found that pain relief in IBS is possible with both TCAs as well as SSRIs. However, adverse effects were more commonly encountered with TCAs than with SSRIs. Some of the inconsistencies in treatment efficacy reported in early studies may be due to variations in responsiveness of subsets of IBS patients. Specifically, the utility of TCAs appears to be best among patients with diarrheal-type (as opposed to constipation-type) IBS, presumably due to TCAs’ anticholinergic effects, whereas SSRIs may provide more of a benefit for patients with predominantly constipation-type IBS.^40,70

Other chronic pain conditions

Antidepressants have been used to assist in the management of several other pain conditions, including oral-facial pain, interstitial cystitis, non-cardiac chest pain, and others. The role of antidepressants for such conditions remains unclear due to limitations in the prevailing empirical work, such as few trials, small sample sizes, variations in outcome measures, and insufficient randomization and blinding.^71-76 The interpretation of results from systematic reviews and meta-analyses is limited because of these shortcomings.⁷⁷ Hence, it has not always been possible to determine whether, and to what extent, patients with such conditions may benefit from antidepressants.

Neuromodulatory effects and efficacy for pain

The interplay of norepinephrine (NE) and serotonin (5-HT) neurotransmitter systems and cellular mechanisms involved in the descending modulation of pain pathways is complex. Experimental animal models of pain modulation suggest that 5-HT can both inhibit as well as promote pain perception by different physiological mechanisms, in contrast to NE, which is predominately inhibitory. While 5-HT in the descending modulating system can inhibit pain transmission ascending to the brain from the periphery, it appears that an intact noradrenergic system is necessary for the inhibitory influences of the serotonergic system to be appreciated.^16,78,79 Deficiencies in one or both of these neurotransmitter systems may contribute to hyperactive pain processing, and thereby precipitate or maintain chronic pain.

Pain mitigation may be achieved best by enhancing both neurotransmitters simultaneously, less so by enhancing NE alone, and least by enhancing 5-HT alone.⁶ The ability to impact pain modulation would, therefore, depend on the degree to which an antidepressant capitalizes on both noradrenergic and serotonergic neurotransmission. Antidepressants commonly employed to manage pain are presented in Table 1^{47,60,68,80-88} according to their primary neurotransmitter effects. Thus, the literature summarized above suggests that antidepressants that influence both NE and 5-HT transmission have greater analgesic effects than antidepressants with more specific effects, such as influencing 5-HT reuptake alone.^80-85 It is unsurprising, therefore, that the SSRIs have not been demonstrated to be as consistently analgesic.^{47,60,68,80,86-88}

Similarly, pharmacodynamic and pharmacokinetic differences within antidepressant classes may influence analgesic effectiveness. Simultaneous effects on NE and 5-HT are achieved at low doses with duloxetine and milnacipran. By contrast, 5-HT effects predominate at low doses for venlafaxine. To achieve pain-mitigating effects, higher doses of venlafaxine generally are required.⁸⁹ Therefore, inconsistencies across studies regarding the analgesic benefits of venlafaxine may be attributable to variability in dosing; patients treated with lower doses may not have experienced sufficient NE effects to garner positive results.

Continue to: The differences in analgesic efficacy...

The differences in analgesic efficacy among specific TCAs may be understood in a similar fashion. Specifically, tertiary TCAs (imipramine and amitriptyline) inhibit both 5-HT and NE reuptake.^6,90 Secondary amines (desipramine and nortriptyline) predominantly impact NE reuptake, possibly accounting for the lesser pain-mitigating benefit achieved with these agents, such as for treating neuro­pathic pain. Further, in vivo imipramine and amitriptyline are rapidly metabolized to secondary amines that are potent and selective NE reuptake inhibitors. In this way, the secondary amines may substantially lose the ability to modulate pain transmission because of the loss of concurrent 5-HT influences.⁹⁰

Clinical pearls

The following practical points can help guide clinicians regarding the usefulness of antidepressants for pain management:

• Antidepressants can alleviate symptoms of depression and pain. The pain-mitigating effects of antidepressants are possible even among chronic pain patients who are not depressed. Antidepressants may confer benefits for chronic pain patients with depression and other comorbid conditions, such as somatic symptom and related disorders.
• Antidepressants are useful for select chronic pain states. Although the noradrenergic and serotonergic antidepressants (SNRIs and, to some extent, amitriptyline) appear to have efficacy for neuropathic pain and FM, the benefits of SSRIs appear to be less robust. On the other hand, SSRIs and TCAs may have potential benefit for patients with IBS. However, the results of meta-analyses are limited in the ability to provide information about which patients will best respond to which specific antidepressant or how well. Future research directed at identifying characteristics that can predict which patients are likely to benefit from one antidepressant vs another would help inform how best to tailor treatment to individual needs.
• The pain-mitigating effects of antidepressants often emerge early in the course of treatment (often before mood-elevating effects are observed). For example, in the case of amitriptyline, pain relief may be possible for some patients at doses generally lower than those required for mood-elevating effects. To date, there is limited information in the literature to determine what constitutes a sufficient duration of treatment, or when treatment should be modified.
• Failure to reduce pain should raise questions about whether the dose should be increased, an alternative agent should be tried, or combinations with other analgesic agents should be considered. Failure to achieve pain-mitigating effects with one antidepressant does not mean failure with others. Hence, failure to achieve desired effects with one agent might warrant an empirical trial with another agent. Presently, too few double-blind RCTs have been conducted to assess the pain-mitigating effects of other antidepressants (eg, bupropion and newer SNRIs such as desvenlafaxine and levomilnacipran). Meta-analysis of the analgesic effectiveness of these agents or comparisons to the efficacy of other antidepressant classes is, therefore, impossible at this time.

Because many chronic pain states are complex, patients will seldom experience clinically relevant benefit from any one intervention.⁵³ The bigger implication for clinical research is to determine whether there is a sequence or combination of medication use that will provide overall better clinical effectiveness.⁵³ Only limited data are available exploring the utility of combining pharmacologic approaches to address pain.⁹¹ For example, preliminary evidence suggests that combinations of complementary strategies, such as duloxetine combined with pregabalin, may result in significantly greater numbers of FM patients achieving ≥30% pain reduction compared with monotherapy with either agent alone or placebo.⁹²

• Antidepressant selection may need to be based on medication-related adverse effect profiles and the potential for drug interactions. These factors are useful to consider in delineating multimodal treatment regimens for chronic pain in light of patients’ comorbidities and co-medication regimen. For example, the adverse effects of TCAs (anticholinergic and alpha-adrenergic influences) limit their utility for treating pain. Some of these effects can be more problematic in select populations, such as older adults or those with orthostatic difficulties, among others. TCAs are contraindicated in patients with closed-angle glaucoma, recent myocardial infarction, cardiac arrhythmias, poorly controlled seizures, or severe benign prostatic hypertrophy. Although the pain-mitigating effects of SNRIs have not been demonstrated to significantly exceed those of TCAs,^68,93,94 SNRIs would offer an advantage of greater tolerability of adverse effects and relative safety in patients with comorbid medical conditions that would otherwise preclude TCA use. The adverse effects and common drug interactions associated with antidepressants are summarized in Table 2⁹⁵.

Conclusion

Chronic, nonmalignant pain conditions afflict many patients and significantly impair their ability to function. Because of heightened concerns related to the appropriateness of, and restricting inordinate access to, long-term opioid analgesics, clinicians need to explore the usefulness of co-analgesic agents, such as antidepressants. Significant comorbidities exist between psychiatric disorders and chronic pain, and psychiatrists are uniquely positioned to diagnose and treat psychiatric comorbidities, as well as pain, among their patients, especially since they understand the kinetics and dynamics of antidepressants.

Bottom Line

Antidepressants can alleviate symptoms of depression and pain. Noradrenergic and serotonergic antidepressants appear to have efficacy for pain associated with neuropathy and fibromyalgia, while selective serotonin reuptake inhibitors and tricyclic antidepressants may have benefit for patients with irritable bowel syndrome. However, evidence regarding which patients will best respond to which specific antidepressant is limited.

Continue to: Related Resources

• Williams AM, Knox ED. When to prescribe antidepressants to treat comorbid depression and pain disorders. Current Psychiatry. 2017;16(1):55-58.
• Maletic V, Demuri B. Chronic pain and depression: treatment of 2 culprits in common. Current Psychiatry. 2016;15(3):41,47-50,52.

Drug Brand Names

Amitriptyline • Elavil, Endep
Bupropion • Wellbutrin, Zyban
Carisoprodol • Rela, Soma
Cyclobenzaprine • Amrix, Flexeril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Horizant, Neurontin
Imipramine • Tofranil
Levomilnacipran • Fetzima
Methadone • Dolophine, Methadose
Milnacipran • Savella
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Pregabalin • Lyrica, Lyrica CR
Tapentadol • Nucynta
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Warfarin • Coumadin, Jantoven

Approximately 55 years ago, tricyclic antidepressants (TCAs) began to be used to treat neuropathic pain.¹ Eventually, clinical trials emerged suggesting the utility of TCAs for other chronic pain conditions, such as fibromyalgia (FM) and migraine prophylaxis. However, despite TCAs’ effectiveness in mitigating painful conditions, their adverse effects limited their use.

Pharmacologic advancements have led to the development of other antidepressant classes, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and the use of these agents has come to eclipse that of TCAs. In the realm of pain management, such developments have raised the hope of possible alternative co-analgesic agents that could avoid the adverse effects associated with TCAs. Some of these agents have demonstrated efficacy for managing chronic pain states, while others have demonstrated only limited utility.

This article provides a synopsis of systematic reviews and meta-analyses examining the role of antidepressant therapy for managing several chronic pain conditions, including pain associated with neuropathy, FM, headache, and irritable bowel syndrome (IBS). Because the literature base is rapidly evolving, it is necessary to revisit the information gleaned from clinical data with respect to treatment effectiveness, and to clarify how antidepressants might be positioned in the management of chronic pain.

The effectiveness of antidepressants for pain

The pathophysiologic processes that precipitate and maintain chronic pain conditions are complex (Box 1^2-10). The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects and indirect effects (Box 2^{2,3,8,10,11-33}).

Box 1

During the last several decades, anti­depressants have been used to address—and have demonstrated clinical utility for—a variety of chronic pain states. However, antidepressants are not a panacea; some chronic pain conditions are more responsive to antidepressants than are others. The chronic painful states most amenable to antidepressants are those that result primarily from a process of neural sensitization, as opposed to acute somatic or visceral nociception. Hence, several meta-analyses and evidence-based reviews have long suggested the usefulness of antidepressants for mitigating pain associated with neuropathy,^34,35 FM,^36,37 headache,³⁸ and IBS.^39,40

Box 2

Continue to: Neuropathic pain

Several treatment guidelines advocate for the use of antidepressants for neuropathic pain.^41-44 For decades, TCAs have been employed off-label to successfully treat many patients with neuropathic pain states. Early investigations suggested that TCAs were robustly efficacious in managing patients with neuropathy.^45-48 Calculated number-needed-to-treat (NNT) values for TCAs were quite low (ie, reflecting that few patients would need to be treated to yield a positive response in one patient compared with placebo), and were comparable to, if not slightly better than, the NNTs generated for anticonvulsants and α2-δ ligands, such as gabapentin or pregabalin.^45-48

Unfortunately, early studies involving TCAs conducted many years ago do not meet contemporary standards of methodological rigor; they featured relatively small samples of patients assessed for brief post-treatment intervals with variable outcome measures. Thus, the NNT values obtained in meta-analyses based on these studies may overestimate treatment benefits.⁴⁹ Further, NNT values derived from meta-analyses tended to combine all drugs within a particular antidepressant class (eg, amitriptyline, nortriptyline, desipramine, and imipramine among the TCAs) employed at diverse doses. Taken together, these limitations raise questions about the results of those meta-analyses.

Subsequent meta-analyses, which employed strict criteria to eliminate data from studies with potential sources of bias and used a primary outcome of frequencies of patients reporting at least 30% pain reduction compared with a placebo-controlled sample, suggest that the effectiveness of TCAs as a class for treating neuropathic pain is not as compelling as once was thought. Meta-analyses of studies employing specific TCAs revealed that there was little evidence to support the use of desipramine,⁵⁰ imipramine,⁵¹ or nortriptyline⁵² in managing diabetic neuropathy or postherpetic neuralgia. Studies evaluating amitriptyline (dose range 12.5 to 150 mg/d), found low-level evidence of effectiveness; the benefit was expected to be present for a small subset (approximately 25%) of patients with neuropathic pain.⁵³

There is moderate-quality evidence that duloxetine (60 to 120 mg/d) can produce a ≥50% improvement in pain severity ratings among patients with diabetic peripheral neuropathy.⁵⁴ Although head-to-head studies with other antidepressants are limited, it appears that duloxetine and amitriptyline have comparable efficacy, even though the NNTs for amitriptyline were derived from lower-quality studies than those for duloxetine. Duloxetine is the only antidepressant to receive FDA approval for managing diabetic neuropathy. By contrast, studies assessing the utility of venlafaxine in neuropathic pain comprised small samples for brief durations, which limits the ability to draw clear (unbiased) support for its usefulness.⁵⁵

Given the diversity of pathophysiologic processes underlying the disturbances that cause neuropathic pain disorders, it is unsurprising that the effectiveness of amitriptyline and duloxetine were not generalizable to all neuropathic pain states. Although amitriptyline produced pain-mitigating effects in patients with diabetic neuropathy and post-herpetic neuralgia, and duloxetine mitigated pain among patients with diabetic neuropathy, there was no evidence to suggest their effectiveness in phantom limb pain or human immunodeficiency virus-related and spinal cord-related neuropathies.^{35,53,54,56-58}

Continue to: Fibromyalgia

As with the issues encountered in interpreting the effectiveness of antidepressants in neuropathic pain, interpreting results gleaned from clinical trials of antidepressants for treating FM are fraught with similar difficulties. Although amitriptyline has been a first-line treatment for FM for many years, the evidence upon which such recommendations were based consisted of low-level studies that had a significant potential for bias.⁵⁹ Large randomized trials would offer more compelling data regarding the efficacy of amitriptyline, but the prohibitive costs of such studies makes it unlikely they will be conducted. Amitriptyline (25 to 50 mg/d) was effective in mitigating FM-related pain in a small percentage of patients studied, with an estimated NNT of 4.⁵⁹ Adverse effects, often contributing to treatment discontinuation, were encountered more frequently among patients who received amitriptyline compared with placebo.

Selective serotonin reuptake inhibitors failed to demonstrate significant pain relief (estimated NNT of 10), or improvement in fatigue or sleep problems, even though the studies upon which such conclusions were based were low-level studies with a high potential for bias.⁶⁰ Although SSRIs have limited utility for mitigating pain, they are still quite useful for reducing depression among patients with FM.⁶⁰

By contrast, the SNRIs duloxetine and milnacipran provided clinically relevant benefit over placebo in the frequency of patients reporting pain relief of ≥30%, as well as patients’ global impression of change.⁶¹ These agents, however, failed to provide clinically relevant benefit over placebo in improving health-related quality of life, reducing sleep problems, or improving fatigue. Nonetheless, duloxetine and milnacipran are FDA-approved for managing pain in FM. Studies assessing the efficacy of venlafaxine in the treatment of FM to date have been limited by small sample sizes, inconsistent dosing, lack of a placebo control, and lack of blinding, which limits the ability to clearly delineate the role of venlafaxine in managing FM.⁶²

Mirtazapine (15 to 45 mg/d) showed a clinically relevant benefit compared with placebo for participant-reported pain relief of ≥30% and sleep disturbances. There was no benefit in terms of participant-reported improvement of quality of life, fatigue, or negative mood.⁶³ The evidence was considered to be of low quality overall.

Headache

Amitriptyline has been employed off-label to address headache prophylaxis since 1964.⁶⁴ Compared with placebo, it is efficacious in ameliorating migraine frequency and intensity as well as the frequency of tension headache.^65,66 However, SSRIs and SNRIs (venlafaxine) failed to produce significant reductions in migraine frequency or severity or the frequencies of tension headache when compared with placebo.^67,68

Continue to: Irritable bowel syndrome

Early studies addressing antidepressant efficacy in IBS reveal inconsistencies. For example, whereas some suggest that TCAs are effective in mitigating chronic, severe abdominal pain,^39,40 others concluded that TCAs failed to demonstrate a significant analgesic benefit.⁶⁹ A recent meta-analysis that restricted analysis of efficacy to randomized controlled trials (RCTs) with more rigorous methodological adherence found that pain relief in IBS is possible with both TCAs as well as SSRIs. However, adverse effects were more commonly encountered with TCAs than with SSRIs. Some of the inconsistencies in treatment efficacy reported in early studies may be due to variations in responsiveness of subsets of IBS patients. Specifically, the utility of TCAs appears to be best among patients with diarrheal-type (as opposed to constipation-type) IBS, presumably due to TCAs’ anticholinergic effects, whereas SSRIs may provide more of a benefit for patients with predominantly constipation-type IBS.^40,70

Other chronic pain conditions

Antidepressants have been used to assist in the management of several other pain conditions, including oral-facial pain, interstitial cystitis, non-cardiac chest pain, and others. The role of antidepressants for such conditions remains unclear due to limitations in the prevailing empirical work, such as few trials, small sample sizes, variations in outcome measures, and insufficient randomization and blinding.^71-76 The interpretation of results from systematic reviews and meta-analyses is limited because of these shortcomings.⁷⁷ Hence, it has not always been possible to determine whether, and to what extent, patients with such conditions may benefit from antidepressants.

Neuromodulatory effects and efficacy for pain

The interplay of norepinephrine (NE) and serotonin (5-HT) neurotransmitter systems and cellular mechanisms involved in the descending modulation of pain pathways is complex. Experimental animal models of pain modulation suggest that 5-HT can both inhibit as well as promote pain perception by different physiological mechanisms, in contrast to NE, which is predominately inhibitory. While 5-HT in the descending modulating system can inhibit pain transmission ascending to the brain from the periphery, it appears that an intact noradrenergic system is necessary for the inhibitory influences of the serotonergic system to be appreciated.^16,78,79 Deficiencies in one or both of these neurotransmitter systems may contribute to hyperactive pain processing, and thereby precipitate or maintain chronic pain.

Pain mitigation may be achieved best by enhancing both neurotransmitters simultaneously, less so by enhancing NE alone, and least by enhancing 5-HT alone.⁶ The ability to impact pain modulation would, therefore, depend on the degree to which an antidepressant capitalizes on both noradrenergic and serotonergic neurotransmission. Antidepressants commonly employed to manage pain are presented in Table 1^{47,60,68,80-88} according to their primary neurotransmitter effects. Thus, the literature summarized above suggests that antidepressants that influence both NE and 5-HT transmission have greater analgesic effects than antidepressants with more specific effects, such as influencing 5-HT reuptake alone.^80-85 It is unsurprising, therefore, that the SSRIs have not been demonstrated to be as consistently analgesic.^{47,60,68,80,86-88}

Similarly, pharmacodynamic and pharmacokinetic differences within antidepressant classes may influence analgesic effectiveness. Simultaneous effects on NE and 5-HT are achieved at low doses with duloxetine and milnacipran. By contrast, 5-HT effects predominate at low doses for venlafaxine. To achieve pain-mitigating effects, higher doses of venlafaxine generally are required.⁸⁹ Therefore, inconsistencies across studies regarding the analgesic benefits of venlafaxine may be attributable to variability in dosing; patients treated with lower doses may not have experienced sufficient NE effects to garner positive results.

Continue to: The differences in analgesic efficacy...

The differences in analgesic efficacy among specific TCAs may be understood in a similar fashion. Specifically, tertiary TCAs (imipramine and amitriptyline) inhibit both 5-HT and NE reuptake.^6,90 Secondary amines (desipramine and nortriptyline) predominantly impact NE reuptake, possibly accounting for the lesser pain-mitigating benefit achieved with these agents, such as for treating neuro­pathic pain. Further, in vivo imipramine and amitriptyline are rapidly metabolized to secondary amines that are potent and selective NE reuptake inhibitors. In this way, the secondary amines may substantially lose the ability to modulate pain transmission because of the loss of concurrent 5-HT influences.⁹⁰

Clinical pearls

The following practical points can help guide clinicians regarding the usefulness of antidepressants for pain management:

• Antidepressants can alleviate symptoms of depression and pain. The pain-mitigating effects of antidepressants are possible even among chronic pain patients who are not depressed. Antidepressants may confer benefits for chronic pain patients with depression and other comorbid conditions, such as somatic symptom and related disorders.
• Antidepressants are useful for select chronic pain states. Although the noradrenergic and serotonergic antidepressants (SNRIs and, to some extent, amitriptyline) appear to have efficacy for neuropathic pain and FM, the benefits of SSRIs appear to be less robust. On the other hand, SSRIs and TCAs may have potential benefit for patients with IBS. However, the results of meta-analyses are limited in the ability to provide information about which patients will best respond to which specific antidepressant or how well. Future research directed at identifying characteristics that can predict which patients are likely to benefit from one antidepressant vs another would help inform how best to tailor treatment to individual needs.
• The pain-mitigating effects of antidepressants often emerge early in the course of treatment (often before mood-elevating effects are observed). For example, in the case of amitriptyline, pain relief may be possible for some patients at doses generally lower than those required for mood-elevating effects. To date, there is limited information in the literature to determine what constitutes a sufficient duration of treatment, or when treatment should be modified.
• Failure to reduce pain should raise questions about whether the dose should be increased, an alternative agent should be tried, or combinations with other analgesic agents should be considered. Failure to achieve pain-mitigating effects with one antidepressant does not mean failure with others. Hence, failure to achieve desired effects with one agent might warrant an empirical trial with another agent. Presently, too few double-blind RCTs have been conducted to assess the pain-mitigating effects of other antidepressants (eg, bupropion and newer SNRIs such as desvenlafaxine and levomilnacipran). Meta-analysis of the analgesic effectiveness of these agents or comparisons to the efficacy of other antidepressant classes is, therefore, impossible at this time.

Because many chronic pain states are complex, patients will seldom experience clinically relevant benefit from any one intervention.⁵³ The bigger implication for clinical research is to determine whether there is a sequence or combination of medication use that will provide overall better clinical effectiveness.⁵³ Only limited data are available exploring the utility of combining pharmacologic approaches to address pain.⁹¹ For example, preliminary evidence suggests that combinations of complementary strategies, such as duloxetine combined with pregabalin, may result in significantly greater numbers of FM patients achieving ≥30% pain reduction compared with monotherapy with either agent alone or placebo.⁹²

• Antidepressant selection may need to be based on medication-related adverse effect profiles and the potential for drug interactions. These factors are useful to consider in delineating multimodal treatment regimens for chronic pain in light of patients’ comorbidities and co-medication regimen. For example, the adverse effects of TCAs (anticholinergic and alpha-adrenergic influences) limit their utility for treating pain. Some of these effects can be more problematic in select populations, such as older adults or those with orthostatic difficulties, among others. TCAs are contraindicated in patients with closed-angle glaucoma, recent myocardial infarction, cardiac arrhythmias, poorly controlled seizures, or severe benign prostatic hypertrophy. Although the pain-mitigating effects of SNRIs have not been demonstrated to significantly exceed those of TCAs,^68,93,94 SNRIs would offer an advantage of greater tolerability of adverse effects and relative safety in patients with comorbid medical conditions that would otherwise preclude TCA use. The adverse effects and common drug interactions associated with antidepressants are summarized in Table 2⁹⁵.

Conclusion

Chronic, nonmalignant pain conditions afflict many patients and significantly impair their ability to function. Because of heightened concerns related to the appropriateness of, and restricting inordinate access to, long-term opioid analgesics, clinicians need to explore the usefulness of co-analgesic agents, such as antidepressants. Significant comorbidities exist between psychiatric disorders and chronic pain, and psychiatrists are uniquely positioned to diagnose and treat psychiatric comorbidities, as well as pain, among their patients, especially since they understand the kinetics and dynamics of antidepressants.

Bottom Line

Antidepressants can alleviate symptoms of depression and pain. Noradrenergic and serotonergic antidepressants appear to have efficacy for pain associated with neuropathy and fibromyalgia, while selective serotonin reuptake inhibitors and tricyclic antidepressants may have benefit for patients with irritable bowel syndrome. However, evidence regarding which patients will best respond to which specific antidepressant is limited.

Continue to: Related Resources

• Williams AM, Knox ED. When to prescribe antidepressants to treat comorbid depression and pain disorders. Current Psychiatry. 2017;16(1):55-58.
• Maletic V, Demuri B. Chronic pain and depression: treatment of 2 culprits in common. Current Psychiatry. 2016;15(3):41,47-50,52.

Drug Brand Names

Amitriptyline • Elavil, Endep
Bupropion • Wellbutrin, Zyban
Carisoprodol • Rela, Soma
Cyclobenzaprine • Amrix, Flexeril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Horizant, Neurontin
Imipramine • Tofranil
Levomilnacipran • Fetzima
Methadone • Dolophine, Methadose
Milnacipran • Savella
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Pregabalin • Lyrica, Lyrica CR
Tapentadol • Nucynta
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Warfarin • Coumadin, Jantoven

Introduction

Acute pancreatitis (AP) is a major clinical and financial burden in the United States. Several major clinical guidelines provide evidence-based recommendations for the clinical management decisions in AP, including those from the American College of Gastroenterology (ACG; 2013),¹ and the International Association of Pancreatology (IAP; 2013).² More recently, the American Gastroenterological Association (AGA) released their own set of guidelines.^3,4 In this update on AP, we review these guidelines and reference recent literature focused on epidemiology, risk factors, etiology, diagnosis, risk stratification, and recent advances in the early medical management of AP. Regarding the latter, we review six treatment interventions (pain management, intravenous fluid resuscitation, feeding, prophylactic antibiotics, probiotics, and timing of endoscopic retrograde cholangiopancreatography (ERCP) in acute biliary pancreatitis) and four preventive interventions (alcohol and smoking cessation, same-admission cholecystectomy for acute biliary pancreatitis, and chemoprevention and fluid administration for post-ERCP pancreatitis [PEP]). Updates on multidisciplinary management of (infected) pancreatic necrosis is beyond the scope of this review. Table 1 summarizes the concepts discussed in this article.

Recent advances in epidemiology and evaluation of AP

Epidemiology

AP is the third most common cause of gastrointestinal-related hospitalizations and fourth most common cause of readmission in 2014.⁵ Recent epidemiologic studies show conflicting trends for the incidence of AP, both increasing⁶ and decreasing,⁷ likely attributable to significant differences in study designs. Importantly, multiple studies have demonstrated that hospital length of stay, costs, and mortality have declined since 2009.^6,8-10

Persistent organ failure (POF), defined as organ failure lasting more than 48 hours, is the major cause of death in AP. POF, if only a single organ during AP, is associated with 27%-36% mortality; if it is multiorgan, it is associated with 47% mortality.^1,11 Other factors associated with increased hospital mortality include infected pancreatic necrosis,^12-14 diabetes mellitus,¹⁵ hospital-acquired infection,¹⁶ advanced age (70 years and older),¹⁷ and obesity.¹⁸ Predictive factors of 1-year mortality include readmission within 30 days, higher Charlson Comorbidity Index, and longer hospitalization.¹⁹

Risk factors

We briefly highlight recent insights into risk factors for AP (Table 1) and refer to a recent review for further discussion.²⁰ Current and former tobacco use are independent risk factors for AP.²¹ The dose-response relationship of alcohol to the risk of pancreatitis is complex,²² but five standard drinks per day for 5 years is a commonly used cut-off.^1,23 New evidence suggests that the relationship between the dose of alcohol and risk of AP differs by sex, linearly in men but nonlinearly (J-shaped) in women.²⁴ Risk of AP in women was decreased with alcohol consumption of up to 40 g/day (one standard drink contains 14 g of alcohol) and increased above this amount. Cannabis is a possible risk factor for toxin-induced AP and abstinence appears to abolish risk of recurrent attacks.²⁵

Patients with inflammatory bowel disease (IBD) have a 2.9-fold higher risk for AP versus non-IBD cohorts²⁶ with the most common etiologies are from gallstones and medications.²⁷ In patients with end-stage renal disease (ESRD), the risk of AP is higher in those who receive peritoneal dialysis, compared with hemodialysis^28-33 and who are women, older, or have cholelithiasis or liver disease.³⁴As recently reviewed,³⁵ pancreatic cancer appears to be associated with first-attack pancreatitis with few exceptions.³⁶ In this setting, the overall incidence of pancreatic cancer is low (1.5%). The risk is greatest within the first year of the attack of AP, negligible below age 40 years but steadily rising through the fifth to eighth decades.³⁷ Pancreatic cancer screening is a conditional recommendation of the ACG guidelines in patients with unexplained AP, particularly those aged 40 years or older.¹

Etiology and diagnosis

Alcohol and gallstones remain the most prevalent etiologies for AP.¹ While hypertriglyceridemia accounted for 9% of AP in a systematic review of acute pancreatitis in 15 different countries,³⁸ it is the second most common cause of acute pancreatitis in Asia (especially China).³⁹ Figure 1 provides a breakdown of the etiologies and risk factors of pancreatitis. Importantly, it remains challenging to assign several toxic-metabolic etiologies as either a cause or risk factor for AP, particularly with regards to alcohol, smoking, and cannabis to name a few.

Guidelines and recent studies of AP raise questions about the threshold above which hypertriglyceridemia causes or poses as an important cofactor for AP. American and European societies define the threshold for triglycerides at 885-1,000 mg/dL.^1,42,43 Pedersen et al. provide evidence of a graded risk of AP with hypertriglyceridemia: In multivariable analysis, adjusted hazard ratios for AP were much higher with nonfasting mild to moderately elevated plasma triglycerides (177-885 mg/dL), compared with normal values (below 89 mg/dL).⁴⁴ Moreover, the risk of severe AP (developing POF) increases in proportion to triglyceride value, independent of the underlying cause of AP.⁴⁵

Vidyard Video

Diagnosis of AP is derived from the revised Atlanta classification.⁴⁶ The recommended timing and indications for offering cross-sectional imaging are after 48-72 hours in patients with no improvement to initial care.¹ Endoscopic ultrasonography (EUS) has better diagnostic accuracy and sensitivity, compared with magnetic resonance cholangiopancreatography (MRCP) for choledocholithiasis, and has comparable specificity.^47,48 Among noninvasive imaging modalities, MRCP is more sensitive than computed tomography (CT) for diagnosing choledocholithiasis.⁴⁹ Despite guideline recommendations for more selective use of pancreatic imaging in the early assessment of AP, utilization of early CT or MRCP imaging (within the first 24 hours of care) remained high during 2014-2015, compared with 2006-2007.⁵⁰

ERCP is not recommended as a pure diagnostic tool, owing to the availability of other diagnostic tests and a complication rate of 5%-10% with risks involving PEP, cholangitis, perforation, and hemorrhage.⁵¹ A recent systematic review of EUS and ERCP in acute biliary pancreatitis concluded that EUS had lower failure rates and had no complications, and the use of EUS avoided ERCP in 71.2% of cases.⁵²

 

 

 

Risk stratification

The goals of using risk stratification tools in AP are to identify patients at risk for developing major outcomes, including POF, infected pancreatic necrosis, and death, and to ensure timely triaging of patients to an appropriate level of care. Existing prediction models have only moderate predictive value.^53,54 Examples include simple risk stratification tools such as blood urea nitrogen (BUN) and hemoconcentration,^55,56 disease-modifying patient variables (age, obesity, etc.), biomarkers (i.e., angiopoietin 2),⁵⁷ and more complex clinical scoring systems such as Acute Physiology and Chronic Health Evaluation II (APACHE II), BISAP (BUN, impaired mental status, SIRS criteria, age, pleural effusion) score, early warning system (EWS), Glasgow-Imrie score, Japanese severity score, and recently the Pancreatitis Activity Scoring System (PASS).⁵⁸ Two recent guidelines affirmed the importance of predicting the severity of AP, using one or more predictive tools.^1,2 The recent 2018 AGA technical review does not debate this commonsense approach, but does highlight that there is no published observational study or randomized, controlled trial (RCT) investigating whether prediction tools affect clinical outcomes.⁴

Recent advances in early treatment of AP

Literature review and definitions

The AP literature contains heterogeneous definitions of severe AP and of what constitutes a major outcome in AP. Based on definitions of the 2013 revised Atlanta Criteria, the 2018 AGA technical review and clinical guidelines emphasized precise definitions of primary outcomes of clinical importance in AP, including death, persistent single organ failure, or persistent multiple organ failure, each requiring a duration of more than 48 hours, and infected pancreatic or peripancreatic necrosis or both (Table 2).^3,4

 

Pain management

Management of pain in AP is complex and requires a detailed discussion beyond the scope of this review, but recent clinical and translational studies raise questions about the current practice of using opioids for pain management in AP. A provocative, multicenter, retrospective cohort study reported lower 30-day mortality among critically ill patients who received epidural analgesia versus standard care without epidural analgesia.⁵⁹ The possible mechanism of protection and the drugs administered are unclear. An interesting hypothesis is that the epidural cohort may have received lower exposure to morphine, which may increase gut permeability, the risk of infectious complications, and severity of AP, based on a translational study in mice.⁶⁰

Intravenous fluid administration

Supportive care with the use of IV fluid hydration is a mainstay of treatment for AP in the first 12-24 hours. Table 3 summarizes the guidelines in regards to IV fluid administration as delineated by the ACG and AGA guidelines on the management of pancreatitis.^1,3 Guidelines advocate for early fluid resuscitation to correct intravascular depletion in order to reduce morbidity and mortality associated with AP.^1,2,4 The 2018 AGA guidelines endorse a conditional recommendation for using goal-directed therapy for initial fluid management,³ do not recommend for or against normal saline versus lactated Ringer’s (LR), but do advise against the use of hydroxyethyl starch fluids.³ Consistent with these recommendations, two recent RCTs published subsequent to the prespecified time periods of the AGA technical review and guideline, observed no significant differences between LR and normal saline on clinically meaningful outcomes.^61,62 The AGA guidelines acknowledge that evidence was of very-low quality in support of goal-directed therapy,^3,4 which has not been shown to have a significant reduction in persistent multiple organ failure, mortality, or pancreatic necrosis, compared with usual care. As the authors noted, interpretation of the data was limited by the absence of other critical outcomes in these trials (infected pancreatic necrosis), lack of uniformity of specific outcomes and definitions of transient and POF, few trials, and risk of bias. There is a clear need for a large RCT to provide evidence to guide decision making with fluid resuscitation in AP, particularly in regard to fluid type, volume, rate, duration, endpoints, and clinical outcomes.

 

 

Feeding

More recently, the focus of nutrition in the management of AP has shifted away from patients remaining nil per os (NPO). Current guidelines advocate for early oral feeding (within 24 hours) in mild AP,^3,4 in order to protect the gut-mucosal barrier. Remaining NPO when compared with early oral feeding has a 2.5-fold higher risk for interventions for necrosis.⁴ The recently published AGA technical review identified no significant impact on outcomes of early versus delayed oral feeding, which is consistent with observations of a landmark Dutch PYTHON trial entitled “Early versus on-demand nasoenteric tube feeding in acute pancreatitis.”^4,63 There is no clear cutoff point for initiating feeding for those with severe AP. A suggested practical approach is to initiate feeding within 24-72 hours and offer enteral nutrition for those intolerant to oral feeds. In severe AP and moderately severe AP, enteral nutrition is recommended over parenteral nutrition.^3,4 Enteral nutrition significantly reduces the risk of infected peripancreatic necrosis, single organ failure, and multiorgan failure.⁴ Finally, the AGA guidelines provide a conditional recommendation for providing enteral nutrition support through either the nasogastric or nasoenteric route.³ Further studies are required to determine the optimal timing, rate, and formulation of enteral nutrition in severe AP.

 

Antibiotics and probiotics

Current guidelines do not support the use of prophylactic antibiotics to prevent infection in necrotizing AP and severe AP.^1-3 The AGA technical review reported that prophylactic antibiotics did not reduce infected pancreatic or peripancreatic necrosis, persistent single organ failure, or mortality.⁴ Guidelines advocate against the use of probiotics for severe AP, because of increased mortality risk.¹

Timing of ERCP in acute biliary pancreatitis

There is universal agreement for offering urgent ERCP (within 24 hours) in biliary AP complicated by cholangitis.^1-3,64 Figure 2 demonstrates an example of a cholangiogram completed within 24 hours of presentation of biliary AP complicated by cholangitis.

In the absence of cholangitis, the timing of ERCP for AP with persistent biliary obstruction is less clear.^1-3 In line with recent guidelines, the 2018 AGA guidelines advocate against routine use of urgent ERCP for biliary AP without cholangitis,³ a conditional recommendation with overall low quality of data.⁴ The AGA technical review found that urgent ERCP, compared with conservative management in acute biliary pancreatitis without cholangitis had no significant effect on mortality, organ failure, infected pancreatic necrosis, and total necrotizing pancreatitis, but did significantly shorten hospital length of stay.⁴ There are limited data to guide decision making of when nonurgent ERCP should be performed in hospitalized patients with biliary AP with persistent obstruction and no cholangitis.^3,64

 

 

Alcohol and smoking cessation

The AGA technical review advocates for brief alcohol intervention during hospitalization for alcohol-induced AP on the basis of one RCT that addresses the impact of alcohol counseling on recurrent bouts of AP⁴ plus evidence from a Cochrane review of alcohol-reduction strategies in primary care populations.⁶⁵ Cessation of smoking – an established independent risk factor of AP – recurrent AP and chronic pancreatitis, should also be recommended as part of the management of AP.

Cholecystectomy

Evidence supports same-admission cholecystectomy for mild gallstone AP, a strong recommendation of published AGA guidelines.³ When compared with delayed cholecystectomy, same-admission cholecystectomy significantly reduced gallstone-related complications, readmissions for recurrent pancreatitis, and pancreaticobiliary complications, without having a significant impact on mortality during a 6-month follow-up period.⁶⁶ Delaying cholecystectomy 6 weeks in patients with moderate-severe gallstone AP appears to reduce morbidity, including the development of infected collections, and mortality.⁴ An ongoing RCT, the APEC trial, aims to determine whether early ERCP with biliary sphincterotomy reduces major complications or death when compared with no intervention for biliary AP in patients at high risk of complications.⁶⁷

Chemoprevention and IV fluid management of post-ERCP pancreatitis

Accumulating data support the effectiveness of chemoprevention, pancreatic stent placement, and fluid administration to prevent post-ERCP pancreatitis. Multiple RCTs, meta-analyses, and systematic reviews indicate that rectal NSAIDs) reduce post-ERCP pancreatitis onset^68-71 and moderate-severe post-ERCP pancreatitis. Additionally, placement of a pancreatic duct stent may decrease the risk of severe post-ERCP pancreatitis in high-risk patients.³ Guidelines do not comment on fluid administrations for prevention of post-ERCP pancreatitis, but studies have shown that greater periprocedural IV fluid was an independent protective factor against moderate to severe PEP⁷² and was associated with shorter hospital length of stay.⁷³ Recent meta-analyses and RCTs support using LR prior to ERCP to prevent PEP.^74-77 Interestingly, a recent RCT shows that the combination of rectal indomethacin and LR, compared with combination placebo and normal saline reduced the risk of PEP in high-risk patients.⁷⁸

Two ongoing multicenter RCTs will clarify the role of combination therapy. The Dutch FLUYT RCT aims to determine the optimal combination of rectal NSAIDs and periprocedural infusion of IV fluids to reduce the incidence of PEP and moderate-severe PEP⁷⁹ and the Stent vs. Indomethacin (SVI) trial aims to determine the whether combination pancreatic stent placement plus rectal indomethacin is superior to monotherapy indomethacin for preventing post-ERCP pancreatitis in high-risk cases.⁸⁰

Implications for clinical practice

The diagnosis and optimal management of AP require a systematic approach with multidisciplinary decision making. Morbidity and mortality in AP are driven by early or late POF, and the latter often is triggered by infected necrosis. Risk stratification of these patients at the point of contact is a commonsense approach to enable triaging of patients to the appropriate level of care. Regardless of pancreatitis severity, recommended treatment interventions include goal-directed IV fluid resuscitation, early feeding by mouth or enteral tube when necessary, avoidance of prophylactic antibiotics, avoidance of probiotics, and urgent ERCP for patients with acute biliary pancreatitis complicated by cholangitis. Key measures for preventing hospital readmission and pancreatitis include same-admission cholecystectomy for acute biliary pancreatitis and alcohol and smoking cessation. Preventive measures for post-ERCP pancreatitis in patients undergoing ERCP include rectal indomethacin, prophylactic pancreatic duct stent placement, and periprocedural fluid resuscitation.

Dr. Mandalia is a fellow, gastroenterology, department of internal medicine, division of gastroenterology, Michigan Medicine, Ann Arbor; Dr. DiMagno is associate professor of medicine, director, comprehensive pancreas program, department of internal medicine, division of gastroenterology, University of Michigan, Ann Arbor. Dr. Mandalia reports no conflicts of interest.

 

 

References

1. Tenner S et al. Am J Gastroenterol. 2013;108:1400.

2. Besseline M et al. Pancreatology. 2013;13(4, Supplement 2):e1-15.

3. Crockett SD et al. Gastroenterology. 2018;154(4):1096-101.

4. Vege SS et al. Gastroenterology. 2018;154(4):1103-39.

5. Peery AF et al. Gastroenterology. 2019 Jan;156(1):254-72.e11.

6. Krishna SG et al. Pancreas. 2017;46(4):482-8.

7. Sellers ZM et al. Gastroenterology. 2018;155(2):469-78.e1.

8. Brown A et al. JOP. 2008;9(4):408-14.

9. Fagenholz PJ et al. Ann Epidemiol. 2007;17(7):491.e1-.e8.

10. McNabb-Baltar J et al. Pancreas. 2014;43(5):687-91.

11. Johnson CD et al. Gut. 2004;53(9):1340-4.

12. Dellinger EP et al. Ann Surg. 2012;256(6):875-80.

13. Petrov MS et al. Gastroenterology. 2010;139(3):813-20.

14. Sternby H et al. Ann Surg. Apr 18. doi: 10.1097/SLA.0000000000002766.

15. Huh JH et al. J Clin Gastroenterol. 2018;52(2):178-83.

16. Wu BU et al. Gastroenterology. 2008;135(3):816-20.

17. Gardner TB et al. Clin Gastroenterol Hepatol. 2008;6(10):1070-6.

18. Krishna SG et al. Am J Gastroenterol. 2015;110(11):1608-19.

19. Lee PJ et al. Pancreas. 2016;45(4):561-4.

20. Mandalia A et al. F1000Research. 2018 Jun 28;7.

21. Majumder S et al. Pancreas. 2015;44(4):540-6.

22. DiMagno MJ. Clin Gastroenterol Hepatol. 2011;9(11):920-2.

23. Yadav D, Whitcomb DC. Nature Rev Gastroenterol Hepatol. 2010;7(3):131-45.

24. Samokhvalov AV et al. EBioMedicine. 2015;2(12):1996-2002.

25. Barkin JA et al. Pancreas. 2017;46(8):1035-8.

26. Chen Y-T et al. J Gastroenterol Hepatol. 2016;31(4):782-7.

27. Ramos LR et al. J Crohns Colitis. 2016;10(1):95-104.

28. Avram MM. Nephron. 1977;18(1):68-71.

29. Lankisch PG et al. Nephrol Dial Transplant. 2008;23(4):1401-5.

30. Owyang C et al. Mayo Clin Proc. 1979;54(12):769-73.

31. Owyang Cet al. Gut. 1982;23(5):357-61.

32. Quraishi ER et al. Am J Gastroenterol. 2005;100:2288.

33. Vaziri ND et al. Nephron. 1987;46(4):347-9.

34. Chen HJ et al. Nephrol Dial Transplant. 2017;32(10):1731-6.

35. Kirkegard J et al. Gastroenterology. 2018;May;154(6):1729-36.

36. Karlson BM, et al. Gastroenterology. 1997;113(2):587-92.

37. Munigala S et al. Clin Gastroenterol Hepatol. 2014;12(7):1143-50.e1.

38. Carr RA et al. Pancreatology. 2016;16(4):469-76.

39. Li X et al. BMC Gastroenterol. 2018;18(1):89.

40. Ahmed AU et al. Clin Gastroenterol Hepatol. 2016;14(5):738-46.

41. Sankaran SJ et al. Gastroenterology. 2015;149(6):1490-500.e1.

42. Berglund L et al. J Clin Endocrinol Metab. 2012;97(9):2969-89.

43. Catapano AL et al. Atherosclerosis. 2011;217(1):3-46.

44. Pedersen SB et al. JAMA Intern Med. 2016;176(12):1834-42.

45. Nawaz H et al. Am J Gastroenterol. 2015;110(10):1497-503.

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47. Kondo S et al. Eur J Radiol. 2005;54(2):271-5.

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74. Choi JH et al. Clin Gastroenterol Hepatol. 2017;15(1):86-92.e1.

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76. Zhang ZF et al. J Clin Gastroenterol. 2017;51(3):e17-e26.

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78. Mok SRS et al. Gastrointest Endosc. 2017;85(5):1005-13.

79. Smeets XJN et al. Trials. 2018;19(1):207.

80. Elmunzer BJ et al. Trials. 2016;17(1):120.

 

Introduction

Acute pancreatitis (AP) is a major clinical and financial burden in the United States. Several major clinical guidelines provide evidence-based recommendations for the clinical management decisions in AP, including those from the American College of Gastroenterology (ACG; 2013),¹ and the International Association of Pancreatology (IAP; 2013).² More recently, the American Gastroenterological Association (AGA) released their own set of guidelines.^3,4 In this update on AP, we review these guidelines and reference recent literature focused on epidemiology, risk factors, etiology, diagnosis, risk stratification, and recent advances in the early medical management of AP. Regarding the latter, we review six treatment interventions (pain management, intravenous fluid resuscitation, feeding, prophylactic antibiotics, probiotics, and timing of endoscopic retrograde cholangiopancreatography (ERCP) in acute biliary pancreatitis) and four preventive interventions (alcohol and smoking cessation, same-admission cholecystectomy for acute biliary pancreatitis, and chemoprevention and fluid administration for post-ERCP pancreatitis [PEP]). Updates on multidisciplinary management of (infected) pancreatic necrosis is beyond the scope of this review. Table 1 summarizes the concepts discussed in this article.

Recent advances in epidemiology and evaluation of AP

Epidemiology

AP is the third most common cause of gastrointestinal-related hospitalizations and fourth most common cause of readmission in 2014.⁵ Recent epidemiologic studies show conflicting trends for the incidence of AP, both increasing⁶ and decreasing,⁷ likely attributable to significant differences in study designs. Importantly, multiple studies have demonstrated that hospital length of stay, costs, and mortality have declined since 2009.^6,8-10

Persistent organ failure (POF), defined as organ failure lasting more than 48 hours, is the major cause of death in AP. POF, if only a single organ during AP, is associated with 27%-36% mortality; if it is multiorgan, it is associated with 47% mortality.^1,11 Other factors associated with increased hospital mortality include infected pancreatic necrosis,^12-14 diabetes mellitus,¹⁵ hospital-acquired infection,¹⁶ advanced age (70 years and older),¹⁷ and obesity.¹⁸ Predictive factors of 1-year mortality include readmission within 30 days, higher Charlson Comorbidity Index, and longer hospitalization.¹⁹

Risk factors

We briefly highlight recent insights into risk factors for AP (Table 1) and refer to a recent review for further discussion.²⁰ Current and former tobacco use are independent risk factors for AP.²¹ The dose-response relationship of alcohol to the risk of pancreatitis is complex,²² but five standard drinks per day for 5 years is a commonly used cut-off.^1,23 New evidence suggests that the relationship between the dose of alcohol and risk of AP differs by sex, linearly in men but nonlinearly (J-shaped) in women.²⁴ Risk of AP in women was decreased with alcohol consumption of up to 40 g/day (one standard drink contains 14 g of alcohol) and increased above this amount. Cannabis is a possible risk factor for toxin-induced AP and abstinence appears to abolish risk of recurrent attacks.²⁵

Patients with inflammatory bowel disease (IBD) have a 2.9-fold higher risk for AP versus non-IBD cohorts²⁶ with the most common etiologies are from gallstones and medications.²⁷ In patients with end-stage renal disease (ESRD), the risk of AP is higher in those who receive peritoneal dialysis, compared with hemodialysis^28-33 and who are women, older, or have cholelithiasis or liver disease.³⁴As recently reviewed,³⁵ pancreatic cancer appears to be associated with first-attack pancreatitis with few exceptions.³⁶ In this setting, the overall incidence of pancreatic cancer is low (1.5%). The risk is greatest within the first year of the attack of AP, negligible below age 40 years but steadily rising through the fifth to eighth decades.³⁷ Pancreatic cancer screening is a conditional recommendation of the ACG guidelines in patients with unexplained AP, particularly those aged 40 years or older.¹

Etiology and diagnosis

Alcohol and gallstones remain the most prevalent etiologies for AP.¹ While hypertriglyceridemia accounted for 9% of AP in a systematic review of acute pancreatitis in 15 different countries,³⁸ it is the second most common cause of acute pancreatitis in Asia (especially China).³⁹ Figure 1 provides a breakdown of the etiologies and risk factors of pancreatitis. Importantly, it remains challenging to assign several toxic-metabolic etiologies as either a cause or risk factor for AP, particularly with regards to alcohol, smoking, and cannabis to name a few.

Guidelines and recent studies of AP raise questions about the threshold above which hypertriglyceridemia causes or poses as an important cofactor for AP. American and European societies define the threshold for triglycerides at 885-1,000 mg/dL.^1,42,43 Pedersen et al. provide evidence of a graded risk of AP with hypertriglyceridemia: In multivariable analysis, adjusted hazard ratios for AP were much higher with nonfasting mild to moderately elevated plasma triglycerides (177-885 mg/dL), compared with normal values (below 89 mg/dL).⁴⁴ Moreover, the risk of severe AP (developing POF) increases in proportion to triglyceride value, independent of the underlying cause of AP.⁴⁵

Vidyard Video

Diagnosis of AP is derived from the revised Atlanta classification.⁴⁶ The recommended timing and indications for offering cross-sectional imaging are after 48-72 hours in patients with no improvement to initial care.¹ Endoscopic ultrasonography (EUS) has better diagnostic accuracy and sensitivity, compared with magnetic resonance cholangiopancreatography (MRCP) for choledocholithiasis, and has comparable specificity.^47,48 Among noninvasive imaging modalities, MRCP is more sensitive than computed tomography (CT) for diagnosing choledocholithiasis.⁴⁹ Despite guideline recommendations for more selective use of pancreatic imaging in the early assessment of AP, utilization of early CT or MRCP imaging (within the first 24 hours of care) remained high during 2014-2015, compared with 2006-2007.⁵⁰

ERCP is not recommended as a pure diagnostic tool, owing to the availability of other diagnostic tests and a complication rate of 5%-10% with risks involving PEP, cholangitis, perforation, and hemorrhage.⁵¹ A recent systematic review of EUS and ERCP in acute biliary pancreatitis concluded that EUS had lower failure rates and had no complications, and the use of EUS avoided ERCP in 71.2% of cases.⁵²

 

 

 

Risk stratification

The goals of using risk stratification tools in AP are to identify patients at risk for developing major outcomes, including POF, infected pancreatic necrosis, and death, and to ensure timely triaging of patients to an appropriate level of care. Existing prediction models have only moderate predictive value.^53,54 Examples include simple risk stratification tools such as blood urea nitrogen (BUN) and hemoconcentration,^55,56 disease-modifying patient variables (age, obesity, etc.), biomarkers (i.e., angiopoietin 2),⁵⁷ and more complex clinical scoring systems such as Acute Physiology and Chronic Health Evaluation II (APACHE II), BISAP (BUN, impaired mental status, SIRS criteria, age, pleural effusion) score, early warning system (EWS), Glasgow-Imrie score, Japanese severity score, and recently the Pancreatitis Activity Scoring System (PASS).⁵⁸ Two recent guidelines affirmed the importance of predicting the severity of AP, using one or more predictive tools.^1,2 The recent 2018 AGA technical review does not debate this commonsense approach, but does highlight that there is no published observational study or randomized, controlled trial (RCT) investigating whether prediction tools affect clinical outcomes.⁴

Recent advances in early treatment of AP

Literature review and definitions

The AP literature contains heterogeneous definitions of severe AP and of what constitutes a major outcome in AP. Based on definitions of the 2013 revised Atlanta Criteria, the 2018 AGA technical review and clinical guidelines emphasized precise definitions of primary outcomes of clinical importance in AP, including death, persistent single organ failure, or persistent multiple organ failure, each requiring a duration of more than 48 hours, and infected pancreatic or peripancreatic necrosis or both (Table 2).^3,4

 

Pain management

Management of pain in AP is complex and requires a detailed discussion beyond the scope of this review, but recent clinical and translational studies raise questions about the current practice of using opioids for pain management in AP. A provocative, multicenter, retrospective cohort study reported lower 30-day mortality among critically ill patients who received epidural analgesia versus standard care without epidural analgesia.⁵⁹ The possible mechanism of protection and the drugs administered are unclear. An interesting hypothesis is that the epidural cohort may have received lower exposure to morphine, which may increase gut permeability, the risk of infectious complications, and severity of AP, based on a translational study in mice.⁶⁰

Intravenous fluid administration

Supportive care with the use of IV fluid hydration is a mainstay of treatment for AP in the first 12-24 hours. Table 3 summarizes the guidelines in regards to IV fluid administration as delineated by the ACG and AGA guidelines on the management of pancreatitis.^1,3 Guidelines advocate for early fluid resuscitation to correct intravascular depletion in order to reduce morbidity and mortality associated with AP.^1,2,4 The 2018 AGA guidelines endorse a conditional recommendation for using goal-directed therapy for initial fluid management,³ do not recommend for or against normal saline versus lactated Ringer’s (LR), but do advise against the use of hydroxyethyl starch fluids.³ Consistent with these recommendations, two recent RCTs published subsequent to the prespecified time periods of the AGA technical review and guideline, observed no significant differences between LR and normal saline on clinically meaningful outcomes.^61,62 The AGA guidelines acknowledge that evidence was of very-low quality in support of goal-directed therapy,^3,4 which has not been shown to have a significant reduction in persistent multiple organ failure, mortality, or pancreatic necrosis, compared with usual care. As the authors noted, interpretation of the data was limited by the absence of other critical outcomes in these trials (infected pancreatic necrosis), lack of uniformity of specific outcomes and definitions of transient and POF, few trials, and risk of bias. There is a clear need for a large RCT to provide evidence to guide decision making with fluid resuscitation in AP, particularly in regard to fluid type, volume, rate, duration, endpoints, and clinical outcomes.

 

 

Feeding

More recently, the focus of nutrition in the management of AP has shifted away from patients remaining nil per os (NPO). Current guidelines advocate for early oral feeding (within 24 hours) in mild AP,^3,4 in order to protect the gut-mucosal barrier. Remaining NPO when compared with early oral feeding has a 2.5-fold higher risk for interventions for necrosis.⁴ The recently published AGA technical review identified no significant impact on outcomes of early versus delayed oral feeding, which is consistent with observations of a landmark Dutch PYTHON trial entitled “Early versus on-demand nasoenteric tube feeding in acute pancreatitis.”^4,63 There is no clear cutoff point for initiating feeding for those with severe AP. A suggested practical approach is to initiate feeding within 24-72 hours and offer enteral nutrition for those intolerant to oral feeds. In severe AP and moderately severe AP, enteral nutrition is recommended over parenteral nutrition.^3,4 Enteral nutrition significantly reduces the risk of infected peripancreatic necrosis, single organ failure, and multiorgan failure.⁴ Finally, the AGA guidelines provide a conditional recommendation for providing enteral nutrition support through either the nasogastric or nasoenteric route.³ Further studies are required to determine the optimal timing, rate, and formulation of enteral nutrition in severe AP.

 

Antibiotics and probiotics

Current guidelines do not support the use of prophylactic antibiotics to prevent infection in necrotizing AP and severe AP.^1-3 The AGA technical review reported that prophylactic antibiotics did not reduce infected pancreatic or peripancreatic necrosis, persistent single organ failure, or mortality.⁴ Guidelines advocate against the use of probiotics for severe AP, because of increased mortality risk.¹

Timing of ERCP in acute biliary pancreatitis

There is universal agreement for offering urgent ERCP (within 24 hours) in biliary AP complicated by cholangitis.^1-3,64 Figure 2 demonstrates an example of a cholangiogram completed within 24 hours of presentation of biliary AP complicated by cholangitis.

In the absence of cholangitis, the timing of ERCP for AP with persistent biliary obstruction is less clear.^1-3 In line with recent guidelines, the 2018 AGA guidelines advocate against routine use of urgent ERCP for biliary AP without cholangitis,³ a conditional recommendation with overall low quality of data.⁴ The AGA technical review found that urgent ERCP, compared with conservative management in acute biliary pancreatitis without cholangitis had no significant effect on mortality, organ failure, infected pancreatic necrosis, and total necrotizing pancreatitis, but did significantly shorten hospital length of stay.⁴ There are limited data to guide decision making of when nonurgent ERCP should be performed in hospitalized patients with biliary AP with persistent obstruction and no cholangitis.^3,64

 

 

Alcohol and smoking cessation

The AGA technical review advocates for brief alcohol intervention during hospitalization for alcohol-induced AP on the basis of one RCT that addresses the impact of alcohol counseling on recurrent bouts of AP⁴ plus evidence from a Cochrane review of alcohol-reduction strategies in primary care populations.⁶⁵ Cessation of smoking – an established independent risk factor of AP – recurrent AP and chronic pancreatitis, should also be recommended as part of the management of AP.

Cholecystectomy

Evidence supports same-admission cholecystectomy for mild gallstone AP, a strong recommendation of published AGA guidelines.³ When compared with delayed cholecystectomy, same-admission cholecystectomy significantly reduced gallstone-related complications, readmissions for recurrent pancreatitis, and pancreaticobiliary complications, without having a significant impact on mortality during a 6-month follow-up period.⁶⁶ Delaying cholecystectomy 6 weeks in patients with moderate-severe gallstone AP appears to reduce morbidity, including the development of infected collections, and mortality.⁴ An ongoing RCT, the APEC trial, aims to determine whether early ERCP with biliary sphincterotomy reduces major complications or death when compared with no intervention for biliary AP in patients at high risk of complications.⁶⁷

Chemoprevention and IV fluid management of post-ERCP pancreatitis

Accumulating data support the effectiveness of chemoprevention, pancreatic stent placement, and fluid administration to prevent post-ERCP pancreatitis. Multiple RCTs, meta-analyses, and systematic reviews indicate that rectal NSAIDs) reduce post-ERCP pancreatitis onset^68-71 and moderate-severe post-ERCP pancreatitis. Additionally, placement of a pancreatic duct stent may decrease the risk of severe post-ERCP pancreatitis in high-risk patients.³ Guidelines do not comment on fluid administrations for prevention of post-ERCP pancreatitis, but studies have shown that greater periprocedural IV fluid was an independent protective factor against moderate to severe PEP⁷² and was associated with shorter hospital length of stay.⁷³ Recent meta-analyses and RCTs support using LR prior to ERCP to prevent PEP.^74-77 Interestingly, a recent RCT shows that the combination of rectal indomethacin and LR, compared with combination placebo and normal saline reduced the risk of PEP in high-risk patients.⁷⁸

Two ongoing multicenter RCTs will clarify the role of combination therapy. The Dutch FLUYT RCT aims to determine the optimal combination of rectal NSAIDs and periprocedural infusion of IV fluids to reduce the incidence of PEP and moderate-severe PEP⁷⁹ and the Stent vs. Indomethacin (SVI) trial aims to determine the whether combination pancreatic stent placement plus rectal indomethacin is superior to monotherapy indomethacin for preventing post-ERCP pancreatitis in high-risk cases.⁸⁰

Implications for clinical practice

The diagnosis and optimal management of AP require a systematic approach with multidisciplinary decision making. Morbidity and mortality in AP are driven by early or late POF, and the latter often is triggered by infected necrosis. Risk stratification of these patients at the point of contact is a commonsense approach to enable triaging of patients to the appropriate level of care. Regardless of pancreatitis severity, recommended treatment interventions include goal-directed IV fluid resuscitation, early feeding by mouth or enteral tube when necessary, avoidance of prophylactic antibiotics, avoidance of probiotics, and urgent ERCP for patients with acute biliary pancreatitis complicated by cholangitis. Key measures for preventing hospital readmission and pancreatitis include same-admission cholecystectomy for acute biliary pancreatitis and alcohol and smoking cessation. Preventive measures for post-ERCP pancreatitis in patients undergoing ERCP include rectal indomethacin, prophylactic pancreatic duct stent placement, and periprocedural fluid resuscitation.

Dr. Mandalia is a fellow, gastroenterology, department of internal medicine, division of gastroenterology, Michigan Medicine, Ann Arbor; Dr. DiMagno is associate professor of medicine, director, comprehensive pancreas program, department of internal medicine, division of gastroenterology, University of Michigan, Ann Arbor. Dr. Mandalia reports no conflicts of interest.

 

 

References

1. Tenner S et al. Am J Gastroenterol. 2013;108:1400.

2. Besseline M et al. Pancreatology. 2013;13(4, Supplement 2):e1-15.

3. Crockett SD et al. Gastroenterology. 2018;154(4):1096-101.

4. Vege SS et al. Gastroenterology. 2018;154(4):1103-39.

5. Peery AF et al. Gastroenterology. 2019 Jan;156(1):254-72.e11.

6. Krishna SG et al. Pancreas. 2017;46(4):482-8.

7. Sellers ZM et al. Gastroenterology. 2018;155(2):469-78.e1.

8. Brown A et al. JOP. 2008;9(4):408-14.

9. Fagenholz PJ et al. Ann Epidemiol. 2007;17(7):491.e1-.e8.

10. McNabb-Baltar J et al. Pancreas. 2014;43(5):687-91.

11. Johnson CD et al. Gut. 2004;53(9):1340-4.

12. Dellinger EP et al. Ann Surg. 2012;256(6):875-80.

13. Petrov MS et al. Gastroenterology. 2010;139(3):813-20.

14. Sternby H et al. Ann Surg. Apr 18. doi: 10.1097/SLA.0000000000002766.

15. Huh JH et al. J Clin Gastroenterol. 2018;52(2):178-83.

16. Wu BU et al. Gastroenterology. 2008;135(3):816-20.

17. Gardner TB et al. Clin Gastroenterol Hepatol. 2008;6(10):1070-6.

18. Krishna SG et al. Am J Gastroenterol. 2015;110(11):1608-19.

19. Lee PJ et al. Pancreas. 2016;45(4):561-4.

20. Mandalia A et al. F1000Research. 2018 Jun 28;7.

21. Majumder S et al. Pancreas. 2015;44(4):540-6.

22. DiMagno MJ. Clin Gastroenterol Hepatol. 2011;9(11):920-2.

23. Yadav D, Whitcomb DC. Nature Rev Gastroenterol Hepatol. 2010;7(3):131-45.

24. Samokhvalov AV et al. EBioMedicine. 2015;2(12):1996-2002.

25. Barkin JA et al. Pancreas. 2017;46(8):1035-8.

26. Chen Y-T et al. J Gastroenterol Hepatol. 2016;31(4):782-7.

27. Ramos LR et al. J Crohns Colitis. 2016;10(1):95-104.

28. Avram MM. Nephron. 1977;18(1):68-71.

29. Lankisch PG et al. Nephrol Dial Transplant. 2008;23(4):1401-5.

30. Owyang C et al. Mayo Clin Proc. 1979;54(12):769-73.

31. Owyang Cet al. Gut. 1982;23(5):357-61.

32. Quraishi ER et al. Am J Gastroenterol. 2005;100:2288.

33. Vaziri ND et al. Nephron. 1987;46(4):347-9.

34. Chen HJ et al. Nephrol Dial Transplant. 2017;32(10):1731-6.

35. Kirkegard J et al. Gastroenterology. 2018;May;154(6):1729-36.

36. Karlson BM, et al. Gastroenterology. 1997;113(2):587-92.

37. Munigala S et al. Clin Gastroenterol Hepatol. 2014;12(7):1143-50.e1.

38. Carr RA et al. Pancreatology. 2016;16(4):469-76.

39. Li X et al. BMC Gastroenterol. 2018;18(1):89.

40. Ahmed AU et al. Clin Gastroenterol Hepatol. 2016;14(5):738-46.

41. Sankaran SJ et al. Gastroenterology. 2015;149(6):1490-500.e1.

42. Berglund L et al. J Clin Endocrinol Metab. 2012;97(9):2969-89.

43. Catapano AL et al. Atherosclerosis. 2011;217(1):3-46.

44. Pedersen SB et al. JAMA Intern Med. 2016;176(12):1834-42.

45. Nawaz H et al. Am J Gastroenterol. 2015;110(10):1497-503.

46. Banks PA et al. Gut. 2013;62(1):102-11.

47. Kondo S et al. Eur J Radiol. 2005;54(2):271-5.

48. Meeralam Y et al. Gastrointest Endosc. 2017;86(6):986-93.

49. Stimac D et al. Am J Gastroenterol. 2007;102(5):997-1004.

50. Jin DX et al. Dig Dis Sci. 2017;62(10):2894-9.

51. Freeman ML. Gastrointest Endosc Clin N Am. 2012;22(3):567-86.

52. De Lisi S et al. Eur J Gastroenterol Hepatol. 2011;23(5):367-74.

53. Di MY et al. Ann Int Med. 2016;165(7):482-90.

54. Mounzer R et al. Gastroenterology. 2012;142(7):1476-82; quiz e15-6.

55. Koutroumpakis E et al. Am J Gastroenterol. 2015;110(12):1707-16.

56. Wu BU et al. Gastroenterology. 2009;137(1):129-35.

57. Buddingh KT et al. J Am Coll Surg. 2014;218(1):26-32.

58. Buxbaum J et al. Am J Gastroenterol. 2018;113(5):755-64.

59. Jabaudon M et al. Crit Car Med. 2018;46(3):e198-e205.

60. Barlass U et al. Gut. 2018;67(4):600-2.

61. Buxbaum JL et al. Am J Gastroenterol. 2017;112(5):797-803.

62. de-Madaria E et al. United Eur Gastroenterol J. 2018;6(1):63-72.

63. Bakker OJ et al. N Engl J Med. 2014;371(21):1983-93.

64. Tse F et al. Cochrane Database Syst Rev. 2012(5):Cd009779.

65. Kaner EFS et al. Cochrane Database Syst Rev. 2007(2):Cd004148.

66. da Costa DW et al. Lancet. 2015;386(10000):1261-8.

67. Schepers NJ et al. Trials. 2016;17:5.

68. Vadala di Prampero SF et al. Eur J Gastroenterol Hepatol. 2016;28(12):1415-24.

69. Kubiliun NM et al. Clin Gastroenterol Hepatol. 2015;13(7):1231-9; quiz e70-1.

70. Wan J et al. BMC Gastroenterol. 2017;17(1):43.

71. Yang C et al. Pancreatology. 2017;17(5):681-8.

72. DiMagno MJ et al. Pancreas. 2014;43(4):642-7.

73. Sagi SV et al. J Gastroenterol Hepatol. 2014;29(6):1316-20.

74. Choi JH et al. Clin Gastroenterol Hepatol. 2017;15(1):86-92.e1.

75. Wu D et al. J Clin Gastroenterol. 2017;51(8):e68-e76.

76. Zhang ZF et al. J Clin Gastroenterol. 2017;51(3):e17-e26.

77. Park CH et al. Endoscopy 2018 Apr;50(4):378-85.

78. Mok SRS et al. Gastrointest Endosc. 2017;85(5):1005-13.

79. Smeets XJN et al. Trials. 2018;19(1):207.

80. Elmunzer BJ et al. Trials. 2016;17(1):120.

 

Introduction

Acute pancreatitis (AP) is a major clinical and financial burden in the United States. Several major clinical guidelines provide evidence-based recommendations for the clinical management decisions in AP, including those from the American College of Gastroenterology (ACG; 2013),¹ and the International Association of Pancreatology (IAP; 2013).² More recently, the American Gastroenterological Association (AGA) released their own set of guidelines.^3,4 In this update on AP, we review these guidelines and reference recent literature focused on epidemiology, risk factors, etiology, diagnosis, risk stratification, and recent advances in the early medical management of AP. Regarding the latter, we review six treatment interventions (pain management, intravenous fluid resuscitation, feeding, prophylactic antibiotics, probiotics, and timing of endoscopic retrograde cholangiopancreatography (ERCP) in acute biliary pancreatitis) and four preventive interventions (alcohol and smoking cessation, same-admission cholecystectomy for acute biliary pancreatitis, and chemoprevention and fluid administration for post-ERCP pancreatitis [PEP]). Updates on multidisciplinary management of (infected) pancreatic necrosis is beyond the scope of this review. Table 1 summarizes the concepts discussed in this article.

Recent advances in epidemiology and evaluation of AP

Epidemiology

AP is the third most common cause of gastrointestinal-related hospitalizations and fourth most common cause of readmission in 2014.⁵ Recent epidemiologic studies show conflicting trends for the incidence of AP, both increasing⁶ and decreasing,⁷ likely attributable to significant differences in study designs. Importantly, multiple studies have demonstrated that hospital length of stay, costs, and mortality have declined since 2009.^6,8-10

Persistent organ failure (POF), defined as organ failure lasting more than 48 hours, is the major cause of death in AP. POF, if only a single organ during AP, is associated with 27%-36% mortality; if it is multiorgan, it is associated with 47% mortality.^1,11 Other factors associated with increased hospital mortality include infected pancreatic necrosis,^12-14 diabetes mellitus,¹⁵ hospital-acquired infection,¹⁶ advanced age (70 years and older),¹⁷ and obesity.¹⁸ Predictive factors of 1-year mortality include readmission within 30 days, higher Charlson Comorbidity Index, and longer hospitalization.¹⁹

Risk factors

We briefly highlight recent insights into risk factors for AP (Table 1) and refer to a recent review for further discussion.²⁰ Current and former tobacco use are independent risk factors for AP.²¹ The dose-response relationship of alcohol to the risk of pancreatitis is complex,²² but five standard drinks per day for 5 years is a commonly used cut-off.^1,23 New evidence suggests that the relationship between the dose of alcohol and risk of AP differs by sex, linearly in men but nonlinearly (J-shaped) in women.²⁴ Risk of AP in women was decreased with alcohol consumption of up to 40 g/day (one standard drink contains 14 g of alcohol) and increased above this amount. Cannabis is a possible risk factor for toxin-induced AP and abstinence appears to abolish risk of recurrent attacks.²⁵

Patients with inflammatory bowel disease (IBD) have a 2.9-fold higher risk for AP versus non-IBD cohorts²⁶ with the most common etiologies are from gallstones and medications.²⁷ In patients with end-stage renal disease (ESRD), the risk of AP is higher in those who receive peritoneal dialysis, compared with hemodialysis^28-33 and who are women, older, or have cholelithiasis or liver disease.³⁴As recently reviewed,³⁵ pancreatic cancer appears to be associated with first-attack pancreatitis with few exceptions.³⁶ In this setting, the overall incidence of pancreatic cancer is low (1.5%). The risk is greatest within the first year of the attack of AP, negligible below age 40 years but steadily rising through the fifth to eighth decades.³⁷ Pancreatic cancer screening is a conditional recommendation of the ACG guidelines in patients with unexplained AP, particularly those aged 40 years or older.¹

Etiology and diagnosis

Alcohol and gallstones remain the most prevalent etiologies for AP.¹ While hypertriglyceridemia accounted for 9% of AP in a systematic review of acute pancreatitis in 15 different countries,³⁸ it is the second most common cause of acute pancreatitis in Asia (especially China).³⁹ Figure 1 provides a breakdown of the etiologies and risk factors of pancreatitis. Importantly, it remains challenging to assign several toxic-metabolic etiologies as either a cause or risk factor for AP, particularly with regards to alcohol, smoking, and cannabis to name a few.

Guidelines and recent studies of AP raise questions about the threshold above which hypertriglyceridemia causes or poses as an important cofactor for AP. American and European societies define the threshold for triglycerides at 885-1,000 mg/dL.^1,42,43 Pedersen et al. provide evidence of a graded risk of AP with hypertriglyceridemia: In multivariable analysis, adjusted hazard ratios for AP were much higher with nonfasting mild to moderately elevated plasma triglycerides (177-885 mg/dL), compared with normal values (below 89 mg/dL).⁴⁴ Moreover, the risk of severe AP (developing POF) increases in proportion to triglyceride value, independent of the underlying cause of AP.⁴⁵

Vidyard Video

Diagnosis of AP is derived from the revised Atlanta classification.⁴⁶ The recommended timing and indications for offering cross-sectional imaging are after 48-72 hours in patients with no improvement to initial care.¹ Endoscopic ultrasonography (EUS) has better diagnostic accuracy and sensitivity, compared with magnetic resonance cholangiopancreatography (MRCP) for choledocholithiasis, and has comparable specificity.^47,48 Among noninvasive imaging modalities, MRCP is more sensitive than computed tomography (CT) for diagnosing choledocholithiasis.⁴⁹ Despite guideline recommendations for more selective use of pancreatic imaging in the early assessment of AP, utilization of early CT or MRCP imaging (within the first 24 hours of care) remained high during 2014-2015, compared with 2006-2007.⁵⁰

ERCP is not recommended as a pure diagnostic tool, owing to the availability of other diagnostic tests and a complication rate of 5%-10% with risks involving PEP, cholangitis, perforation, and hemorrhage.⁵¹ A recent systematic review of EUS and ERCP in acute biliary pancreatitis concluded that EUS had lower failure rates and had no complications, and the use of EUS avoided ERCP in 71.2% of cases.⁵²

 

 

 

Risk stratification

The goals of using risk stratification tools in AP are to identify patients at risk for developing major outcomes, including POF, infected pancreatic necrosis, and death, and to ensure timely triaging of patients to an appropriate level of care. Existing prediction models have only moderate predictive value.^53,54 Examples include simple risk stratification tools such as blood urea nitrogen (BUN) and hemoconcentration,^55,56 disease-modifying patient variables (age, obesity, etc.), biomarkers (i.e., angiopoietin 2),⁵⁷ and more complex clinical scoring systems such as Acute Physiology and Chronic Health Evaluation II (APACHE II), BISAP (BUN, impaired mental status, SIRS criteria, age, pleural effusion) score, early warning system (EWS), Glasgow-Imrie score, Japanese severity score, and recently the Pancreatitis Activity Scoring System (PASS).⁵⁸ Two recent guidelines affirmed the importance of predicting the severity of AP, using one or more predictive tools.^1,2 The recent 2018 AGA technical review does not debate this commonsense approach, but does highlight that there is no published observational study or randomized, controlled trial (RCT) investigating whether prediction tools affect clinical outcomes.⁴

Recent advances in early treatment of AP

Literature review and definitions

The AP literature contains heterogeneous definitions of severe AP and of what constitutes a major outcome in AP. Based on definitions of the 2013 revised Atlanta Criteria, the 2018 AGA technical review and clinical guidelines emphasized precise definitions of primary outcomes of clinical importance in AP, including death, persistent single organ failure, or persistent multiple organ failure, each requiring a duration of more than 48 hours, and infected pancreatic or peripancreatic necrosis or both (Table 2).^3,4

 

Pain management

Management of pain in AP is complex and requires a detailed discussion beyond the scope of this review, but recent clinical and translational studies raise questions about the current practice of using opioids for pain management in AP. A provocative, multicenter, retrospective cohort study reported lower 30-day mortality among critically ill patients who received epidural analgesia versus standard care without epidural analgesia.⁵⁹ The possible mechanism of protection and the drugs administered are unclear. An interesting hypothesis is that the epidural cohort may have received lower exposure to morphine, which may increase gut permeability, the risk of infectious complications, and severity of AP, based on a translational study in mice.⁶⁰

Intravenous fluid administration

Supportive care with the use of IV fluid hydration is a mainstay of treatment for AP in the first 12-24 hours. Table 3 summarizes the guidelines in regards to IV fluid administration as delineated by the ACG and AGA guidelines on the management of pancreatitis.^1,3 Guidelines advocate for early fluid resuscitation to correct intravascular depletion in order to reduce morbidity and mortality associated with AP.^1,2,4 The 2018 AGA guidelines endorse a conditional recommendation for using goal-directed therapy for initial fluid management,³ do not recommend for or against normal saline versus lactated Ringer’s (LR), but do advise against the use of hydroxyethyl starch fluids.³ Consistent with these recommendations, two recent RCTs published subsequent to the prespecified time periods of the AGA technical review and guideline, observed no significant differences between LR and normal saline on clinically meaningful outcomes.^61,62 The AGA guidelines acknowledge that evidence was of very-low quality in support of goal-directed therapy,^3,4 which has not been shown to have a significant reduction in persistent multiple organ failure, mortality, or pancreatic necrosis, compared with usual care. As the authors noted, interpretation of the data was limited by the absence of other critical outcomes in these trials (infected pancreatic necrosis), lack of uniformity of specific outcomes and definitions of transient and POF, few trials, and risk of bias. There is a clear need for a large RCT to provide evidence to guide decision making with fluid resuscitation in AP, particularly in regard to fluid type, volume, rate, duration, endpoints, and clinical outcomes.

 

 

Feeding

More recently, the focus of nutrition in the management of AP has shifted away from patients remaining nil per os (NPO). Current guidelines advocate for early oral feeding (within 24 hours) in mild AP,^3,4 in order to protect the gut-mucosal barrier. Remaining NPO when compared with early oral feeding has a 2.5-fold higher risk for interventions for necrosis.⁴ The recently published AGA technical review identified no significant impact on outcomes of early versus delayed oral feeding, which is consistent with observations of a landmark Dutch PYTHON trial entitled “Early versus on-demand nasoenteric tube feeding in acute pancreatitis.”^4,63 There is no clear cutoff point for initiating feeding for those with severe AP. A suggested practical approach is to initiate feeding within 24-72 hours and offer enteral nutrition for those intolerant to oral feeds. In severe AP and moderately severe AP, enteral nutrition is recommended over parenteral nutrition.^3,4 Enteral nutrition significantly reduces the risk of infected peripancreatic necrosis, single organ failure, and multiorgan failure.⁴ Finally, the AGA guidelines provide a conditional recommendation for providing enteral nutrition support through either the nasogastric or nasoenteric route.³ Further studies are required to determine the optimal timing, rate, and formulation of enteral nutrition in severe AP.

 

Antibiotics and probiotics

Current guidelines do not support the use of prophylactic antibiotics to prevent infection in necrotizing AP and severe AP.^1-3 The AGA technical review reported that prophylactic antibiotics did not reduce infected pancreatic or peripancreatic necrosis, persistent single organ failure, or mortality.⁴ Guidelines advocate against the use of probiotics for severe AP, because of increased mortality risk.¹

Timing of ERCP in acute biliary pancreatitis

There is universal agreement for offering urgent ERCP (within 24 hours) in biliary AP complicated by cholangitis.^1-3,64 Figure 2 demonstrates an example of a cholangiogram completed within 24 hours of presentation of biliary AP complicated by cholangitis.

In the absence of cholangitis, the timing of ERCP for AP with persistent biliary obstruction is less clear.^1-3 In line with recent guidelines, the 2018 AGA guidelines advocate against routine use of urgent ERCP for biliary AP without cholangitis,³ a conditional recommendation with overall low quality of data.⁴ The AGA technical review found that urgent ERCP, compared with conservative management in acute biliary pancreatitis without cholangitis had no significant effect on mortality, organ failure, infected pancreatic necrosis, and total necrotizing pancreatitis, but did significantly shorten hospital length of stay.⁴ There are limited data to guide decision making of when nonurgent ERCP should be performed in hospitalized patients with biliary AP with persistent obstruction and no cholangitis.^3,64

 

 

Alcohol and smoking cessation

The AGA technical review advocates for brief alcohol intervention during hospitalization for alcohol-induced AP on the basis of one RCT that addresses the impact of alcohol counseling on recurrent bouts of AP⁴ plus evidence from a Cochrane review of alcohol-reduction strategies in primary care populations.⁶⁵ Cessation of smoking – an established independent risk factor of AP – recurrent AP and chronic pancreatitis, should also be recommended as part of the management of AP.

Cholecystectomy

Evidence supports same-admission cholecystectomy for mild gallstone AP, a strong recommendation of published AGA guidelines.³ When compared with delayed cholecystectomy, same-admission cholecystectomy significantly reduced gallstone-related complications, readmissions for recurrent pancreatitis, and pancreaticobiliary complications, without having a significant impact on mortality during a 6-month follow-up period.⁶⁶ Delaying cholecystectomy 6 weeks in patients with moderate-severe gallstone AP appears to reduce morbidity, including the development of infected collections, and mortality.⁴ An ongoing RCT, the APEC trial, aims to determine whether early ERCP with biliary sphincterotomy reduces major complications or death when compared with no intervention for biliary AP in patients at high risk of complications.⁶⁷

Chemoprevention and IV fluid management of post-ERCP pancreatitis

Accumulating data support the effectiveness of chemoprevention, pancreatic stent placement, and fluid administration to prevent post-ERCP pancreatitis. Multiple RCTs, meta-analyses, and systematic reviews indicate that rectal NSAIDs) reduce post-ERCP pancreatitis onset^68-71 and moderate-severe post-ERCP pancreatitis. Additionally, placement of a pancreatic duct stent may decrease the risk of severe post-ERCP pancreatitis in high-risk patients.³ Guidelines do not comment on fluid administrations for prevention of post-ERCP pancreatitis, but studies have shown that greater periprocedural IV fluid was an independent protective factor against moderate to severe PEP⁷² and was associated with shorter hospital length of stay.⁷³ Recent meta-analyses and RCTs support using LR prior to ERCP to prevent PEP.^74-77 Interestingly, a recent RCT shows that the combination of rectal indomethacin and LR, compared with combination placebo and normal saline reduced the risk of PEP in high-risk patients.⁷⁸

Two ongoing multicenter RCTs will clarify the role of combination therapy. The Dutch FLUYT RCT aims to determine the optimal combination of rectal NSAIDs and periprocedural infusion of IV fluids to reduce the incidence of PEP and moderate-severe PEP⁷⁹ and the Stent vs. Indomethacin (SVI) trial aims to determine the whether combination pancreatic stent placement plus rectal indomethacin is superior to monotherapy indomethacin for preventing post-ERCP pancreatitis in high-risk cases.⁸⁰

Implications for clinical practice

The diagnosis and optimal management of AP require a systematic approach with multidisciplinary decision making. Morbidity and mortality in AP are driven by early or late POF, and the latter often is triggered by infected necrosis. Risk stratification of these patients at the point of contact is a commonsense approach to enable triaging of patients to the appropriate level of care. Regardless of pancreatitis severity, recommended treatment interventions include goal-directed IV fluid resuscitation, early feeding by mouth or enteral tube when necessary, avoidance of prophylactic antibiotics, avoidance of probiotics, and urgent ERCP for patients with acute biliary pancreatitis complicated by cholangitis. Key measures for preventing hospital readmission and pancreatitis include same-admission cholecystectomy for acute biliary pancreatitis and alcohol and smoking cessation. Preventive measures for post-ERCP pancreatitis in patients undergoing ERCP include rectal indomethacin, prophylactic pancreatic duct stent placement, and periprocedural fluid resuscitation.

Dr. Mandalia is a fellow, gastroenterology, department of internal medicine, division of gastroenterology, Michigan Medicine, Ann Arbor; Dr. DiMagno is associate professor of medicine, director, comprehensive pancreas program, department of internal medicine, division of gastroenterology, University of Michigan, Ann Arbor. Dr. Mandalia reports no conflicts of interest.

 

 

References

1. Tenner S et al. Am J Gastroenterol. 2013;108:1400.

2. Besseline M et al. Pancreatology. 2013;13(4, Supplement 2):e1-15.

3. Crockett SD et al. Gastroenterology. 2018;154(4):1096-101.

4. Vege SS et al. Gastroenterology. 2018;154(4):1103-39.

5. Peery AF et al. Gastroenterology. 2019 Jan;156(1):254-72.e11.

6. Krishna SG et al. Pancreas. 2017;46(4):482-8.

7. Sellers ZM et al. Gastroenterology. 2018;155(2):469-78.e1.

8. Brown A et al. JOP. 2008;9(4):408-14.

9. Fagenholz PJ et al. Ann Epidemiol. 2007;17(7):491.e1-.e8.

10. McNabb-Baltar J et al. Pancreas. 2014;43(5):687-91.

11. Johnson CD et al. Gut. 2004;53(9):1340-4.

12. Dellinger EP et al. Ann Surg. 2012;256(6):875-80.

13. Petrov MS et al. Gastroenterology. 2010;139(3):813-20.

14. Sternby H et al. Ann Surg. Apr 18. doi: 10.1097/SLA.0000000000002766.

15. Huh JH et al. J Clin Gastroenterol. 2018;52(2):178-83.

16. Wu BU et al. Gastroenterology. 2008;135(3):816-20.

17. Gardner TB et al. Clin Gastroenterol Hepatol. 2008;6(10):1070-6.

18. Krishna SG et al. Am J Gastroenterol. 2015;110(11):1608-19.

19. Lee PJ et al. Pancreas. 2016;45(4):561-4.

20. Mandalia A et al. F1000Research. 2018 Jun 28;7.

21. Majumder S et al. Pancreas. 2015;44(4):540-6.

22. DiMagno MJ. Clin Gastroenterol Hepatol. 2011;9(11):920-2.

23. Yadav D, Whitcomb DC. Nature Rev Gastroenterol Hepatol. 2010;7(3):131-45.

24. Samokhvalov AV et al. EBioMedicine. 2015;2(12):1996-2002.

25. Barkin JA et al. Pancreas. 2017;46(8):1035-8.

26. Chen Y-T et al. J Gastroenterol Hepatol. 2016;31(4):782-7.

27. Ramos LR et al. J Crohns Colitis. 2016;10(1):95-104.

28. Avram MM. Nephron. 1977;18(1):68-71.

29. Lankisch PG et al. Nephrol Dial Transplant. 2008;23(4):1401-5.

30. Owyang C et al. Mayo Clin Proc. 1979;54(12):769-73.

31. Owyang Cet al. Gut. 1982;23(5):357-61.

32. Quraishi ER et al. Am J Gastroenterol. 2005;100:2288.

33. Vaziri ND et al. Nephron. 1987;46(4):347-9.

34. Chen HJ et al. Nephrol Dial Transplant. 2017;32(10):1731-6.

35. Kirkegard J et al. Gastroenterology. 2018;May;154(6):1729-36.

36. Karlson BM, et al. Gastroenterology. 1997;113(2):587-92.

37. Munigala S et al. Clin Gastroenterol Hepatol. 2014;12(7):1143-50.e1.

38. Carr RA et al. Pancreatology. 2016;16(4):469-76.

39. Li X et al. BMC Gastroenterol. 2018;18(1):89.

40. Ahmed AU et al. Clin Gastroenterol Hepatol. 2016;14(5):738-46.

41. Sankaran SJ et al. Gastroenterology. 2015;149(6):1490-500.e1.

42. Berglund L et al. J Clin Endocrinol Metab. 2012;97(9):2969-89.

43. Catapano AL et al. Atherosclerosis. 2011;217(1):3-46.

44. Pedersen SB et al. JAMA Intern Med. 2016;176(12):1834-42.

45. Nawaz H et al. Am J Gastroenterol. 2015;110(10):1497-503.

46. Banks PA et al. Gut. 2013;62(1):102-11.

47. Kondo S et al. Eur J Radiol. 2005;54(2):271-5.

48. Meeralam Y et al. Gastrointest Endosc. 2017;86(6):986-93.

49. Stimac D et al. Am J Gastroenterol. 2007;102(5):997-1004.

50. Jin DX et al. Dig Dis Sci. 2017;62(10):2894-9.

51. Freeman ML. Gastrointest Endosc Clin N Am. 2012;22(3):567-86.

52. De Lisi S et al. Eur J Gastroenterol Hepatol. 2011;23(5):367-74.

53. Di MY et al. Ann Int Med. 2016;165(7):482-90.

54. Mounzer R et al. Gastroenterology. 2012;142(7):1476-82; quiz e15-6.

55. Koutroumpakis E et al. Am J Gastroenterol. 2015;110(12):1707-16.

56. Wu BU et al. Gastroenterology. 2009;137(1):129-35.

57. Buddingh KT et al. J Am Coll Surg. 2014;218(1):26-32.

58. Buxbaum J et al. Am J Gastroenterol. 2018;113(5):755-64.

59. Jabaudon M et al. Crit Car Med. 2018;46(3):e198-e205.

60. Barlass U et al. Gut. 2018;67(4):600-2.

61. Buxbaum JL et al. Am J Gastroenterol. 2017;112(5):797-803.

62. de-Madaria E et al. United Eur Gastroenterol J. 2018;6(1):63-72.

63. Bakker OJ et al. N Engl J Med. 2014;371(21):1983-93.

64. Tse F et al. Cochrane Database Syst Rev. 2012(5):Cd009779.

65. Kaner EFS et al. Cochrane Database Syst Rev. 2007(2):Cd004148.

66. da Costa DW et al. Lancet. 2015;386(10000):1261-8.

67. Schepers NJ et al. Trials. 2016;17:5.

68. Vadala di Prampero SF et al. Eur J Gastroenterol Hepatol. 2016;28(12):1415-24.

69. Kubiliun NM et al. Clin Gastroenterol Hepatol. 2015;13(7):1231-9; quiz e70-1.

70. Wan J et al. BMC Gastroenterol. 2017;17(1):43.

71. Yang C et al. Pancreatology. 2017;17(5):681-8.

72. DiMagno MJ et al. Pancreas. 2014;43(4):642-7.

73. Sagi SV et al. J Gastroenterol Hepatol. 2014;29(6):1316-20.

74. Choi JH et al. Clin Gastroenterol Hepatol. 2017;15(1):86-92.e1.

75. Wu D et al. J Clin Gastroenterol. 2017;51(8):e68-e76.

76. Zhang ZF et al. J Clin Gastroenterol. 2017;51(3):e17-e26.

77. Park CH et al. Endoscopy 2018 Apr;50(4):378-85.

78. Mok SRS et al. Gastrointest Endosc. 2017;85(5):1005-13.

79. Smeets XJN et al. Trials. 2018;19(1):207.

80. Elmunzer BJ et al. Trials. 2016;17(1):120.

 

As I write this editorial, we are within the longest federal government shutdown in our nation’s history, a federal judge in Texas has ruled the Affordable Care Act unconstitutional, and there is a class action suit against the American Board of Internal Medicine (ABIM) regarding maintenance of certification. Being a doctor, these days, is neither easy nor relaxing.

The government shutdown is cheered by some, but it has real consequences for 800,000 government workers who are not getting paid, and our scientific community, where grant applications, hiring, data collection, and other critical roles of government are needed, is at a standstill. The class action suit against ABIM is the latest action of physicians telling the ABIM that enough is enough. Read more and form your opinion from our page one article. The ACA continues to be attacked in a variety of ways. To those who want to abolish it, please have a reasonable alternative in place so that real people with real diseases are not left in a desperate situation.

Drug prices continue to make news. The most recent example is the enormous increase in the cost of insulin. I read a lot about the inner workings of the pharmaceutical industry and cannot fathom how such prices are justified. Perhaps we physicians and our medical societies should consider raising our voices for our patients.

In this month’s issue there are several articles about polyp detection and the long-term protective effect of colonoscopy. We are doing really important and excellent work to reduce the burden of colon cancer.

As a heads up, Digestive Disease Week® (DDW) returns to San Diego this year. Housing choices are opening up and in San Diego fill rapidly; visit www.DDW.org/registration for more information. This year’s science is ground-breaking and will continue to advance our knowledge about IBD, the microbiome, and other important topics.
 

John I. Allen, MD, MBA, AGAF
Editor in Chief

As I write this editorial, we are within the longest federal government shutdown in our nation’s history, a federal judge in Texas has ruled the Affordable Care Act unconstitutional, and there is a class action suit against the American Board of Internal Medicine (ABIM) regarding maintenance of certification. Being a doctor, these days, is neither easy nor relaxing.

The government shutdown is cheered by some, but it has real consequences for 800,000 government workers who are not getting paid, and our scientific community, where grant applications, hiring, data collection, and other critical roles of government are needed, is at a standstill. The class action suit against ABIM is the latest action of physicians telling the ABIM that enough is enough. Read more and form your opinion from our page one article. The ACA continues to be attacked in a variety of ways. To those who want to abolish it, please have a reasonable alternative in place so that real people with real diseases are not left in a desperate situation.

Drug prices continue to make news. The most recent example is the enormous increase in the cost of insulin. I read a lot about the inner workings of the pharmaceutical industry and cannot fathom how such prices are justified. Perhaps we physicians and our medical societies should consider raising our voices for our patients.

In this month’s issue there are several articles about polyp detection and the long-term protective effect of colonoscopy. We are doing really important and excellent work to reduce the burden of colon cancer.

As a heads up, Digestive Disease Week® (DDW) returns to San Diego this year. Housing choices are opening up and in San Diego fill rapidly; visit www.DDW.org/registration for more information. This year’s science is ground-breaking and will continue to advance our knowledge about IBD, the microbiome, and other important topics.
 

John I. Allen, MD, MBA, AGAF
Editor in Chief

As I write this editorial, we are within the longest federal government shutdown in our nation’s history, a federal judge in Texas has ruled the Affordable Care Act unconstitutional, and there is a class action suit against the American Board of Internal Medicine (ABIM) regarding maintenance of certification. Being a doctor, these days, is neither easy nor relaxing.

The government shutdown is cheered by some, but it has real consequences for 800,000 government workers who are not getting paid, and our scientific community, where grant applications, hiring, data collection, and other critical roles of government are needed, is at a standstill. The class action suit against ABIM is the latest action of physicians telling the ABIM that enough is enough. Read more and form your opinion from our page one article. The ACA continues to be attacked in a variety of ways. To those who want to abolish it, please have a reasonable alternative in place so that real people with real diseases are not left in a desperate situation.

Drug prices continue to make news. The most recent example is the enormous increase in the cost of insulin. I read a lot about the inner workings of the pharmaceutical industry and cannot fathom how such prices are justified. Perhaps we physicians and our medical societies should consider raising our voices for our patients.

In this month’s issue there are several articles about polyp detection and the long-term protective effect of colonoscopy. We are doing really important and excellent work to reduce the burden of colon cancer.

As a heads up, Digestive Disease Week® (DDW) returns to San Diego this year. Housing choices are opening up and in San Diego fill rapidly; visit www.DDW.org/registration for more information. This year’s science is ground-breaking and will continue to advance our knowledge about IBD, the microbiome, and other important topics.
 

John I. Allen, MD, MBA, AGAF
Editor in Chief

For patients with extensive mild to moderate ulcerative colitis, numerous randomized controlled trials support the use of either standard-dose mesalamine (2-3 grams per day) or diazo-bonded 5-aminosalicylic acid (ASA) instead of low-dose mesalamine, sulfasalazine, or no therapy, state new guidelines from the American Gastroenterological Association, published in Gastroenterology.

©selvanegra/thinkstockphotos.com

Sulfasalazine (2-4 grams per day) is less likely to be tolerated but remains a “reasonable option” for remitted patients who are already on it and for patients with prominent arthritis symptoms, especially if alternative treatments are cost prohibitive, wrote Cynthia W. Ko, MD, MS, of the University of Washington, Seattle, and her associates.

According to the guideline, patients with mild to moderate ulcerative colitis have less than four to six bowel movements per day, only mild or moderate rectal bleeding, no constitutional symptoms, and no high overall inflammatory burden or signs of high inflammatory activity on the Mayo Clinic score and Truelove and Witt’s criteria. These patients usually do not require colectomy, but this outcome is more likely when patients are diagnosed before age 40 years or have extensive disease or deep ulcers, extraintestinal manifestations, or elevated inflammatory markers. These higher-risk patients need more aggressive initial treatment and faster treatment intensification in cases of inadequate response, the guideline emphasizes. Even for cases of mild to moderate ulcerative colitis, treatment intensification is preferable to repeated courses of corticosteroids.

The guideline recommends adding rectal mesalamine to oral 5-ASA if patients have extensive or left-sided mild to moderate ulcerative colitis. In randomized controlled trials, this combination was significantly more likely to induce and maintain remission than was standard-dose oral mesalamine monotherapy, the authors noted. “In the maintenance trials, enemas were used twice per week or for 1 week per month. Both oral and topical mesalamine were well tolerated.”

For patients with moderate disease activity or a suboptimal response to standard-dose mesalamine or diazo-bonded 5-ASA, the guideline recommends adding rectal mesalamine to high-dose oral mesalamine (more than 3 grams daily). Combination therapy maximizes the delivery of mesalamine to the affected area of the colon, which optimizes the trial of 5-ASA before opting for treatment escalation, the authors noted. They recommend once-daily oral mesalamine dosing, since this is easier to adhere to and studies have found no benefit of more frequent dosing.

For inducing remission of mild to moderate ulcerative colitis, the guideline recommends standard-dose oral mesalamine or diazo-bonded 5-ASA over budesonide. “Overall, the budesonide preparations are not superior to mesalamine for induction of remission,” the authors wrote. Oral 5-ASAs are preferred, especially given the absence of data on the efficacy or safety of maintenance budesonide therapy.

SOURCE: Crocket SD et al.  Gastro 2019;156(2).  doi: org/10.1053/j.gastro.2018.12.009.

For patients with extensive mild to moderate ulcerative colitis, numerous randomized controlled trials support the use of either standard-dose mesalamine (2-3 grams per day) or diazo-bonded 5-aminosalicylic acid (ASA) instead of low-dose mesalamine, sulfasalazine, or no therapy, state new guidelines from the American Gastroenterological Association, published in Gastroenterology.

©selvanegra/thinkstockphotos.com

Sulfasalazine (2-4 grams per day) is less likely to be tolerated but remains a “reasonable option” for remitted patients who are already on it and for patients with prominent arthritis symptoms, especially if alternative treatments are cost prohibitive, wrote Cynthia W. Ko, MD, MS, of the University of Washington, Seattle, and her associates.

According to the guideline, patients with mild to moderate ulcerative colitis have less than four to six bowel movements per day, only mild or moderate rectal bleeding, no constitutional symptoms, and no high overall inflammatory burden or signs of high inflammatory activity on the Mayo Clinic score and Truelove and Witt’s criteria. These patients usually do not require colectomy, but this outcome is more likely when patients are diagnosed before age 40 years or have extensive disease or deep ulcers, extraintestinal manifestations, or elevated inflammatory markers. These higher-risk patients need more aggressive initial treatment and faster treatment intensification in cases of inadequate response, the guideline emphasizes. Even for cases of mild to moderate ulcerative colitis, treatment intensification is preferable to repeated courses of corticosteroids.

The guideline recommends adding rectal mesalamine to oral 5-ASA if patients have extensive or left-sided mild to moderate ulcerative colitis. In randomized controlled trials, this combination was significantly more likely to induce and maintain remission than was standard-dose oral mesalamine monotherapy, the authors noted. “In the maintenance trials, enemas were used twice per week or for 1 week per month. Both oral and topical mesalamine were well tolerated.”

For patients with moderate disease activity or a suboptimal response to standard-dose mesalamine or diazo-bonded 5-ASA, the guideline recommends adding rectal mesalamine to high-dose oral mesalamine (more than 3 grams daily). Combination therapy maximizes the delivery of mesalamine to the affected area of the colon, which optimizes the trial of 5-ASA before opting for treatment escalation, the authors noted. They recommend once-daily oral mesalamine dosing, since this is easier to adhere to and studies have found no benefit of more frequent dosing.

For inducing remission of mild to moderate ulcerative colitis, the guideline recommends standard-dose oral mesalamine or diazo-bonded 5-ASA over budesonide. “Overall, the budesonide preparations are not superior to mesalamine for induction of remission,” the authors wrote. Oral 5-ASAs are preferred, especially given the absence of data on the efficacy or safety of maintenance budesonide therapy.

SOURCE: Crocket SD et al.  Gastro 2019;156(2).  doi: org/10.1053/j.gastro.2018.12.009.

For patients with extensive mild to moderate ulcerative colitis, numerous randomized controlled trials support the use of either standard-dose mesalamine (2-3 grams per day) or diazo-bonded 5-aminosalicylic acid (ASA) instead of low-dose mesalamine, sulfasalazine, or no therapy, state new guidelines from the American Gastroenterological Association, published in Gastroenterology.

©selvanegra/thinkstockphotos.com

Sulfasalazine (2-4 grams per day) is less likely to be tolerated but remains a “reasonable option” for remitted patients who are already on it and for patients with prominent arthritis symptoms, especially if alternative treatments are cost prohibitive, wrote Cynthia W. Ko, MD, MS, of the University of Washington, Seattle, and her associates.

According to the guideline, patients with mild to moderate ulcerative colitis have less than four to six bowel movements per day, only mild or moderate rectal bleeding, no constitutional symptoms, and no high overall inflammatory burden or signs of high inflammatory activity on the Mayo Clinic score and Truelove and Witt’s criteria. These patients usually do not require colectomy, but this outcome is more likely when patients are diagnosed before age 40 years or have extensive disease or deep ulcers, extraintestinal manifestations, or elevated inflammatory markers. These higher-risk patients need more aggressive initial treatment and faster treatment intensification in cases of inadequate response, the guideline emphasizes. Even for cases of mild to moderate ulcerative colitis, treatment intensification is preferable to repeated courses of corticosteroids.

The guideline recommends adding rectal mesalamine to oral 5-ASA if patients have extensive or left-sided mild to moderate ulcerative colitis. In randomized controlled trials, this combination was significantly more likely to induce and maintain remission than was standard-dose oral mesalamine monotherapy, the authors noted. “In the maintenance trials, enemas were used twice per week or for 1 week per month. Both oral and topical mesalamine were well tolerated.”

For patients with moderate disease activity or a suboptimal response to standard-dose mesalamine or diazo-bonded 5-ASA, the guideline recommends adding rectal mesalamine to high-dose oral mesalamine (more than 3 grams daily). Combination therapy maximizes the delivery of mesalamine to the affected area of the colon, which optimizes the trial of 5-ASA before opting for treatment escalation, the authors noted. They recommend once-daily oral mesalamine dosing, since this is easier to adhere to and studies have found no benefit of more frequent dosing.

For inducing remission of mild to moderate ulcerative colitis, the guideline recommends standard-dose oral mesalamine or diazo-bonded 5-ASA over budesonide. “Overall, the budesonide preparations are not superior to mesalamine for induction of remission,” the authors wrote. Oral 5-ASAs are preferred, especially given the absence of data on the efficacy or safety of maintenance budesonide therapy.

SOURCE: Crocket SD et al.  Gastro 2019;156(2).  doi: org/10.1053/j.gastro.2018.12.009.

Findings from an ongoing study of individuals with seropositive arthralgia, as well as from numerous other ongoing research efforts, suggest that it will soon be possible to predict a future rheumatoid arthritis diagnosis, according to Douglas J. Veale, MD.

Evidence also suggests that disease onset can be delayed, and that there is potential for disease prevention in those cases, Dr. Veale, a professor and consultant rheumatologist at St. Vincent’s University Hospital in Dublin said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
 

Cellular and molecular profiling of RA risk

Dr. Veale’s current research focuses on patients presenting with joint pain but no joint swelling or clinical evidence of soft tissue swelling, who are found to be seropositive for anticitrullinated protein antibodies (ACPA) and/or rheumatoid factor (RF).

“We have termed these patients [as having] ‘seropositive arthralgia,’ and we started a study in our institution because we started seeing more of these patients being referred in by the general practitioners,” said Dr. Veale, who is also director of translational research at the Dublin Academic Medical Centre of University College Dublin.

The aim of the study is to biopsy synovial tissue obtained during knee joint arthroscopy (which has been shown in prior studies to provide the same synovial findings as can be obtained through wrist and ankle biopsies) and to assess cellular and molecular profiles and clinical outcomes in these subjects, he said.

Of 36 seropositive arthralgia patients recruited to date, 22 are women, and 19 developed RA by 2010 ACR criteria within 12 months; most of those did so within 2-3 months, he said.

Median swollen joint counts were zero, and tender joint counts were slightly raised (median = 0, interquartile range = 0-4) in the subjects at baseline. Overall, 82% were RF positive, 91% were ACPA positive, and 73% were both RF and ACPA positive.

“The median [C-reactive protein (CRP) level] was 3 [mg/dL] with a range of 2-7, so most of these are normal when they’re coming to see us,” he said.

The level of synovitis seen on knee arthroscopy was a median of 60 on a visual analog scale of 0-100.

“So the level of synovitis that we’re seeing is certainly over a median of 50%,” he added.

Of 22 patients who were followed for at least 1 year – including the 19 who developed RA – none were on therapy at baseline, and none had CRP over 5 mg/dL at baseline. Two of the 19 who later developed RA elected to begin treatment before they developed the disease – one with hydroxychloroquine and one with methotrexate – and treatment was initiated in the remaining 17 RA patients as soon as they met the ACR RA criteria. Currently, 14 are on synthetic disease-modifying antirheumatic drugs (DMARDs), and 5 are on biologic DMARDs. Overall, 13 of the 22 patients followed for 1 year have no disease activity, 5 have low disease activity, and 4 have moderate disease activity, he said.

One question addressed in this study is whether immunostaining predicts arthritis, Dr. Veale noted.

“The short answer is ‘no,’ ” he said, explaining that activated T and B cells are seen in the biopsies of subjects who remain as seropositive arthralgia patients, and also in patients who actually develop RA. “So the immunohistology of these biopsies is not telling us a great deal.”

Immunophenotyping to establish RA risk

Another finding of interest is an increase in the synovial tissue CD38 plasmablasts as detected by RNA sequencing in seropositive arthralgia subjects.

“Their pattern looks more like early RA or established RA,” he noted.

Similarly, the proportion of B cells is already increased in the seropositive arthralgia subjects, compared with healthy subjects, and is similar to that seen in established seropositive and seronegative RA patients.

After looking at “a whole range of immunophenotypes,” Dr. Veale and his colleagues found that several other genes (not just for CD38) are expressed at increased levels in the arthralgia patients.

“The pattern that we’re seeing is that the seropositive arthralgia patients look more like the early rheumatoid and the established rheumatoid patients when we actually analyze their gene signatures using immunophenotyping,” he said.

The patients in this study were all referred by general practitioners, but another study – the PRAIRI study – recruited seropositive arthralgia patients from the community and randomized them to receive a single rituximab infusion or placebo (Ann Rheum Dis. 2019;78:179-85).

“What they showed is that patients who received one dose of rituximab actually developed rheumatoid arthritis at a slower rate and at a later time than the patients who received placebo,” he said.

At 1-year follow-up, there was no difference in the rate of development of RA between the groups; rituximab had merely delayed the onset of RA, he said.

“They do discuss in this paper what the effect would be if you continued treatment in these patients: Would we actually prevent the onset of rheumatoid arthritis in a significant cohort of patients?” he said. “But we don’t know that.”
 

Could immune checkpoint inhibition reveal RA risk?

Recent findings from work with immune checkpoint therapy in the hematology/oncology arena, however, raise other interesting possibilities with respect to early treatment and prevention of RA.

A number of case reports have documented the development of autoimmune diseases in patients with cancer who have undergone treatment with checkpoint inhibitors.

“Essentially what happens in cancer is that the activated T cells upregulate immune checkpoint molecules. ... and what these molecules do is they make the T cells essentially resistant to attacking the tumor cells,” he explained, noting that the molecules include programmed death 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4).

Checkpoint inhibitors bind to these molecules and “free up these activated T cells to attack the tumor cells” both through cytokines (interferon release) and direct cell cytotoxicity, he said.

This is relevant for rheumatology patients, because the PD-1 checkpoint molecule is overexpressed in pathogenic T cells in RA and systemic lupus erythematosus.

A closer look at his own RA patients showed that those who were ACPA positive had higher levels of soluble PD-1 than did the ACPA-negative RA patients – a finding that has been replicated in two other cohorts, he noted.

“So we wanted to look at our seropositive arthralgia subjects and see if there is something in their gene signatures on immunophenotyping which actually would give us a clue in terms of this checkpoint inhibitor pathway,” he said. “What we found is that the anti–PD-1 signature is increased in our arthralgia patients, and again, the pattern of expression is more similar to early rheumatoid arthritis and established rheumatoid arthritis, and is significantly different from both healthy controls and patients with osteoarthritis.”

PD-1 expression was also found to be increased on CD4- and CD8-positive T cells taken from the synovial tissues in these patients, he said.

Immunostaining of the T cells showed, interestingly, that the ligand for PD-1 is “almost absent,” he noted.

“So there’s an overexpression of PD-1, but there’s a downregulation of the ligand for PD-1, so that means that the PD-1 pathway is not active in these patients because the PD-1 ... has no ligand to actually bind on to.”

This suggests that “something else may happen that will upregulate the ligand – maybe a second hit,” thereby allowing PD-1 to bind and become active, he said.

“I realize what I’ve been talking about is fairly controversial, but I think it may be possible soon to predict a diagnosis of rheumatoid arthritis before clinical arthritis develops, but not in everybody,” he said, noting that current diagnostic tools are often unreliable.

For example, CRP levels in most of his study subjects remained normal even after converting to meet RA criteria, he explained.

However, “the checkpoint inhibitor story is absolutely fascinating,” he said.

“It’s unmasked an RA phenotype in patients who are receiving these drugs, and we have identified that the PD-1 pathway is altered in the synovial tissue, not just in patients with established rheumatoid arthritis, but also in subjects before they have developed arthritis and they have circulating autoantibodies,” he said.

The CD38 plasmablasts found to be present in the synovial tissue before RA presents clinically may also represent a therapeutic target, he added.

Dr. Veale disclosed financial relationships (research grants, consulting fees, speaker’s bureau, and “other” relationships) with AbbVie, Pfizer, UCB, Roche, and Janssen.

sworcester@mdedge.com

Findings from an ongoing study of individuals with seropositive arthralgia, as well as from numerous other ongoing research efforts, suggest that it will soon be possible to predict a future rheumatoid arthritis diagnosis, according to Douglas J. Veale, MD.

Evidence also suggests that disease onset can be delayed, and that there is potential for disease prevention in those cases, Dr. Veale, a professor and consultant rheumatologist at St. Vincent’s University Hospital in Dublin said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
 

Cellular and molecular profiling of RA risk

Dr. Veale’s current research focuses on patients presenting with joint pain but no joint swelling or clinical evidence of soft tissue swelling, who are found to be seropositive for anticitrullinated protein antibodies (ACPA) and/or rheumatoid factor (RF).

“We have termed these patients [as having] ‘seropositive arthralgia,’ and we started a study in our institution because we started seeing more of these patients being referred in by the general practitioners,” said Dr. Veale, who is also director of translational research at the Dublin Academic Medical Centre of University College Dublin.

The aim of the study is to biopsy synovial tissue obtained during knee joint arthroscopy (which has been shown in prior studies to provide the same synovial findings as can be obtained through wrist and ankle biopsies) and to assess cellular and molecular profiles and clinical outcomes in these subjects, he said.

Of 36 seropositive arthralgia patients recruited to date, 22 are women, and 19 developed RA by 2010 ACR criteria within 12 months; most of those did so within 2-3 months, he said.

Median swollen joint counts were zero, and tender joint counts were slightly raised (median = 0, interquartile range = 0-4) in the subjects at baseline. Overall, 82% were RF positive, 91% were ACPA positive, and 73% were both RF and ACPA positive.

“The median [C-reactive protein (CRP) level] was 3 [mg/dL] with a range of 2-7, so most of these are normal when they’re coming to see us,” he said.

The level of synovitis seen on knee arthroscopy was a median of 60 on a visual analog scale of 0-100.

“So the level of synovitis that we’re seeing is certainly over a median of 50%,” he added.

Of 22 patients who were followed for at least 1 year – including the 19 who developed RA – none were on therapy at baseline, and none had CRP over 5 mg/dL at baseline. Two of the 19 who later developed RA elected to begin treatment before they developed the disease – one with hydroxychloroquine and one with methotrexate – and treatment was initiated in the remaining 17 RA patients as soon as they met the ACR RA criteria. Currently, 14 are on synthetic disease-modifying antirheumatic drugs (DMARDs), and 5 are on biologic DMARDs. Overall, 13 of the 22 patients followed for 1 year have no disease activity, 5 have low disease activity, and 4 have moderate disease activity, he said.

One question addressed in this study is whether immunostaining predicts arthritis, Dr. Veale noted.

“The short answer is ‘no,’ ” he said, explaining that activated T and B cells are seen in the biopsies of subjects who remain as seropositive arthralgia patients, and also in patients who actually develop RA. “So the immunohistology of these biopsies is not telling us a great deal.”

Immunophenotyping to establish RA risk

Another finding of interest is an increase in the synovial tissue CD38 plasmablasts as detected by RNA sequencing in seropositive arthralgia subjects.

“Their pattern looks more like early RA or established RA,” he noted.

Similarly, the proportion of B cells is already increased in the seropositive arthralgia subjects, compared with healthy subjects, and is similar to that seen in established seropositive and seronegative RA patients.

After looking at “a whole range of immunophenotypes,” Dr. Veale and his colleagues found that several other genes (not just for CD38) are expressed at increased levels in the arthralgia patients.

“The pattern that we’re seeing is that the seropositive arthralgia patients look more like the early rheumatoid and the established rheumatoid patients when we actually analyze their gene signatures using immunophenotyping,” he said.

The patients in this study were all referred by general practitioners, but another study – the PRAIRI study – recruited seropositive arthralgia patients from the community and randomized them to receive a single rituximab infusion or placebo (Ann Rheum Dis. 2019;78:179-85).

“What they showed is that patients who received one dose of rituximab actually developed rheumatoid arthritis at a slower rate and at a later time than the patients who received placebo,” he said.

At 1-year follow-up, there was no difference in the rate of development of RA between the groups; rituximab had merely delayed the onset of RA, he said.

“They do discuss in this paper what the effect would be if you continued treatment in these patients: Would we actually prevent the onset of rheumatoid arthritis in a significant cohort of patients?” he said. “But we don’t know that.”
 

Could immune checkpoint inhibition reveal RA risk?

Recent findings from work with immune checkpoint therapy in the hematology/oncology arena, however, raise other interesting possibilities with respect to early treatment and prevention of RA.

A number of case reports have documented the development of autoimmune diseases in patients with cancer who have undergone treatment with checkpoint inhibitors.

“Essentially what happens in cancer is that the activated T cells upregulate immune checkpoint molecules. ... and what these molecules do is they make the T cells essentially resistant to attacking the tumor cells,” he explained, noting that the molecules include programmed death 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4).

Checkpoint inhibitors bind to these molecules and “free up these activated T cells to attack the tumor cells” both through cytokines (interferon release) and direct cell cytotoxicity, he said.

This is relevant for rheumatology patients, because the PD-1 checkpoint molecule is overexpressed in pathogenic T cells in RA and systemic lupus erythematosus.

A closer look at his own RA patients showed that those who were ACPA positive had higher levels of soluble PD-1 than did the ACPA-negative RA patients – a finding that has been replicated in two other cohorts, he noted.

“So we wanted to look at our seropositive arthralgia subjects and see if there is something in their gene signatures on immunophenotyping which actually would give us a clue in terms of this checkpoint inhibitor pathway,” he said. “What we found is that the anti–PD-1 signature is increased in our arthralgia patients, and again, the pattern of expression is more similar to early rheumatoid arthritis and established rheumatoid arthritis, and is significantly different from both healthy controls and patients with osteoarthritis.”

PD-1 expression was also found to be increased on CD4- and CD8-positive T cells taken from the synovial tissues in these patients, he said.

Immunostaining of the T cells showed, interestingly, that the ligand for PD-1 is “almost absent,” he noted.

“So there’s an overexpression of PD-1, but there’s a downregulation of the ligand for PD-1, so that means that the PD-1 pathway is not active in these patients because the PD-1 ... has no ligand to actually bind on to.”

This suggests that “something else may happen that will upregulate the ligand – maybe a second hit,” thereby allowing PD-1 to bind and become active, he said.

“I realize what I’ve been talking about is fairly controversial, but I think it may be possible soon to predict a diagnosis of rheumatoid arthritis before clinical arthritis develops, but not in everybody,” he said, noting that current diagnostic tools are often unreliable.

For example, CRP levels in most of his study subjects remained normal even after converting to meet RA criteria, he explained.

However, “the checkpoint inhibitor story is absolutely fascinating,” he said.

“It’s unmasked an RA phenotype in patients who are receiving these drugs, and we have identified that the PD-1 pathway is altered in the synovial tissue, not just in patients with established rheumatoid arthritis, but also in subjects before they have developed arthritis and they have circulating autoantibodies,” he said.

The CD38 plasmablasts found to be present in the synovial tissue before RA presents clinically may also represent a therapeutic target, he added.

Dr. Veale disclosed financial relationships (research grants, consulting fees, speaker’s bureau, and “other” relationships) with AbbVie, Pfizer, UCB, Roche, and Janssen.

sworcester@mdedge.com

Findings from an ongoing study of individuals with seropositive arthralgia, as well as from numerous other ongoing research efforts, suggest that it will soon be possible to predict a future rheumatoid arthritis diagnosis, according to Douglas J. Veale, MD.

Evidence also suggests that disease onset can be delayed, and that there is potential for disease prevention in those cases, Dr. Veale, a professor and consultant rheumatologist at St. Vincent’s University Hospital in Dublin said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
 

Cellular and molecular profiling of RA risk

Dr. Veale’s current research focuses on patients presenting with joint pain but no joint swelling or clinical evidence of soft tissue swelling, who are found to be seropositive for anticitrullinated protein antibodies (ACPA) and/or rheumatoid factor (RF).

“We have termed these patients [as having] ‘seropositive arthralgia,’ and we started a study in our institution because we started seeing more of these patients being referred in by the general practitioners,” said Dr. Veale, who is also director of translational research at the Dublin Academic Medical Centre of University College Dublin.

The aim of the study is to biopsy synovial tissue obtained during knee joint arthroscopy (which has been shown in prior studies to provide the same synovial findings as can be obtained through wrist and ankle biopsies) and to assess cellular and molecular profiles and clinical outcomes in these subjects, he said.

Of 36 seropositive arthralgia patients recruited to date, 22 are women, and 19 developed RA by 2010 ACR criteria within 12 months; most of those did so within 2-3 months, he said.

Median swollen joint counts were zero, and tender joint counts were slightly raised (median = 0, interquartile range = 0-4) in the subjects at baseline. Overall, 82% were RF positive, 91% were ACPA positive, and 73% were both RF and ACPA positive.

“The median [C-reactive protein (CRP) level] was 3 [mg/dL] with a range of 2-7, so most of these are normal when they’re coming to see us,” he said.

The level of synovitis seen on knee arthroscopy was a median of 60 on a visual analog scale of 0-100.

“So the level of synovitis that we’re seeing is certainly over a median of 50%,” he added.

Of 22 patients who were followed for at least 1 year – including the 19 who developed RA – none were on therapy at baseline, and none had CRP over 5 mg/dL at baseline. Two of the 19 who later developed RA elected to begin treatment before they developed the disease – one with hydroxychloroquine and one with methotrexate – and treatment was initiated in the remaining 17 RA patients as soon as they met the ACR RA criteria. Currently, 14 are on synthetic disease-modifying antirheumatic drugs (DMARDs), and 5 are on biologic DMARDs. Overall, 13 of the 22 patients followed for 1 year have no disease activity, 5 have low disease activity, and 4 have moderate disease activity, he said.

One question addressed in this study is whether immunostaining predicts arthritis, Dr. Veale noted.

“The short answer is ‘no,’ ” he said, explaining that activated T and B cells are seen in the biopsies of subjects who remain as seropositive arthralgia patients, and also in patients who actually develop RA. “So the immunohistology of these biopsies is not telling us a great deal.”

Immunophenotyping to establish RA risk

Another finding of interest is an increase in the synovial tissue CD38 plasmablasts as detected by RNA sequencing in seropositive arthralgia subjects.

“Their pattern looks more like early RA or established RA,” he noted.

Similarly, the proportion of B cells is already increased in the seropositive arthralgia subjects, compared with healthy subjects, and is similar to that seen in established seropositive and seronegative RA patients.

After looking at “a whole range of immunophenotypes,” Dr. Veale and his colleagues found that several other genes (not just for CD38) are expressed at increased levels in the arthralgia patients.

“The pattern that we’re seeing is that the seropositive arthralgia patients look more like the early rheumatoid and the established rheumatoid patients when we actually analyze their gene signatures using immunophenotyping,” he said.

The patients in this study were all referred by general practitioners, but another study – the PRAIRI study – recruited seropositive arthralgia patients from the community and randomized them to receive a single rituximab infusion or placebo (Ann Rheum Dis. 2019;78:179-85).

“What they showed is that patients who received one dose of rituximab actually developed rheumatoid arthritis at a slower rate and at a later time than the patients who received placebo,” he said.

At 1-year follow-up, there was no difference in the rate of development of RA between the groups; rituximab had merely delayed the onset of RA, he said.

“They do discuss in this paper what the effect would be if you continued treatment in these patients: Would we actually prevent the onset of rheumatoid arthritis in a significant cohort of patients?” he said. “But we don’t know that.”
 

Could immune checkpoint inhibition reveal RA risk?

Recent findings from work with immune checkpoint therapy in the hematology/oncology arena, however, raise other interesting possibilities with respect to early treatment and prevention of RA.

A number of case reports have documented the development of autoimmune diseases in patients with cancer who have undergone treatment with checkpoint inhibitors.

“Essentially what happens in cancer is that the activated T cells upregulate immune checkpoint molecules. ... and what these molecules do is they make the T cells essentially resistant to attacking the tumor cells,” he explained, noting that the molecules include programmed death 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4).

Checkpoint inhibitors bind to these molecules and “free up these activated T cells to attack the tumor cells” both through cytokines (interferon release) and direct cell cytotoxicity, he said.

This is relevant for rheumatology patients, because the PD-1 checkpoint molecule is overexpressed in pathogenic T cells in RA and systemic lupus erythematosus.

A closer look at his own RA patients showed that those who were ACPA positive had higher levels of soluble PD-1 than did the ACPA-negative RA patients – a finding that has been replicated in two other cohorts, he noted.

“So we wanted to look at our seropositive arthralgia subjects and see if there is something in their gene signatures on immunophenotyping which actually would give us a clue in terms of this checkpoint inhibitor pathway,” he said. “What we found is that the anti–PD-1 signature is increased in our arthralgia patients, and again, the pattern of expression is more similar to early rheumatoid arthritis and established rheumatoid arthritis, and is significantly different from both healthy controls and patients with osteoarthritis.”

PD-1 expression was also found to be increased on CD4- and CD8-positive T cells taken from the synovial tissues in these patients, he said.

Immunostaining of the T cells showed, interestingly, that the ligand for PD-1 is “almost absent,” he noted.

“So there’s an overexpression of PD-1, but there’s a downregulation of the ligand for PD-1, so that means that the PD-1 pathway is not active in these patients because the PD-1 ... has no ligand to actually bind on to.”

This suggests that “something else may happen that will upregulate the ligand – maybe a second hit,” thereby allowing PD-1 to bind and become active, he said.

“I realize what I’ve been talking about is fairly controversial, but I think it may be possible soon to predict a diagnosis of rheumatoid arthritis before clinical arthritis develops, but not in everybody,” he said, noting that current diagnostic tools are often unreliable.

For example, CRP levels in most of his study subjects remained normal even after converting to meet RA criteria, he explained.

However, “the checkpoint inhibitor story is absolutely fascinating,” he said.

“It’s unmasked an RA phenotype in patients who are receiving these drugs, and we have identified that the PD-1 pathway is altered in the synovial tissue, not just in patients with established rheumatoid arthritis, but also in subjects before they have developed arthritis and they have circulating autoantibodies,” he said.

The CD38 plasmablasts found to be present in the synovial tissue before RA presents clinically may also represent a therapeutic target, he added.

Dr. Veale disclosed financial relationships (research grants, consulting fees, speaker’s bureau, and “other” relationships) with AbbVie, Pfizer, UCB, Roche, and Janssen.

sworcester@mdedge.com

GRAND CAYMAN, CAYMAN ISLANDS – Not all honeys are created equal, Theodore Rosen, MD, said at the meeting provided by Global Academy for Medical Education.

LazingBee/Getty Images

“It seems that kanuka is the new manuka,” said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. These lesser-known New Zealand bush honeys may be something to watch because research and case reports continue to provide intriguing hints of how these honeys exert their immunomodulatory effects on skin, he commented, describing a recent case report describing the elimination of a large, long-standing actinic keratosis (AK) with application of kanuka honey.

Manuka (Leptospermum scoparium) is a large bush native to both Australia and New Zealand. Kanuka (Kunzea ericoides) is quite similar in size and appearance, but native only to New Zealand. Honey made from the flowers of these bushes possesses some unique properties that make it an attractive addition to wound healing regimens, according to a 2014 study (Int J Gen Med. 2014;7:149-58).

The study examined samples of manuka, kanuka, a manuka/kanuka blend, and clover honey. The investigators found that kanuka honey, and to a lesser extent manuka honey, exerted a potent anti-inflammatory effect in human embryonic kidney cells. The honeys interfered with toll-like receptor 1 and 2 signaling, which would reduce the production of proinflammatory cytokines.

Kanuka’s potency seems directly related to its unusually high level of arabinogalactan, according to Saras Mane, MD, primary author of the AK case report (Case Rep Dermatol Med. 2018 May 31;2018:4628971). Dr. Mane is with the Medical Research Institute of New Zealand in Wellington.

Saras Mane, MD

“This gentleman decided he’d just try the honey on his AK, too,” Dr. Rosen said. The man reported applying a small amount to the lesion and erythematous area once a day, leaving it on for about 30 to 60 minutes. After 5 days, he stopped because the lesion became tender. During the next two days, the patient reported “picking at” the lesion, which was softening. He repeated this cycle of treatment for 3 months with no other therapy to the lesion.

“The lesion gradually reduced in size with an initial rapid reduction in its dry, crusted nature,” the authors reported. “After 3 months, residual appearance of the lesion was a 20 mm by 17 mm area of pink skin with no elements of hypertrophy, crusting, or loss of skin integrity,” they noted. “At 6 months, there were no signs of recurrence. At 9 months, the appearance of the skin had fully returned to normal. A telephone follow-up was conducted at 2 years after treatment, and the patient reported that his skin in the area was still completely normal and that there were no signs of recurrence.”

Dr. Mane noted that they had only clinical evidence, and no histology of the lesion either before or after its change. “The AK was diagnosed and treated in primary care, where it is not usual for AKs to be biopsied, and the decision to write up the case was made after the course of treatment had finished,” they said.

“Immunomodulatory topical agents are already widely used in the treatment of AK as an immune component is evident in its etiology,” they wrote. “Immunocompromised patients have 250 times the risk of developing an AK than the general population.”

Dr. Rosen said that kanuka honey is also being investigated in psoriasis, eczema, acne, herpes simplex virus, and diaper dermatitis. It is also being studied for rosacea.

Dr. Mane declared no conflicts of interest. Some coauthors disclosed that they have previously received funding from HoneyLab NZ. Dr. Rosen has no commercial interest in HoneyLab.

The meeting was sponsored by Global Academy for Medical Education; Global Academy and this news organization are owned by the same parent company.

msullivan@mdege.com

GRAND CAYMAN, CAYMAN ISLANDS – Not all honeys are created equal, Theodore Rosen, MD, said at the meeting provided by Global Academy for Medical Education.

LazingBee/Getty Images

“It seems that kanuka is the new manuka,” said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. These lesser-known New Zealand bush honeys may be something to watch because research and case reports continue to provide intriguing hints of how these honeys exert their immunomodulatory effects on skin, he commented, describing a recent case report describing the elimination of a large, long-standing actinic keratosis (AK) with application of kanuka honey.

Manuka (Leptospermum scoparium) is a large bush native to both Australia and New Zealand. Kanuka (Kunzea ericoides) is quite similar in size and appearance, but native only to New Zealand. Honey made from the flowers of these bushes possesses some unique properties that make it an attractive addition to wound healing regimens, according to a 2014 study (Int J Gen Med. 2014;7:149-58).

The study examined samples of manuka, kanuka, a manuka/kanuka blend, and clover honey. The investigators found that kanuka honey, and to a lesser extent manuka honey, exerted a potent anti-inflammatory effect in human embryonic kidney cells. The honeys interfered with toll-like receptor 1 and 2 signaling, which would reduce the production of proinflammatory cytokines.

Kanuka’s potency seems directly related to its unusually high level of arabinogalactan, according to Saras Mane, MD, primary author of the AK case report (Case Rep Dermatol Med. 2018 May 31;2018:4628971). Dr. Mane is with the Medical Research Institute of New Zealand in Wellington.

Saras Mane, MD

“This gentleman decided he’d just try the honey on his AK, too,” Dr. Rosen said. The man reported applying a small amount to the lesion and erythematous area once a day, leaving it on for about 30 to 60 minutes. After 5 days, he stopped because the lesion became tender. During the next two days, the patient reported “picking at” the lesion, which was softening. He repeated this cycle of treatment for 3 months with no other therapy to the lesion.

“The lesion gradually reduced in size with an initial rapid reduction in its dry, crusted nature,” the authors reported. “After 3 months, residual appearance of the lesion was a 20 mm by 17 mm area of pink skin with no elements of hypertrophy, crusting, or loss of skin integrity,” they noted. “At 6 months, there were no signs of recurrence. At 9 months, the appearance of the skin had fully returned to normal. A telephone follow-up was conducted at 2 years after treatment, and the patient reported that his skin in the area was still completely normal and that there were no signs of recurrence.”

Dr. Mane noted that they had only clinical evidence, and no histology of the lesion either before or after its change. “The AK was diagnosed and treated in primary care, where it is not usual for AKs to be biopsied, and the decision to write up the case was made after the course of treatment had finished,” they said.

“Immunomodulatory topical agents are already widely used in the treatment of AK as an immune component is evident in its etiology,” they wrote. “Immunocompromised patients have 250 times the risk of developing an AK than the general population.”

Dr. Rosen said that kanuka honey is also being investigated in psoriasis, eczema, acne, herpes simplex virus, and diaper dermatitis. It is also being studied for rosacea.

Dr. Mane declared no conflicts of interest. Some coauthors disclosed that they have previously received funding from HoneyLab NZ. Dr. Rosen has no commercial interest in HoneyLab.

The meeting was sponsored by Global Academy for Medical Education; Global Academy and this news organization are owned by the same parent company.

msullivan@mdege.com

GRAND CAYMAN, CAYMAN ISLANDS – Not all honeys are created equal, Theodore Rosen, MD, said at the meeting provided by Global Academy for Medical Education.

LazingBee/Getty Images

“It seems that kanuka is the new manuka,” said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. These lesser-known New Zealand bush honeys may be something to watch because research and case reports continue to provide intriguing hints of how these honeys exert their immunomodulatory effects on skin, he commented, describing a recent case report describing the elimination of a large, long-standing actinic keratosis (AK) with application of kanuka honey.

Manuka (Leptospermum scoparium) is a large bush native to both Australia and New Zealand. Kanuka (Kunzea ericoides) is quite similar in size and appearance, but native only to New Zealand. Honey made from the flowers of these bushes possesses some unique properties that make it an attractive addition to wound healing regimens, according to a 2014 study (Int J Gen Med. 2014;7:149-58).

The study examined samples of manuka, kanuka, a manuka/kanuka blend, and clover honey. The investigators found that kanuka honey, and to a lesser extent manuka honey, exerted a potent anti-inflammatory effect in human embryonic kidney cells. The honeys interfered with toll-like receptor 1 and 2 signaling, which would reduce the production of proinflammatory cytokines.

Kanuka’s potency seems directly related to its unusually high level of arabinogalactan, according to Saras Mane, MD, primary author of the AK case report (Case Rep Dermatol Med. 2018 May 31;2018:4628971). Dr. Mane is with the Medical Research Institute of New Zealand in Wellington.

Saras Mane, MD

“This gentleman decided he’d just try the honey on his AK, too,” Dr. Rosen said. The man reported applying a small amount to the lesion and erythematous area once a day, leaving it on for about 30 to 60 minutes. After 5 days, he stopped because the lesion became tender. During the next two days, the patient reported “picking at” the lesion, which was softening. He repeated this cycle of treatment for 3 months with no other therapy to the lesion.

“The lesion gradually reduced in size with an initial rapid reduction in its dry, crusted nature,” the authors reported. “After 3 months, residual appearance of the lesion was a 20 mm by 17 mm area of pink skin with no elements of hypertrophy, crusting, or loss of skin integrity,” they noted. “At 6 months, there were no signs of recurrence. At 9 months, the appearance of the skin had fully returned to normal. A telephone follow-up was conducted at 2 years after treatment, and the patient reported that his skin in the area was still completely normal and that there were no signs of recurrence.”

Dr. Mane noted that they had only clinical evidence, and no histology of the lesion either before or after its change. “The AK was diagnosed and treated in primary care, where it is not usual for AKs to be biopsied, and the decision to write up the case was made after the course of treatment had finished,” they said.

“Immunomodulatory topical agents are already widely used in the treatment of AK as an immune component is evident in its etiology,” they wrote. “Immunocompromised patients have 250 times the risk of developing an AK than the general population.”

Dr. Rosen said that kanuka honey is also being investigated in psoriasis, eczema, acne, herpes simplex virus, and diaper dermatitis. It is also being studied for rosacea.

Dr. Mane declared no conflicts of interest. Some coauthors disclosed that they have previously received funding from HoneyLab NZ. Dr. Rosen has no commercial interest in HoneyLab.

The meeting was sponsored by Global Academy for Medical Education; Global Academy and this news organization are owned by the same parent company.

msullivan@mdege.com

To the Editor:

A 50-year-old woman presented with an asymptomatic eruption on the dorsal aspect of the hands, abdomen, and face of 6 months’ duration. The eruption was associated with generalized arthralgia and fatigue. Within several weeks of onset of the cutaneous eruption, the patient developed swelling in the hands as well as worsening arthralgia. She was treated for presumed Lyme borreliosis but reported no improvement in the symptoms. She was then referred to dermatology for further management.

Physical examination revealed red-orange, edematous, monomorphic papulonodules scattered on the nasolabial folds, upper lip, and along the dorsal aspect of the hands and fingers (Figure 1). A brown rippled plaque was present on the left lower abdomen. The oral mucosa and nails were unremarkable. Laboratory studies showed elevated total cholesterol (244 mg/dL [reference range, <200 mg/dL]), low-density lipoproteins (130 mg/dL [reference range, 10–30 mg/dL]), aspartate aminotransferase (140 U/L [reference range, 10–30 U/L]), alanine aminotransferase (110 U/L [reference range, 10–40 U/L]), and total bilirubin (1.5 mg/dL [reference range, 0.3–1.2 mg/dL]). White blood cell count and C-reactive protein levels were within reference range. An antinuclear antibody titer of 1:80 with a homogenous pattern was found, and aldolase levels were elevated. Laboratory investigations for rheumatoid factor, Lyme disease, tuberculosis, hepatitis, and human immunodeficiency virus were negative. A chest radiograph was normal.

Multicentric reticulohistiocytosis typically presents with a severe erosive arthropathy known as arthritis mutilans. Patients display a symmetric polyarthritis that commonly involves the elbows, wrists, and proximal and distal aspects of the interphalangeal joints. Onset and progression can be rapid, and the erosive nature leads to deformities in up to 45% of patients.^2,5,6 Cutaneous findings arise an average of 3 years after the development of arthritis, though one-fifth of patients will initially present with cutaneous findings followed by the development of arthritis at any time.^3,6 Clinical features include flesh-colored to reddish brown or yellow papulonodules that range in size from several millimeters to 2 cm. The lesions most commonly occur on the face (eg, ears, nose, paranasal cheeks), scalp, dorsal and lateral aspects of the hands and fingers, and overlying articular regions of the extremities. Characteristic periungual lesions classically are referred to as coral beads.^4,6 Patients commonly report pruritus that may precede the development of the papules and nodules. Other cutaneous manifestations include xanthelasma, nail changes, and a photodistributed erythematous maculopapular eruption that may mimic dermatomyositis.⁶

Cutaneous findings of MRH can mimic rheumatoid nodules, gout, Gottron papules of dermatomyositis, lipoid proteinosis, sarcoidosis, lepromatous leprosy, granuloma annulare, xanthoma, xanthogranuloma, and fibroxanthoma.^6,7 Histopathologic features may distinguish MRH from such entities. Findings include fairly well-circumscribed aggregates of large multinucleated giant cells with characteristic eosinophilic ground-glass cytoplasm. Histiocytes stain positively for CD68, HAM56, CD11b, and CD14, and variably for factor XIIIa. CD68, which is expressed by monocytes/macrophages, has been universally reported to be the most reliable marker of MRH. Negative staining for S-100 and CD1a supports a non-Langerhans origin for the involved histiocytes. If arthritic symptoms predominate, MRH must be distinguished from rheumatoid and psoriatic arthritis.^6,7

Mucosal involvement occurs in approximately 50% of patients and includes the presence of nodules in the oral, nasal, and pharyngeal mucosae, as well as eye structures.^2,3 Histiocytic infiltration has been documented in the heart, lungs, thyroid, liver, stomach, kidneys, muscle, bone marrow, and urogenital tract. Histiocytes also can invade the cartilage of the ears and nose causing disfigurement and characteristic leonine facies. Pathologic fractures may occur with bone involvement.⁵

Systemic features associated with MRH include hyperlipidemia, diabetes mellitus, thyroid disease, hypergammaglobulinemia, and various autoimmune diseases. Patients less frequently report fever and weight loss.^2,5,6,8 Additionally, a positive tuberculin test occurs in 12% to 50% of patients.⁶ Various autoimmune diseases occur in 6% to 17% of cases including systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, dermatomyositis, Sjögren syndrome, and primary biliary cirrhosis.^2,5,6,8 The most clinically salient feature of MRH is its association with malignant conditions, which occur in up to 31% of patients. A variety of cancers have been reported in association with MRH, including breast, cervical, ovarian, stomach, penile, lymphoma, mesothelioma, and melanoma.⁷

The etiology of MRH is unclear. Although onset may precede the development of a malignant condition and regress with treatment, it cannot be considered a true paraneoplastic disorder, as it has no association with a specific cancer and does not typically parallel the disease course.^6,9 Reports of increased levels of inflammatory mediators released from macrophages and endothelial cells, specifically IL-12, IL-1β, IL-6, and tumor necrosis factor α (TNF-α), have been thought to drive the destruction of bone and cartilage.⁶ In particular, TNF-α acts to indirectly induce destruction by stimulating proteolytic activity in macrophages, similar to the pathogenesis of joint damage in rheumatoid arthritis.⁸ Osteoclastic activity may play a role in the pathogenesis of MRH, as multinucleated giant cells in MRH can mature into osteoclasts by receptor activated nuclear factor–κB ligand signaling. In addition, patients treated with bisphosphonates have had decreased lacunar resorption.^2,8

Initial management of MRH should include screening for hyperlipidemia, hypergammaglobulinemia, hyperglycemia, thyroid dysfunction, and autoimmune diseases, as well as age-appropriate cancer screening. Imaging studies should evaluate for the presence of erosive arthritis. There are no well-defined treatment algorithms for MRH due to the rarity of the disease, and recommendations largely rely on case reports. Although spontaneous remission typically occurs within 5 to 10 years, the risk for joint destruction argues for early pharmacologic intervention. Current management includes the use of nonsteroidal anti-inflammatory drugs and various immunosuppressants including oral glucocorticoids, cyclophosphamide, chlorambucil, methotrexate, or azathioprine.² A combination of methotrexate with cyclophosphamide or glucocorticoids also has shown efficacy.¹⁰ Anti–TNF-α agents, such as etanercept, adalimumab, and infliximab, have been used with some success.² Tumor necrosis factor α inhibitors used in combination with oral glucocorticoids and methotrexate may have an increased benefit.^2,9,11 Evidence suggesting that TNF-α plays a role in the destruction of bone and cartilage led to the successful use of infliximab in combination with oral glucocorticoids and methotrexate, which prevented possible development of antibodies to infliximab and increased its efficacy.¹² Bisphosphonate use in combination with glucocorticoids and methotrexate may prevent joint destruction without the serious adverse events associated with anti–TNF-α agents.^2,9,13,14

To the Editor:

A 50-year-old woman presented with an asymptomatic eruption on the dorsal aspect of the hands, abdomen, and face of 6 months’ duration. The eruption was associated with generalized arthralgia and fatigue. Within several weeks of onset of the cutaneous eruption, the patient developed swelling in the hands as well as worsening arthralgia. She was treated for presumed Lyme borreliosis but reported no improvement in the symptoms. She was then referred to dermatology for further management.

Physical examination revealed red-orange, edematous, monomorphic papulonodules scattered on the nasolabial folds, upper lip, and along the dorsal aspect of the hands and fingers (Figure 1). A brown rippled plaque was present on the left lower abdomen. The oral mucosa and nails were unremarkable. Laboratory studies showed elevated total cholesterol (244 mg/dL [reference range, <200 mg/dL]), low-density lipoproteins (130 mg/dL [reference range, 10–30 mg/dL]), aspartate aminotransferase (140 U/L [reference range, 10–30 U/L]), alanine aminotransferase (110 U/L [reference range, 10–40 U/L]), and total bilirubin (1.5 mg/dL [reference range, 0.3–1.2 mg/dL]). White blood cell count and C-reactive protein levels were within reference range. An antinuclear antibody titer of 1:80 with a homogenous pattern was found, and aldolase levels were elevated. Laboratory investigations for rheumatoid factor, Lyme disease, tuberculosis, hepatitis, and human immunodeficiency virus were negative. A chest radiograph was normal.

Multicentric reticulohistiocytosis typically presents with a severe erosive arthropathy known as arthritis mutilans. Patients display a symmetric polyarthritis that commonly involves the elbows, wrists, and proximal and distal aspects of the interphalangeal joints. Onset and progression can be rapid, and the erosive nature leads to deformities in up to 45% of patients.^2,5,6 Cutaneous findings arise an average of 3 years after the development of arthritis, though one-fifth of patients will initially present with cutaneous findings followed by the development of arthritis at any time.^3,6 Clinical features include flesh-colored to reddish brown or yellow papulonodules that range in size from several millimeters to 2 cm. The lesions most commonly occur on the face (eg, ears, nose, paranasal cheeks), scalp, dorsal and lateral aspects of the hands and fingers, and overlying articular regions of the extremities. Characteristic periungual lesions classically are referred to as coral beads.^4,6 Patients commonly report pruritus that may precede the development of the papules and nodules. Other cutaneous manifestations include xanthelasma, nail changes, and a photodistributed erythematous maculopapular eruption that may mimic dermatomyositis.⁶

Cutaneous findings of MRH can mimic rheumatoid nodules, gout, Gottron papules of dermatomyositis, lipoid proteinosis, sarcoidosis, lepromatous leprosy, granuloma annulare, xanthoma, xanthogranuloma, and fibroxanthoma.^6,7 Histopathologic features may distinguish MRH from such entities. Findings include fairly well-circumscribed aggregates of large multinucleated giant cells with characteristic eosinophilic ground-glass cytoplasm. Histiocytes stain positively for CD68, HAM56, CD11b, and CD14, and variably for factor XIIIa. CD68, which is expressed by monocytes/macrophages, has been universally reported to be the most reliable marker of MRH. Negative staining for S-100 and CD1a supports a non-Langerhans origin for the involved histiocytes. If arthritic symptoms predominate, MRH must be distinguished from rheumatoid and psoriatic arthritis.^6,7

Mucosal involvement occurs in approximately 50% of patients and includes the presence of nodules in the oral, nasal, and pharyngeal mucosae, as well as eye structures.^2,3 Histiocytic infiltration has been documented in the heart, lungs, thyroid, liver, stomach, kidneys, muscle, bone marrow, and urogenital tract. Histiocytes also can invade the cartilage of the ears and nose causing disfigurement and characteristic leonine facies. Pathologic fractures may occur with bone involvement.⁵

Systemic features associated with MRH include hyperlipidemia, diabetes mellitus, thyroid disease, hypergammaglobulinemia, and various autoimmune diseases. Patients less frequently report fever and weight loss.^2,5,6,8 Additionally, a positive tuberculin test occurs in 12% to 50% of patients.⁶ Various autoimmune diseases occur in 6% to 17% of cases including systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, dermatomyositis, Sjögren syndrome, and primary biliary cirrhosis.^2,5,6,8 The most clinically salient feature of MRH is its association with malignant conditions, which occur in up to 31% of patients. A variety of cancers have been reported in association with MRH, including breast, cervical, ovarian, stomach, penile, lymphoma, mesothelioma, and melanoma.⁷

The etiology of MRH is unclear. Although onset may precede the development of a malignant condition and regress with treatment, it cannot be considered a true paraneoplastic disorder, as it has no association with a specific cancer and does not typically parallel the disease course.^6,9 Reports of increased levels of inflammatory mediators released from macrophages and endothelial cells, specifically IL-12, IL-1β, IL-6, and tumor necrosis factor α (TNF-α), have been thought to drive the destruction of bone and cartilage.⁶ In particular, TNF-α acts to indirectly induce destruction by stimulating proteolytic activity in macrophages, similar to the pathogenesis of joint damage in rheumatoid arthritis.⁸ Osteoclastic activity may play a role in the pathogenesis of MRH, as multinucleated giant cells in MRH can mature into osteoclasts by receptor activated nuclear factor–κB ligand signaling. In addition, patients treated with bisphosphonates have had decreased lacunar resorption.^2,8

Initial management of MRH should include screening for hyperlipidemia, hypergammaglobulinemia, hyperglycemia, thyroid dysfunction, and autoimmune diseases, as well as age-appropriate cancer screening. Imaging studies should evaluate for the presence of erosive arthritis. There are no well-defined treatment algorithms for MRH due to the rarity of the disease, and recommendations largely rely on case reports. Although spontaneous remission typically occurs within 5 to 10 years, the risk for joint destruction argues for early pharmacologic intervention. Current management includes the use of nonsteroidal anti-inflammatory drugs and various immunosuppressants including oral glucocorticoids, cyclophosphamide, chlorambucil, methotrexate, or azathioprine.² A combination of methotrexate with cyclophosphamide or glucocorticoids also has shown efficacy.¹⁰ Anti–TNF-α agents, such as etanercept, adalimumab, and infliximab, have been used with some success.² Tumor necrosis factor α inhibitors used in combination with oral glucocorticoids and methotrexate may have an increased benefit.^2,9,11 Evidence suggesting that TNF-α plays a role in the destruction of bone and cartilage led to the successful use of infliximab in combination with oral glucocorticoids and methotrexate, which prevented possible development of antibodies to infliximab and increased its efficacy.¹² Bisphosphonate use in combination with glucocorticoids and methotrexate may prevent joint destruction without the serious adverse events associated with anti–TNF-α agents.^2,9,13,14

To the Editor:

A 50-year-old woman presented with an asymptomatic eruption on the dorsal aspect of the hands, abdomen, and face of 6 months’ duration. The eruption was associated with generalized arthralgia and fatigue. Within several weeks of onset of the cutaneous eruption, the patient developed swelling in the hands as well as worsening arthralgia. She was treated for presumed Lyme borreliosis but reported no improvement in the symptoms. She was then referred to dermatology for further management.

Physical examination revealed red-orange, edematous, monomorphic papulonodules scattered on the nasolabial folds, upper lip, and along the dorsal aspect of the hands and fingers (Figure 1). A brown rippled plaque was present on the left lower abdomen. The oral mucosa and nails were unremarkable. Laboratory studies showed elevated total cholesterol (244 mg/dL [reference range, <200 mg/dL]), low-density lipoproteins (130 mg/dL [reference range, 10–30 mg/dL]), aspartate aminotransferase (140 U/L [reference range, 10–30 U/L]), alanine aminotransferase (110 U/L [reference range, 10–40 U/L]), and total bilirubin (1.5 mg/dL [reference range, 0.3–1.2 mg/dL]). White blood cell count and C-reactive protein levels were within reference range. An antinuclear antibody titer of 1:80 with a homogenous pattern was found, and aldolase levels were elevated. Laboratory investigations for rheumatoid factor, Lyme disease, tuberculosis, hepatitis, and human immunodeficiency virus were negative. A chest radiograph was normal.

Multicentric reticulohistiocytosis typically presents with a severe erosive arthropathy known as arthritis mutilans. Patients display a symmetric polyarthritis that commonly involves the elbows, wrists, and proximal and distal aspects of the interphalangeal joints. Onset and progression can be rapid, and the erosive nature leads to deformities in up to 45% of patients.^2,5,6 Cutaneous findings arise an average of 3 years after the development of arthritis, though one-fifth of patients will initially present with cutaneous findings followed by the development of arthritis at any time.^3,6 Clinical features include flesh-colored to reddish brown or yellow papulonodules that range in size from several millimeters to 2 cm. The lesions most commonly occur on the face (eg, ears, nose, paranasal cheeks), scalp, dorsal and lateral aspects of the hands and fingers, and overlying articular regions of the extremities. Characteristic periungual lesions classically are referred to as coral beads.^4,6 Patients commonly report pruritus that may precede the development of the papules and nodules. Other cutaneous manifestations include xanthelasma, nail changes, and a photodistributed erythematous maculopapular eruption that may mimic dermatomyositis.⁶

Cutaneous findings of MRH can mimic rheumatoid nodules, gout, Gottron papules of dermatomyositis, lipoid proteinosis, sarcoidosis, lepromatous leprosy, granuloma annulare, xanthoma, xanthogranuloma, and fibroxanthoma.^6,7 Histopathologic features may distinguish MRH from such entities. Findings include fairly well-circumscribed aggregates of large multinucleated giant cells with characteristic eosinophilic ground-glass cytoplasm. Histiocytes stain positively for CD68, HAM56, CD11b, and CD14, and variably for factor XIIIa. CD68, which is expressed by monocytes/macrophages, has been universally reported to be the most reliable marker of MRH. Negative staining for S-100 and CD1a supports a non-Langerhans origin for the involved histiocytes. If arthritic symptoms predominate, MRH must be distinguished from rheumatoid and psoriatic arthritis.^6,7

Mucosal involvement occurs in approximately 50% of patients and includes the presence of nodules in the oral, nasal, and pharyngeal mucosae, as well as eye structures.^2,3 Histiocytic infiltration has been documented in the heart, lungs, thyroid, liver, stomach, kidneys, muscle, bone marrow, and urogenital tract. Histiocytes also can invade the cartilage of the ears and nose causing disfigurement and characteristic leonine facies. Pathologic fractures may occur with bone involvement.⁵

Systemic features associated with MRH include hyperlipidemia, diabetes mellitus, thyroid disease, hypergammaglobulinemia, and various autoimmune diseases. Patients less frequently report fever and weight loss.^2,5,6,8 Additionally, a positive tuberculin test occurs in 12% to 50% of patients.⁶ Various autoimmune diseases occur in 6% to 17% of cases including systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, dermatomyositis, Sjögren syndrome, and primary biliary cirrhosis.^2,5,6,8 The most clinically salient feature of MRH is its association with malignant conditions, which occur in up to 31% of patients. A variety of cancers have been reported in association with MRH, including breast, cervical, ovarian, stomach, penile, lymphoma, mesothelioma, and melanoma.⁷

The etiology of MRH is unclear. Although onset may precede the development of a malignant condition and regress with treatment, it cannot be considered a true paraneoplastic disorder, as it has no association with a specific cancer and does not typically parallel the disease course.^6,9 Reports of increased levels of inflammatory mediators released from macrophages and endothelial cells, specifically IL-12, IL-1β, IL-6, and tumor necrosis factor α (TNF-α), have been thought to drive the destruction of bone and cartilage.⁶ In particular, TNF-α acts to indirectly induce destruction by stimulating proteolytic activity in macrophages, similar to the pathogenesis of joint damage in rheumatoid arthritis.⁸ Osteoclastic activity may play a role in the pathogenesis of MRH, as multinucleated giant cells in MRH can mature into osteoclasts by receptor activated nuclear factor–κB ligand signaling. In addition, patients treated with bisphosphonates have had decreased lacunar resorption.^2,8

Initial management of MRH should include screening for hyperlipidemia, hypergammaglobulinemia, hyperglycemia, thyroid dysfunction, and autoimmune diseases, as well as age-appropriate cancer screening. Imaging studies should evaluate for the presence of erosive arthritis. There are no well-defined treatment algorithms for MRH due to the rarity of the disease, and recommendations largely rely on case reports. Although spontaneous remission typically occurs within 5 to 10 years, the risk for joint destruction argues for early pharmacologic intervention. Current management includes the use of nonsteroidal anti-inflammatory drugs and various immunosuppressants including oral glucocorticoids, cyclophosphamide, chlorambucil, methotrexate, or azathioprine.² A combination of methotrexate with cyclophosphamide or glucocorticoids also has shown efficacy.¹⁰ Anti–TNF-α agents, such as etanercept, adalimumab, and infliximab, have been used with some success.² Tumor necrosis factor α inhibitors used in combination with oral glucocorticoids and methotrexate may have an increased benefit.^2,9,11 Evidence suggesting that TNF-α plays a role in the destruction of bone and cartilage led to the successful use of infliximab in combination with oral glucocorticoids and methotrexate, which prevented possible development of antibodies to infliximab and increased its efficacy.¹² Bisphosphonate use in combination with glucocorticoids and methotrexate may prevent joint destruction without the serious adverse events associated with anti–TNF-α agents.^2,9,13,14

According to the American Cancer Society, about 22,530 women will receive a new diagnosis of ovarian cancer this year. In this video series, Drs. Mark Einstein, Jenna Marcus, and Stuart Lichtman discuss new therapeutics, surgical innovations, and treatment options for primary and advanced/recurrent ovarian cancer.

Click here to visit the site.

This video roundtable was produced by the Custom Programs division. The faculty received modest honoraria from Custom Programs for participating in this roundtable.

The faculty was solely responsible for the content presented.

Disclosures

Dr. Einstein discloses that he has participated in educational speaking activties for Altum Pharma, Cynvec, Papivax, PDS Biotechnologies, and Photocure. He also was the overall or local primary investigator for clinical trials for AstraZeneca, Becton-Dickinson, Inovio, Johnson & Johnson, Pfizer, and PDS Biotechnologies.

Dr. Marcus has no conflicts to disclose.

Dr. Lichtman has no conflicts to disclose.

According to the American Cancer Society, about 22,530 women will receive a new diagnosis of ovarian cancer this year. In this video series, Drs. Mark Einstein, Jenna Marcus, and Stuart Lichtman discuss new therapeutics, surgical innovations, and treatment options for primary and advanced/recurrent ovarian cancer.

Click here to visit the site.

This video roundtable was produced by the Custom Programs division. The faculty received modest honoraria from Custom Programs for participating in this roundtable.

The faculty was solely responsible for the content presented.

Disclosures

Dr. Einstein discloses that he has participated in educational speaking activties for Altum Pharma, Cynvec, Papivax, PDS Biotechnologies, and Photocure. He also was the overall or local primary investigator for clinical trials for AstraZeneca, Becton-Dickinson, Inovio, Johnson & Johnson, Pfizer, and PDS Biotechnologies.

Dr. Marcus has no conflicts to disclose.

Dr. Lichtman has no conflicts to disclose.

According to the American Cancer Society, about 22,530 women will receive a new diagnosis of ovarian cancer this year. In this video series, Drs. Mark Einstein, Jenna Marcus, and Stuart Lichtman discuss new therapeutics, surgical innovations, and treatment options for primary and advanced/recurrent ovarian cancer.

Click here to visit the site.

This video roundtable was produced by the Custom Programs division. The faculty received modest honoraria from Custom Programs for participating in this roundtable.

The faculty was solely responsible for the content presented.

Disclosures

Dr. Einstein discloses that he has participated in educational speaking activties for Altum Pharma, Cynvec, Papivax, PDS Biotechnologies, and Photocure. He also was the overall or local primary investigator for clinical trials for AstraZeneca, Becton-Dickinson, Inovio, Johnson & Johnson, Pfizer, and PDS Biotechnologies.

Dr. Marcus has no conflicts to disclose.

Dr. Lichtman has no conflicts to disclose.