Lemborexant, FDA-approved for the treatment of insomnia, has demonstrated efficacy in improving both sleep onset and sleep maintenance.¹ This novel compound is now the second approved insomnia medication classed as a dual orexin receptor antagonist (Table 1). This targeted mechanism of action aims to enhance sleep while limiting the adverse effects associated with traditional hypnotics.

Clinical implications

Insomnia symptoms affect approximately one-third of the general population at least occasionally. Approximately 10% of individuals meet DSM-5 criteria for insomnia disorder, which require nighttime sleep difficulty and daytime consequences persisting for a minimum of 3 months.² The prevalence is considerably higher in patients with chronic medical disorders and comorbid psychiatric conditions, especially mood, anxiety, substance use, and stress- and trauma-related disorders. Clinical guidelines for treating insomnia disorder typically recommend cognitive-behavioral therapy for insomnia as a first choice and FDA-approved insomnia medications as secondary options.³

Currently approved insomnia medi­cations fall into 4 distinct pharmaco­dynamics categories.⁴ Benzodiazepine receptor agonist hypnotics include 5 medications with classic benzodiazepine structures (estazolam, flurazepam, quazepam, temazepam, and triazolam) and 3 compounds (eszopiclone, zaleplon, and zolpidem) with alternate structures but similar mechanisms of action. There is 1 melatonin receptor agonist (ramelteon) and 1 histamine receptor antagonist (low-dose doxepin). Joining suvorexant (approved in 2014), lemborexant is the second dual orexin receptor antagonist.

The orexin (also called hypocretin) system was first described in 1998 and its fundamental role in promoting and coordinating wakefulness was quickly established.⁵ A relatively small number of hypothalamic neurons located in the lateral and perifornical regions produce 2 similar orexin neuropeptides (orexin A and orexin B) with widespread distributions, notably reinforcing the wake-promoting activity of histamine, acetylcholine, dopamine, serotonin, and norepinephrine. Consistent with the typical sleep-wake cycle, orexin release is limited during the nighttime. The orexin neuropeptides interact with 2 G-protein-coupled orexin receptors (OX1R, OX2R).

Animal studies showed that impairment in orexin system activity was associated with symptoms characteristic of narcolepsy, including cataplexy and excessive sleep episodes. Soon after, it was found that humans diagnosed with narcolepsy with cataplexy had markedly low CSF orexin levels.⁶ This recognition that excessively sleepy people with narcolepsy had a profound decrease in orexin production led to the hypothesis that pharmacologically decreasing orexin activity might be sleep-enhancing for insomnia patients, who presumably are excessively aroused. Numerous compounds soon were evaluated for their potential as orexin receptor antagonists. The efficacy of treating insomnia with a dual orexin receptor antagonist in humans was first reported in 2007 with almorexant, a compound that remains investigational.⁷ Research continues to investigate both single and dual orexin antagonist molecules for insomnia and other potential indications.

How it works

Unlike most hypnotics, which have widespread CNS depressant effects, lemborexant has a more targeted action in promoting sleep by suppressing the wake drive supported by the orexin system.⁸ Lemborexant is highly selective for the OX1R and OX2R orexin receptors, where it functions as a competitive antagonist. It is hypothesized that by modulating orexin activity with a receptor antagonist, excessive arousal associated with insomnia can be reduced, thus improving nighttime sleep. The pharmacokinetic properties allow benefits for both sleep onset and maintenance.

Pharmacokinetics

Lemborexant is available in immediate-release tablets with a peak concentration time (T_max) of approximately 1 to 3 hours after ingestion. When taken after a high-fat and high-calorie meal, there is a delay in the T_max, a decrease in the maximum plasma concentration (C_max), and an increase in the concentration area under the curve (AUC_0-inf).¹

Continue to: Metabolism is primarily through...

Metabolism is primarily through the cytochrome P450 (CYP) 3A4 pathway, and to a lesser extent through CYP3A5. Concomitant use with moderate or strong CYP3A inhibitors or inducers should be avoided, while use with weak CYP3A inhibitors should be limited to the 5-mg dose of lemborexant.

Lemborexant has the potential to induce the metabolism of CYP2B6 substrates, such as bupropion and methadone, possibly leading to reduced efficacy for these medications. Accordingly, the clinical responses to any CYP2B6 substrates should be monitored and dosage adjustments considered.

Concomitant use of lemborexant with alcohol should be avoided because there may be increased impairment in postural stability and memory, in part due to increases in the medication’s C_max and AUC, as well as the direct effects of alcohol.

Efficacy

In randomized, placebo-controlled trials, lemborexant demonstrated both objective and subjective evidence of clinically significant benefits for sleep onset and sleep maintenance in patients diagnosed with insomnia disorder.¹ The 2 pivotal efficacy studies were:

• Sunrise 1, a 4-week trial with older adults that included laboratory polysomnography (PSG) studies (objective) and patient-reported sleep measures (subjective) on selected nights⁹
• Sunrise 2, a 6-month trial assessing patient-reported sleep characteristics in adults and older adults.¹⁰

Sunrise 1 was performed with older adults with insomnia who were randomized to groups with nightly use of lemborexant, 5 mg (n = 266), lemborexant, 10 mg (n = 269), zolpidem extended-release, 6.25 mg, as an active comparator (n = 263), or placebo (n = 208).⁹ The age range was 55 to 88 years with a median age of 63 years. Most patients (86.4%) were women. Because this study focused on the assessment of efficacy for treating sleep maintenance difficulty, the inclusion criteria required a subjective report of experiencing a wake time after sleep onset (sWASO) of at least 60 minutes for 3 or more nights per week over the previous 4 weeks. The zolpidem extended-release 6.25 mg comparison was chosen because it has an indication for sleep maintenance insomnia with this recommended dose for older adults.

Continue to: Laboratory PSG monitoring...

Laboratory PSG monitoring was performed for 2 consecutive nights at baseline (before treatment), the first 2 treatment nights, and the final 2 treatment nights (Nights 29 and 30). The primary study endpoint was the change in latency to persistent sleep (LPS) from baseline to the final 2 nights for the lemborexant doses compared with placebo. Additional PSG-based endpoints were similar comparisons for sleep efficiency (percent time asleep during the 8-hour laboratory recording period) and objective wake after sleep onset (WASO) compared with placebo, and WASO during the second half of the night (WASO2H) compared with zolpidem. Patients completed Insomnia Severity Index (ISI) questionnaires at baseline and the end of the treatment to compare disease severity. Subjective assessments were done daily with electronic diary entries that included sleep onset latency (sSOL), sWASO, and subjective sleep efficiency.

In comparison with placebo, both lemborexant doses were associated with significantly improved PSG measures of LPS, WASO, and sleep efficiency during nights 1 and 2 that were maintained through Nights 29 and 30 (Table 2^1,9). The lemborexant doses also demonstrated significant improvements in WASO2H compared with zolpidem and placebo on the first 2 and final 2 treatment nights. Analyses of the subjective assessments (sSOL, sWASO, and sleep efficiency) compared the baseline with means for the first and the last treatment weeks. At both lemborexant doses, the sSOL was significantly reduced during the first and last weeks compared with placebo and zolpidem. Subjective sleep efficiency was significantly improved at both time points for the lemborexant doses, though these were not significantly different from the zolpidem values. The sWASO values were significantly decreased for both lemborexant doses at both time points compared with placebo. During the first treatment week, both lemborexant doses did not differ significantly from zolpidem in the sWASO change from baseline; however, at the final treatment week, the zolpidem value was significantly improved compared with lemborexant, 5 mg, but not significantly different from lemborexant, 10 mg. The ISI change from baseline to the end of the treatment period showed significant improvement for the lemborexant doses and zolpidem extended-release compared with placebo.

In the Sunrise 2 study, patients who met the criteria for insomnia disorder (age range 18 to 88, mean 55; 68% female) were randomized to groups taking nightly doses of lemborexant, 5 mg (n = 323), lemborexant, 10 mg (n = 323), or placebo (n = 325) for 6 months.¹⁰ Inclusion criteria required an sSOL of at least 30 minutes and/or a sWASO of at least 60 minutes 3 times a week or more during the previous 4 weeks. Efficacy was assessed with daily electronic diary entries, with analyses of change from baseline for sSOL (primary endpoint, baseline to end of 6-month study period), sWASO, and patient-reported sleep efficiency (sSEF). Subjective total sleep time (sTST) represented the estimated time asleep during the time in bed. Additional diary assessments related to sleep quality and morning alertness. All of these subjective assessments were compared as 7-day means for the first week of treatment and the last week of each treatment month.

The superiority of lemborexant, 5 mg and 10 mg, compared with placebo was demonstrated by significant improvements in sSOL, sSEF, sWASO, and sTST during the initial week of the treatment period that remained significant at the end of the 6-month placebo-controlled period (Table 3^1,10). At the end of 6 months, there were significantly more sleep-onset responders and sleep-maintenance responders among patients taking lemborexant compared with those taking placebo. Sleep-onset responders were patients with a baseline sSOL >30 minutes and a mean sSOL ≤20 minutes at the end of the study. Sleep-maintenance responders were participants with a baseline sWASO >60 minutes who at the end of the study had a mean sWASO ≤60 minutes that included a reduction of at least 10 minutes.

Following the 6-month placebo-controlled treatment period, the Sunrise 2 study continued for an additional 6 months of nightly active treatment for continued safety and efficacy assessment. Patients assigned to lemborexant, 5 mg or 10 mg, during the initial period continued on those doses. Those in the placebo group were randomized to either of the 2 lemborexant doses.

Continue to: Safety studies and adverse reactions

Safety studies and adverse reactions

Potential medication effects on middle-of-the-night and next-morning postural stability (body sway measured with an ataxiameter) and cognitive performance, as well as middle-of-the-night auditory awakening threshold, were assessed in a randomized, 4-way crossover study of 56 healthy older adults (women age ≥55 [77.8%], men age ≥65) given a single bedtime dose of placebo, lemborexant, 5 mg, lemborexant, 10 mg, and zolpidem extended-release, 6.25 mg, on separate nights.¹¹ The results were compared with data from a baseline night with the same measures performed prior to the randomization. The middle-of-the-night assessments were done approximately 4 hours after the dose and the next-morning measures were done after 8 hours in bed. The auditory threshold analysis showed no significant differences among the 4 study nights. Compared with placebo, the middle-of-the-night postural stability was significantly worse for both lemborexant doses and zolpidem; however, the zolpidem effect was significantly worse than with either lemborexant dose. The next-morning postural stability measures showed no significant difference from placebo for the lemborexant doses, but zolpidem continued to show a significantly worsened result. The cognitive performance assessment battery provided 4 domain factor scores (power of attention, continuity of attention, quality of memory, and speed of memory retrieval). The middle-of-the-night battery showed no significant difference between lemborexant, 5 mg, and placebo in any domain, while both lemborexant, 10 mg, and zolpidem showed worse performance on some of the attention and/or memory tests. The next-morning cognitive assessment revealed no significant differences from placebo for the treatments.

Respiratory safety was examined in a placebo-controlled, 2-period crossover study of 38 patients diagnosed with mild obstructive sleep apnea who received lemborexant, 10 mg, or placebo nightly during each 8-day period.¹² Neither the apnea-hypopnea index nor the mean oxygen saturation during the lemborexant nights were significantly different from the placebo nights.

The most common adverse reaction during the month-long Sunrise 1 study and the first 30 days of the Sunrise 2 study was somnolence or fatigue, which occurred in 1% receiving placebo, 7% receiving lemborexant, 5 mg, and 10% receiving lemborexant, 10 mg. Headache was reported by 3.5% receiving placebo, 5.9% receiving lemborexant, 5 mg, and 4.5% receiving lemborexant, 10 mg. Nightmare or abnormal dreams occurred with 0.9% receiving placebo, 0.9% receiving lemborexant, 5 mg, and 2.2% receiving lemborexant, 10 mg.¹

Unique clinical issues

Because investigations of individuals who abused sedatives for recreational purposes showed lemborexant had a likeability rating similar to zolpidem and significantly greater than placebo, the US Drug Enforcement Agency has categorized lemborexant as a Schedule IV controlled substance. Research has not shown evidence of physical dependence or withdrawal signs or symptoms upon discontinuation of lemborexant.¹

Contraindications

Narcolepsy is the only contraindication to the use of lemborexant.¹ Narcolepsy is associated with a decrease in the orexin-producing neurons in the hypothalamus, presumably causing the excessive sleepiness, sleep paralysis, hypnagogic hallucinations, and cataplexy characteristic of the disorder. Hypothetically, an orexin antagonist medication could exacerbate these symptoms.

Continue to: Dosing

Lemborexant should be taken no more than once per night immediately before going to bed and with at least 7 hours remaining before the planned time of awakening.¹ The recommended starting dose is 5 mg. The dosage may be increased to a maximum of 10 mg if the initial dose is well tolerated but insufficiently effective. Patients with moderate hepatic impairment or who are concomitantly taking weak CYP3A inhibitors should receive a maximum of 5 mg once nightly. Lemborexant should be avoided in patients with severe hepatic impairment and in those taking moderate or strong CYP3A inhibitors or inducers.

Orexin receptor antagonists do not share cross-tolerance with other hypnotics; this should be taken into consideration when switching to lemborexant. Abruptly stopping a benzodiazepine receptor agonist hypnotic may lead to rebound insomnia and thus may confound the interpretation of the clinical response when starting lemborexant.

Patients prescribed lemborexant should be educated about possible impairment in alertness and motor coordination, especially with the 10-mg dose, which may affect next-morning driving in sensitive individuals.¹³ Caution is advised with doses >5 mg in patients age ≥65 due to possible somnolence and a higher risk of falls.¹

Bottom Line

Lemborexant is a dual orexin receptor antagonist indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. It promotes sleep by suppressing the wake drive supported by the orexin system. In randomized, placebo-controlled trials, lemborexant demonstrated objective and subjective evidence of clinically significant benefits for sleep onset and sleep maintenance.

Related Resource

• Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307-349.

Drug Brand Names

Bupropion • Wellbutrin
Doxepin • Silenor
Eszopiclone • Lunesta
Lemborexant • Dayvigo
Methadone • Methadose, Dolophine
Quazepam • Doral
Ramelteon • Rozerem
Suvorexant • Belsomra
Temazepam • Restoril
Triazolam • Halcion
Zaleplon • Sonata
Zolpidem • Ambien, Intermezzo

Lemborexant, FDA-approved for the treatment of insomnia, has demonstrated efficacy in improving both sleep onset and sleep maintenance.¹ This novel compound is now the second approved insomnia medication classed as a dual orexin receptor antagonist (Table 1). This targeted mechanism of action aims to enhance sleep while limiting the adverse effects associated with traditional hypnotics.

Clinical implications

Insomnia symptoms affect approximately one-third of the general population at least occasionally. Approximately 10% of individuals meet DSM-5 criteria for insomnia disorder, which require nighttime sleep difficulty and daytime consequences persisting for a minimum of 3 months.² The prevalence is considerably higher in patients with chronic medical disorders and comorbid psychiatric conditions, especially mood, anxiety, substance use, and stress- and trauma-related disorders. Clinical guidelines for treating insomnia disorder typically recommend cognitive-behavioral therapy for insomnia as a first choice and FDA-approved insomnia medications as secondary options.³

Currently approved insomnia medi­cations fall into 4 distinct pharmaco­dynamics categories.⁴ Benzodiazepine receptor agonist hypnotics include 5 medications with classic benzodiazepine structures (estazolam, flurazepam, quazepam, temazepam, and triazolam) and 3 compounds (eszopiclone, zaleplon, and zolpidem) with alternate structures but similar mechanisms of action. There is 1 melatonin receptor agonist (ramelteon) and 1 histamine receptor antagonist (low-dose doxepin). Joining suvorexant (approved in 2014), lemborexant is the second dual orexin receptor antagonist.

The orexin (also called hypocretin) system was first described in 1998 and its fundamental role in promoting and coordinating wakefulness was quickly established.⁵ A relatively small number of hypothalamic neurons located in the lateral and perifornical regions produce 2 similar orexin neuropeptides (orexin A and orexin B) with widespread distributions, notably reinforcing the wake-promoting activity of histamine, acetylcholine, dopamine, serotonin, and norepinephrine. Consistent with the typical sleep-wake cycle, orexin release is limited during the nighttime. The orexin neuropeptides interact with 2 G-protein-coupled orexin receptors (OX1R, OX2R).

Animal studies showed that impairment in orexin system activity was associated with symptoms characteristic of narcolepsy, including cataplexy and excessive sleep episodes. Soon after, it was found that humans diagnosed with narcolepsy with cataplexy had markedly low CSF orexin levels.⁶ This recognition that excessively sleepy people with narcolepsy had a profound decrease in orexin production led to the hypothesis that pharmacologically decreasing orexin activity might be sleep-enhancing for insomnia patients, who presumably are excessively aroused. Numerous compounds soon were evaluated for their potential as orexin receptor antagonists. The efficacy of treating insomnia with a dual orexin receptor antagonist in humans was first reported in 2007 with almorexant, a compound that remains investigational.⁷ Research continues to investigate both single and dual orexin antagonist molecules for insomnia and other potential indications.

How it works

Unlike most hypnotics, which have widespread CNS depressant effects, lemborexant has a more targeted action in promoting sleep by suppressing the wake drive supported by the orexin system.⁸ Lemborexant is highly selective for the OX1R and OX2R orexin receptors, where it functions as a competitive antagonist. It is hypothesized that by modulating orexin activity with a receptor antagonist, excessive arousal associated with insomnia can be reduced, thus improving nighttime sleep. The pharmacokinetic properties allow benefits for both sleep onset and maintenance.

Pharmacokinetics

Lemborexant is available in immediate-release tablets with a peak concentration time (T_max) of approximately 1 to 3 hours after ingestion. When taken after a high-fat and high-calorie meal, there is a delay in the T_max, a decrease in the maximum plasma concentration (C_max), and an increase in the concentration area under the curve (AUC_0-inf).¹

Continue to: Metabolism is primarily through...

Metabolism is primarily through the cytochrome P450 (CYP) 3A4 pathway, and to a lesser extent through CYP3A5. Concomitant use with moderate or strong CYP3A inhibitors or inducers should be avoided, while use with weak CYP3A inhibitors should be limited to the 5-mg dose of lemborexant.

Lemborexant has the potential to induce the metabolism of CYP2B6 substrates, such as bupropion and methadone, possibly leading to reduced efficacy for these medications. Accordingly, the clinical responses to any CYP2B6 substrates should be monitored and dosage adjustments considered.

Concomitant use of lemborexant with alcohol should be avoided because there may be increased impairment in postural stability and memory, in part due to increases in the medication’s C_max and AUC, as well as the direct effects of alcohol.

Efficacy

In randomized, placebo-controlled trials, lemborexant demonstrated both objective and subjective evidence of clinically significant benefits for sleep onset and sleep maintenance in patients diagnosed with insomnia disorder.¹ The 2 pivotal efficacy studies were:

• Sunrise 1, a 4-week trial with older adults that included laboratory polysomnography (PSG) studies (objective) and patient-reported sleep measures (subjective) on selected nights⁹
• Sunrise 2, a 6-month trial assessing patient-reported sleep characteristics in adults and older adults.¹⁰

Sunrise 1 was performed with older adults with insomnia who were randomized to groups with nightly use of lemborexant, 5 mg (n = 266), lemborexant, 10 mg (n = 269), zolpidem extended-release, 6.25 mg, as an active comparator (n = 263), or placebo (n = 208).⁹ The age range was 55 to 88 years with a median age of 63 years. Most patients (86.4%) were women. Because this study focused on the assessment of efficacy for treating sleep maintenance difficulty, the inclusion criteria required a subjective report of experiencing a wake time after sleep onset (sWASO) of at least 60 minutes for 3 or more nights per week over the previous 4 weeks. The zolpidem extended-release 6.25 mg comparison was chosen because it has an indication for sleep maintenance insomnia with this recommended dose for older adults.

Continue to: Laboratory PSG monitoring...

Laboratory PSG monitoring was performed for 2 consecutive nights at baseline (before treatment), the first 2 treatment nights, and the final 2 treatment nights (Nights 29 and 30). The primary study endpoint was the change in latency to persistent sleep (LPS) from baseline to the final 2 nights for the lemborexant doses compared with placebo. Additional PSG-based endpoints were similar comparisons for sleep efficiency (percent time asleep during the 8-hour laboratory recording period) and objective wake after sleep onset (WASO) compared with placebo, and WASO during the second half of the night (WASO2H) compared with zolpidem. Patients completed Insomnia Severity Index (ISI) questionnaires at baseline and the end of the treatment to compare disease severity. Subjective assessments were done daily with electronic diary entries that included sleep onset latency (sSOL), sWASO, and subjective sleep efficiency.

In comparison with placebo, both lemborexant doses were associated with significantly improved PSG measures of LPS, WASO, and sleep efficiency during nights 1 and 2 that were maintained through Nights 29 and 30 (Table 2^1,9). The lemborexant doses also demonstrated significant improvements in WASO2H compared with zolpidem and placebo on the first 2 and final 2 treatment nights. Analyses of the subjective assessments (sSOL, sWASO, and sleep efficiency) compared the baseline with means for the first and the last treatment weeks. At both lemborexant doses, the sSOL was significantly reduced during the first and last weeks compared with placebo and zolpidem. Subjective sleep efficiency was significantly improved at both time points for the lemborexant doses, though these were not significantly different from the zolpidem values. The sWASO values were significantly decreased for both lemborexant doses at both time points compared with placebo. During the first treatment week, both lemborexant doses did not differ significantly from zolpidem in the sWASO change from baseline; however, at the final treatment week, the zolpidem value was significantly improved compared with lemborexant, 5 mg, but not significantly different from lemborexant, 10 mg. The ISI change from baseline to the end of the treatment period showed significant improvement for the lemborexant doses and zolpidem extended-release compared with placebo.

In the Sunrise 2 study, patients who met the criteria for insomnia disorder (age range 18 to 88, mean 55; 68% female) were randomized to groups taking nightly doses of lemborexant, 5 mg (n = 323), lemborexant, 10 mg (n = 323), or placebo (n = 325) for 6 months.¹⁰ Inclusion criteria required an sSOL of at least 30 minutes and/or a sWASO of at least 60 minutes 3 times a week or more during the previous 4 weeks. Efficacy was assessed with daily electronic diary entries, with analyses of change from baseline for sSOL (primary endpoint, baseline to end of 6-month study period), sWASO, and patient-reported sleep efficiency (sSEF). Subjective total sleep time (sTST) represented the estimated time asleep during the time in bed. Additional diary assessments related to sleep quality and morning alertness. All of these subjective assessments were compared as 7-day means for the first week of treatment and the last week of each treatment month.

The superiority of lemborexant, 5 mg and 10 mg, compared with placebo was demonstrated by significant improvements in sSOL, sSEF, sWASO, and sTST during the initial week of the treatment period that remained significant at the end of the 6-month placebo-controlled period (Table 3^1,10). At the end of 6 months, there were significantly more sleep-onset responders and sleep-maintenance responders among patients taking lemborexant compared with those taking placebo. Sleep-onset responders were patients with a baseline sSOL >30 minutes and a mean sSOL ≤20 minutes at the end of the study. Sleep-maintenance responders were participants with a baseline sWASO >60 minutes who at the end of the study had a mean sWASO ≤60 minutes that included a reduction of at least 10 minutes.

Following the 6-month placebo-controlled treatment period, the Sunrise 2 study continued for an additional 6 months of nightly active treatment for continued safety and efficacy assessment. Patients assigned to lemborexant, 5 mg or 10 mg, during the initial period continued on those doses. Those in the placebo group were randomized to either of the 2 lemborexant doses.

Continue to: Safety studies and adverse reactions

Safety studies and adverse reactions

Potential medication effects on middle-of-the-night and next-morning postural stability (body sway measured with an ataxiameter) and cognitive performance, as well as middle-of-the-night auditory awakening threshold, were assessed in a randomized, 4-way crossover study of 56 healthy older adults (women age ≥55 [77.8%], men age ≥65) given a single bedtime dose of placebo, lemborexant, 5 mg, lemborexant, 10 mg, and zolpidem extended-release, 6.25 mg, on separate nights.¹¹ The results were compared with data from a baseline night with the same measures performed prior to the randomization. The middle-of-the-night assessments were done approximately 4 hours after the dose and the next-morning measures were done after 8 hours in bed. The auditory threshold analysis showed no significant differences among the 4 study nights. Compared with placebo, the middle-of-the-night postural stability was significantly worse for both lemborexant doses and zolpidem; however, the zolpidem effect was significantly worse than with either lemborexant dose. The next-morning postural stability measures showed no significant difference from placebo for the lemborexant doses, but zolpidem continued to show a significantly worsened result. The cognitive performance assessment battery provided 4 domain factor scores (power of attention, continuity of attention, quality of memory, and speed of memory retrieval). The middle-of-the-night battery showed no significant difference between lemborexant, 5 mg, and placebo in any domain, while both lemborexant, 10 mg, and zolpidem showed worse performance on some of the attention and/or memory tests. The next-morning cognitive assessment revealed no significant differences from placebo for the treatments.

Respiratory safety was examined in a placebo-controlled, 2-period crossover study of 38 patients diagnosed with mild obstructive sleep apnea who received lemborexant, 10 mg, or placebo nightly during each 8-day period.¹² Neither the apnea-hypopnea index nor the mean oxygen saturation during the lemborexant nights were significantly different from the placebo nights.

The most common adverse reaction during the month-long Sunrise 1 study and the first 30 days of the Sunrise 2 study was somnolence or fatigue, which occurred in 1% receiving placebo, 7% receiving lemborexant, 5 mg, and 10% receiving lemborexant, 10 mg. Headache was reported by 3.5% receiving placebo, 5.9% receiving lemborexant, 5 mg, and 4.5% receiving lemborexant, 10 mg. Nightmare or abnormal dreams occurred with 0.9% receiving placebo, 0.9% receiving lemborexant, 5 mg, and 2.2% receiving lemborexant, 10 mg.¹

Unique clinical issues

Because investigations of individuals who abused sedatives for recreational purposes showed lemborexant had a likeability rating similar to zolpidem and significantly greater than placebo, the US Drug Enforcement Agency has categorized lemborexant as a Schedule IV controlled substance. Research has not shown evidence of physical dependence or withdrawal signs or symptoms upon discontinuation of lemborexant.¹

Contraindications

Narcolepsy is the only contraindication to the use of lemborexant.¹ Narcolepsy is associated with a decrease in the orexin-producing neurons in the hypothalamus, presumably causing the excessive sleepiness, sleep paralysis, hypnagogic hallucinations, and cataplexy characteristic of the disorder. Hypothetically, an orexin antagonist medication could exacerbate these symptoms.

Continue to: Dosing

Lemborexant should be taken no more than once per night immediately before going to bed and with at least 7 hours remaining before the planned time of awakening.¹ The recommended starting dose is 5 mg. The dosage may be increased to a maximum of 10 mg if the initial dose is well tolerated but insufficiently effective. Patients with moderate hepatic impairment or who are concomitantly taking weak CYP3A inhibitors should receive a maximum of 5 mg once nightly. Lemborexant should be avoided in patients with severe hepatic impairment and in those taking moderate or strong CYP3A inhibitors or inducers.

Orexin receptor antagonists do not share cross-tolerance with other hypnotics; this should be taken into consideration when switching to lemborexant. Abruptly stopping a benzodiazepine receptor agonist hypnotic may lead to rebound insomnia and thus may confound the interpretation of the clinical response when starting lemborexant.

Patients prescribed lemborexant should be educated about possible impairment in alertness and motor coordination, especially with the 10-mg dose, which may affect next-morning driving in sensitive individuals.¹³ Caution is advised with doses >5 mg in patients age ≥65 due to possible somnolence and a higher risk of falls.¹

Bottom Line

Lemborexant is a dual orexin receptor antagonist indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. It promotes sleep by suppressing the wake drive supported by the orexin system. In randomized, placebo-controlled trials, lemborexant demonstrated objective and subjective evidence of clinically significant benefits for sleep onset and sleep maintenance.

Related Resource

• Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307-349.

Drug Brand Names

Bupropion • Wellbutrin
Doxepin • Silenor
Eszopiclone • Lunesta
Lemborexant • Dayvigo
Methadone • Methadose, Dolophine
Quazepam • Doral
Ramelteon • Rozerem
Suvorexant • Belsomra
Temazepam • Restoril
Triazolam • Halcion
Zaleplon • Sonata
Zolpidem • Ambien, Intermezzo

Lemborexant, FDA-approved for the treatment of insomnia, has demonstrated efficacy in improving both sleep onset and sleep maintenance.¹ This novel compound is now the second approved insomnia medication classed as a dual orexin receptor antagonist (Table 1). This targeted mechanism of action aims to enhance sleep while limiting the adverse effects associated with traditional hypnotics.

Clinical implications

Insomnia symptoms affect approximately one-third of the general population at least occasionally. Approximately 10% of individuals meet DSM-5 criteria for insomnia disorder, which require nighttime sleep difficulty and daytime consequences persisting for a minimum of 3 months.² The prevalence is considerably higher in patients with chronic medical disorders and comorbid psychiatric conditions, especially mood, anxiety, substance use, and stress- and trauma-related disorders. Clinical guidelines for treating insomnia disorder typically recommend cognitive-behavioral therapy for insomnia as a first choice and FDA-approved insomnia medications as secondary options.³

Currently approved insomnia medi­cations fall into 4 distinct pharmaco­dynamics categories.⁴ Benzodiazepine receptor agonist hypnotics include 5 medications with classic benzodiazepine structures (estazolam, flurazepam, quazepam, temazepam, and triazolam) and 3 compounds (eszopiclone, zaleplon, and zolpidem) with alternate structures but similar mechanisms of action. There is 1 melatonin receptor agonist (ramelteon) and 1 histamine receptor antagonist (low-dose doxepin). Joining suvorexant (approved in 2014), lemborexant is the second dual orexin receptor antagonist.

The orexin (also called hypocretin) system was first described in 1998 and its fundamental role in promoting and coordinating wakefulness was quickly established.⁵ A relatively small number of hypothalamic neurons located in the lateral and perifornical regions produce 2 similar orexin neuropeptides (orexin A and orexin B) with widespread distributions, notably reinforcing the wake-promoting activity of histamine, acetylcholine, dopamine, serotonin, and norepinephrine. Consistent with the typical sleep-wake cycle, orexin release is limited during the nighttime. The orexin neuropeptides interact with 2 G-protein-coupled orexin receptors (OX1R, OX2R).

Animal studies showed that impairment in orexin system activity was associated with symptoms characteristic of narcolepsy, including cataplexy and excessive sleep episodes. Soon after, it was found that humans diagnosed with narcolepsy with cataplexy had markedly low CSF orexin levels.⁶ This recognition that excessively sleepy people with narcolepsy had a profound decrease in orexin production led to the hypothesis that pharmacologically decreasing orexin activity might be sleep-enhancing for insomnia patients, who presumably are excessively aroused. Numerous compounds soon were evaluated for their potential as orexin receptor antagonists. The efficacy of treating insomnia with a dual orexin receptor antagonist in humans was first reported in 2007 with almorexant, a compound that remains investigational.⁷ Research continues to investigate both single and dual orexin antagonist molecules for insomnia and other potential indications.

How it works

Unlike most hypnotics, which have widespread CNS depressant effects, lemborexant has a more targeted action in promoting sleep by suppressing the wake drive supported by the orexin system.⁸ Lemborexant is highly selective for the OX1R and OX2R orexin receptors, where it functions as a competitive antagonist. It is hypothesized that by modulating orexin activity with a receptor antagonist, excessive arousal associated with insomnia can be reduced, thus improving nighttime sleep. The pharmacokinetic properties allow benefits for both sleep onset and maintenance.

Pharmacokinetics

Lemborexant is available in immediate-release tablets with a peak concentration time (T_max) of approximately 1 to 3 hours after ingestion. When taken after a high-fat and high-calorie meal, there is a delay in the T_max, a decrease in the maximum plasma concentration (C_max), and an increase in the concentration area under the curve (AUC_0-inf).¹

Continue to: Metabolism is primarily through...

Metabolism is primarily through the cytochrome P450 (CYP) 3A4 pathway, and to a lesser extent through CYP3A5. Concomitant use with moderate or strong CYP3A inhibitors or inducers should be avoided, while use with weak CYP3A inhibitors should be limited to the 5-mg dose of lemborexant.

Lemborexant has the potential to induce the metabolism of CYP2B6 substrates, such as bupropion and methadone, possibly leading to reduced efficacy for these medications. Accordingly, the clinical responses to any CYP2B6 substrates should be monitored and dosage adjustments considered.

Concomitant use of lemborexant with alcohol should be avoided because there may be increased impairment in postural stability and memory, in part due to increases in the medication’s C_max and AUC, as well as the direct effects of alcohol.

Efficacy

In randomized, placebo-controlled trials, lemborexant demonstrated both objective and subjective evidence of clinically significant benefits for sleep onset and sleep maintenance in patients diagnosed with insomnia disorder.¹ The 2 pivotal efficacy studies were:

• Sunrise 1, a 4-week trial with older adults that included laboratory polysomnography (PSG) studies (objective) and patient-reported sleep measures (subjective) on selected nights⁹
• Sunrise 2, a 6-month trial assessing patient-reported sleep characteristics in adults and older adults.¹⁰

Sunrise 1 was performed with older adults with insomnia who were randomized to groups with nightly use of lemborexant, 5 mg (n = 266), lemborexant, 10 mg (n = 269), zolpidem extended-release, 6.25 mg, as an active comparator (n = 263), or placebo (n = 208).⁹ The age range was 55 to 88 years with a median age of 63 years. Most patients (86.4%) were women. Because this study focused on the assessment of efficacy for treating sleep maintenance difficulty, the inclusion criteria required a subjective report of experiencing a wake time after sleep onset (sWASO) of at least 60 minutes for 3 or more nights per week over the previous 4 weeks. The zolpidem extended-release 6.25 mg comparison was chosen because it has an indication for sleep maintenance insomnia with this recommended dose for older adults.

Continue to: Laboratory PSG monitoring...

Laboratory PSG monitoring was performed for 2 consecutive nights at baseline (before treatment), the first 2 treatment nights, and the final 2 treatment nights (Nights 29 and 30). The primary study endpoint was the change in latency to persistent sleep (LPS) from baseline to the final 2 nights for the lemborexant doses compared with placebo. Additional PSG-based endpoints were similar comparisons for sleep efficiency (percent time asleep during the 8-hour laboratory recording period) and objective wake after sleep onset (WASO) compared with placebo, and WASO during the second half of the night (WASO2H) compared with zolpidem. Patients completed Insomnia Severity Index (ISI) questionnaires at baseline and the end of the treatment to compare disease severity. Subjective assessments were done daily with electronic diary entries that included sleep onset latency (sSOL), sWASO, and subjective sleep efficiency.

In comparison with placebo, both lemborexant doses were associated with significantly improved PSG measures of LPS, WASO, and sleep efficiency during nights 1 and 2 that were maintained through Nights 29 and 30 (Table 2^1,9). The lemborexant doses also demonstrated significant improvements in WASO2H compared with zolpidem and placebo on the first 2 and final 2 treatment nights. Analyses of the subjective assessments (sSOL, sWASO, and sleep efficiency) compared the baseline with means for the first and the last treatment weeks. At both lemborexant doses, the sSOL was significantly reduced during the first and last weeks compared with placebo and zolpidem. Subjective sleep efficiency was significantly improved at both time points for the lemborexant doses, though these were not significantly different from the zolpidem values. The sWASO values were significantly decreased for both lemborexant doses at both time points compared with placebo. During the first treatment week, both lemborexant doses did not differ significantly from zolpidem in the sWASO change from baseline; however, at the final treatment week, the zolpidem value was significantly improved compared with lemborexant, 5 mg, but not significantly different from lemborexant, 10 mg. The ISI change from baseline to the end of the treatment period showed significant improvement for the lemborexant doses and zolpidem extended-release compared with placebo.

In the Sunrise 2 study, patients who met the criteria for insomnia disorder (age range 18 to 88, mean 55; 68% female) were randomized to groups taking nightly doses of lemborexant, 5 mg (n = 323), lemborexant, 10 mg (n = 323), or placebo (n = 325) for 6 months.¹⁰ Inclusion criteria required an sSOL of at least 30 minutes and/or a sWASO of at least 60 minutes 3 times a week or more during the previous 4 weeks. Efficacy was assessed with daily electronic diary entries, with analyses of change from baseline for sSOL (primary endpoint, baseline to end of 6-month study period), sWASO, and patient-reported sleep efficiency (sSEF). Subjective total sleep time (sTST) represented the estimated time asleep during the time in bed. Additional diary assessments related to sleep quality and morning alertness. All of these subjective assessments were compared as 7-day means for the first week of treatment and the last week of each treatment month.

The superiority of lemborexant, 5 mg and 10 mg, compared with placebo was demonstrated by significant improvements in sSOL, sSEF, sWASO, and sTST during the initial week of the treatment period that remained significant at the end of the 6-month placebo-controlled period (Table 3^1,10). At the end of 6 months, there were significantly more sleep-onset responders and sleep-maintenance responders among patients taking lemborexant compared with those taking placebo. Sleep-onset responders were patients with a baseline sSOL >30 minutes and a mean sSOL ≤20 minutes at the end of the study. Sleep-maintenance responders were participants with a baseline sWASO >60 minutes who at the end of the study had a mean sWASO ≤60 minutes that included a reduction of at least 10 minutes.

Following the 6-month placebo-controlled treatment period, the Sunrise 2 study continued for an additional 6 months of nightly active treatment for continued safety and efficacy assessment. Patients assigned to lemborexant, 5 mg or 10 mg, during the initial period continued on those doses. Those in the placebo group were randomized to either of the 2 lemborexant doses.

Continue to: Safety studies and adverse reactions

Safety studies and adverse reactions

Potential medication effects on middle-of-the-night and next-morning postural stability (body sway measured with an ataxiameter) and cognitive performance, as well as middle-of-the-night auditory awakening threshold, were assessed in a randomized, 4-way crossover study of 56 healthy older adults (women age ≥55 [77.8%], men age ≥65) given a single bedtime dose of placebo, lemborexant, 5 mg, lemborexant, 10 mg, and zolpidem extended-release, 6.25 mg, on separate nights.¹¹ The results were compared with data from a baseline night with the same measures performed prior to the randomization. The middle-of-the-night assessments were done approximately 4 hours after the dose and the next-morning measures were done after 8 hours in bed. The auditory threshold analysis showed no significant differences among the 4 study nights. Compared with placebo, the middle-of-the-night postural stability was significantly worse for both lemborexant doses and zolpidem; however, the zolpidem effect was significantly worse than with either lemborexant dose. The next-morning postural stability measures showed no significant difference from placebo for the lemborexant doses, but zolpidem continued to show a significantly worsened result. The cognitive performance assessment battery provided 4 domain factor scores (power of attention, continuity of attention, quality of memory, and speed of memory retrieval). The middle-of-the-night battery showed no significant difference between lemborexant, 5 mg, and placebo in any domain, while both lemborexant, 10 mg, and zolpidem showed worse performance on some of the attention and/or memory tests. The next-morning cognitive assessment revealed no significant differences from placebo for the treatments.

Respiratory safety was examined in a placebo-controlled, 2-period crossover study of 38 patients diagnosed with mild obstructive sleep apnea who received lemborexant, 10 mg, or placebo nightly during each 8-day period.¹² Neither the apnea-hypopnea index nor the mean oxygen saturation during the lemborexant nights were significantly different from the placebo nights.

The most common adverse reaction during the month-long Sunrise 1 study and the first 30 days of the Sunrise 2 study was somnolence or fatigue, which occurred in 1% receiving placebo, 7% receiving lemborexant, 5 mg, and 10% receiving lemborexant, 10 mg. Headache was reported by 3.5% receiving placebo, 5.9% receiving lemborexant, 5 mg, and 4.5% receiving lemborexant, 10 mg. Nightmare or abnormal dreams occurred with 0.9% receiving placebo, 0.9% receiving lemborexant, 5 mg, and 2.2% receiving lemborexant, 10 mg.¹

Unique clinical issues

Because investigations of individuals who abused sedatives for recreational purposes showed lemborexant had a likeability rating similar to zolpidem and significantly greater than placebo, the US Drug Enforcement Agency has categorized lemborexant as a Schedule IV controlled substance. Research has not shown evidence of physical dependence or withdrawal signs or symptoms upon discontinuation of lemborexant.¹

Contraindications

Narcolepsy is the only contraindication to the use of lemborexant.¹ Narcolepsy is associated with a decrease in the orexin-producing neurons in the hypothalamus, presumably causing the excessive sleepiness, sleep paralysis, hypnagogic hallucinations, and cataplexy characteristic of the disorder. Hypothetically, an orexin antagonist medication could exacerbate these symptoms.

Continue to: Dosing

Lemborexant should be taken no more than once per night immediately before going to bed and with at least 7 hours remaining before the planned time of awakening.¹ The recommended starting dose is 5 mg. The dosage may be increased to a maximum of 10 mg if the initial dose is well tolerated but insufficiently effective. Patients with moderate hepatic impairment or who are concomitantly taking weak CYP3A inhibitors should receive a maximum of 5 mg once nightly. Lemborexant should be avoided in patients with severe hepatic impairment and in those taking moderate or strong CYP3A inhibitors or inducers.

Orexin receptor antagonists do not share cross-tolerance with other hypnotics; this should be taken into consideration when switching to lemborexant. Abruptly stopping a benzodiazepine receptor agonist hypnotic may lead to rebound insomnia and thus may confound the interpretation of the clinical response when starting lemborexant.

Patients prescribed lemborexant should be educated about possible impairment in alertness and motor coordination, especially with the 10-mg dose, which may affect next-morning driving in sensitive individuals.¹³ Caution is advised with doses >5 mg in patients age ≥65 due to possible somnolence and a higher risk of falls.¹

Bottom Line

Lemborexant is a dual orexin receptor antagonist indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. It promotes sleep by suppressing the wake drive supported by the orexin system. In randomized, placebo-controlled trials, lemborexant demonstrated objective and subjective evidence of clinically significant benefits for sleep onset and sleep maintenance.

Related Resource

• Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307-349.

Drug Brand Names

Bupropion • Wellbutrin
Doxepin • Silenor
Eszopiclone • Lunesta
Lemborexant • Dayvigo
Methadone • Methadose, Dolophine
Quazepam • Doral
Ramelteon • Rozerem
Suvorexant • Belsomra
Temazepam • Restoril
Triazolam • Halcion
Zaleplon • Sonata
Zolpidem • Ambien, Intermezzo

CASE Prolonged, painful erections

Mr. G, age 27, who has a history of obsessive-compulsive disorder (OCD), presents to his internist’s office with complaints of “masturbating several times a day” and having ejaculatory delay of up to 50 minutes with intercourse. The frequent masturbation was an attempt to “cure” the ejaculatory delay. In addition, Mr. G reports that for the past 5 nights, he has awoke every 3 hours with a painful erection that lasted 1.5 to 2.5 hours, after which he would fall asleep, only to wake once again to the same phenomenon.

Mr. G’s symptoms began 3 weeks ago after his psychiatrist adjusted the dose of his medication for OCD. Mr. G had been receiving fluoxetine, 10 mg/d, for the past 3 years to manage his OCD, without improvement. During a recent consultation, his psychiatrist increased the dose to 20 mg/d, with the expectation that further dose increases might be necessary to treat his OCD.

HISTORY Concurrent GAD

Mr. G is single and in a monogamous heterosexual relationship. Three weeks earlier, when he was examined by his psychiatrist, Mr. G’s Yale-Brown Obsessive Compulsive Scale score was 28 and his Beck Anxiety Inventory score was 24. Based on these scores, the psychiatrist concluded Mr. G had concurrent generalized anxiety disorder (GAD).

EVALUATION Workup is normal

On presentation to his internist’s office, Mr. G’s laboratory values are all within normal range, including a chemistry panel, complete blood count with differential, and electrocardiogram. A human immunodeficiency virus test is negative. His internist instructs Mr. G to return to his psychiatrist.

[polldaddy:10640161]

TREATMENT Dose adjustment

Based on Mr. G’s description of painful and persistent erections in the absence of sexual stimulation or arousal, and because these episodes have occurred 5 consecutive nights, the psychiatrist makes a provisional diagnosis of stuttering priapism and reduces the fluoxetine dose from 20 to 10 mg/d.

The author’s observations

Priapism is classically defined as a persistent, unwanted penile or clitoral engorgement in the absence of sexual desire/arousal or stimulation. It can last for up to 4 to 6 hours¹ orit can take a so-called “stuttering form” characterized by brief, recurrent, self-limited episodes. Priapism is a urologic emergency resulting in erectile dysfunction in 30% to 90% of patients. It is multifactorial and can be characterized as low-flow (occlusive) or high-flow (nonischemic). Most priapism is primary or idiopathic in nature; the incidence is 1.5 per 100,000 individuals (primarily men), with bimodal peaks, and it can occur in all age groups.² Secondary priapism can occur from many causes (Table).

Mechanism is unclear

The molecular mechanism of priapism is not completely understood. Normally, nitrous oxide mediates penile erection. However, cyclic guanosine monophosphate (cGMP) acts at several levels to create smooth muscle reaction, leading to either penile tumescence or, in some cases, priapism. Stuttering or intermittent ischemic priapism is thought to be a downregulation of phosphodiesterase type 5, causing excess cGMP with subsequent smooth muscle relaxation in the penis.³

Continue to: Drug-induced priapism

Drug-induced priapism

Drug-induced priapism is commonly believed to be associated with alpha-1 adrenergic receptor blockade.⁴ This also results in dizziness and orthostatic hypotension.⁵ Trazodone is commonly associated with the development of secondary priapism; however, in the last 30 years, multiple case reports have demonstrated that a variety of psycho­active agents have been associated with low-flowpriapism.⁶ Most case reports have focused on new-onset priapism associated with the introduction of a new medication. Based on a recent informal search of Medline, since 1989, there have been >36 case reports of priapism associated with psychotropic use. Stuttering priapism is less frequently discussed in the literature.⁷

Ischemic priapism accounts for 95% of all reports. It can be associated with medication use or hematologic disorders, or it can be triggered by sexual activity. Often, patients who experience an episode will abstain from sexual contact.

The etiology of stuttering priapism is less clear. Episodes of stuttering priapism often occur during sleep and can resolve spontaneously.⁸ They are a form of ischemic priapism and are seen in patients with sickle cell anemia. It is not known how many patients with stuttering priapism will convert to the nonremitting form, which may require chemical or surgical intervention.⁹ Stuttering priapism may go unreported and perhaps may be overlooked by patients based on its frequency and intensity.

The activating selective serotonin reuptake inhibitor fluoxetine has a long half-life and is a potent inhibitor of the cytochrome P450 2D6 isoenzyme system. It inhibits serotonin transporter proteins. It is also a weak norepinephrine reuptake inhibitor, an effect that increases with increasing doses of the medication. Its 5HT2C antagonism is proposed as the mechanism of its activating properties.¹⁰ In Mr. G’s case, it is possible that fluoxetine’s weak norepinephrine reuptake inhibition resulted in an intermittent priapism effect mediated through the pathways described above.

OUTCOME Symptoms resolve

Approximately 1 week after Mr. G’s fluoxetine dose is reduced, his symptoms of priapism abated. The fluoxetine is discontinued and his ejaculatory delay resolves. Mr. G is started on fluvoxamine, 150 mg/d, which results in a significant decrease of both GAD and OCD symptoms with no notable ejaculatory delay, and no recurrence of priapism.

Continue to: The author's observations

Mr. G’s case and other case reports suggest that psychiatrists should caution patients who are prescribed antidepressants or antipsychotics that stuttering priapism is a possible adverse effect.¹¹ As seen in Mr. G’s case, fluoxetine (when used chronically) can moderate vascular responses at the pre- and post-synaptic adrenergic receptor.¹¹ Priapism induced by a psychotropic medication will not necessarily lead to a longer-term, unremitting priapism, but it can be dramatic, frightening, and lead to noncompliance. Along with obtaining a standard history that includes asking patients about prior adverse medication events, psychiatrists also should ask their patients if they have experienced any instances of transient priapism that may require further evaluation.

Bottom Line

Any psychotropic medication that has the capacity to act on alpha adrenergic receptors can cause priapism. Ask patients if they have had any unusual erections/ clitoral engorgement while taking any psychotropic medications, because many patients will be hesitant to volunteer such information.

Related Resource

• Thippaiah SM, Nagaraja S, Birur B, et al. Successful management of psychotropics induced stuttering priapism with pseudoephedrine in a patient with schizophrenia. Psychopharmacol Bull. 2018;48(2):29-33.

Drug Brand Names

Fluoxetine • Prozac
Fluvoxamine • Luvox
Trazodone • Desyrel, Oleptro

CASE Prolonged, painful erections

Mr. G, age 27, who has a history of obsessive-compulsive disorder (OCD), presents to his internist’s office with complaints of “masturbating several times a day” and having ejaculatory delay of up to 50 minutes with intercourse. The frequent masturbation was an attempt to “cure” the ejaculatory delay. In addition, Mr. G reports that for the past 5 nights, he has awoke every 3 hours with a painful erection that lasted 1.5 to 2.5 hours, after which he would fall asleep, only to wake once again to the same phenomenon.

Mr. G’s symptoms began 3 weeks ago after his psychiatrist adjusted the dose of his medication for OCD. Mr. G had been receiving fluoxetine, 10 mg/d, for the past 3 years to manage his OCD, without improvement. During a recent consultation, his psychiatrist increased the dose to 20 mg/d, with the expectation that further dose increases might be necessary to treat his OCD.

HISTORY Concurrent GAD

Mr. G is single and in a monogamous heterosexual relationship. Three weeks earlier, when he was examined by his psychiatrist, Mr. G’s Yale-Brown Obsessive Compulsive Scale score was 28 and his Beck Anxiety Inventory score was 24. Based on these scores, the psychiatrist concluded Mr. G had concurrent generalized anxiety disorder (GAD).

EVALUATION Workup is normal

On presentation to his internist’s office, Mr. G’s laboratory values are all within normal range, including a chemistry panel, complete blood count with differential, and electrocardiogram. A human immunodeficiency virus test is negative. His internist instructs Mr. G to return to his psychiatrist.

[polldaddy:10640161]

TREATMENT Dose adjustment

Based on Mr. G’s description of painful and persistent erections in the absence of sexual stimulation or arousal, and because these episodes have occurred 5 consecutive nights, the psychiatrist makes a provisional diagnosis of stuttering priapism and reduces the fluoxetine dose from 20 to 10 mg/d.

The author’s observations

Priapism is classically defined as a persistent, unwanted penile or clitoral engorgement in the absence of sexual desire/arousal or stimulation. It can last for up to 4 to 6 hours¹ orit can take a so-called “stuttering form” characterized by brief, recurrent, self-limited episodes. Priapism is a urologic emergency resulting in erectile dysfunction in 30% to 90% of patients. It is multifactorial and can be characterized as low-flow (occlusive) or high-flow (nonischemic). Most priapism is primary or idiopathic in nature; the incidence is 1.5 per 100,000 individuals (primarily men), with bimodal peaks, and it can occur in all age groups.² Secondary priapism can occur from many causes (Table).

Mechanism is unclear

The molecular mechanism of priapism is not completely understood. Normally, nitrous oxide mediates penile erection. However, cyclic guanosine monophosphate (cGMP) acts at several levels to create smooth muscle reaction, leading to either penile tumescence or, in some cases, priapism. Stuttering or intermittent ischemic priapism is thought to be a downregulation of phosphodiesterase type 5, causing excess cGMP with subsequent smooth muscle relaxation in the penis.³

Continue to: Drug-induced priapism

Drug-induced priapism

Drug-induced priapism is commonly believed to be associated with alpha-1 adrenergic receptor blockade.⁴ This also results in dizziness and orthostatic hypotension.⁵ Trazodone is commonly associated with the development of secondary priapism; however, in the last 30 years, multiple case reports have demonstrated that a variety of psycho­active agents have been associated with low-flowpriapism.⁶ Most case reports have focused on new-onset priapism associated with the introduction of a new medication. Based on a recent informal search of Medline, since 1989, there have been >36 case reports of priapism associated with psychotropic use. Stuttering priapism is less frequently discussed in the literature.⁷

Ischemic priapism accounts for 95% of all reports. It can be associated with medication use or hematologic disorders, or it can be triggered by sexual activity. Often, patients who experience an episode will abstain from sexual contact.

The etiology of stuttering priapism is less clear. Episodes of stuttering priapism often occur during sleep and can resolve spontaneously.⁸ They are a form of ischemic priapism and are seen in patients with sickle cell anemia. It is not known how many patients with stuttering priapism will convert to the nonremitting form, which may require chemical or surgical intervention.⁹ Stuttering priapism may go unreported and perhaps may be overlooked by patients based on its frequency and intensity.

The activating selective serotonin reuptake inhibitor fluoxetine has a long half-life and is a potent inhibitor of the cytochrome P450 2D6 isoenzyme system. It inhibits serotonin transporter proteins. It is also a weak norepinephrine reuptake inhibitor, an effect that increases with increasing doses of the medication. Its 5HT2C antagonism is proposed as the mechanism of its activating properties.¹⁰ In Mr. G’s case, it is possible that fluoxetine’s weak norepinephrine reuptake inhibition resulted in an intermittent priapism effect mediated through the pathways described above.

OUTCOME Symptoms resolve

Approximately 1 week after Mr. G’s fluoxetine dose is reduced, his symptoms of priapism abated. The fluoxetine is discontinued and his ejaculatory delay resolves. Mr. G is started on fluvoxamine, 150 mg/d, which results in a significant decrease of both GAD and OCD symptoms with no notable ejaculatory delay, and no recurrence of priapism.

Continue to: The author's observations

Mr. G’s case and other case reports suggest that psychiatrists should caution patients who are prescribed antidepressants or antipsychotics that stuttering priapism is a possible adverse effect.¹¹ As seen in Mr. G’s case, fluoxetine (when used chronically) can moderate vascular responses at the pre- and post-synaptic adrenergic receptor.¹¹ Priapism induced by a psychotropic medication will not necessarily lead to a longer-term, unremitting priapism, but it can be dramatic, frightening, and lead to noncompliance. Along with obtaining a standard history that includes asking patients about prior adverse medication events, psychiatrists also should ask their patients if they have experienced any instances of transient priapism that may require further evaluation.

Bottom Line

Any psychotropic medication that has the capacity to act on alpha adrenergic receptors can cause priapism. Ask patients if they have had any unusual erections/ clitoral engorgement while taking any psychotropic medications, because many patients will be hesitant to volunteer such information.

Related Resource

• Thippaiah SM, Nagaraja S, Birur B, et al. Successful management of psychotropics induced stuttering priapism with pseudoephedrine in a patient with schizophrenia. Psychopharmacol Bull. 2018;48(2):29-33.

Drug Brand Names

Fluoxetine • Prozac
Fluvoxamine • Luvox
Trazodone • Desyrel, Oleptro

CASE Prolonged, painful erections

Mr. G, age 27, who has a history of obsessive-compulsive disorder (OCD), presents to his internist’s office with complaints of “masturbating several times a day” and having ejaculatory delay of up to 50 minutes with intercourse. The frequent masturbation was an attempt to “cure” the ejaculatory delay. In addition, Mr. G reports that for the past 5 nights, he has awoke every 3 hours with a painful erection that lasted 1.5 to 2.5 hours, after which he would fall asleep, only to wake once again to the same phenomenon.

Mr. G’s symptoms began 3 weeks ago after his psychiatrist adjusted the dose of his medication for OCD. Mr. G had been receiving fluoxetine, 10 mg/d, for the past 3 years to manage his OCD, without improvement. During a recent consultation, his psychiatrist increased the dose to 20 mg/d, with the expectation that further dose increases might be necessary to treat his OCD.

HISTORY Concurrent GAD

Mr. G is single and in a monogamous heterosexual relationship. Three weeks earlier, when he was examined by his psychiatrist, Mr. G’s Yale-Brown Obsessive Compulsive Scale score was 28 and his Beck Anxiety Inventory score was 24. Based on these scores, the psychiatrist concluded Mr. G had concurrent generalized anxiety disorder (GAD).

EVALUATION Workup is normal

On presentation to his internist’s office, Mr. G’s laboratory values are all within normal range, including a chemistry panel, complete blood count with differential, and electrocardiogram. A human immunodeficiency virus test is negative. His internist instructs Mr. G to return to his psychiatrist.

[polldaddy:10640161]

TREATMENT Dose adjustment

Based on Mr. G’s description of painful and persistent erections in the absence of sexual stimulation or arousal, and because these episodes have occurred 5 consecutive nights, the psychiatrist makes a provisional diagnosis of stuttering priapism and reduces the fluoxetine dose from 20 to 10 mg/d.

The author’s observations

Priapism is classically defined as a persistent, unwanted penile or clitoral engorgement in the absence of sexual desire/arousal or stimulation. It can last for up to 4 to 6 hours¹ orit can take a so-called “stuttering form” characterized by brief, recurrent, self-limited episodes. Priapism is a urologic emergency resulting in erectile dysfunction in 30% to 90% of patients. It is multifactorial and can be characterized as low-flow (occlusive) or high-flow (nonischemic). Most priapism is primary or idiopathic in nature; the incidence is 1.5 per 100,000 individuals (primarily men), with bimodal peaks, and it can occur in all age groups.² Secondary priapism can occur from many causes (Table).

Mechanism is unclear

The molecular mechanism of priapism is not completely understood. Normally, nitrous oxide mediates penile erection. However, cyclic guanosine monophosphate (cGMP) acts at several levels to create smooth muscle reaction, leading to either penile tumescence or, in some cases, priapism. Stuttering or intermittent ischemic priapism is thought to be a downregulation of phosphodiesterase type 5, causing excess cGMP with subsequent smooth muscle relaxation in the penis.³

Continue to: Drug-induced priapism

Drug-induced priapism

Drug-induced priapism is commonly believed to be associated with alpha-1 adrenergic receptor blockade.⁴ This also results in dizziness and orthostatic hypotension.⁵ Trazodone is commonly associated with the development of secondary priapism; however, in the last 30 years, multiple case reports have demonstrated that a variety of psycho­active agents have been associated with low-flowpriapism.⁶ Most case reports have focused on new-onset priapism associated with the introduction of a new medication. Based on a recent informal search of Medline, since 1989, there have been >36 case reports of priapism associated with psychotropic use. Stuttering priapism is less frequently discussed in the literature.⁷

Ischemic priapism accounts for 95% of all reports. It can be associated with medication use or hematologic disorders, or it can be triggered by sexual activity. Often, patients who experience an episode will abstain from sexual contact.

The etiology of stuttering priapism is less clear. Episodes of stuttering priapism often occur during sleep and can resolve spontaneously.⁸ They are a form of ischemic priapism and are seen in patients with sickle cell anemia. It is not known how many patients with stuttering priapism will convert to the nonremitting form, which may require chemical or surgical intervention.⁹ Stuttering priapism may go unreported and perhaps may be overlooked by patients based on its frequency and intensity.

The activating selective serotonin reuptake inhibitor fluoxetine has a long half-life and is a potent inhibitor of the cytochrome P450 2D6 isoenzyme system. It inhibits serotonin transporter proteins. It is also a weak norepinephrine reuptake inhibitor, an effect that increases with increasing doses of the medication. Its 5HT2C antagonism is proposed as the mechanism of its activating properties.¹⁰ In Mr. G’s case, it is possible that fluoxetine’s weak norepinephrine reuptake inhibition resulted in an intermittent priapism effect mediated through the pathways described above.

OUTCOME Symptoms resolve

Approximately 1 week after Mr. G’s fluoxetine dose is reduced, his symptoms of priapism abated. The fluoxetine is discontinued and his ejaculatory delay resolves. Mr. G is started on fluvoxamine, 150 mg/d, which results in a significant decrease of both GAD and OCD symptoms with no notable ejaculatory delay, and no recurrence of priapism.

Continue to: The author's observations

Mr. G’s case and other case reports suggest that psychiatrists should caution patients who are prescribed antidepressants or antipsychotics that stuttering priapism is a possible adverse effect.¹¹ As seen in Mr. G’s case, fluoxetine (when used chronically) can moderate vascular responses at the pre- and post-synaptic adrenergic receptor.¹¹ Priapism induced by a psychotropic medication will not necessarily lead to a longer-term, unremitting priapism, but it can be dramatic, frightening, and lead to noncompliance. Along with obtaining a standard history that includes asking patients about prior adverse medication events, psychiatrists also should ask their patients if they have experienced any instances of transient priapism that may require further evaluation.

Bottom Line

Any psychotropic medication that has the capacity to act on alpha adrenergic receptors can cause priapism. Ask patients if they have had any unusual erections/ clitoral engorgement while taking any psychotropic medications, because many patients will be hesitant to volunteer such information.

Related Resource

• Thippaiah SM, Nagaraja S, Birur B, et al. Successful management of psychotropics induced stuttering priapism with pseudoephedrine in a patient with schizophrenia. Psychopharmacol Bull. 2018;48(2):29-33.

Drug Brand Names

Fluoxetine • Prozac
Fluvoxamine • Luvox
Trazodone • Desyrel, Oleptro

“Becoming is better than being.”

—Carol Dweck

The words spoken about her in the staff meeting were flattering. She’d just been acknowledged with a departmental teaching award for the second year in a row. With only 3 years under her belt since completing training, the former chief resident was living up to all they’d anticipated.

Eager students requested to be on her team and colleagues delighted in sharing patients with her. “Great, as always,” her peers and learners said in hallways and evaluations. This would come to define her identity.

Things were going well. She was succeeding. But she began to wonder if this reciprocating engine of accolades represented who she truly was. Was she really that good? Was she an imposter? In her performance meetings, the feedback never wavered: “Great, as always.”

The following year she would leave for a different job.

While specific plans for growth and improvement often get laid out for struggling colleagues and learners, far less effort is devoted to coaching high performers. Feedback that consists of nonspecific compliments may hinder potential, growth, and job satisfaction. We outline strategies for preventing this professional plateau in those you lead.

In Mindset: The New Psychology of Success, psychologist Carol Dweck describes how emphasis on qualities such as “being smart” or, in this example, “great,” underscores this “fixed mindset” that certain attributes are set in stone.¹ Conversely, she defines the “growth mindset” as a belief that potential can be cultivated through efforts. Even when there aren’t obvious issues with performance, the failure, fine-tuning, and feedback necessary for resilience and, ultimately, sustained growth require intention.

Emphasize Effort

Instead of lauding an individual for being “great, as always,” consider focusing on the effort it required to get there. For example, regarding the aforementioned junior colleague who’d just won awards, a typical compliment might be: “Wow, you’re on fire!” An option, to promote a growth mindset, might be: “You work very hard at bedside teaching and innovative curriculum development. I’m happy to see that our learners and department have recognized your commitment and effort.” This language also affirms others and makes achievements seem attainable to all.

Provide Active Coaching

Identifying specific opportunities for development can challenge individuals to expand their skills. Even those who are doing well have room to become even better. Coproduction of new milestones that push beyond current comfort zones can acknowledge current achievements while encouraging continued growth—and make things personal. For example, encouraging an individual to apply to a national faculty development program, such as the Society of Hospital Medicine’s Academic Hospitalist Academy, could help them expand their skills and social network.

Offer Meaningful Feedback

Prioritizing feedback is essential for growth and peak performance. This can be particularly powerful when the observer moves beyond basic expectations to incorporate personal goals. Concrete feedback measured against individual potential then takes the place of nondescript compliments. For example, you could say: “Your teaching on systolic ejection murmurs was on target for the students. Next time I want to challenge you to broaden your teaching script to include points appropriate for more seasoned learners.” This feedback leaves them with a set of tailored “marching orders” to guide practice and improvement.

No matter where a person stands on the spectrum of performance, growth in medicine relies on deliberate practice, active coaching, meaningful feedback, and graduated opportunities. Even the most proficient among us can stagnate without these things. If we aren’t careful, this reputational inertia could amplify imposter syndrome, prevent individuals from achieving their full potential, and threaten faculty retention. Intentional work toward a growth mindset allows everyone to grow—and be seen.

The authors have nothing to disclose.

“Becoming is better than being.”

—Carol Dweck

The words spoken about her in the staff meeting were flattering. She’d just been acknowledged with a departmental teaching award for the second year in a row. With only 3 years under her belt since completing training, the former chief resident was living up to all they’d anticipated.

Eager students requested to be on her team and colleagues delighted in sharing patients with her. “Great, as always,” her peers and learners said in hallways and evaluations. This would come to define her identity.

Things were going well. She was succeeding. But she began to wonder if this reciprocating engine of accolades represented who she truly was. Was she really that good? Was she an imposter? In her performance meetings, the feedback never wavered: “Great, as always.”

The following year she would leave for a different job.

While specific plans for growth and improvement often get laid out for struggling colleagues and learners, far less effort is devoted to coaching high performers. Feedback that consists of nonspecific compliments may hinder potential, growth, and job satisfaction. We outline strategies for preventing this professional plateau in those you lead.

In Mindset: The New Psychology of Success, psychologist Carol Dweck describes how emphasis on qualities such as “being smart” or, in this example, “great,” underscores this “fixed mindset” that certain attributes are set in stone.¹ Conversely, she defines the “growth mindset” as a belief that potential can be cultivated through efforts. Even when there aren’t obvious issues with performance, the failure, fine-tuning, and feedback necessary for resilience and, ultimately, sustained growth require intention.

Emphasize Effort

Instead of lauding an individual for being “great, as always,” consider focusing on the effort it required to get there. For example, regarding the aforementioned junior colleague who’d just won awards, a typical compliment might be: “Wow, you’re on fire!” An option, to promote a growth mindset, might be: “You work very hard at bedside teaching and innovative curriculum development. I’m happy to see that our learners and department have recognized your commitment and effort.” This language also affirms others and makes achievements seem attainable to all.

Provide Active Coaching

Identifying specific opportunities for development can challenge individuals to expand their skills. Even those who are doing well have room to become even better. Coproduction of new milestones that push beyond current comfort zones can acknowledge current achievements while encouraging continued growth—and make things personal. For example, encouraging an individual to apply to a national faculty development program, such as the Society of Hospital Medicine’s Academic Hospitalist Academy, could help them expand their skills and social network.

Offer Meaningful Feedback

Prioritizing feedback is essential for growth and peak performance. This can be particularly powerful when the observer moves beyond basic expectations to incorporate personal goals. Concrete feedback measured against individual potential then takes the place of nondescript compliments. For example, you could say: “Your teaching on systolic ejection murmurs was on target for the students. Next time I want to challenge you to broaden your teaching script to include points appropriate for more seasoned learners.” This feedback leaves them with a set of tailored “marching orders” to guide practice and improvement.

No matter where a person stands on the spectrum of performance, growth in medicine relies on deliberate practice, active coaching, meaningful feedback, and graduated opportunities. Even the most proficient among us can stagnate without these things. If we aren’t careful, this reputational inertia could amplify imposter syndrome, prevent individuals from achieving their full potential, and threaten faculty retention. Intentional work toward a growth mindset allows everyone to grow—and be seen.

The authors have nothing to disclose.

“Becoming is better than being.”

—Carol Dweck

The words spoken about her in the staff meeting were flattering. She’d just been acknowledged with a departmental teaching award for the second year in a row. With only 3 years under her belt since completing training, the former chief resident was living up to all they’d anticipated.

Eager students requested to be on her team and colleagues delighted in sharing patients with her. “Great, as always,” her peers and learners said in hallways and evaluations. This would come to define her identity.

Things were going well. She was succeeding. But she began to wonder if this reciprocating engine of accolades represented who she truly was. Was she really that good? Was she an imposter? In her performance meetings, the feedback never wavered: “Great, as always.”

The following year she would leave for a different job.

While specific plans for growth and improvement often get laid out for struggling colleagues and learners, far less effort is devoted to coaching high performers. Feedback that consists of nonspecific compliments may hinder potential, growth, and job satisfaction. We outline strategies for preventing this professional plateau in those you lead.

In Mindset: The New Psychology of Success, psychologist Carol Dweck describes how emphasis on qualities such as “being smart” or, in this example, “great,” underscores this “fixed mindset” that certain attributes are set in stone.¹ Conversely, she defines the “growth mindset” as a belief that potential can be cultivated through efforts. Even when there aren’t obvious issues with performance, the failure, fine-tuning, and feedback necessary for resilience and, ultimately, sustained growth require intention.

Emphasize Effort

Instead of lauding an individual for being “great, as always,” consider focusing on the effort it required to get there. For example, regarding the aforementioned junior colleague who’d just won awards, a typical compliment might be: “Wow, you’re on fire!” An option, to promote a growth mindset, might be: “You work very hard at bedside teaching and innovative curriculum development. I’m happy to see that our learners and department have recognized your commitment and effort.” This language also affirms others and makes achievements seem attainable to all.

Provide Active Coaching

Identifying specific opportunities for development can challenge individuals to expand their skills. Even those who are doing well have room to become even better. Coproduction of new milestones that push beyond current comfort zones can acknowledge current achievements while encouraging continued growth—and make things personal. For example, encouraging an individual to apply to a national faculty development program, such as the Society of Hospital Medicine’s Academic Hospitalist Academy, could help them expand their skills and social network.

Offer Meaningful Feedback

Prioritizing feedback is essential for growth and peak performance. This can be particularly powerful when the observer moves beyond basic expectations to incorporate personal goals. Concrete feedback measured against individual potential then takes the place of nondescript compliments. For example, you could say: “Your teaching on systolic ejection murmurs was on target for the students. Next time I want to challenge you to broaden your teaching script to include points appropriate for more seasoned learners.” This feedback leaves them with a set of tailored “marching orders” to guide practice and improvement.

No matter where a person stands on the spectrum of performance, growth in medicine relies on deliberate practice, active coaching, meaningful feedback, and graduated opportunities. Even the most proficient among us can stagnate without these things. If we aren’t careful, this reputational inertia could amplify imposter syndrome, prevent individuals from achieving their full potential, and threaten faculty retention. Intentional work toward a growth mindset allows everyone to grow—and be seen.

The authors have nothing to disclose.

Dear colleagues,

I’m excited to introduce the November issue of The New Gastroenterologist – the last edition of 2020 features a fantastic line-up of articles! As the year comes to a close, we reflect on what has certainly been an interesting year, defined by a set of unique challenges we have faced as a nation and as a specialty.

AGA Institute

The fellowship recruitment season is one that has looked starkly different as interviews have converted to a virtual format. Dr. Wissam Khan, Dr. Nada Al Masalmeh, Dr. Stephanie Judd, and Dr. Diane Levine (Wayne State University) compile a helpful list of tips and tricks on proper interview etiquette in the new era of web-based interviews.

Financial planning in the face of a pandemic is a formidable task – Jonathan Tudor (Fidelity Investments) offers valuable advice for gastroenterologists on how to remain secure in your finances even in uncertain circumstances.

This quarter’s “In Focus” feature, written by Dr. Yutaka Tomizawa (University of Washington), is a comprehensive piece elucidating the role of gastroenterologists in the management of gastric cancer. The article reviews the individual risk factors that exist for gastric cancer and provides guidance on how to stratify patients accordingly, which is critical in the ethnically diverse population of the United States.

Keeping a procedure log during fellowship can seem daunting and cumbersome, but it is important. Dr. Houman Rezaizadeh (University of Connecticut) shares his program’s experience with the AGA Procedure Log, a convenient online tracking tool, which can provide accurate and secure documentation of endoscopic procedures performed throughout fellowship.

Dr. Nazia Hasan (North Bay Health Care) and Dr. Allison Schulman (University of Michigan) broach an incredibly important topic: the paucity of women in interventional endoscopy. Dr. Hasan and Dr. Shulman candidly discuss the barriers women face in pursuing this subspecialty and offer practical solutions on how to approach these challenges – a piece that will surely resonate with many young gastroenterologists.

We wrap up our first year of TNG’s ethics series with two cases discussing the utilization of cannabis therapy in inflammatory bowel disease (IBD). Dr. Jami Kinnucan (University of Michigan) and Dr. Arun Swaminath (Lenox Hill Hospital) systematically review existing data on the efficacy of cannabis use in IBD, the risks associated with therapy, and legal implications for both physicians and patients.

Also in this issue is a high-yield clinical review on the endoscopic drainage of pancreatic fluid collections by Dr. Robert Moran and Dr. Joseph Elmunzer (Medical University of South Carolina). Dr. Manol Jovani (Johns Hopkins) teaches us about confounding – a critical concept to keep in mind when evaluating any manuscript. Lastly, our DHPA Private Practice Perspectives article, written by Dr. Mehul Lalani (US Digestive), reviews how quality measures and initiatives are tracked and implemented in private practice.

If you have interest in contributing or have ideas for future TNG topics, please contact me ([email protected]), or Ryan Farrell ([email protected]), managing editor of TNG.
 

Stay well,

Vijaya L. Rao, MD
Editor in Chief
Assistant Professor of Medicine, University of Chicago, Section of Gastroenterology, Hepatology & Nutrition

Dear colleagues,

I’m excited to introduce the November issue of The New Gastroenterologist – the last edition of 2020 features a fantastic line-up of articles! As the year comes to a close, we reflect on what has certainly been an interesting year, defined by a set of unique challenges we have faced as a nation and as a specialty.

AGA Institute

The fellowship recruitment season is one that has looked starkly different as interviews have converted to a virtual format. Dr. Wissam Khan, Dr. Nada Al Masalmeh, Dr. Stephanie Judd, and Dr. Diane Levine (Wayne State University) compile a helpful list of tips and tricks on proper interview etiquette in the new era of web-based interviews.

Financial planning in the face of a pandemic is a formidable task – Jonathan Tudor (Fidelity Investments) offers valuable advice for gastroenterologists on how to remain secure in your finances even in uncertain circumstances.

This quarter’s “In Focus” feature, written by Dr. Yutaka Tomizawa (University of Washington), is a comprehensive piece elucidating the role of gastroenterologists in the management of gastric cancer. The article reviews the individual risk factors that exist for gastric cancer and provides guidance on how to stratify patients accordingly, which is critical in the ethnically diverse population of the United States.

Keeping a procedure log during fellowship can seem daunting and cumbersome, but it is important. Dr. Houman Rezaizadeh (University of Connecticut) shares his program’s experience with the AGA Procedure Log, a convenient online tracking tool, which can provide accurate and secure documentation of endoscopic procedures performed throughout fellowship.

Dr. Nazia Hasan (North Bay Health Care) and Dr. Allison Schulman (University of Michigan) broach an incredibly important topic: the paucity of women in interventional endoscopy. Dr. Hasan and Dr. Shulman candidly discuss the barriers women face in pursuing this subspecialty and offer practical solutions on how to approach these challenges – a piece that will surely resonate with many young gastroenterologists.

We wrap up our first year of TNG’s ethics series with two cases discussing the utilization of cannabis therapy in inflammatory bowel disease (IBD). Dr. Jami Kinnucan (University of Michigan) and Dr. Arun Swaminath (Lenox Hill Hospital) systematically review existing data on the efficacy of cannabis use in IBD, the risks associated with therapy, and legal implications for both physicians and patients.

Also in this issue is a high-yield clinical review on the endoscopic drainage of pancreatic fluid collections by Dr. Robert Moran and Dr. Joseph Elmunzer (Medical University of South Carolina). Dr. Manol Jovani (Johns Hopkins) teaches us about confounding – a critical concept to keep in mind when evaluating any manuscript. Lastly, our DHPA Private Practice Perspectives article, written by Dr. Mehul Lalani (US Digestive), reviews how quality measures and initiatives are tracked and implemented in private practice.

If you have interest in contributing or have ideas for future TNG topics, please contact me ([email protected]), or Ryan Farrell ([email protected]), managing editor of TNG.
 

Stay well,

Vijaya L. Rao, MD
Editor in Chief
Assistant Professor of Medicine, University of Chicago, Section of Gastroenterology, Hepatology & Nutrition

Dear colleagues,

I’m excited to introduce the November issue of The New Gastroenterologist – the last edition of 2020 features a fantastic line-up of articles! As the year comes to a close, we reflect on what has certainly been an interesting year, defined by a set of unique challenges we have faced as a nation and as a specialty.

AGA Institute

The fellowship recruitment season is one that has looked starkly different as interviews have converted to a virtual format. Dr. Wissam Khan, Dr. Nada Al Masalmeh, Dr. Stephanie Judd, and Dr. Diane Levine (Wayne State University) compile a helpful list of tips and tricks on proper interview etiquette in the new era of web-based interviews.

Financial planning in the face of a pandemic is a formidable task – Jonathan Tudor (Fidelity Investments) offers valuable advice for gastroenterologists on how to remain secure in your finances even in uncertain circumstances.

This quarter’s “In Focus” feature, written by Dr. Yutaka Tomizawa (University of Washington), is a comprehensive piece elucidating the role of gastroenterologists in the management of gastric cancer. The article reviews the individual risk factors that exist for gastric cancer and provides guidance on how to stratify patients accordingly, which is critical in the ethnically diverse population of the United States.

Keeping a procedure log during fellowship can seem daunting and cumbersome, but it is important. Dr. Houman Rezaizadeh (University of Connecticut) shares his program’s experience with the AGA Procedure Log, a convenient online tracking tool, which can provide accurate and secure documentation of endoscopic procedures performed throughout fellowship.

Dr. Nazia Hasan (North Bay Health Care) and Dr. Allison Schulman (University of Michigan) broach an incredibly important topic: the paucity of women in interventional endoscopy. Dr. Hasan and Dr. Shulman candidly discuss the barriers women face in pursuing this subspecialty and offer practical solutions on how to approach these challenges – a piece that will surely resonate with many young gastroenterologists.

We wrap up our first year of TNG’s ethics series with two cases discussing the utilization of cannabis therapy in inflammatory bowel disease (IBD). Dr. Jami Kinnucan (University of Michigan) and Dr. Arun Swaminath (Lenox Hill Hospital) systematically review existing data on the efficacy of cannabis use in IBD, the risks associated with therapy, and legal implications for both physicians and patients.

Also in this issue is a high-yield clinical review on the endoscopic drainage of pancreatic fluid collections by Dr. Robert Moran and Dr. Joseph Elmunzer (Medical University of South Carolina). Dr. Manol Jovani (Johns Hopkins) teaches us about confounding – a critical concept to keep in mind when evaluating any manuscript. Lastly, our DHPA Private Practice Perspectives article, written by Dr. Mehul Lalani (US Digestive), reviews how quality measures and initiatives are tracked and implemented in private practice.

If you have interest in contributing or have ideas for future TNG topics, please contact me ([email protected]), or Ryan Farrell ([email protected]), managing editor of TNG.
 

Stay well,

Vijaya L. Rao, MD
Editor in Chief
Assistant Professor of Medicine, University of Chicago, Section of Gastroenterology, Hepatology & Nutrition

Introduction

Although gastric cancer is one of the most common causes of cancer death in the world, the burden of gastric cancer in the United States tends to be underestimated relative to that of other cancers of the digestive system. In fact, the 5-year survival rate from gastric cancer remains poor (~32%)¹ in the United States, and this is largely because gastric cancers are not diagnosed at an early stage when curative therapeutic options are available. Cumulative epidemiologic data consistently demonstrate that the incidence of gastric cancer in the United States varies according to ethnicity, immigrant status, and country of origin. It is important for practicing gastroenterologists in the United States to recognize individual risk profiles and identify people at higher risk for gastric cancer. Hereditary diffuse gastric cancer is an inherited form of diffuse-type gastric cancer and has pathogenic variants in the E-cadherin gene that are inherited in an autosomal dominant pattern. The lifetime risk of gastric cancer in individuals with HDGC is very high, and prophylactic total gastrectomy is usually advised. This article focuses on intestinal type cancer.

Epidemiology

Gastric cancer (proximal and distal gastric cancer combined) is the fifth most frequently diagnosed cancer and the third most common cause of cancer death worldwide, with 1,033,701 new cases and 782,685 deaths in 2018.² Gastric cancer is subcategorized based on location (proximal [i.e., esophagogastric junctional, gastric cardia] and distal) and histology (intestinal and diffuse type), and each subtype is considered to have a distinct pathogenesis. Distal intestinal type gastric cancer is most commonly encountered in clinical practice. In this article, gastric cancer will signify distal intestinal type gastric cancer unless it is otherwise noted. In general, incidence rates are about twofold higher in men than in women. There is marked geographic variation in incidence rates, and the age-standardized incidence rates in eastern Asia (32.1 and 13.2, per 100,000) are approximately six times higher than those in northern America (5.6 and 2.8, per 100,000) in both men and women, respectively.² Recent studies evaluating global trends in the incidence and mortality of gastric cancer have demonstrated decreases worldwide.^3-5 However, the degree of decrease in the incidence and mortality of gastric cancer varies substantially across geographic regions, reflecting the heterogeneous distribution of risk profiles. A comprehensive analysis of a U.S. population registry demonstrated a linear decrease in the incidence of gastric cancer in the United States (0.94% decrease per year between 2001 and 2015),⁶ though the annual percent change in the gastric cancer mortality in the United States was lower (around 2% decrease per year between 1980 and 2011) than in other countries.³Several population-based studies conducted in the United States have demonstrated that the incidence of gastric cancer varied by ethnicity, immigrant status, and country of origin, and the highest incidence was observed among Asian immigrants.^7,8 A comprehensive meta-analysis examining the risk of gastric cancer in immigrants from high-incidence regions to low-incidence regions found a persistently higher risk of gastric cancer and related mortality among immigrants.⁹ These results indicate that there are important risk factors such as environmental and dietary factors in addition to the traditionally considered risk factors including male gender, age, family history, and tobacco use. A survey conducted in an ethnically and culturally diverse U.S. city showed that gastroenterology providers demonstrated knowledge deficiencies in identifying and managing patients with increased risk of gastric cancer.¹⁰ Recognizing individualized risk profiles in higher-risk groups (e.g., immigrants from higher-incidence/prevalence regions) is important for optimizing management of gastric cancer in the United States.
 

Assessment and management of modifiable risk factors

Helicobacter pylori, a group 1 carcinogen, is the most well-recognized risk factor for gastric cancer, particularly noncardia gastric cancer.¹¹ Since a landmark longitudinal follow-up study in Japan demonstrated that people with H. pylori infection are more likely to develop gastric cancer than those without H. pylori infection,¹² accumulating evidence largely from Asian countries has shown that eradication of H. pylori is associated with a reduced incidence of gastric cancer regardless of baseline risk.¹³ There are also data on the protective effect for gastric cancer of H. pylori eradication in asymptomatic individuals. Another meta-analysis of six international randomized control trials demonstrated a 34% relative risk reduction of gastric cancer occurrence in asymptomatic people (relative risk of developing gastric cancer was 0.66 in those who received eradication therapy compared with those with placebo or no treatment, 95% CI, 0.46-0.95).¹⁴ A U.S. practice guideline published after these meta-analyses recommends that all patients with a positive test indicating active infection with H. pylori should be offered treatment and testing to prove eradication,¹⁵ though the recommendation was not purely intended to reduce the gastric cancer risk in U.S. population. Subsequently, a Department of Veterans Affairs cohort study added valuable insights from a U.S. experience to the body of evidence from other countries with higher prevalence. In this study of more than 370,000 patients with a history of H. pylori infection, the detection and successful eradication of H. pylori was associated with a 76% lower incidence of gastric cancer compared with people without H. pylori treatment.¹⁶ This study also provided insight into H. pylori treatment practice patterns. Of patients with a positive H. pylori test result (stool antigen, urea breath test, or pathology), approximately 75% were prescribed an eradication regimen and only 21% of those underwent eradication tests. A low rate (24%) of eradication testing was subsequently reported by the same group among U.S. patients regardless of gastric cancer risk profiles.¹⁷ The lesson from the aforementioned study is that treatment and eradication of H. pylori even among asymptomatic U.S. patients reduces the risk of subsequent gastric cancer. However, it may be difficult to generalize the results of this study given the nature of the Veterans Affairs cohort, and more data are required to justify the implementation of nationwide preventive H. pylori screening in the general U.S. population.

Who should we consider high risk and offer screening EGD?

With available evidence to date, screening for gastric cancer in a general U.S. population is not recommended. However, it is important to acknowledge the aforementioned varying incidence of gastric cancer in the United States among ethnicity, immigrant status, and country of origin. Immigrants from high-incidence regions maintain a higher risk of gastric cancer and related mortality even after migration to lower-incidence regions. The latter comprehensive study estimated that as many as 12.7 million people (29.4% of total U.S. immigrant population) have emigrated from higher-incidence regions including East Asian and some Central American countries.⁹ Indeed, an opportunistic nationwide gastric cancer screening program has been implemented in South Korea (beginning at age 40, biannually)²³ and Japan (beginning at age 50, biannually).²⁴ Two decision-analytic simulation studies have provided insight into the uncertainty about the cost effectiveness for potential targeted gastric cancer screening in higher-risk populations in the United States. One study demonstrated that esophagogastroduodenoscopy (EGD) screening for otherwise asymptomatic Asian American people (as well as Hispanics and non-Hispanic Blacks) at the time of screening colonoscopy at 50 years of age with continued endoscopic surveillance every 3 years was cost effective, only if gastric intestinal metaplasia (GIM) or more advanced lesions were diagnosed at the index screening EGD.²⁵ Previous studies analyzing the cost effectiveness for gastric cancer screening in the United States had the limitation of not stratifying according to race or ethnicity, or accounting for patients diagnosed with GIM. Subsequently, the same research group extended this model analysis and has published additional findings that this strategy is cost effective for each of the most prevalent Asian American ethnicities (Chinese, Filipino, Southeast Asian, Vietnamese, Korean, and Japanese Americans) in the United States irrespective of sex.²⁶ Although the authors raised a limitation that additional risk factors such as family history, tobacco use, or persistent H. pylori infection were not considered in the model because data regarding differentiated noncardia gastric cancer risk among Asian American ethnicities based on these risk factors are not available.

Practical consideration when we perform EGD for early gastric cancer screening

Identification of higher-risk patients should alert an endoscopist to observe mucosa with greater care with a lower threshold to biopsy any suspicious lesions. Preprocedural risk stratification for each individual before performing diagnostic EGD will improve early gastric cancer detection. While we perform EGD, detecting precursor lesions (atrophic gastritis and GIM) is as important as diagnosing an early gastric cancer. Screening and management of patients with precursor lesions (i.e., atrophic gastritis and GIM) is beyond the scope of this article, and this was published in a previous issue of the New Gastroenterologist. It is important to first grossly survey the entire gastric mucosa using high-definition while light (HDWL) endoscopy and screen for any focal irregular (raised or depressed) mucosal lesions. These lesions are often erythematous and should be examined carefully. Use of mucolytic and/or deforming agents (e.g., N-acetylcysteine or simethicone) is recommended for the improvement of visual clarity of gastric mucosa.³¹ Simethicone is widely used in the United States for colonoscopy and should also be available at the time of EGD for better gastric mucosal visibility. If irregular mucosal lesions are noted, this area should also be examined under narrowband imaging (NBI) in addition to HDWL. According to a simplified classification consisting of mucosal and vascular irregularity, NBI provides better mucosal surface morphology for diagnosis of early gastric cancer compared with HDWL, and a thorough examination of the surface characteristics is a prerequisite.³² This classification was further validated in a randomized control trial, and NBI increased sensitivity for the diagnosis of neoplasia compared with HDWL (92 % vs. 74 %).³³ The majority of institutions in the United States have a newer-generation NBI (Olympus America, EVIS EXERA III video system, GIF-HQ190), which provides brighter endoscopic images to better characterize gastric neoplastic lesions. Once we recognize an area suspicious for neoplasia, we should describe the macroscopic features according to a classification system.

Conclusion

As summarized above, cumulative epidemiologic data consistently demonstrate that the incidence of gastric cancer in the U.S. varies according to ethnicity, immigrant status, and country of origin. New gastroenterologists will need to recognize individual risk profiles and identify people at higher risk for gastric cancer. Risk stratification before performing endoscopic evaluation will improve early gastric cancer detection and make noninvasive, effective therapies an option.

References

1. Surveillance, Epidemiology, and End Results Program cancer statistics. https://seer.cancer.gov/statfacts/html/stomach.html.

2. Bray F et al. Ca Cancer J Clin. 2018;68:394-424.

3. Ferro A et al. Eur J Cancer. 2014;50:1330-44.

4. Luo G et al. Int J Cancer. 2017;141:1333-44.

5. Arnold M et al. Eur J Cancer. 2015;51:1164-87.

6. Thrift AP, El-Serag HB. Clin Gastroenterol Hepatol. 2020;18:534-42.

7. Kim Y et al. Epidemiol Health. 2015;37:e2015066.

8. Kamineni A et al. Cancer Causes Control. 1999;10:77-83.

9. Pabla BS et al. Clin Gastroenterol Hepatol. 2020;18:347-59.

10. Shah SC et al. Knowledge Gaps among Physicians Caring for Multiethnic Populations at Increased Gastric Cancer Risk. Gut Liver. 2018 Jan 15;12(1):38-45.

11. International Agency for Research on Cancer. Monographs on the Identification of Carcinogenic Hazards to Humans. IARC. July 7, 2019. 12. Uemura N et al. N Engl J Med. 2001;345:784-9.

13. Lee YC et al. Gastroenterology. 2016;150:1113-24.

14. Ford AC et al. BMJ. 2014;348:g3174.

15. Chey W et al. Am J Gastroenterol. 2017;112:212-39.

16. Kumar S et al. Gastroenterology. 2020;158:527-36.

17. Kumar S et al. Clin Gastroenterol Hepatol. 2020 Apr 6;S1542-3565(20)30436-5.

18. González CA et al. Int J Cancer. 2003;107:629-34.

19. Ladeiras-Lopes R et al. Cancer Causes Control. 2008;19:689-701.

20. Cavaleiro-Pinto M et al. Cancer Causes Control. 2011;22:375-87.

21. Lauby-Secretan B et al. N Engl J Med. 2016;375:794-8.

22. Choi IJ et al. N Engl J Med. 2020;382:427-36.

23. Kim BJ et al. World J Gastroenterol. 2013;19:736-41.

24. Hamashima C. Jpn J Clin Oncol. 2018;48:278–86.

25. Saumoy M et al. Gastroenterology. 2018;155:648-60.

26. Shah SC et al. Clin Gastroenterol Hepatol. 2020 Jul 21:S1542-3565(20)30993-9. doi: 10.1016/j.cgh.2020.07.031.

27. Brinton LA et al. Br J Cancer. 1989;59:810-3.

28. Hsing AW et al. Cancer. 1993;71:745-50.

29. Schafer LW et al. Mayo Clin Proc. 1985;60:444-8.

30. American Society for Gastrointestinal Endoscopy Standards of Practice Committee. Gastrointest Endosc. 2015;82:1-8.

31. Chiu PWY et al. Gut. 2019;68:186-97.

32. Pimentel-Nunes P et al. Endoscopy. 2012;44:236-46.

33. Pimentel-Nunes P et al. Endoscopy. 2016;48:723-30.

34. Participants in the Paris Workshop. Gastrointest Endosc. 2003;58:S3-43.

35. Draganov PV et al. Clin Gastroenterol Hepatol. 2019;17:16-25.

36. Ngamruengphong S et al. Clin Gastroenterol Hepatol. 2020 Jun 18;S1542-3565(20)30834-X. Online ahead of print.

37. Choi IJ et al. N Engl J Med. 2018;378:1085-95.

Dr. Tomizawa is a clinical assistant professor of medicine in the division of gastroenterology, University of Washington, Seattle.

Introduction

Although gastric cancer is one of the most common causes of cancer death in the world, the burden of gastric cancer in the United States tends to be underestimated relative to that of other cancers of the digestive system. In fact, the 5-year survival rate from gastric cancer remains poor (~32%)¹ in the United States, and this is largely because gastric cancers are not diagnosed at an early stage when curative therapeutic options are available. Cumulative epidemiologic data consistently demonstrate that the incidence of gastric cancer in the United States varies according to ethnicity, immigrant status, and country of origin. It is important for practicing gastroenterologists in the United States to recognize individual risk profiles and identify people at higher risk for gastric cancer. Hereditary diffuse gastric cancer is an inherited form of diffuse-type gastric cancer and has pathogenic variants in the E-cadherin gene that are inherited in an autosomal dominant pattern. The lifetime risk of gastric cancer in individuals with HDGC is very high, and prophylactic total gastrectomy is usually advised. This article focuses on intestinal type cancer.

Epidemiology

Gastric cancer (proximal and distal gastric cancer combined) is the fifth most frequently diagnosed cancer and the third most common cause of cancer death worldwide, with 1,033,701 new cases and 782,685 deaths in 2018.² Gastric cancer is subcategorized based on location (proximal [i.e., esophagogastric junctional, gastric cardia] and distal) and histology (intestinal and diffuse type), and each subtype is considered to have a distinct pathogenesis. Distal intestinal type gastric cancer is most commonly encountered in clinical practice. In this article, gastric cancer will signify distal intestinal type gastric cancer unless it is otherwise noted. In general, incidence rates are about twofold higher in men than in women. There is marked geographic variation in incidence rates, and the age-standardized incidence rates in eastern Asia (32.1 and 13.2, per 100,000) are approximately six times higher than those in northern America (5.6 and 2.8, per 100,000) in both men and women, respectively.² Recent studies evaluating global trends in the incidence and mortality of gastric cancer have demonstrated decreases worldwide.^3-5 However, the degree of decrease in the incidence and mortality of gastric cancer varies substantially across geographic regions, reflecting the heterogeneous distribution of risk profiles. A comprehensive analysis of a U.S. population registry demonstrated a linear decrease in the incidence of gastric cancer in the United States (0.94% decrease per year between 2001 and 2015),⁶ though the annual percent change in the gastric cancer mortality in the United States was lower (around 2% decrease per year between 1980 and 2011) than in other countries.³Several population-based studies conducted in the United States have demonstrated that the incidence of gastric cancer varied by ethnicity, immigrant status, and country of origin, and the highest incidence was observed among Asian immigrants.^7,8 A comprehensive meta-analysis examining the risk of gastric cancer in immigrants from high-incidence regions to low-incidence regions found a persistently higher risk of gastric cancer and related mortality among immigrants.⁹ These results indicate that there are important risk factors such as environmental and dietary factors in addition to the traditionally considered risk factors including male gender, age, family history, and tobacco use. A survey conducted in an ethnically and culturally diverse U.S. city showed that gastroenterology providers demonstrated knowledge deficiencies in identifying and managing patients with increased risk of gastric cancer.¹⁰ Recognizing individualized risk profiles in higher-risk groups (e.g., immigrants from higher-incidence/prevalence regions) is important for optimizing management of gastric cancer in the United States.
 

Assessment and management of modifiable risk factors

Helicobacter pylori, a group 1 carcinogen, is the most well-recognized risk factor for gastric cancer, particularly noncardia gastric cancer.¹¹ Since a landmark longitudinal follow-up study in Japan demonstrated that people with H. pylori infection are more likely to develop gastric cancer than those without H. pylori infection,¹² accumulating evidence largely from Asian countries has shown that eradication of H. pylori is associated with a reduced incidence of gastric cancer regardless of baseline risk.¹³ There are also data on the protective effect for gastric cancer of H. pylori eradication in asymptomatic individuals. Another meta-analysis of six international randomized control trials demonstrated a 34% relative risk reduction of gastric cancer occurrence in asymptomatic people (relative risk of developing gastric cancer was 0.66 in those who received eradication therapy compared with those with placebo or no treatment, 95% CI, 0.46-0.95).¹⁴ A U.S. practice guideline published after these meta-analyses recommends that all patients with a positive test indicating active infection with H. pylori should be offered treatment and testing to prove eradication,¹⁵ though the recommendation was not purely intended to reduce the gastric cancer risk in U.S. population. Subsequently, a Department of Veterans Affairs cohort study added valuable insights from a U.S. experience to the body of evidence from other countries with higher prevalence. In this study of more than 370,000 patients with a history of H. pylori infection, the detection and successful eradication of H. pylori was associated with a 76% lower incidence of gastric cancer compared with people without H. pylori treatment.¹⁶ This study also provided insight into H. pylori treatment practice patterns. Of patients with a positive H. pylori test result (stool antigen, urea breath test, or pathology), approximately 75% were prescribed an eradication regimen and only 21% of those underwent eradication tests. A low rate (24%) of eradication testing was subsequently reported by the same group among U.S. patients regardless of gastric cancer risk profiles.¹⁷ The lesson from the aforementioned study is that treatment and eradication of H. pylori even among asymptomatic U.S. patients reduces the risk of subsequent gastric cancer. However, it may be difficult to generalize the results of this study given the nature of the Veterans Affairs cohort, and more data are required to justify the implementation of nationwide preventive H. pylori screening in the general U.S. population.

Who should we consider high risk and offer screening EGD?

With available evidence to date, screening for gastric cancer in a general U.S. population is not recommended. However, it is important to acknowledge the aforementioned varying incidence of gastric cancer in the United States among ethnicity, immigrant status, and country of origin. Immigrants from high-incidence regions maintain a higher risk of gastric cancer and related mortality even after migration to lower-incidence regions. The latter comprehensive study estimated that as many as 12.7 million people (29.4% of total U.S. immigrant population) have emigrated from higher-incidence regions including East Asian and some Central American countries.⁹ Indeed, an opportunistic nationwide gastric cancer screening program has been implemented in South Korea (beginning at age 40, biannually)²³ and Japan (beginning at age 50, biannually).²⁴ Two decision-analytic simulation studies have provided insight into the uncertainty about the cost effectiveness for potential targeted gastric cancer screening in higher-risk populations in the United States. One study demonstrated that esophagogastroduodenoscopy (EGD) screening for otherwise asymptomatic Asian American people (as well as Hispanics and non-Hispanic Blacks) at the time of screening colonoscopy at 50 years of age with continued endoscopic surveillance every 3 years was cost effective, only if gastric intestinal metaplasia (GIM) or more advanced lesions were diagnosed at the index screening EGD.²⁵ Previous studies analyzing the cost effectiveness for gastric cancer screening in the United States had the limitation of not stratifying according to race or ethnicity, or accounting for patients diagnosed with GIM. Subsequently, the same research group extended this model analysis and has published additional findings that this strategy is cost effective for each of the most prevalent Asian American ethnicities (Chinese, Filipino, Southeast Asian, Vietnamese, Korean, and Japanese Americans) in the United States irrespective of sex.²⁶ Although the authors raised a limitation that additional risk factors such as family history, tobacco use, or persistent H. pylori infection were not considered in the model because data regarding differentiated noncardia gastric cancer risk among Asian American ethnicities based on these risk factors are not available.

Practical consideration when we perform EGD for early gastric cancer screening

Identification of higher-risk patients should alert an endoscopist to observe mucosa with greater care with a lower threshold to biopsy any suspicious lesions. Preprocedural risk stratification for each individual before performing diagnostic EGD will improve early gastric cancer detection. While we perform EGD, detecting precursor lesions (atrophic gastritis and GIM) is as important as diagnosing an early gastric cancer. Screening and management of patients with precursor lesions (i.e., atrophic gastritis and GIM) is beyond the scope of this article, and this was published in a previous issue of the New Gastroenterologist. It is important to first grossly survey the entire gastric mucosa using high-definition while light (HDWL) endoscopy and screen for any focal irregular (raised or depressed) mucosal lesions. These lesions are often erythematous and should be examined carefully. Use of mucolytic and/or deforming agents (e.g., N-acetylcysteine or simethicone) is recommended for the improvement of visual clarity of gastric mucosa.³¹ Simethicone is widely used in the United States for colonoscopy and should also be available at the time of EGD for better gastric mucosal visibility. If irregular mucosal lesions are noted, this area should also be examined under narrowband imaging (NBI) in addition to HDWL. According to a simplified classification consisting of mucosal and vascular irregularity, NBI provides better mucosal surface morphology for diagnosis of early gastric cancer compared with HDWL, and a thorough examination of the surface characteristics is a prerequisite.³² This classification was further validated in a randomized control trial, and NBI increased sensitivity for the diagnosis of neoplasia compared with HDWL (92 % vs. 74 %).³³ The majority of institutions in the United States have a newer-generation NBI (Olympus America, EVIS EXERA III video system, GIF-HQ190), which provides brighter endoscopic images to better characterize gastric neoplastic lesions. Once we recognize an area suspicious for neoplasia, we should describe the macroscopic features according to a classification system.

Conclusion

As summarized above, cumulative epidemiologic data consistently demonstrate that the incidence of gastric cancer in the U.S. varies according to ethnicity, immigrant status, and country of origin. New gastroenterologists will need to recognize individual risk profiles and identify people at higher risk for gastric cancer. Risk stratification before performing endoscopic evaluation will improve early gastric cancer detection and make noninvasive, effective therapies an option.

References

1. Surveillance, Epidemiology, and End Results Program cancer statistics. https://seer.cancer.gov/statfacts/html/stomach.html.

2. Bray F et al. Ca Cancer J Clin. 2018;68:394-424.

3. Ferro A et al. Eur J Cancer. 2014;50:1330-44.

4. Luo G et al. Int J Cancer. 2017;141:1333-44.

5. Arnold M et al. Eur J Cancer. 2015;51:1164-87.

6. Thrift AP, El-Serag HB. Clin Gastroenterol Hepatol. 2020;18:534-42.

7. Kim Y et al. Epidemiol Health. 2015;37:e2015066.

8. Kamineni A et al. Cancer Causes Control. 1999;10:77-83.

9. Pabla BS et al. Clin Gastroenterol Hepatol. 2020;18:347-59.

10. Shah SC et al. Knowledge Gaps among Physicians Caring for Multiethnic Populations at Increased Gastric Cancer Risk. Gut Liver. 2018 Jan 15;12(1):38-45.

11. International Agency for Research on Cancer. Monographs on the Identification of Carcinogenic Hazards to Humans. IARC. July 7, 2019. 12. Uemura N et al. N Engl J Med. 2001;345:784-9.

13. Lee YC et al. Gastroenterology. 2016;150:1113-24.

14. Ford AC et al. BMJ. 2014;348:g3174.

15. Chey W et al. Am J Gastroenterol. 2017;112:212-39.

16. Kumar S et al. Gastroenterology. 2020;158:527-36.

17. Kumar S et al. Clin Gastroenterol Hepatol. 2020 Apr 6;S1542-3565(20)30436-5.

18. González CA et al. Int J Cancer. 2003;107:629-34.

19. Ladeiras-Lopes R et al. Cancer Causes Control. 2008;19:689-701.

20. Cavaleiro-Pinto M et al. Cancer Causes Control. 2011;22:375-87.

21. Lauby-Secretan B et al. N Engl J Med. 2016;375:794-8.

22. Choi IJ et al. N Engl J Med. 2020;382:427-36.

23. Kim BJ et al. World J Gastroenterol. 2013;19:736-41.

24. Hamashima C. Jpn J Clin Oncol. 2018;48:278–86.

25. Saumoy M et al. Gastroenterology. 2018;155:648-60.

26. Shah SC et al. Clin Gastroenterol Hepatol. 2020 Jul 21:S1542-3565(20)30993-9. doi: 10.1016/j.cgh.2020.07.031.

27. Brinton LA et al. Br J Cancer. 1989;59:810-3.

28. Hsing AW et al. Cancer. 1993;71:745-50.

29. Schafer LW et al. Mayo Clin Proc. 1985;60:444-8.

30. American Society for Gastrointestinal Endoscopy Standards of Practice Committee. Gastrointest Endosc. 2015;82:1-8.

31. Chiu PWY et al. Gut. 2019;68:186-97.

32. Pimentel-Nunes P et al. Endoscopy. 2012;44:236-46.

33. Pimentel-Nunes P et al. Endoscopy. 2016;48:723-30.

34. Participants in the Paris Workshop. Gastrointest Endosc. 2003;58:S3-43.

35. Draganov PV et al. Clin Gastroenterol Hepatol. 2019;17:16-25.

36. Ngamruengphong S et al. Clin Gastroenterol Hepatol. 2020 Jun 18;S1542-3565(20)30834-X. Online ahead of print.

37. Choi IJ et al. N Engl J Med. 2018;378:1085-95.

Dr. Tomizawa is a clinical assistant professor of medicine in the division of gastroenterology, University of Washington, Seattle.

Introduction

Although gastric cancer is one of the most common causes of cancer death in the world, the burden of gastric cancer in the United States tends to be underestimated relative to that of other cancers of the digestive system. In fact, the 5-year survival rate from gastric cancer remains poor (~32%)¹ in the United States, and this is largely because gastric cancers are not diagnosed at an early stage when curative therapeutic options are available. Cumulative epidemiologic data consistently demonstrate that the incidence of gastric cancer in the United States varies according to ethnicity, immigrant status, and country of origin. It is important for practicing gastroenterologists in the United States to recognize individual risk profiles and identify people at higher risk for gastric cancer. Hereditary diffuse gastric cancer is an inherited form of diffuse-type gastric cancer and has pathogenic variants in the E-cadherin gene that are inherited in an autosomal dominant pattern. The lifetime risk of gastric cancer in individuals with HDGC is very high, and prophylactic total gastrectomy is usually advised. This article focuses on intestinal type cancer.

Epidemiology

Gastric cancer (proximal and distal gastric cancer combined) is the fifth most frequently diagnosed cancer and the third most common cause of cancer death worldwide, with 1,033,701 new cases and 782,685 deaths in 2018.² Gastric cancer is subcategorized based on location (proximal [i.e., esophagogastric junctional, gastric cardia] and distal) and histology (intestinal and diffuse type), and each subtype is considered to have a distinct pathogenesis. Distal intestinal type gastric cancer is most commonly encountered in clinical practice. In this article, gastric cancer will signify distal intestinal type gastric cancer unless it is otherwise noted. In general, incidence rates are about twofold higher in men than in women. There is marked geographic variation in incidence rates, and the age-standardized incidence rates in eastern Asia (32.1 and 13.2, per 100,000) are approximately six times higher than those in northern America (5.6 and 2.8, per 100,000) in both men and women, respectively.² Recent studies evaluating global trends in the incidence and mortality of gastric cancer have demonstrated decreases worldwide.^3-5 However, the degree of decrease in the incidence and mortality of gastric cancer varies substantially across geographic regions, reflecting the heterogeneous distribution of risk profiles. A comprehensive analysis of a U.S. population registry demonstrated a linear decrease in the incidence of gastric cancer in the United States (0.94% decrease per year between 2001 and 2015),⁶ though the annual percent change in the gastric cancer mortality in the United States was lower (around 2% decrease per year between 1980 and 2011) than in other countries.³Several population-based studies conducted in the United States have demonstrated that the incidence of gastric cancer varied by ethnicity, immigrant status, and country of origin, and the highest incidence was observed among Asian immigrants.^7,8 A comprehensive meta-analysis examining the risk of gastric cancer in immigrants from high-incidence regions to low-incidence regions found a persistently higher risk of gastric cancer and related mortality among immigrants.⁹ These results indicate that there are important risk factors such as environmental and dietary factors in addition to the traditionally considered risk factors including male gender, age, family history, and tobacco use. A survey conducted in an ethnically and culturally diverse U.S. city showed that gastroenterology providers demonstrated knowledge deficiencies in identifying and managing patients with increased risk of gastric cancer.¹⁰ Recognizing individualized risk profiles in higher-risk groups (e.g., immigrants from higher-incidence/prevalence regions) is important for optimizing management of gastric cancer in the United States.
 

Assessment and management of modifiable risk factors

Helicobacter pylori, a group 1 carcinogen, is the most well-recognized risk factor for gastric cancer, particularly noncardia gastric cancer.¹¹ Since a landmark longitudinal follow-up study in Japan demonstrated that people with H. pylori infection are more likely to develop gastric cancer than those without H. pylori infection,¹² accumulating evidence largely from Asian countries has shown that eradication of H. pylori is associated with a reduced incidence of gastric cancer regardless of baseline risk.¹³ There are also data on the protective effect for gastric cancer of H. pylori eradication in asymptomatic individuals. Another meta-analysis of six international randomized control trials demonstrated a 34% relative risk reduction of gastric cancer occurrence in asymptomatic people (relative risk of developing gastric cancer was 0.66 in those who received eradication therapy compared with those with placebo or no treatment, 95% CI, 0.46-0.95).¹⁴ A U.S. practice guideline published after these meta-analyses recommends that all patients with a positive test indicating active infection with H. pylori should be offered treatment and testing to prove eradication,¹⁵ though the recommendation was not purely intended to reduce the gastric cancer risk in U.S. population. Subsequently, a Department of Veterans Affairs cohort study added valuable insights from a U.S. experience to the body of evidence from other countries with higher prevalence. In this study of more than 370,000 patients with a history of H. pylori infection, the detection and successful eradication of H. pylori was associated with a 76% lower incidence of gastric cancer compared with people without H. pylori treatment.¹⁶ This study also provided insight into H. pylori treatment practice patterns. Of patients with a positive H. pylori test result (stool antigen, urea breath test, or pathology), approximately 75% were prescribed an eradication regimen and only 21% of those underwent eradication tests. A low rate (24%) of eradication testing was subsequently reported by the same group among U.S. patients regardless of gastric cancer risk profiles.¹⁷ The lesson from the aforementioned study is that treatment and eradication of H. pylori even among asymptomatic U.S. patients reduces the risk of subsequent gastric cancer. However, it may be difficult to generalize the results of this study given the nature of the Veterans Affairs cohort, and more data are required to justify the implementation of nationwide preventive H. pylori screening in the general U.S. population.

Who should we consider high risk and offer screening EGD?

With available evidence to date, screening for gastric cancer in a general U.S. population is not recommended. However, it is important to acknowledge the aforementioned varying incidence of gastric cancer in the United States among ethnicity, immigrant status, and country of origin. Immigrants from high-incidence regions maintain a higher risk of gastric cancer and related mortality even after migration to lower-incidence regions. The latter comprehensive study estimated that as many as 12.7 million people (29.4% of total U.S. immigrant population) have emigrated from higher-incidence regions including East Asian and some Central American countries.⁹ Indeed, an opportunistic nationwide gastric cancer screening program has been implemented in South Korea (beginning at age 40, biannually)²³ and Japan (beginning at age 50, biannually).²⁴ Two decision-analytic simulation studies have provided insight into the uncertainty about the cost effectiveness for potential targeted gastric cancer screening in higher-risk populations in the United States. One study demonstrated that esophagogastroduodenoscopy (EGD) screening for otherwise asymptomatic Asian American people (as well as Hispanics and non-Hispanic Blacks) at the time of screening colonoscopy at 50 years of age with continued endoscopic surveillance every 3 years was cost effective, only if gastric intestinal metaplasia (GIM) or more advanced lesions were diagnosed at the index screening EGD.²⁵ Previous studies analyzing the cost effectiveness for gastric cancer screening in the United States had the limitation of not stratifying according to race or ethnicity, or accounting for patients diagnosed with GIM. Subsequently, the same research group extended this model analysis and has published additional findings that this strategy is cost effective for each of the most prevalent Asian American ethnicities (Chinese, Filipino, Southeast Asian, Vietnamese, Korean, and Japanese Americans) in the United States irrespective of sex.²⁶ Although the authors raised a limitation that additional risk factors such as family history, tobacco use, or persistent H. pylori infection were not considered in the model because data regarding differentiated noncardia gastric cancer risk among Asian American ethnicities based on these risk factors are not available.

Practical consideration when we perform EGD for early gastric cancer screening

Identification of higher-risk patients should alert an endoscopist to observe mucosa with greater care with a lower threshold to biopsy any suspicious lesions. Preprocedural risk stratification for each individual before performing diagnostic EGD will improve early gastric cancer detection. While we perform EGD, detecting precursor lesions (atrophic gastritis and GIM) is as important as diagnosing an early gastric cancer. Screening and management of patients with precursor lesions (i.e., atrophic gastritis and GIM) is beyond the scope of this article, and this was published in a previous issue of the New Gastroenterologist. It is important to first grossly survey the entire gastric mucosa using high-definition while light (HDWL) endoscopy and screen for any focal irregular (raised or depressed) mucosal lesions. These lesions are often erythematous and should be examined carefully. Use of mucolytic and/or deforming agents (e.g., N-acetylcysteine or simethicone) is recommended for the improvement of visual clarity of gastric mucosa.³¹ Simethicone is widely used in the United States for colonoscopy and should also be available at the time of EGD for better gastric mucosal visibility. If irregular mucosal lesions are noted, this area should also be examined under narrowband imaging (NBI) in addition to HDWL. According to a simplified classification consisting of mucosal and vascular irregularity, NBI provides better mucosal surface morphology for diagnosis of early gastric cancer compared with HDWL, and a thorough examination of the surface characteristics is a prerequisite.³² This classification was further validated in a randomized control trial, and NBI increased sensitivity for the diagnosis of neoplasia compared with HDWL (92 % vs. 74 %).³³ The majority of institutions in the United States have a newer-generation NBI (Olympus America, EVIS EXERA III video system, GIF-HQ190), which provides brighter endoscopic images to better characterize gastric neoplastic lesions. Once we recognize an area suspicious for neoplasia, we should describe the macroscopic features according to a classification system.

Conclusion

As summarized above, cumulative epidemiologic data consistently demonstrate that the incidence of gastric cancer in the U.S. varies according to ethnicity, immigrant status, and country of origin. New gastroenterologists will need to recognize individual risk profiles and identify people at higher risk for gastric cancer. Risk stratification before performing endoscopic evaluation will improve early gastric cancer detection and make noninvasive, effective therapies an option.

References

1. Surveillance, Epidemiology, and End Results Program cancer statistics. https://seer.cancer.gov/statfacts/html/stomach.html.

2. Bray F et al. Ca Cancer J Clin. 2018;68:394-424.

3. Ferro A et al. Eur J Cancer. 2014;50:1330-44.

4. Luo G et al. Int J Cancer. 2017;141:1333-44.

5. Arnold M et al. Eur J Cancer. 2015;51:1164-87.

6. Thrift AP, El-Serag HB. Clin Gastroenterol Hepatol. 2020;18:534-42.

7. Kim Y et al. Epidemiol Health. 2015;37:e2015066.

8. Kamineni A et al. Cancer Causes Control. 1999;10:77-83.

9. Pabla BS et al. Clin Gastroenterol Hepatol. 2020;18:347-59.

10. Shah SC et al. Knowledge Gaps among Physicians Caring for Multiethnic Populations at Increased Gastric Cancer Risk. Gut Liver. 2018 Jan 15;12(1):38-45.

11. International Agency for Research on Cancer. Monographs on the Identification of Carcinogenic Hazards to Humans. IARC. July 7, 2019. 12. Uemura N et al. N Engl J Med. 2001;345:784-9.

13. Lee YC et al. Gastroenterology. 2016;150:1113-24.

14. Ford AC et al. BMJ. 2014;348:g3174.

15. Chey W et al. Am J Gastroenterol. 2017;112:212-39.

16. Kumar S et al. Gastroenterology. 2020;158:527-36.

17. Kumar S et al. Clin Gastroenterol Hepatol. 2020 Apr 6;S1542-3565(20)30436-5.

18. González CA et al. Int J Cancer. 2003;107:629-34.

19. Ladeiras-Lopes R et al. Cancer Causes Control. 2008;19:689-701.

20. Cavaleiro-Pinto M et al. Cancer Causes Control. 2011;22:375-87.

21. Lauby-Secretan B et al. N Engl J Med. 2016;375:794-8.

22. Choi IJ et al. N Engl J Med. 2020;382:427-36.

23. Kim BJ et al. World J Gastroenterol. 2013;19:736-41.

24. Hamashima C. Jpn J Clin Oncol. 2018;48:278–86.

25. Saumoy M et al. Gastroenterology. 2018;155:648-60.

26. Shah SC et al. Clin Gastroenterol Hepatol. 2020 Jul 21:S1542-3565(20)30993-9. doi: 10.1016/j.cgh.2020.07.031.

27. Brinton LA et al. Br J Cancer. 1989;59:810-3.

28. Hsing AW et al. Cancer. 1993;71:745-50.

29. Schafer LW et al. Mayo Clin Proc. 1985;60:444-8.

30. American Society for Gastrointestinal Endoscopy Standards of Practice Committee. Gastrointest Endosc. 2015;82:1-8.

31. Chiu PWY et al. Gut. 2019;68:186-97.

32. Pimentel-Nunes P et al. Endoscopy. 2012;44:236-46.

33. Pimentel-Nunes P et al. Endoscopy. 2016;48:723-30.

34. Participants in the Paris Workshop. Gastrointest Endosc. 2003;58:S3-43.

35. Draganov PV et al. Clin Gastroenterol Hepatol. 2019;17:16-25.

36. Ngamruengphong S et al. Clin Gastroenterol Hepatol. 2020 Jun 18;S1542-3565(20)30834-X. Online ahead of print.

37. Choi IJ et al. N Engl J Med. 2018;378:1085-95.

Dr. Tomizawa is a clinical assistant professor of medicine in the division of gastroenterology, University of Washington, Seattle.

When this editorial is published, we will know the results of the national election (hopefully) and whether there will be a smooth transition of power. We should know whether the Affordable Care Act will remain intact, and we will have indications about the impact of a COVID/flu combination. Health care will never be the same.

According to a recent Medscape survey, 62% of U.S. physicians saw a reduction of monthly income (12% saw a reduction of over 70%) in the first 6 months of this year. Almost a third of the physician workforce is contemplating retirement earlier than anticipated. As worrisome, according to a JAMA article (Aug 4, 2020;324:510-3) the United States saw a 35% increase in excess deaths because of non-COVID etiologies, an indication of health care deferral and avoidance. We all are scrambling to catch up and accommodate an enormous demand.

We are witnessing a “K” shaped recovery for both individuals and GI practices. If your health care is covered by Medicare, you own a mortgage-free home and your wealth is based on a balanced equity/bond portfolio, then all of your assets increased in value compared to last year’s peak valuations. For the other 90% of Americans, the recovery is modest, neutral, or more often nonexistent. Gastroenterologists who work in academic centers or large health systems did not lose income this year and were protected by billion-dollar credit lines and cash-on-hand accounts from robust days available to these entities. Independent practices (critically dependent on monthly cash flow) were decimated, furthering the trend towards consolidation, retirement, and acquisitions. With the new CMS E/M valuations we will see further reduction in procedural reimbursement.

Our postpandemic world will be dramatically different from pre-COVID times. However, disruption always precipitates innovation. Challenges are great but opportunities are clearly evident for those willing to risk.
 

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

When this editorial is published, we will know the results of the national election (hopefully) and whether there will be a smooth transition of power. We should know whether the Affordable Care Act will remain intact, and we will have indications about the impact of a COVID/flu combination. Health care will never be the same.

According to a recent Medscape survey, 62% of U.S. physicians saw a reduction of monthly income (12% saw a reduction of over 70%) in the first 6 months of this year. Almost a third of the physician workforce is contemplating retirement earlier than anticipated. As worrisome, according to a JAMA article (Aug 4, 2020;324:510-3) the United States saw a 35% increase in excess deaths because of non-COVID etiologies, an indication of health care deferral and avoidance. We all are scrambling to catch up and accommodate an enormous demand.

We are witnessing a “K” shaped recovery for both individuals and GI practices. If your health care is covered by Medicare, you own a mortgage-free home and your wealth is based on a balanced equity/bond portfolio, then all of your assets increased in value compared to last year’s peak valuations. For the other 90% of Americans, the recovery is modest, neutral, or more often nonexistent. Gastroenterologists who work in academic centers or large health systems did not lose income this year and were protected by billion-dollar credit lines and cash-on-hand accounts from robust days available to these entities. Independent practices (critically dependent on monthly cash flow) were decimated, furthering the trend towards consolidation, retirement, and acquisitions. With the new CMS E/M valuations we will see further reduction in procedural reimbursement.

Our postpandemic world will be dramatically different from pre-COVID times. However, disruption always precipitates innovation. Challenges are great but opportunities are clearly evident for those willing to risk.
 

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

When this editorial is published, we will know the results of the national election (hopefully) and whether there will be a smooth transition of power. We should know whether the Affordable Care Act will remain intact, and we will have indications about the impact of a COVID/flu combination. Health care will never be the same.

According to a recent Medscape survey, 62% of U.S. physicians saw a reduction of monthly income (12% saw a reduction of over 70%) in the first 6 months of this year. Almost a third of the physician workforce is contemplating retirement earlier than anticipated. As worrisome, according to a JAMA article (Aug 4, 2020;324:510-3) the United States saw a 35% increase in excess deaths because of non-COVID etiologies, an indication of health care deferral and avoidance. We all are scrambling to catch up and accommodate an enormous demand.

We are witnessing a “K” shaped recovery for both individuals and GI practices. If your health care is covered by Medicare, you own a mortgage-free home and your wealth is based on a balanced equity/bond portfolio, then all of your assets increased in value compared to last year’s peak valuations. For the other 90% of Americans, the recovery is modest, neutral, or more often nonexistent. Gastroenterologists who work in academic centers or large health systems did not lose income this year and were protected by billion-dollar credit lines and cash-on-hand accounts from robust days available to these entities. Independent practices (critically dependent on monthly cash flow) were decimated, furthering the trend towards consolidation, retirement, and acquisitions. With the new CMS E/M valuations we will see further reduction in procedural reimbursement.

Our postpandemic world will be dramatically different from pre-COVID times. However, disruption always precipitates innovation. Challenges are great but opportunities are clearly evident for those willing to risk.
 

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

No clinically meaningful changes in laboratory values occurred in adolescents during 52 weeks on dupilumab for atopic dermatitis in a large, open-label safety study, Michael J. Cork, MBBS, PhD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.

These reassuring results from the ongoing LIBERTY AD PED-OLE study confirm that, as previously established in adults, no blood monitoring is required in adolescents on the monoclonal antibody, which inhibits signaling of interleukins-4 and -13, said Dr. Cork, professor of dermatology and head of Sheffield Dermatology Research at the University of Sheffield (England).

“The practical importance of this finding is that there are no other systemic drugs available that don’t require blood samples. Cyclosporine, methotrexate, and the others used for atopic dermatitis require a lot of blood monitoring, and they’re off-license anyway for use in children and adolescents,” he said in an interview.

Many pediatric patients are afraid of needles and have an intense dislike of blood draws. And in a pandemic, no one wants to come into the office for blood draws if they don’t need to.

“Blood draws are very different from the injection for dupilumab. Taking a blood sample is much more painful for children. The needle in the autoinjector is really, really tiny; you can hardly feel it, and with the autoinjector you can’t even see it,” noted Dr. Cork, who is both a pediatric and adult dermatologist.

This report from the ongoing LIBERTY AD PED-OLE study included 105 patients aged 12-17 years who completed 52 weeks on dupilumab (Dupixent) with assessments of hematologic and serum chemistry parameters at baseline and weeks 16 and 52.

“The results were anticipated, but we want to know the drug is safe in every age group. The immune system is different in different age groups, so we have to be really careful,” Dr. Cork said.

The clinical side-effect profile was the same as in adults, consisting mainly of mild conjunctivitis and injection-site reactions. It’s a much less problematic side effect picture than with the older drugs.

“We’re finding the conjunctivitis to be slightly less severe than in adults, maybe because we’ve learned from the first trials in adults and from clinical experience to use prophylactic therapy. There would be no child going on dupilumab now – and no adult – that I wouldn’t put on prophylactic eye drops with replacement tears. I start them 2 weeks before I start dupilumab,” the dermatologist explained.

He and others with extensive experience using the biologic agent also work closely with an ophthalmologist.

“If we see an eye problem before going on dupilumab we get an assessment and then ophthalmologic monitoring during treatment,” Dr. Cork said.

As a dermatologist specializing in atopic dermatitis, he confessed to feeling deprived over the years as he watched the multitude of targeted biologic agents being developed for psoriasis. When he became involved in the first pediatric clinical trials of dupilumab, he had a realization: “It’s a miraculous treatment.”

“The first child I put on dupilumab spent 70 days in the hospital for IV antibiotics in the prior year. Seventy days! He almost died from MRSA septicemia. His serum IgE was 155,000 kU/L. And his IgE just went down and down and down as the dupilumab took effect. It was just incredible,” he recalled.

Dr. Cork reported receiving research funding from and serving as a consultant to Sanofi and Regeneron, which fund the LIBERTY AD PED-OLE study, as well as numerous other pharmaceutical companies.

[email protected]

SOURCE: Cork MJ. EADV 2020, Abstract 1772.

No clinically meaningful changes in laboratory values occurred in adolescents during 52 weeks on dupilumab for atopic dermatitis in a large, open-label safety study, Michael J. Cork, MBBS, PhD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.

These reassuring results from the ongoing LIBERTY AD PED-OLE study confirm that, as previously established in adults, no blood monitoring is required in adolescents on the monoclonal antibody, which inhibits signaling of interleukins-4 and -13, said Dr. Cork, professor of dermatology and head of Sheffield Dermatology Research at the University of Sheffield (England).

“The practical importance of this finding is that there are no other systemic drugs available that don’t require blood samples. Cyclosporine, methotrexate, and the others used for atopic dermatitis require a lot of blood monitoring, and they’re off-license anyway for use in children and adolescents,” he said in an interview.

Many pediatric patients are afraid of needles and have an intense dislike of blood draws. And in a pandemic, no one wants to come into the office for blood draws if they don’t need to.

“Blood draws are very different from the injection for dupilumab. Taking a blood sample is much more painful for children. The needle in the autoinjector is really, really tiny; you can hardly feel it, and with the autoinjector you can’t even see it,” noted Dr. Cork, who is both a pediatric and adult dermatologist.

This report from the ongoing LIBERTY AD PED-OLE study included 105 patients aged 12-17 years who completed 52 weeks on dupilumab (Dupixent) with assessments of hematologic and serum chemistry parameters at baseline and weeks 16 and 52.

“The results were anticipated, but we want to know the drug is safe in every age group. The immune system is different in different age groups, so we have to be really careful,” Dr. Cork said.

The clinical side-effect profile was the same as in adults, consisting mainly of mild conjunctivitis and injection-site reactions. It’s a much less problematic side effect picture than with the older drugs.

“We’re finding the conjunctivitis to be slightly less severe than in adults, maybe because we’ve learned from the first trials in adults and from clinical experience to use prophylactic therapy. There would be no child going on dupilumab now – and no adult – that I wouldn’t put on prophylactic eye drops with replacement tears. I start them 2 weeks before I start dupilumab,” the dermatologist explained.

He and others with extensive experience using the biologic agent also work closely with an ophthalmologist.

“If we see an eye problem before going on dupilumab we get an assessment and then ophthalmologic monitoring during treatment,” Dr. Cork said.

As a dermatologist specializing in atopic dermatitis, he confessed to feeling deprived over the years as he watched the multitude of targeted biologic agents being developed for psoriasis. When he became involved in the first pediatric clinical trials of dupilumab, he had a realization: “It’s a miraculous treatment.”

“The first child I put on dupilumab spent 70 days in the hospital for IV antibiotics in the prior year. Seventy days! He almost died from MRSA septicemia. His serum IgE was 155,000 kU/L. And his IgE just went down and down and down as the dupilumab took effect. It was just incredible,” he recalled.

Dr. Cork reported receiving research funding from and serving as a consultant to Sanofi and Regeneron, which fund the LIBERTY AD PED-OLE study, as well as numerous other pharmaceutical companies.

[email protected]

SOURCE: Cork MJ. EADV 2020, Abstract 1772.

No clinically meaningful changes in laboratory values occurred in adolescents during 52 weeks on dupilumab for atopic dermatitis in a large, open-label safety study, Michael J. Cork, MBBS, PhD, reported at the virtual annual congress of the European Academy of Dermatology and Venereology.

These reassuring results from the ongoing LIBERTY AD PED-OLE study confirm that, as previously established in adults, no blood monitoring is required in adolescents on the monoclonal antibody, which inhibits signaling of interleukins-4 and -13, said Dr. Cork, professor of dermatology and head of Sheffield Dermatology Research at the University of Sheffield (England).

“The practical importance of this finding is that there are no other systemic drugs available that don’t require blood samples. Cyclosporine, methotrexate, and the others used for atopic dermatitis require a lot of blood monitoring, and they’re off-license anyway for use in children and adolescents,” he said in an interview.

Many pediatric patients are afraid of needles and have an intense dislike of blood draws. And in a pandemic, no one wants to come into the office for blood draws if they don’t need to.

“Blood draws are very different from the injection for dupilumab. Taking a blood sample is much more painful for children. The needle in the autoinjector is really, really tiny; you can hardly feel it, and with the autoinjector you can’t even see it,” noted Dr. Cork, who is both a pediatric and adult dermatologist.

This report from the ongoing LIBERTY AD PED-OLE study included 105 patients aged 12-17 years who completed 52 weeks on dupilumab (Dupixent) with assessments of hematologic and serum chemistry parameters at baseline and weeks 16 and 52.

“The results were anticipated, but we want to know the drug is safe in every age group. The immune system is different in different age groups, so we have to be really careful,” Dr. Cork said.

The clinical side-effect profile was the same as in adults, consisting mainly of mild conjunctivitis and injection-site reactions. It’s a much less problematic side effect picture than with the older drugs.

“We’re finding the conjunctivitis to be slightly less severe than in adults, maybe because we’ve learned from the first trials in adults and from clinical experience to use prophylactic therapy. There would be no child going on dupilumab now – and no adult – that I wouldn’t put on prophylactic eye drops with replacement tears. I start them 2 weeks before I start dupilumab,” the dermatologist explained.

He and others with extensive experience using the biologic agent also work closely with an ophthalmologist.

“If we see an eye problem before going on dupilumab we get an assessment and then ophthalmologic monitoring during treatment,” Dr. Cork said.

As a dermatologist specializing in atopic dermatitis, he confessed to feeling deprived over the years as he watched the multitude of targeted biologic agents being developed for psoriasis. When he became involved in the first pediatric clinical trials of dupilumab, he had a realization: “It’s a miraculous treatment.”

“The first child I put on dupilumab spent 70 days in the hospital for IV antibiotics in the prior year. Seventy days! He almost died from MRSA septicemia. His serum IgE was 155,000 kU/L. And his IgE just went down and down and down as the dupilumab took effect. It was just incredible,” he recalled.

Dr. Cork reported receiving research funding from and serving as a consultant to Sanofi and Regeneron, which fund the LIBERTY AD PED-OLE study, as well as numerous other pharmaceutical companies.

[email protected]

SOURCE: Cork MJ. EADV 2020, Abstract 1772.

Adding a second-generation antipsychotic to an antidepressant to treat depression carries an increased mortality risk for middle-aged adults, results of a large, observational study show.

“Our study suggests physicians should consider prescribing antipsychotics to adults with depression carefully, as the potential health risks are substantial and the benefits are quite modest and controversially debated,” lead investigator Tobias Gerhard, PhD, Center for Pharmacoepidemiology and Treatment Science, Rutgers University, New Brunswick, N.J., said in a news release.

The results, he added, “emphasize the importance of considering newer antipsychotics only after nonresponse to less risky, evidence-based treatment options has been established.”

The study was published online September 30 in PLOS ONE.
 

A last resort

Previous research has demonstrated an increased mortality risk for elderly patients with dementia who take an atypical antipsychotic, but it’s unclear whether this risk occurs among nonelderly adults who use newer antipsychotics as augmentation treatment for depression.

To investigate, Gerhard and colleagues analyzed national healthcare claims from the Medicaid program from 2001 to 2010 for 39,582 Medicaid beneficiaries (mean age, 44.5 years; 78.5% women) who had been diagnosed with depression. Patients with alternative indications for antipsychotic therapy, such as schizophrenia, psychotic depression, or bipolar disorder, were excluded.

After at least 3 months of treatment with a single antidepressant, for more than half of the patients (56.6%), treatment was augmented with an atypical antipsychotic (quetiapine, risperidone, aripiprazole or olanzapine). For the remainder (43.4%), a second antidepressant was added.

The average chlorpromazine equivalent starting dose for all atypical antipsychotics was 68 mg/d. The dose was increased to 100 mg/d during follow-up.

A total of 153 patients died during 13,328 person-years of follow-up, including 105 for whom treatment was augmented with an atypical antipsychotic and 48 for whom treatment was augmented with a second antidepressant.

Compared to those who received a second antidepressant, among those for whom an antipsychotic was added, there was a 45% increased risk of dying during follow-up (adjusted hazard ratio, 1.45; 95% CI, 1.02 – 2.06).

This equates to an absolute risk difference of 37.7 deaths per 10,000 person-years of treatment (0.38% per year) and a number needed to harm of roughly 265 per year. For higher-risk subgroups, the number needed to harm decreased substantially, the authors note. The results were robust across several sensitivity analyses.

“We don’t know the mechanisms of the increased mortality risk, but cardiac and infectious causes are leading candidates,” said Gerhard.

“Our study in nonelderly adults with depression did not identify a single predominant cause of death. However, this may be a result of both the relatively small number of deaths in our study as well as of the well-recognized concerns regarding the accuracy of cause-of-death attribution in death certificates,” Gerhard said.

“As with the potential causes of death, the pathophysiological pathways involved are not well understood but could, among others, involve adverse metabolic effects, including weight gain, diabetes, dyslipidemia, QT prolongation, sedation, and falls – all of which have been associated with at least some of the newer antipsychotics,” he added.

The researchers state that atypical antipsychotics should be considered only “after non-response to evidence-based treatment options that are less risky.”
 

Another red flag

Commenting for Medscape Medical News, Timothy Sullivan, MD, chair of psychiatry and behavioral sciences at Northwell Health’s Staten Island University Hospital in New York, said this is a “valid contribution” and represents the second large study that “raises the same concern.”

“We’ve been probably underestimating the risk in administering them, and that’s something people really need to know, because if you’re prescribing it for someone with mild to moderate depression, it may be helpful, but is it really worth the risk if you’re significantly increasing their risk of death?” said Sullivan, who wasn’t involved in the study.

Clearly, he said, this “raises a flag that we have to look at this a little more carefully and be a little clearer with patients about the risk. One could argue that we should not be so quick to add these drugs, even though they could be helpful, before we exhaust other less potentially risky options.”

Sullivan’s advice: “Do the three trials of antidepressants, look at antidepressant combinations, don’t be quick to jump to this particular option, because of the concerns. Certainly there are situations like psychotic depression where the risk of use is outweighed by the benefits, given the clinical syndrome, but for less severe forms, we probably should reformulate some of our algorithms.”

The study was supported by the National Institute of Mental Health (NIMH). Gerhard received grants from the NIMH and the National Institute on Aging during the conduct of the study; grants and personal fees from Bristol-Myers Squibb; and personal fees from Eisai, Merck, Pfizer, Lilly, and IntraCellular Therapies outside the submitted work. Sullivan has disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Adding a second-generation antipsychotic to an antidepressant to treat depression carries an increased mortality risk for middle-aged adults, results of a large, observational study show.

“Our study suggests physicians should consider prescribing antipsychotics to adults with depression carefully, as the potential health risks are substantial and the benefits are quite modest and controversially debated,” lead investigator Tobias Gerhard, PhD, Center for Pharmacoepidemiology and Treatment Science, Rutgers University, New Brunswick, N.J., said in a news release.

The results, he added, “emphasize the importance of considering newer antipsychotics only after nonresponse to less risky, evidence-based treatment options has been established.”

The study was published online September 30 in PLOS ONE.
 

A last resort

Previous research has demonstrated an increased mortality risk for elderly patients with dementia who take an atypical antipsychotic, but it’s unclear whether this risk occurs among nonelderly adults who use newer antipsychotics as augmentation treatment for depression.

To investigate, Gerhard and colleagues analyzed national healthcare claims from the Medicaid program from 2001 to 2010 for 39,582 Medicaid beneficiaries (mean age, 44.5 years; 78.5% women) who had been diagnosed with depression. Patients with alternative indications for antipsychotic therapy, such as schizophrenia, psychotic depression, or bipolar disorder, were excluded.

After at least 3 months of treatment with a single antidepressant, for more than half of the patients (56.6%), treatment was augmented with an atypical antipsychotic (quetiapine, risperidone, aripiprazole or olanzapine). For the remainder (43.4%), a second antidepressant was added.

The average chlorpromazine equivalent starting dose for all atypical antipsychotics was 68 mg/d. The dose was increased to 100 mg/d during follow-up.

A total of 153 patients died during 13,328 person-years of follow-up, including 105 for whom treatment was augmented with an atypical antipsychotic and 48 for whom treatment was augmented with a second antidepressant.

Compared to those who received a second antidepressant, among those for whom an antipsychotic was added, there was a 45% increased risk of dying during follow-up (adjusted hazard ratio, 1.45; 95% CI, 1.02 – 2.06).

This equates to an absolute risk difference of 37.7 deaths per 10,000 person-years of treatment (0.38% per year) and a number needed to harm of roughly 265 per year. For higher-risk subgroups, the number needed to harm decreased substantially, the authors note. The results were robust across several sensitivity analyses.

“We don’t know the mechanisms of the increased mortality risk, but cardiac and infectious causes are leading candidates,” said Gerhard.

“Our study in nonelderly adults with depression did not identify a single predominant cause of death. However, this may be a result of both the relatively small number of deaths in our study as well as of the well-recognized concerns regarding the accuracy of cause-of-death attribution in death certificates,” Gerhard said.

“As with the potential causes of death, the pathophysiological pathways involved are not well understood but could, among others, involve adverse metabolic effects, including weight gain, diabetes, dyslipidemia, QT prolongation, sedation, and falls – all of which have been associated with at least some of the newer antipsychotics,” he added.

The researchers state that atypical antipsychotics should be considered only “after non-response to evidence-based treatment options that are less risky.”
 

Another red flag

Commenting for Medscape Medical News, Timothy Sullivan, MD, chair of psychiatry and behavioral sciences at Northwell Health’s Staten Island University Hospital in New York, said this is a “valid contribution” and represents the second large study that “raises the same concern.”

“We’ve been probably underestimating the risk in administering them, and that’s something people really need to know, because if you’re prescribing it for someone with mild to moderate depression, it may be helpful, but is it really worth the risk if you’re significantly increasing their risk of death?” said Sullivan, who wasn’t involved in the study.

Clearly, he said, this “raises a flag that we have to look at this a little more carefully and be a little clearer with patients about the risk. One could argue that we should not be so quick to add these drugs, even though they could be helpful, before we exhaust other less potentially risky options.”

Sullivan’s advice: “Do the three trials of antidepressants, look at antidepressant combinations, don’t be quick to jump to this particular option, because of the concerns. Certainly there are situations like psychotic depression where the risk of use is outweighed by the benefits, given the clinical syndrome, but for less severe forms, we probably should reformulate some of our algorithms.”

The study was supported by the National Institute of Mental Health (NIMH). Gerhard received grants from the NIMH and the National Institute on Aging during the conduct of the study; grants and personal fees from Bristol-Myers Squibb; and personal fees from Eisai, Merck, Pfizer, Lilly, and IntraCellular Therapies outside the submitted work. Sullivan has disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Adding a second-generation antipsychotic to an antidepressant to treat depression carries an increased mortality risk for middle-aged adults, results of a large, observational study show.

“Our study suggests physicians should consider prescribing antipsychotics to adults with depression carefully, as the potential health risks are substantial and the benefits are quite modest and controversially debated,” lead investigator Tobias Gerhard, PhD, Center for Pharmacoepidemiology and Treatment Science, Rutgers University, New Brunswick, N.J., said in a news release.

The results, he added, “emphasize the importance of considering newer antipsychotics only after nonresponse to less risky, evidence-based treatment options has been established.”

The study was published online September 30 in PLOS ONE.
 

A last resort

Previous research has demonstrated an increased mortality risk for elderly patients with dementia who take an atypical antipsychotic, but it’s unclear whether this risk occurs among nonelderly adults who use newer antipsychotics as augmentation treatment for depression.

To investigate, Gerhard and colleagues analyzed national healthcare claims from the Medicaid program from 2001 to 2010 for 39,582 Medicaid beneficiaries (mean age, 44.5 years; 78.5% women) who had been diagnosed with depression. Patients with alternative indications for antipsychotic therapy, such as schizophrenia, psychotic depression, or bipolar disorder, were excluded.

After at least 3 months of treatment with a single antidepressant, for more than half of the patients (56.6%), treatment was augmented with an atypical antipsychotic (quetiapine, risperidone, aripiprazole or olanzapine). For the remainder (43.4%), a second antidepressant was added.

The average chlorpromazine equivalent starting dose for all atypical antipsychotics was 68 mg/d. The dose was increased to 100 mg/d during follow-up.

A total of 153 patients died during 13,328 person-years of follow-up, including 105 for whom treatment was augmented with an atypical antipsychotic and 48 for whom treatment was augmented with a second antidepressant.

Compared to those who received a second antidepressant, among those for whom an antipsychotic was added, there was a 45% increased risk of dying during follow-up (adjusted hazard ratio, 1.45; 95% CI, 1.02 – 2.06).

This equates to an absolute risk difference of 37.7 deaths per 10,000 person-years of treatment (0.38% per year) and a number needed to harm of roughly 265 per year. For higher-risk subgroups, the number needed to harm decreased substantially, the authors note. The results were robust across several sensitivity analyses.

“We don’t know the mechanisms of the increased mortality risk, but cardiac and infectious causes are leading candidates,” said Gerhard.

“Our study in nonelderly adults with depression did not identify a single predominant cause of death. However, this may be a result of both the relatively small number of deaths in our study as well as of the well-recognized concerns regarding the accuracy of cause-of-death attribution in death certificates,” Gerhard said.

“As with the potential causes of death, the pathophysiological pathways involved are not well understood but could, among others, involve adverse metabolic effects, including weight gain, diabetes, dyslipidemia, QT prolongation, sedation, and falls – all of which have been associated with at least some of the newer antipsychotics,” he added.

The researchers state that atypical antipsychotics should be considered only “after non-response to evidence-based treatment options that are less risky.”
 

Another red flag

Commenting for Medscape Medical News, Timothy Sullivan, MD, chair of psychiatry and behavioral sciences at Northwell Health’s Staten Island University Hospital in New York, said this is a “valid contribution” and represents the second large study that “raises the same concern.”

“We’ve been probably underestimating the risk in administering them, and that’s something people really need to know, because if you’re prescribing it for someone with mild to moderate depression, it may be helpful, but is it really worth the risk if you’re significantly increasing their risk of death?” said Sullivan, who wasn’t involved in the study.

Clearly, he said, this “raises a flag that we have to look at this a little more carefully and be a little clearer with patients about the risk. One could argue that we should not be so quick to add these drugs, even though they could be helpful, before we exhaust other less potentially risky options.”

Sullivan’s advice: “Do the three trials of antidepressants, look at antidepressant combinations, don’t be quick to jump to this particular option, because of the concerns. Certainly there are situations like psychotic depression where the risk of use is outweighed by the benefits, given the clinical syndrome, but for less severe forms, we probably should reformulate some of our algorithms.”

The study was supported by the National Institute of Mental Health (NIMH). Gerhard received grants from the NIMH and the National Institute on Aging during the conduct of the study; grants and personal fees from Bristol-Myers Squibb; and personal fees from Eisai, Merck, Pfizer, Lilly, and IntraCellular Therapies outside the submitted work. Sullivan has disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

The Food and Drug Administration has approved 0.5% lotion formulation of ivermectin (Sklice) as an over-the-counter treatment for head lice infestation in patients aged 6 months and older.

Ivermectin was approved as a prescription treatment for head lice in February 2012, according to an FDA press release, and is now approved as an over-the-counter treatment through an “Rx-to-OTC” switch process. The approval was granted to Arbor Pharmaceuticals.

The expanded approval for ivermectin increases access to effective care for head lice, which is estimated to affect between 6 million and 12 million children each year in the United States, according to the Centers for Disease Control and Prevention.

“The Rx-to-OTC switch process aims to promote public health by increasing consumer access to drugs that would otherwise only be available by prescription,” Theresa Michele, MD, acting director of the Office of Nonprescription Drugs in the FDA’s Center for Drug Evaluation and Research, said in the press release.

The FDA also noted in the press release that “Sklice, and its active ingredient ivermectin, have not been shown to be safe or effective for the treatment or prevention of COVID-19 and they are not FDA-approved for this use.”

The drug is approved only for treating head lice, and should be used on the scalp and dry hair, according to the labeling. In the wake of the approval, ivermectin will no longer be available as a prescription drug, according to the FDA, and patients currently using prescription versions should contact their health care providers.

An Rx-to-OTC switch is contingent on the manufacturer’s data showing that the drug is safe and effective when used as directed. In addition, “the manufacturer must show that consumers can understand how to use the drug safely and effectively without the supervision of a health care professional,” according to the FDA.

The Food and Drug Administration has approved 0.5% lotion formulation of ivermectin (Sklice) as an over-the-counter treatment for head lice infestation in patients aged 6 months and older.

Ivermectin was approved as a prescription treatment for head lice in February 2012, according to an FDA press release, and is now approved as an over-the-counter treatment through an “Rx-to-OTC” switch process. The approval was granted to Arbor Pharmaceuticals.

The expanded approval for ivermectin increases access to effective care for head lice, which is estimated to affect between 6 million and 12 million children each year in the United States, according to the Centers for Disease Control and Prevention.

“The Rx-to-OTC switch process aims to promote public health by increasing consumer access to drugs that would otherwise only be available by prescription,” Theresa Michele, MD, acting director of the Office of Nonprescription Drugs in the FDA’s Center for Drug Evaluation and Research, said in the press release.

The FDA also noted in the press release that “Sklice, and its active ingredient ivermectin, have not been shown to be safe or effective for the treatment or prevention of COVID-19 and they are not FDA-approved for this use.”

The drug is approved only for treating head lice, and should be used on the scalp and dry hair, according to the labeling. In the wake of the approval, ivermectin will no longer be available as a prescription drug, according to the FDA, and patients currently using prescription versions should contact their health care providers.

An Rx-to-OTC switch is contingent on the manufacturer’s data showing that the drug is safe and effective when used as directed. In addition, “the manufacturer must show that consumers can understand how to use the drug safely and effectively without the supervision of a health care professional,” according to the FDA.

The Food and Drug Administration has approved 0.5% lotion formulation of ivermectin (Sklice) as an over-the-counter treatment for head lice infestation in patients aged 6 months and older.

Ivermectin was approved as a prescription treatment for head lice in February 2012, according to an FDA press release, and is now approved as an over-the-counter treatment through an “Rx-to-OTC” switch process. The approval was granted to Arbor Pharmaceuticals.

The expanded approval for ivermectin increases access to effective care for head lice, which is estimated to affect between 6 million and 12 million children each year in the United States, according to the Centers for Disease Control and Prevention.

“The Rx-to-OTC switch process aims to promote public health by increasing consumer access to drugs that would otherwise only be available by prescription,” Theresa Michele, MD, acting director of the Office of Nonprescription Drugs in the FDA’s Center for Drug Evaluation and Research, said in the press release.

The FDA also noted in the press release that “Sklice, and its active ingredient ivermectin, have not been shown to be safe or effective for the treatment or prevention of COVID-19 and they are not FDA-approved for this use.”

The drug is approved only for treating head lice, and should be used on the scalp and dry hair, according to the labeling. In the wake of the approval, ivermectin will no longer be available as a prescription drug, according to the FDA, and patients currently using prescription versions should contact their health care providers.

An Rx-to-OTC switch is contingent on the manufacturer’s data showing that the drug is safe and effective when used as directed. In addition, “the manufacturer must show that consumers can understand how to use the drug safely and effectively without the supervision of a health care professional,” according to the FDA.

Christopher Pribula, MD, a hospitalist at Sanford Broadway Medical Center in Fargo, N.D., didn’t anticipate becoming his hospital’s resident expert on COVID-19. Having just returned from vacation in March, he agreed to cover for a colleague on what would become the special care unit. “When our hospital medicine group decided that it would be the COVID unit, I just ran with it,” he said. Dr. Pribula spent the next 18 days doing 8- to 14-hour shifts and learning as much as he could as the hospital – and the nation – wrestled with the pandemic.

“Because I was the first hospitalist, along with our infectious disease specialist, Dr. Avish Nagpal, to really engage with the virus, people came to me with their questions,” Dr. Pribula said. Working to establish protocols for the care of COVID-19 patients involved a lot of planning, from nursing protocols to discharge planning.

Dr. Pribula was part of the hospital’s incident command structure, thought about how the system could scale up for a potential surge, and worked with the North Dakota Medical Association to reach out to outlying medical centers on safety and infection control. He even drew on his prior work experience as a medical technologist doing negative-pressure containment in a cell-processing facility to help create the hospital’s negative-pressure unit in an old ICU.

“We did a lot of communication from the start. To a certain extent we were making it up as we went along, but we sat down and huddled as a team every day at 9 and 4,” he explained. “We started out with observation and retrospective research, and learned piece by piece. But that’s how science works.”

Hospitalists across the country have played leading roles in their hospitals’ and health systems’ response to the pandemic, and not just because they are on the front lines providing patient care. Their job as doctors who work full-time in the hospital makes them natural leaders in improving clinical quality and hospital administrative protocols as well as studying the latest information and educating their colleagues. Responding to the pandemic has required lots of planning, careful attention to schedules and assignments and staff stress, and working with other departments in the hospital and groups in the community, including public health authorities.
 

Where is hospital treatment for COVID-19 at today?

As knowledge has grown, Dr. Pribula said, COVID-19 treatment in the hospital has come to incorporate remdesivir, a broad-spectrum antiviral; dexamethasone, a common steroid medication; and convalescent plasma, blood products from people who have recovered from the illness. “We went from no steroids to giving steroids. We went from putting patients on ventilators to avoid acute respiratory distress syndrome (ARDS) initially to now working to avoid intubation at all costs,” he said.

“What we found is that we need to pressure-support these patients. We do proning and CPAP while we let the lungs heal. By the time they arrive at the hospital, more often than not they’re on the backside of the viral load. But now we’re dealing with the body’s inflammatory response.”

Navneet Attri, MD, a hospitalist at Sutter Santa Rosa Regional Hospital in Santa Rosa, Calif., 50 miles north of San Francisco, experienced fears and uncertainties working at a hospital that treated early COVID patients from the Grand Princess cruise ship. Early on, she wrote a post describing her experience for The Hospitalist Leader, the Society of Hospital Medicine’s blog page.

Dr. Attri said she has gone through the gamut of emotions while caring for COVID-19 patients, addressing their fears and trying to support family members who aren’t allowed to enter the hospital to be at their loved one’s side. Sometimes, patient after patient with COVID-19 becomes almost too much. But seeing a lot of them in the intervening 6 months has increased her confidence level.

Understanding of how the disease is spread has continued to evolve, with a recent return to focusing on airborne transmission, she said. Frontline workers need N95 masks and eye shields, even if all of that PPE feels like a burden. Dr. Attri said she hardly notices the PPE anymore. “Putting it on is just a habit.”

She sits on Sonoma County’s COVID-19 surge planning group, which has representatives from the three local hospitals, the public health department, and other community agencies. “I report back to my hospitalist group about the situation in the community. Because our facilities were well prepared, our hospitals have not been overwhelmed,” she said.
 

The importance of teamwork

Sunil Shah, MD, a hospitalist with Northwell Health’s Southside Hospital in Bay Shore, N.Y., is part of the massive hospital medicine team, including reassigned specialists and volunteers from across the country, deployed at Northwell hospitals in Greater New York City and Long Island during the COVID-19 surge. Northwell probably has cared for more COVID-19 patients than any other health system in the country, and at the height of the surge the intensity of hospital care was like nothing he’s ever seen. But he also expressed gratitude that doctors from other parts of the country were willing to come and help out.

Southside Hospital went almost overnight from a 200-bed acute facility to a full, 350-bed, regional COVID-19–only hospital. “On busy days, our entire hospital was like a floating ICU,” he said. “You’d hear ‘rapid response’ or ‘code blue’ over the intercom every few seconds. Normally we’d have a designated rapid response person for the day, but with COVID, everybody stepped in to help – whoever was closest,” he said.

Majid Sheikh, MD, a hospitalist at Emory University Hospital in Atlanta, also became a go-to COVID-19 expert for his group. “I didn’t specifically volunteer, but my partner and I had the first cases, and the leadership group was happy to have us there,” he explained.

“One interesting thing I learned was the concept of the ‘happy’ hypoxemic patient, who is having a significant drop in oxygen saturation without developing any obvious signs of respiratory distress,” he said. “We’d be checking the accuracy of the reading and trying to figure out if it was real.” Emory was also one of the leaders in studying anticoagulant treatments for COVID-19 patients.

“Six months later I would say we’re definitely getting better outcomes on the floor, and our COVID patients aren’t landing in the ICU as easily,” Dr. Sheikh said. “It was scary at first, and doubly scary when doctors sometimes don’t feel they can say, ‘Hey, I’m scared too,’ or ‘By the way, I really don’t know what I’m doing.’ So, we’d be trying to reassure the patients when the information was coming to us in fragments.”

But he also believes that the pandemic has afforded hospitalists the opportunity to be the clinical detectives they were trained to be, sifting through clues. “I had to think more and really pay attention clinically in a much different way. You could say it was exciting and scary at the same time,” he said.
 

A human fix in the hospital

Dr. Pribula agreed that the pandemic has been both a difficult experience and a rewarding one. “I think of the people I first admitted. If they had shown up even a month later, would they still be with us?” He believes that his group and his field are going to get to a place where they have solid treatment plans for how to provide optimal care and how to protect providers from exposure.

One of the first COVID-19 patients in Fargo had dementia and was very distressed. “She had no idea why nobody was visiting or why we wouldn’t let her out of her room,” Dr. Pribula said. “Instead of reaching for sedatives, one of our nurses went into the room and talked with her, prayed a rosary, and played two hands of cards with her and didn’t have to sedate her. That’s what people need when they’re alone and scared. It wasn’t a medical fix but a human fix.”
 

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

Christopher Pribula, MD, a hospitalist at Sanford Broadway Medical Center in Fargo, N.D., didn’t anticipate becoming his hospital’s resident expert on COVID-19. Having just returned from vacation in March, he agreed to cover for a colleague on what would become the special care unit. “When our hospital medicine group decided that it would be the COVID unit, I just ran with it,” he said. Dr. Pribula spent the next 18 days doing 8- to 14-hour shifts and learning as much as he could as the hospital – and the nation – wrestled with the pandemic.

“Because I was the first hospitalist, along with our infectious disease specialist, Dr. Avish Nagpal, to really engage with the virus, people came to me with their questions,” Dr. Pribula said. Working to establish protocols for the care of COVID-19 patients involved a lot of planning, from nursing protocols to discharge planning.

Dr. Pribula was part of the hospital’s incident command structure, thought about how the system could scale up for a potential surge, and worked with the North Dakota Medical Association to reach out to outlying medical centers on safety and infection control. He even drew on his prior work experience as a medical technologist doing negative-pressure containment in a cell-processing facility to help create the hospital’s negative-pressure unit in an old ICU.

“We did a lot of communication from the start. To a certain extent we were making it up as we went along, but we sat down and huddled as a team every day at 9 and 4,” he explained. “We started out with observation and retrospective research, and learned piece by piece. But that’s how science works.”

Hospitalists across the country have played leading roles in their hospitals’ and health systems’ response to the pandemic, and not just because they are on the front lines providing patient care. Their job as doctors who work full-time in the hospital makes them natural leaders in improving clinical quality and hospital administrative protocols as well as studying the latest information and educating their colleagues. Responding to the pandemic has required lots of planning, careful attention to schedules and assignments and staff stress, and working with other departments in the hospital and groups in the community, including public health authorities.
 

Where is hospital treatment for COVID-19 at today?

As knowledge has grown, Dr. Pribula said, COVID-19 treatment in the hospital has come to incorporate remdesivir, a broad-spectrum antiviral; dexamethasone, a common steroid medication; and convalescent plasma, blood products from people who have recovered from the illness. “We went from no steroids to giving steroids. We went from putting patients on ventilators to avoid acute respiratory distress syndrome (ARDS) initially to now working to avoid intubation at all costs,” he said.

“What we found is that we need to pressure-support these patients. We do proning and CPAP while we let the lungs heal. By the time they arrive at the hospital, more often than not they’re on the backside of the viral load. But now we’re dealing with the body’s inflammatory response.”

Navneet Attri, MD, a hospitalist at Sutter Santa Rosa Regional Hospital in Santa Rosa, Calif., 50 miles north of San Francisco, experienced fears and uncertainties working at a hospital that treated early COVID patients from the Grand Princess cruise ship. Early on, she wrote a post describing her experience for The Hospitalist Leader, the Society of Hospital Medicine’s blog page.

Dr. Attri said she has gone through the gamut of emotions while caring for COVID-19 patients, addressing their fears and trying to support family members who aren’t allowed to enter the hospital to be at their loved one’s side. Sometimes, patient after patient with COVID-19 becomes almost too much. But seeing a lot of them in the intervening 6 months has increased her confidence level.

Understanding of how the disease is spread has continued to evolve, with a recent return to focusing on airborne transmission, she said. Frontline workers need N95 masks and eye shields, even if all of that PPE feels like a burden. Dr. Attri said she hardly notices the PPE anymore. “Putting it on is just a habit.”

She sits on Sonoma County’s COVID-19 surge planning group, which has representatives from the three local hospitals, the public health department, and other community agencies. “I report back to my hospitalist group about the situation in the community. Because our facilities were well prepared, our hospitals have not been overwhelmed,” she said.
 

The importance of teamwork

Sunil Shah, MD, a hospitalist with Northwell Health’s Southside Hospital in Bay Shore, N.Y., is part of the massive hospital medicine team, including reassigned specialists and volunteers from across the country, deployed at Northwell hospitals in Greater New York City and Long Island during the COVID-19 surge. Northwell probably has cared for more COVID-19 patients than any other health system in the country, and at the height of the surge the intensity of hospital care was like nothing he’s ever seen. But he also expressed gratitude that doctors from other parts of the country were willing to come and help out.

Southside Hospital went almost overnight from a 200-bed acute facility to a full, 350-bed, regional COVID-19–only hospital. “On busy days, our entire hospital was like a floating ICU,” he said. “You’d hear ‘rapid response’ or ‘code blue’ over the intercom every few seconds. Normally we’d have a designated rapid response person for the day, but with COVID, everybody stepped in to help – whoever was closest,” he said.

Majid Sheikh, MD, a hospitalist at Emory University Hospital in Atlanta, also became a go-to COVID-19 expert for his group. “I didn’t specifically volunteer, but my partner and I had the first cases, and the leadership group was happy to have us there,” he explained.

“One interesting thing I learned was the concept of the ‘happy’ hypoxemic patient, who is having a significant drop in oxygen saturation without developing any obvious signs of respiratory distress,” he said. “We’d be checking the accuracy of the reading and trying to figure out if it was real.” Emory was also one of the leaders in studying anticoagulant treatments for COVID-19 patients.

“Six months later I would say we’re definitely getting better outcomes on the floor, and our COVID patients aren’t landing in the ICU as easily,” Dr. Sheikh said. “It was scary at first, and doubly scary when doctors sometimes don’t feel they can say, ‘Hey, I’m scared too,’ or ‘By the way, I really don’t know what I’m doing.’ So, we’d be trying to reassure the patients when the information was coming to us in fragments.”

But he also believes that the pandemic has afforded hospitalists the opportunity to be the clinical detectives they were trained to be, sifting through clues. “I had to think more and really pay attention clinically in a much different way. You could say it was exciting and scary at the same time,” he said.
 

A human fix in the hospital

Dr. Pribula agreed that the pandemic has been both a difficult experience and a rewarding one. “I think of the people I first admitted. If they had shown up even a month later, would they still be with us?” He believes that his group and his field are going to get to a place where they have solid treatment plans for how to provide optimal care and how to protect providers from exposure.

One of the first COVID-19 patients in Fargo had dementia and was very distressed. “She had no idea why nobody was visiting or why we wouldn’t let her out of her room,” Dr. Pribula said. “Instead of reaching for sedatives, one of our nurses went into the room and talked with her, prayed a rosary, and played two hands of cards with her and didn’t have to sedate her. That’s what people need when they’re alone and scared. It wasn’t a medical fix but a human fix.”
 

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

Christopher Pribula, MD, a hospitalist at Sanford Broadway Medical Center in Fargo, N.D., didn’t anticipate becoming his hospital’s resident expert on COVID-19. Having just returned from vacation in March, he agreed to cover for a colleague on what would become the special care unit. “When our hospital medicine group decided that it would be the COVID unit, I just ran with it,” he said. Dr. Pribula spent the next 18 days doing 8- to 14-hour shifts and learning as much as he could as the hospital – and the nation – wrestled with the pandemic.

“Because I was the first hospitalist, along with our infectious disease specialist, Dr. Avish Nagpal, to really engage with the virus, people came to me with their questions,” Dr. Pribula said. Working to establish protocols for the care of COVID-19 patients involved a lot of planning, from nursing protocols to discharge planning.

Dr. Pribula was part of the hospital’s incident command structure, thought about how the system could scale up for a potential surge, and worked with the North Dakota Medical Association to reach out to outlying medical centers on safety and infection control. He even drew on his prior work experience as a medical technologist doing negative-pressure containment in a cell-processing facility to help create the hospital’s negative-pressure unit in an old ICU.

“We did a lot of communication from the start. To a certain extent we were making it up as we went along, but we sat down and huddled as a team every day at 9 and 4,” he explained. “We started out with observation and retrospective research, and learned piece by piece. But that’s how science works.”

Hospitalists across the country have played leading roles in their hospitals’ and health systems’ response to the pandemic, and not just because they are on the front lines providing patient care. Their job as doctors who work full-time in the hospital makes them natural leaders in improving clinical quality and hospital administrative protocols as well as studying the latest information and educating their colleagues. Responding to the pandemic has required lots of planning, careful attention to schedules and assignments and staff stress, and working with other departments in the hospital and groups in the community, including public health authorities.
 

Where is hospital treatment for COVID-19 at today?

As knowledge has grown, Dr. Pribula said, COVID-19 treatment in the hospital has come to incorporate remdesivir, a broad-spectrum antiviral; dexamethasone, a common steroid medication; and convalescent plasma, blood products from people who have recovered from the illness. “We went from no steroids to giving steroids. We went from putting patients on ventilators to avoid acute respiratory distress syndrome (ARDS) initially to now working to avoid intubation at all costs,” he said.

“What we found is that we need to pressure-support these patients. We do proning and CPAP while we let the lungs heal. By the time they arrive at the hospital, more often than not they’re on the backside of the viral load. But now we’re dealing with the body’s inflammatory response.”

Navneet Attri, MD, a hospitalist at Sutter Santa Rosa Regional Hospital in Santa Rosa, Calif., 50 miles north of San Francisco, experienced fears and uncertainties working at a hospital that treated early COVID patients from the Grand Princess cruise ship. Early on, she wrote a post describing her experience for The Hospitalist Leader, the Society of Hospital Medicine’s blog page.

Dr. Attri said she has gone through the gamut of emotions while caring for COVID-19 patients, addressing their fears and trying to support family members who aren’t allowed to enter the hospital to be at their loved one’s side. Sometimes, patient after patient with COVID-19 becomes almost too much. But seeing a lot of them in the intervening 6 months has increased her confidence level.

Understanding of how the disease is spread has continued to evolve, with a recent return to focusing on airborne transmission, she said. Frontline workers need N95 masks and eye shields, even if all of that PPE feels like a burden. Dr. Attri said she hardly notices the PPE anymore. “Putting it on is just a habit.”

She sits on Sonoma County’s COVID-19 surge planning group, which has representatives from the three local hospitals, the public health department, and other community agencies. “I report back to my hospitalist group about the situation in the community. Because our facilities were well prepared, our hospitals have not been overwhelmed,” she said.
 

The importance of teamwork

Sunil Shah, MD, a hospitalist with Northwell Health’s Southside Hospital in Bay Shore, N.Y., is part of the massive hospital medicine team, including reassigned specialists and volunteers from across the country, deployed at Northwell hospitals in Greater New York City and Long Island during the COVID-19 surge. Northwell probably has cared for more COVID-19 patients than any other health system in the country, and at the height of the surge the intensity of hospital care was like nothing he’s ever seen. But he also expressed gratitude that doctors from other parts of the country were willing to come and help out.

Southside Hospital went almost overnight from a 200-bed acute facility to a full, 350-bed, regional COVID-19–only hospital. “On busy days, our entire hospital was like a floating ICU,” he said. “You’d hear ‘rapid response’ or ‘code blue’ over the intercom every few seconds. Normally we’d have a designated rapid response person for the day, but with COVID, everybody stepped in to help – whoever was closest,” he said.

Majid Sheikh, MD, a hospitalist at Emory University Hospital in Atlanta, also became a go-to COVID-19 expert for his group. “I didn’t specifically volunteer, but my partner and I had the first cases, and the leadership group was happy to have us there,” he explained.

“One interesting thing I learned was the concept of the ‘happy’ hypoxemic patient, who is having a significant drop in oxygen saturation without developing any obvious signs of respiratory distress,” he said. “We’d be checking the accuracy of the reading and trying to figure out if it was real.” Emory was also one of the leaders in studying anticoagulant treatments for COVID-19 patients.

“Six months later I would say we’re definitely getting better outcomes on the floor, and our COVID patients aren’t landing in the ICU as easily,” Dr. Sheikh said. “It was scary at first, and doubly scary when doctors sometimes don’t feel they can say, ‘Hey, I’m scared too,’ or ‘By the way, I really don’t know what I’m doing.’ So, we’d be trying to reassure the patients when the information was coming to us in fragments.”

But he also believes that the pandemic has afforded hospitalists the opportunity to be the clinical detectives they were trained to be, sifting through clues. “I had to think more and really pay attention clinically in a much different way. You could say it was exciting and scary at the same time,” he said.
 

A human fix in the hospital

Dr. Pribula agreed that the pandemic has been both a difficult experience and a rewarding one. “I think of the people I first admitted. If they had shown up even a month later, would they still be with us?” He believes that his group and his field are going to get to a place where they have solid treatment plans for how to provide optimal care and how to protect providers from exposure.

One of the first COVID-19 patients in Fargo had dementia and was very distressed. “She had no idea why nobody was visiting or why we wouldn’t let her out of her room,” Dr. Pribula said. “Instead of reaching for sedatives, one of our nurses went into the room and talked with her, prayed a rosary, and played two hands of cards with her and didn’t have to sedate her. That’s what people need when they’re alone and scared. It wasn’t a medical fix but a human fix.”
 

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