Reviews

There is a need for additional treatment options to improve symptoms, enhance the quality of life (QOL), and reduce suffering among patients who have chronic medical illness. Medical marijuana (MM) has the potential to help patients who have certain medical conditions in states where it is legal for prescription by a licensed medical provider.

Cannabis has a long history of medicinal use (Box 1^1-12). Two derivatives of the Cannabis plant—cannabinoid delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)—are responsible for most of its effects. Some of these effects, including analgesia, decreased muscle spasticity, and reduced eye pressure, have been harnessed for their potential therapeutic effects (Box 2^13-19). As of November 2017, 29 states had legalized Cannabis for medical use, and several had legalized its recreational use.¹²

With the increasing availability of MM, psychiatrists are likely to encounter patients who are using it or who will ask them about it. This article reviews evidence related to using MM to treat patients with neuropathic pain; chemotherapyinduced nausea and vomiting (CINV); epilepsy; multiple sclerosis (MS); glaucoma; Crohn’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; dementia-related behavioral disturbances; posttraumatic stress disorder (PTSD); and anxiety.

Box 1 
Cannabis: A history of medicinal use

Medical illnesses

Neuropathic pain. Chronic neuropathic pain affects an estimated 7% to 8% of adults.²⁰ Patients with neuropathic pain are often treated with anticonvulsants, anti­depressants, opioids, and local anesthetics²¹; however, these medications may not provide substantial relief. Research has revealed that THC and CBD can improve central and peripheral neuropathic pain, as well as pain associated with rheumatoid arthritis and fibromyalgia.²²

Wilsey et al²³ evaluated the analgesic effects of smoked MM for neuropathic pain in a small (N = 38) double-blind, randomized controlled trial (RCT). Patients in this study had a preexisting diagnosis of complex regional pain syndrome, spinal cord injury, peripheral neuropathy, or nerve injury. To prevent any unforeseen adverse outcomes related to Cannabis use, participants were required to have previous exposure to Cannabis. Patients were excluded if they had major mental illness, substance abuse, or other major medical ailments.

Participants smoked high-dose Cannabis cigarettes (7% THC), low-dose Cannabis cigarettes (3.5% THC), or placebo cigarettes. Pain was measured on a visual analog scale (VAS) that ranged from 0 (no pain) to 100 (worst possible pain). Compared with the placebo group, significant analgesia was achieved in both Cannabis groups (P = .016). The high-dose group had greater neurocognitive impairment.

Ware et al²⁴ conducted a crossover RCT (N = 23) to determine the efficacy of smoked MM for neuropathic pain. Participants had neuropathic pain for at least 3 months that was caused by trauma or surgery, with an average weekly pain intensity score >4 on scale of 0 to 10. Patients with pain due to cancer, nociceptive causes, unstable medical conditions, current substance abuse, history of a psychotic disorder, or suicidal ideation were excluded. Participants were assigned to a 9.4% THC group or a 0% THC group. Pain intensity was evaluated daily via telephone. Participants in the 9.4% THC group had statistically lower pain intensity compared with the 0% THC group (P = .023). Common adverse effects reported by those in the 9.4% group included headache, dry eyes, burning sensation, dizziness, numbness, and cough.

Box 2
The effects of Cannabis

In an RCT of vaporized Cannabis, 39 patients with a diagnosis of complex regional pain syndrome, thalamic pain, spinal cord injury, peripheral neuropathy, radiculopathy, or nerve injury were assigned to a medium-dose (3.53% THC), low-dose (1.29% THC), or placebo group.²⁵ Serious mental illness, substance abuse, and medical conditions were cause for exclusion. Participants received vaporized marijuana (average 8 to 12 puffs per visit) over 3 sessions. A 30% pain reduction was achieved by 26% of those in the placebo group, 57% of those in the low-dose group, and 61% of individuals in the high-dose group; the difference between placebo and each Cannabis group was statistically significant.

Chemotherapy-induced nausea and vomiting. Up to 80% of patients who receive chemotherapy experience CINV, which occurs from 24 hours to 7 days after receiving such therapy.²⁶ CINV negatively influences a patient’s QOL and may impact the decision to continue with chemotherapy. Use of MM can help to diminish vomiting by binding to central CB₁ receptors and averting the proemetic effects of dopamine and serotonin.²⁷ Two synthetically derived cannabinoids, dronabinol and nabilone, are FDA-approved for treating CINV.

In a small (N = 64) parallel-group RCT, Meiri et al²⁷ compared dronabinol with the commonly used antiemetic ondansetron and with a combination of dronabinol and ondansetron for treating CINV in adults. The primary outcome was prevention of delayed-onset CINV. Patients were eligible for this study if they had a malignancy that did not involve bone marrow, were receiving treatment with a moderately to highly emetogenic regimen, were not pregnant, and had an estimated life expectancy of at least 6 weeks after chemotherapy. The patients were randomized to 1 of 4 treatment groups: dronabinol alone, ondansetron alone, dronabinol plus ondansetron, or placebo. Overall, 47% to 58% of the active treatment groups improved, compared with 20% of the placebo group. Combination therapy did not provide any benefit beyond any single agent alone. All active treatments reduced nausea compared with placebo; there was no difference between active treatment groups. This study was limited by low enrollment.

Tramèr et al²⁸ conducted a systematic review of 30 randomized comparisons of MM with placebo or antiemetics. The reviewed studies were completed between 1975 to 1997 and analyzed a total of 1,366 patients. Nabilone was evaluated in 16 trials; dronabinol was utilized in 13 trials; and IM levonantradol, a synthetic cannabinoid analog of dronabinol, was used in 1 trial. These agents were found to be more effective as an antiemetic compared with prochlorperazine, metoclopramide, chlorpromazine, thiethyl­perazine, haloperidol, domperidone, or alizapride. In addition, 38% to 90% of patients in these studies preferred MM over the traditional antiemetics.

A Cochrane review²⁹ suggested that MM may be a viable option for treatment-resistant CINV; however, further studies are needed because current studies have methodological limitations.

Epilepsy. Maa and Figi³⁰ reported a case of a 5-year-old girl who had Dravet syndrome, which resulted in 50 generalized tonic-clonic seizures daily; multiple anticonvulsants did not alleviate these seizures. Because of her recurring seizures, the patient had multiple cognitive and motor delays and needed a feeding tube. In addition to her existing antiepileptic drug regimen, she was started on adjunctive therapy with a sublingual Cannabis extract containing a high concentration of CBD. Her seizures decreased from 50 per day to 2 to 3 nocturnal convulsions per month. The treatment enabled her to stop using a feeding tube, resume walking and talking, and sleep soundly.

dos Santos et al³¹ reviewed studies of MM for treating epilepsy. One was a double-blind, placebo-controlled trial that included 15 patients ages 14 to 49 who had secondary generalized epilepsy with a temporal lobe focus. Eight patients received 200 to 300 mg/d of oral CBD for 8 to 18 weeks, and 7 received placebo. Seven patients had fewer seizures and 4 had no seizures. Only 1 patient in the placebo group demonstrated any improvement. Another study in this review included 19 children with treatment-resistant epilepsy: Dravet syndrome (n = 13), Doose syndrome (n = 4), Lennox-Gastaut syndrome (n = 1), or idiopathic epilepsy (n = 1). These patients experienced various types of seizures with a frequency ranging from 2 per week to 250 per day. Overall, 84% of children treated with CBD had fewer seizures: 11% were seizure-free, 42% had a >80% reduction in seizures, and 32% had a 25% to 60% reduction in seizures. Parents also noted additional benefits, including increased attention, improved mood, and improved sleep. CBD was well tolerated in most patients in both studies.

Despite these results, a Cochrane review³² found that no reliable conclusions can be drawn regarding the efficacy of MM for treating epilepsy.

Multiple sclerosis. According to American Academy of Neurology guidelines, physicians may provide MM as an alternative treatment for patients with MS-related spasticity.³³ Multiple studies have tested MM and MM-related extracts for treating spasticity related to MS.^34,35 In a placebo-controlled crossover study, Corey-Bloom et al³⁴ reported a significant reduction in spasticity, measured using the modified Ashworth scale, in MS patients receiving Cannabis cigarettes vs placebo cigarettes (P < .0001). However, compared with the placebo group, patients who received MM had significant adverse effects, primarily cognitive impairment (P = .003).

In a multicenter RCT (N = 572 patients with refractory MS spasticity), Novotna et al³⁶ evaluated nabiximols, an oral mucosal spray of a formulated extract of Cannabis that contains THC and CBD in a 1:1 ratio. They assessed spasticity using the Numerical Spasticity Rating Scale (NRS). Results were confirmed by measuring the number of daily spasms, self-report of sleep quality, and activities of daily living. After 4 weeks of single-blind treatment, patients who responded to nabiximols (≥20% improvement in spasticity) were randomized to a placebo group or nabiximols group for 12 additional weeks. After 12 weeks, compared with those who received placebo, those in the nabiximols group experienced a statistically significant reduction in spasticity based on NRS score (P = .0002).
 

For a summary of evidence on MM for treating glaucoma, Crohn’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, see Box 3.^37-43

Box 3
Cannabis for treating glaucoma, Crohn’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis

Psychiatric illnesses

Dementia-related behavioral disturbances. A few clinical trials with small sample sizes have found evidence supporting the use of MM compounds for alleviating neuropsychiatric symptoms of patients with dementia. An open-label pilot study of 6 individuals with late-stage dementia who received dronabinol, 2.5 mg/d, for 2 weeks, found a significant reduction (compared with baseline) in nighttime motor activity as measured with an actometer (P < .0028).⁴⁴ The secondary Neuropsychiatric Inventory (NPI) assessment found reductions in aberrant motor behavior (P = .042), agitation (P = .042), and nighttime behaviors (P = .42).

A 2014 retrospective analysis of 40 inpatients with dementia-related agitation and appetite loss who were treated with dronabinol (mean dosage: 7.03 mg/d) found reductions in all aspects of agitation, including aberrant vocalization, motor agitation, aggressiveness, and treatment resistance, as measured with the Pittsburgh Agitation Scale (P < .0001).⁴⁵ The study found no significant improvements in appetite, Global Assessment of Functioning mean score, or number of times patients awoke during the night. Adverse effects included sedation and delirium.

A RCT of 50 dementia patients with clinically relevant neuropsychiatric symptoms found no significant difference in mean NPI scores between patients given placebo and those who received nabiximols, 1.5 mg, 3 times daily.⁴⁶ There were no significant differences found in agitation, QOL, life activities, or caregiver-scored Caregiver Global Impression of Change scale.

In a small RCT, THC was safe and well tolerated in 10 older patients with dementia.⁴⁷ A 2009 Cochrane review⁴⁸ concluded that there was no evidence for the efficacy of MM in treating the neuropsychiatric symptoms related to dementia.

PTSD. Preclinical evidence shows that the endocannabinoid system is involved in regulating emotional memory. Evidence also suggests that cannabinoids may facilitate the extinction of aversive memories.^49,50

In 2009, New Mexico became the first state to authorize the use of MM for patients with PTSD. In a study of patients applying for the New Mexico Medical Cannabis Program, researchers used the Clinician Administered Posttraumatic Scale (CAPS) to assess PTSD symptoms.⁵¹ A retrospective chart review of the first 80 patients eval­uated found significant (P < .0001) reductions of several PTSD symptoms, including intrusive memories, distressing dreams, flashbacks, numbing and avoidance, and hyperarousal, in the group using MM vs those not using MM. There also was a significant difference in CAPS total score (P < .0001). Patients reported a 75% reduction in PTSD symptoms while using MM. This study has several limitations: It was a retrospective review, not an RCT, and patients were prescreened and knew before the study began that MM helped their PTSD symptoms.

In another retrospective study, researchers evaluated treatment with nabilone, 0.5 to 6 mg/d, in 104 incarcerated men with various major mental illnesses; most (91%) met criteria for Cannabis dependence.⁵² They found significant improvements in sleep and PTSD symptoms.

A double-blind RCT evaluated MM in 10 Canadian male soldiers with PTSD who experienced nightmares despite standard medication treatment. Adjunctive nabilone (maximum dose: 3 mg/d) resulted in a reduction in nightmares as measured by the CAPS recurrent distressing dream of the event item score.⁵³

Currently, there are no adequately powered RCTs of MM in a diverse group of PTSD patients. Most studies are open-label, enriched design, and included white male veterans. No well-conducted trials have evaluated patients with noncombat-related PTSD. Most of the relevant literature consists of case reports of Cannabis use by patients with PTSD.

Anxiety disorders.Patients frequently indicate that smoking Cannabis helps relieve their anxiety, although there is no replicated evidence based on double-blind RCTs to support this. However, in rat models CBD has been shown to facilitate extinction of conditioned fear via the endocannabinoid system.^54-56 The mechanism of action is not completely understood. CBD has been shown to have antagonistic action at CB₁ and CB₂ receptors. It may have similar effects on memory extinction and may be an adjunct to exposure therapies for anxiety disorders.

Das et al⁵⁷ studied the effects of CBD (32 mg) on extinction and consolidation of memory related to contextual fear in 48 individuals. They found that CBD can enhance extinction learning, and suggested it may have potential as an adjunct to extinction-based therapies for anxiety disorders.

Caveats: Adverse effects, lack of RCTs

Cannabis use causes impairment of learning, memory, attention, and working memory. Adolescents are particularly vulnerable to the effects of Cannabis on brain development at a time when synaptic pruning and increased myelination occur. Normal brain development could be disrupted. Some studies have linked Cannabis use to abnormalities in the amygdala, hippocampus, frontal lobe, and cerebellum. From 1995 to 2014, the potency of Cannabis (THC concentration) increased from 4% to 12%.⁵⁸ This has substantial implications for increased abuse among adolescents and the deleterious effects of Cannabis on the brain.

Heavy Cannabis use impairs motivation and could precipitate psychosis in vulnerable individuals. Cannabis use may be linked to the development of schizophrenia.⁵⁹

There are no well-conducted RCTs on the efficacy of MM, and adequate safety data are lacking. There is also lack of consensus among qualified experts. There is soft evidence that MM may be helpful in some medical conditions, including but not limited to CINV, neuropathic pain, epilepsy, and MS-related spasticity. Currently, the benefits of using MM do not appear to outweigh the risks.

Bottom Line

Limited evidence suggests medical marijuana (MM) may be beneficial for treating a few medical conditions, including neuropathic pain and chemotherapy-induced nausea and vomiting. There is no clear and convincing evidence MM is beneficial for psychiatric disorders, and Cannabis can impair cognition and attention and may precipitate psychosis. The risk of deleterious effects are greater in adolescents.

Related Resources

• Nguyen DH, Thant TM. Caring for medical marijuana patients who request controlled prescriptions. Current Psychiatry. 2017;16(8):50-51.
• National Institute on Drug Abuse. Marijuana as medicine. https://www.drugabuse.gov/publications/drugfacts/ marijuana-medicine.

Drug Brand Names

Alizapride • Litican, Superan
Chlorpromazine • Thorazine
Domperidone • Motilium
Dronabinol • Marinol, Syndros
Haloperidol • Haldol
Metoclopramide • Reglan
Nabilone • Cesamet
Nabiximols • Sativex
Ondansetron • Zofran, Zuplenz
Prochlorperazine • Compazine
Thiethylperazine • Torecan

There is a need for additional treatment options to improve symptoms, enhance the quality of life (QOL), and reduce suffering among patients who have chronic medical illness. Medical marijuana (MM) has the potential to help patients who have certain medical conditions in states where it is legal for prescription by a licensed medical provider.

Cannabis has a long history of medicinal use (Box 1^1-12). Two derivatives of the Cannabis plant—cannabinoid delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)—are responsible for most of its effects. Some of these effects, including analgesia, decreased muscle spasticity, and reduced eye pressure, have been harnessed for their potential therapeutic effects (Box 2^13-19). As of November 2017, 29 states had legalized Cannabis for medical use, and several had legalized its recreational use.¹²

With the increasing availability of MM, psychiatrists are likely to encounter patients who are using it or who will ask them about it. This article reviews evidence related to using MM to treat patients with neuropathic pain; chemotherapyinduced nausea and vomiting (CINV); epilepsy; multiple sclerosis (MS); glaucoma; Crohn’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; dementia-related behavioral disturbances; posttraumatic stress disorder (PTSD); and anxiety.

Box 1 
Cannabis: A history of medicinal use

Medical illnesses

Neuropathic pain. Chronic neuropathic pain affects an estimated 7% to 8% of adults.²⁰ Patients with neuropathic pain are often treated with anticonvulsants, anti­depressants, opioids, and local anesthetics²¹; however, these medications may not provide substantial relief. Research has revealed that THC and CBD can improve central and peripheral neuropathic pain, as well as pain associated with rheumatoid arthritis and fibromyalgia.²²

Wilsey et al²³ evaluated the analgesic effects of smoked MM for neuropathic pain in a small (N = 38) double-blind, randomized controlled trial (RCT). Patients in this study had a preexisting diagnosis of complex regional pain syndrome, spinal cord injury, peripheral neuropathy, or nerve injury. To prevent any unforeseen adverse outcomes related to Cannabis use, participants were required to have previous exposure to Cannabis. Patients were excluded if they had major mental illness, substance abuse, or other major medical ailments.

Participants smoked high-dose Cannabis cigarettes (7% THC), low-dose Cannabis cigarettes (3.5% THC), or placebo cigarettes. Pain was measured on a visual analog scale (VAS) that ranged from 0 (no pain) to 100 (worst possible pain). Compared with the placebo group, significant analgesia was achieved in both Cannabis groups (P = .016). The high-dose group had greater neurocognitive impairment.

Ware et al²⁴ conducted a crossover RCT (N = 23) to determine the efficacy of smoked MM for neuropathic pain. Participants had neuropathic pain for at least 3 months that was caused by trauma or surgery, with an average weekly pain intensity score >4 on scale of 0 to 10. Patients with pain due to cancer, nociceptive causes, unstable medical conditions, current substance abuse, history of a psychotic disorder, or suicidal ideation were excluded. Participants were assigned to a 9.4% THC group or a 0% THC group. Pain intensity was evaluated daily via telephone. Participants in the 9.4% THC group had statistically lower pain intensity compared with the 0% THC group (P = .023). Common adverse effects reported by those in the 9.4% group included headache, dry eyes, burning sensation, dizziness, numbness, and cough.

Box 2
The effects of Cannabis

In an RCT of vaporized Cannabis, 39 patients with a diagnosis of complex regional pain syndrome, thalamic pain, spinal cord injury, peripheral neuropathy, radiculopathy, or nerve injury were assigned to a medium-dose (3.53% THC), low-dose (1.29% THC), or placebo group.²⁵ Serious mental illness, substance abuse, and medical conditions were cause for exclusion. Participants received vaporized marijuana (average 8 to 12 puffs per visit) over 3 sessions. A 30% pain reduction was achieved by 26% of those in the placebo group, 57% of those in the low-dose group, and 61% of individuals in the high-dose group; the difference between placebo and each Cannabis group was statistically significant.

Chemotherapy-induced nausea and vomiting. Up to 80% of patients who receive chemotherapy experience CINV, which occurs from 24 hours to 7 days after receiving such therapy.²⁶ CINV negatively influences a patient’s QOL and may impact the decision to continue with chemotherapy. Use of MM can help to diminish vomiting by binding to central CB₁ receptors and averting the proemetic effects of dopamine and serotonin.²⁷ Two synthetically derived cannabinoids, dronabinol and nabilone, are FDA-approved for treating CINV.

In a small (N = 64) parallel-group RCT, Meiri et al²⁷ compared dronabinol with the commonly used antiemetic ondansetron and with a combination of dronabinol and ondansetron for treating CINV in adults. The primary outcome was prevention of delayed-onset CINV. Patients were eligible for this study if they had a malignancy that did not involve bone marrow, were receiving treatment with a moderately to highly emetogenic regimen, were not pregnant, and had an estimated life expectancy of at least 6 weeks after chemotherapy. The patients were randomized to 1 of 4 treatment groups: dronabinol alone, ondansetron alone, dronabinol plus ondansetron, or placebo. Overall, 47% to 58% of the active treatment groups improved, compared with 20% of the placebo group. Combination therapy did not provide any benefit beyond any single agent alone. All active treatments reduced nausea compared with placebo; there was no difference between active treatment groups. This study was limited by low enrollment.

Tramèr et al²⁸ conducted a systematic review of 30 randomized comparisons of MM with placebo or antiemetics. The reviewed studies were completed between 1975 to 1997 and analyzed a total of 1,366 patients. Nabilone was evaluated in 16 trials; dronabinol was utilized in 13 trials; and IM levonantradol, a synthetic cannabinoid analog of dronabinol, was used in 1 trial. These agents were found to be more effective as an antiemetic compared with prochlorperazine, metoclopramide, chlorpromazine, thiethyl­perazine, haloperidol, domperidone, or alizapride. In addition, 38% to 90% of patients in these studies preferred MM over the traditional antiemetics.

A Cochrane review²⁹ suggested that MM may be a viable option for treatment-resistant CINV; however, further studies are needed because current studies have methodological limitations.

Epilepsy. Maa and Figi³⁰ reported a case of a 5-year-old girl who had Dravet syndrome, which resulted in 50 generalized tonic-clonic seizures daily; multiple anticonvulsants did not alleviate these seizures. Because of her recurring seizures, the patient had multiple cognitive and motor delays and needed a feeding tube. In addition to her existing antiepileptic drug regimen, she was started on adjunctive therapy with a sublingual Cannabis extract containing a high concentration of CBD. Her seizures decreased from 50 per day to 2 to 3 nocturnal convulsions per month. The treatment enabled her to stop using a feeding tube, resume walking and talking, and sleep soundly.

dos Santos et al³¹ reviewed studies of MM for treating epilepsy. One was a double-blind, placebo-controlled trial that included 15 patients ages 14 to 49 who had secondary generalized epilepsy with a temporal lobe focus. Eight patients received 200 to 300 mg/d of oral CBD for 8 to 18 weeks, and 7 received placebo. Seven patients had fewer seizures and 4 had no seizures. Only 1 patient in the placebo group demonstrated any improvement. Another study in this review included 19 children with treatment-resistant epilepsy: Dravet syndrome (n = 13), Doose syndrome (n = 4), Lennox-Gastaut syndrome (n = 1), or idiopathic epilepsy (n = 1). These patients experienced various types of seizures with a frequency ranging from 2 per week to 250 per day. Overall, 84% of children treated with CBD had fewer seizures: 11% were seizure-free, 42% had a >80% reduction in seizures, and 32% had a 25% to 60% reduction in seizures. Parents also noted additional benefits, including increased attention, improved mood, and improved sleep. CBD was well tolerated in most patients in both studies.

Despite these results, a Cochrane review³² found that no reliable conclusions can be drawn regarding the efficacy of MM for treating epilepsy.

Multiple sclerosis. According to American Academy of Neurology guidelines, physicians may provide MM as an alternative treatment for patients with MS-related spasticity.³³ Multiple studies have tested MM and MM-related extracts for treating spasticity related to MS.^34,35 In a placebo-controlled crossover study, Corey-Bloom et al³⁴ reported a significant reduction in spasticity, measured using the modified Ashworth scale, in MS patients receiving Cannabis cigarettes vs placebo cigarettes (P < .0001). However, compared with the placebo group, patients who received MM had significant adverse effects, primarily cognitive impairment (P = .003).

In a multicenter RCT (N = 572 patients with refractory MS spasticity), Novotna et al³⁶ evaluated nabiximols, an oral mucosal spray of a formulated extract of Cannabis that contains THC and CBD in a 1:1 ratio. They assessed spasticity using the Numerical Spasticity Rating Scale (NRS). Results were confirmed by measuring the number of daily spasms, self-report of sleep quality, and activities of daily living. After 4 weeks of single-blind treatment, patients who responded to nabiximols (≥20% improvement in spasticity) were randomized to a placebo group or nabiximols group for 12 additional weeks. After 12 weeks, compared with those who received placebo, those in the nabiximols group experienced a statistically significant reduction in spasticity based on NRS score (P = .0002).
 

For a summary of evidence on MM for treating glaucoma, Crohn’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, see Box 3.^37-43

Box 3
Cannabis for treating glaucoma, Crohn’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis

Psychiatric illnesses

Dementia-related behavioral disturbances. A few clinical trials with small sample sizes have found evidence supporting the use of MM compounds for alleviating neuropsychiatric symptoms of patients with dementia. An open-label pilot study of 6 individuals with late-stage dementia who received dronabinol, 2.5 mg/d, for 2 weeks, found a significant reduction (compared with baseline) in nighttime motor activity as measured with an actometer (P < .0028).⁴⁴ The secondary Neuropsychiatric Inventory (NPI) assessment found reductions in aberrant motor behavior (P = .042), agitation (P = .042), and nighttime behaviors (P = .42).

A 2014 retrospective analysis of 40 inpatients with dementia-related agitation and appetite loss who were treated with dronabinol (mean dosage: 7.03 mg/d) found reductions in all aspects of agitation, including aberrant vocalization, motor agitation, aggressiveness, and treatment resistance, as measured with the Pittsburgh Agitation Scale (P < .0001).⁴⁵ The study found no significant improvements in appetite, Global Assessment of Functioning mean score, or number of times patients awoke during the night. Adverse effects included sedation and delirium.

A RCT of 50 dementia patients with clinically relevant neuropsychiatric symptoms found no significant difference in mean NPI scores between patients given placebo and those who received nabiximols, 1.5 mg, 3 times daily.⁴⁶ There were no significant differences found in agitation, QOL, life activities, or caregiver-scored Caregiver Global Impression of Change scale.

In a small RCT, THC was safe and well tolerated in 10 older patients with dementia.⁴⁷ A 2009 Cochrane review⁴⁸ concluded that there was no evidence for the efficacy of MM in treating the neuropsychiatric symptoms related to dementia.

PTSD. Preclinical evidence shows that the endocannabinoid system is involved in regulating emotional memory. Evidence also suggests that cannabinoids may facilitate the extinction of aversive memories.^49,50

In 2009, New Mexico became the first state to authorize the use of MM for patients with PTSD. In a study of patients applying for the New Mexico Medical Cannabis Program, researchers used the Clinician Administered Posttraumatic Scale (CAPS) to assess PTSD symptoms.⁵¹ A retrospective chart review of the first 80 patients eval­uated found significant (P < .0001) reductions of several PTSD symptoms, including intrusive memories, distressing dreams, flashbacks, numbing and avoidance, and hyperarousal, in the group using MM vs those not using MM. There also was a significant difference in CAPS total score (P < .0001). Patients reported a 75% reduction in PTSD symptoms while using MM. This study has several limitations: It was a retrospective review, not an RCT, and patients were prescreened and knew before the study began that MM helped their PTSD symptoms.

In another retrospective study, researchers evaluated treatment with nabilone, 0.5 to 6 mg/d, in 104 incarcerated men with various major mental illnesses; most (91%) met criteria for Cannabis dependence.⁵² They found significant improvements in sleep and PTSD symptoms.

A double-blind RCT evaluated MM in 10 Canadian male soldiers with PTSD who experienced nightmares despite standard medication treatment. Adjunctive nabilone (maximum dose: 3 mg/d) resulted in a reduction in nightmares as measured by the CAPS recurrent distressing dream of the event item score.⁵³

Currently, there are no adequately powered RCTs of MM in a diverse group of PTSD patients. Most studies are open-label, enriched design, and included white male veterans. No well-conducted trials have evaluated patients with noncombat-related PTSD. Most of the relevant literature consists of case reports of Cannabis use by patients with PTSD.

Anxiety disorders.Patients frequently indicate that smoking Cannabis helps relieve their anxiety, although there is no replicated evidence based on double-blind RCTs to support this. However, in rat models CBD has been shown to facilitate extinction of conditioned fear via the endocannabinoid system.^54-56 The mechanism of action is not completely understood. CBD has been shown to have antagonistic action at CB₁ and CB₂ receptors. It may have similar effects on memory extinction and may be an adjunct to exposure therapies for anxiety disorders.

Das et al⁵⁷ studied the effects of CBD (32 mg) on extinction and consolidation of memory related to contextual fear in 48 individuals. They found that CBD can enhance extinction learning, and suggested it may have potential as an adjunct to extinction-based therapies for anxiety disorders.

Caveats: Adverse effects, lack of RCTs

Cannabis use causes impairment of learning, memory, attention, and working memory. Adolescents are particularly vulnerable to the effects of Cannabis on brain development at a time when synaptic pruning and increased myelination occur. Normal brain development could be disrupted. Some studies have linked Cannabis use to abnormalities in the amygdala, hippocampus, frontal lobe, and cerebellum. From 1995 to 2014, the potency of Cannabis (THC concentration) increased from 4% to 12%.⁵⁸ This has substantial implications for increased abuse among adolescents and the deleterious effects of Cannabis on the brain.

Heavy Cannabis use impairs motivation and could precipitate psychosis in vulnerable individuals. Cannabis use may be linked to the development of schizophrenia.⁵⁹

There are no well-conducted RCTs on the efficacy of MM, and adequate safety data are lacking. There is also lack of consensus among qualified experts. There is soft evidence that MM may be helpful in some medical conditions, including but not limited to CINV, neuropathic pain, epilepsy, and MS-related spasticity. Currently, the benefits of using MM do not appear to outweigh the risks.

Bottom Line

Limited evidence suggests medical marijuana (MM) may be beneficial for treating a few medical conditions, including neuropathic pain and chemotherapy-induced nausea and vomiting. There is no clear and convincing evidence MM is beneficial for psychiatric disorders, and Cannabis can impair cognition and attention and may precipitate psychosis. The risk of deleterious effects are greater in adolescents.

Related Resources

• Nguyen DH, Thant TM. Caring for medical marijuana patients who request controlled prescriptions. Current Psychiatry. 2017;16(8):50-51.
• National Institute on Drug Abuse. Marijuana as medicine. https://www.drugabuse.gov/publications/drugfacts/ marijuana-medicine.

Drug Brand Names

Alizapride • Litican, Superan
Chlorpromazine • Thorazine
Domperidone • Motilium
Dronabinol • Marinol, Syndros
Haloperidol • Haldol
Metoclopramide • Reglan
Nabilone • Cesamet
Nabiximols • Sativex
Ondansetron • Zofran, Zuplenz
Prochlorperazine • Compazine
Thiethylperazine • Torecan

There is a need for additional treatment options to improve symptoms, enhance the quality of life (QOL), and reduce suffering among patients who have chronic medical illness. Medical marijuana (MM) has the potential to help patients who have certain medical conditions in states where it is legal for prescription by a licensed medical provider.

Cannabis has a long history of medicinal use (Box 1^1-12). Two derivatives of the Cannabis plant—cannabinoid delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)—are responsible for most of its effects. Some of these effects, including analgesia, decreased muscle spasticity, and reduced eye pressure, have been harnessed for their potential therapeutic effects (Box 2^13-19). As of November 2017, 29 states had legalized Cannabis for medical use, and several had legalized its recreational use.¹²

With the increasing availability of MM, psychiatrists are likely to encounter patients who are using it or who will ask them about it. This article reviews evidence related to using MM to treat patients with neuropathic pain; chemotherapyinduced nausea and vomiting (CINV); epilepsy; multiple sclerosis (MS); glaucoma; Crohn’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; dementia-related behavioral disturbances; posttraumatic stress disorder (PTSD); and anxiety.

Box 1 
Cannabis: A history of medicinal use

Medical illnesses

Neuropathic pain. Chronic neuropathic pain affects an estimated 7% to 8% of adults.²⁰ Patients with neuropathic pain are often treated with anticonvulsants, anti­depressants, opioids, and local anesthetics²¹; however, these medications may not provide substantial relief. Research has revealed that THC and CBD can improve central and peripheral neuropathic pain, as well as pain associated with rheumatoid arthritis and fibromyalgia.²²

Wilsey et al²³ evaluated the analgesic effects of smoked MM for neuropathic pain in a small (N = 38) double-blind, randomized controlled trial (RCT). Patients in this study had a preexisting diagnosis of complex regional pain syndrome, spinal cord injury, peripheral neuropathy, or nerve injury. To prevent any unforeseen adverse outcomes related to Cannabis use, participants were required to have previous exposure to Cannabis. Patients were excluded if they had major mental illness, substance abuse, or other major medical ailments.

Participants smoked high-dose Cannabis cigarettes (7% THC), low-dose Cannabis cigarettes (3.5% THC), or placebo cigarettes. Pain was measured on a visual analog scale (VAS) that ranged from 0 (no pain) to 100 (worst possible pain). Compared with the placebo group, significant analgesia was achieved in both Cannabis groups (P = .016). The high-dose group had greater neurocognitive impairment.

Ware et al²⁴ conducted a crossover RCT (N = 23) to determine the efficacy of smoked MM for neuropathic pain. Participants had neuropathic pain for at least 3 months that was caused by trauma or surgery, with an average weekly pain intensity score >4 on scale of 0 to 10. Patients with pain due to cancer, nociceptive causes, unstable medical conditions, current substance abuse, history of a psychotic disorder, or suicidal ideation were excluded. Participants were assigned to a 9.4% THC group or a 0% THC group. Pain intensity was evaluated daily via telephone. Participants in the 9.4% THC group had statistically lower pain intensity compared with the 0% THC group (P = .023). Common adverse effects reported by those in the 9.4% group included headache, dry eyes, burning sensation, dizziness, numbness, and cough.

Box 2
The effects of Cannabis

In an RCT of vaporized Cannabis, 39 patients with a diagnosis of complex regional pain syndrome, thalamic pain, spinal cord injury, peripheral neuropathy, radiculopathy, or nerve injury were assigned to a medium-dose (3.53% THC), low-dose (1.29% THC), or placebo group.²⁵ Serious mental illness, substance abuse, and medical conditions were cause for exclusion. Participants received vaporized marijuana (average 8 to 12 puffs per visit) over 3 sessions. A 30% pain reduction was achieved by 26% of those in the placebo group, 57% of those in the low-dose group, and 61% of individuals in the high-dose group; the difference between placebo and each Cannabis group was statistically significant.

Chemotherapy-induced nausea and vomiting. Up to 80% of patients who receive chemotherapy experience CINV, which occurs from 24 hours to 7 days after receiving such therapy.²⁶ CINV negatively influences a patient’s QOL and may impact the decision to continue with chemotherapy. Use of MM can help to diminish vomiting by binding to central CB₁ receptors and averting the proemetic effects of dopamine and serotonin.²⁷ Two synthetically derived cannabinoids, dronabinol and nabilone, are FDA-approved for treating CINV.

In a small (N = 64) parallel-group RCT, Meiri et al²⁷ compared dronabinol with the commonly used antiemetic ondansetron and with a combination of dronabinol and ondansetron for treating CINV in adults. The primary outcome was prevention of delayed-onset CINV. Patients were eligible for this study if they had a malignancy that did not involve bone marrow, were receiving treatment with a moderately to highly emetogenic regimen, were not pregnant, and had an estimated life expectancy of at least 6 weeks after chemotherapy. The patients were randomized to 1 of 4 treatment groups: dronabinol alone, ondansetron alone, dronabinol plus ondansetron, or placebo. Overall, 47% to 58% of the active treatment groups improved, compared with 20% of the placebo group. Combination therapy did not provide any benefit beyond any single agent alone. All active treatments reduced nausea compared with placebo; there was no difference between active treatment groups. This study was limited by low enrollment.

Tramèr et al²⁸ conducted a systematic review of 30 randomized comparisons of MM with placebo or antiemetics. The reviewed studies were completed between 1975 to 1997 and analyzed a total of 1,366 patients. Nabilone was evaluated in 16 trials; dronabinol was utilized in 13 trials; and IM levonantradol, a synthetic cannabinoid analog of dronabinol, was used in 1 trial. These agents were found to be more effective as an antiemetic compared with prochlorperazine, metoclopramide, chlorpromazine, thiethyl­perazine, haloperidol, domperidone, or alizapride. In addition, 38% to 90% of patients in these studies preferred MM over the traditional antiemetics.

A Cochrane review²⁹ suggested that MM may be a viable option for treatment-resistant CINV; however, further studies are needed because current studies have methodological limitations.

Epilepsy. Maa and Figi³⁰ reported a case of a 5-year-old girl who had Dravet syndrome, which resulted in 50 generalized tonic-clonic seizures daily; multiple anticonvulsants did not alleviate these seizures. Because of her recurring seizures, the patient had multiple cognitive and motor delays and needed a feeding tube. In addition to her existing antiepileptic drug regimen, she was started on adjunctive therapy with a sublingual Cannabis extract containing a high concentration of CBD. Her seizures decreased from 50 per day to 2 to 3 nocturnal convulsions per month. The treatment enabled her to stop using a feeding tube, resume walking and talking, and sleep soundly.

dos Santos et al³¹ reviewed studies of MM for treating epilepsy. One was a double-blind, placebo-controlled trial that included 15 patients ages 14 to 49 who had secondary generalized epilepsy with a temporal lobe focus. Eight patients received 200 to 300 mg/d of oral CBD for 8 to 18 weeks, and 7 received placebo. Seven patients had fewer seizures and 4 had no seizures. Only 1 patient in the placebo group demonstrated any improvement. Another study in this review included 19 children with treatment-resistant epilepsy: Dravet syndrome (n = 13), Doose syndrome (n = 4), Lennox-Gastaut syndrome (n = 1), or idiopathic epilepsy (n = 1). These patients experienced various types of seizures with a frequency ranging from 2 per week to 250 per day. Overall, 84% of children treated with CBD had fewer seizures: 11% were seizure-free, 42% had a >80% reduction in seizures, and 32% had a 25% to 60% reduction in seizures. Parents also noted additional benefits, including increased attention, improved mood, and improved sleep. CBD was well tolerated in most patients in both studies.

Despite these results, a Cochrane review³² found that no reliable conclusions can be drawn regarding the efficacy of MM for treating epilepsy.

Multiple sclerosis. According to American Academy of Neurology guidelines, physicians may provide MM as an alternative treatment for patients with MS-related spasticity.³³ Multiple studies have tested MM and MM-related extracts for treating spasticity related to MS.^34,35 In a placebo-controlled crossover study, Corey-Bloom et al³⁴ reported a significant reduction in spasticity, measured using the modified Ashworth scale, in MS patients receiving Cannabis cigarettes vs placebo cigarettes (P < .0001). However, compared with the placebo group, patients who received MM had significant adverse effects, primarily cognitive impairment (P = .003).

In a multicenter RCT (N = 572 patients with refractory MS spasticity), Novotna et al³⁶ evaluated nabiximols, an oral mucosal spray of a formulated extract of Cannabis that contains THC and CBD in a 1:1 ratio. They assessed spasticity using the Numerical Spasticity Rating Scale (NRS). Results were confirmed by measuring the number of daily spasms, self-report of sleep quality, and activities of daily living. After 4 weeks of single-blind treatment, patients who responded to nabiximols (≥20% improvement in spasticity) were randomized to a placebo group or nabiximols group for 12 additional weeks. After 12 weeks, compared with those who received placebo, those in the nabiximols group experienced a statistically significant reduction in spasticity based on NRS score (P = .0002).
 

For a summary of evidence on MM for treating glaucoma, Crohn’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, see Box 3.^37-43

Box 3
Cannabis for treating glaucoma, Crohn’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis

Psychiatric illnesses

Dementia-related behavioral disturbances. A few clinical trials with small sample sizes have found evidence supporting the use of MM compounds for alleviating neuropsychiatric symptoms of patients with dementia. An open-label pilot study of 6 individuals with late-stage dementia who received dronabinol, 2.5 mg/d, for 2 weeks, found a significant reduction (compared with baseline) in nighttime motor activity as measured with an actometer (P < .0028).⁴⁴ The secondary Neuropsychiatric Inventory (NPI) assessment found reductions in aberrant motor behavior (P = .042), agitation (P = .042), and nighttime behaviors (P = .42).

A 2014 retrospective analysis of 40 inpatients with dementia-related agitation and appetite loss who were treated with dronabinol (mean dosage: 7.03 mg/d) found reductions in all aspects of agitation, including aberrant vocalization, motor agitation, aggressiveness, and treatment resistance, as measured with the Pittsburgh Agitation Scale (P < .0001).⁴⁵ The study found no significant improvements in appetite, Global Assessment of Functioning mean score, or number of times patients awoke during the night. Adverse effects included sedation and delirium.

A RCT of 50 dementia patients with clinically relevant neuropsychiatric symptoms found no significant difference in mean NPI scores between patients given placebo and those who received nabiximols, 1.5 mg, 3 times daily.⁴⁶ There were no significant differences found in agitation, QOL, life activities, or caregiver-scored Caregiver Global Impression of Change scale.

In a small RCT, THC was safe and well tolerated in 10 older patients with dementia.⁴⁷ A 2009 Cochrane review⁴⁸ concluded that there was no evidence for the efficacy of MM in treating the neuropsychiatric symptoms related to dementia.

PTSD. Preclinical evidence shows that the endocannabinoid system is involved in regulating emotional memory. Evidence also suggests that cannabinoids may facilitate the extinction of aversive memories.^49,50

In 2009, New Mexico became the first state to authorize the use of MM for patients with PTSD. In a study of patients applying for the New Mexico Medical Cannabis Program, researchers used the Clinician Administered Posttraumatic Scale (CAPS) to assess PTSD symptoms.⁵¹ A retrospective chart review of the first 80 patients eval­uated found significant (P < .0001) reductions of several PTSD symptoms, including intrusive memories, distressing dreams, flashbacks, numbing and avoidance, and hyperarousal, in the group using MM vs those not using MM. There also was a significant difference in CAPS total score (P < .0001). Patients reported a 75% reduction in PTSD symptoms while using MM. This study has several limitations: It was a retrospective review, not an RCT, and patients were prescreened and knew before the study began that MM helped their PTSD symptoms.

In another retrospective study, researchers evaluated treatment with nabilone, 0.5 to 6 mg/d, in 104 incarcerated men with various major mental illnesses; most (91%) met criteria for Cannabis dependence.⁵² They found significant improvements in sleep and PTSD symptoms.

A double-blind RCT evaluated MM in 10 Canadian male soldiers with PTSD who experienced nightmares despite standard medication treatment. Adjunctive nabilone (maximum dose: 3 mg/d) resulted in a reduction in nightmares as measured by the CAPS recurrent distressing dream of the event item score.⁵³

Currently, there are no adequately powered RCTs of MM in a diverse group of PTSD patients. Most studies are open-label, enriched design, and included white male veterans. No well-conducted trials have evaluated patients with noncombat-related PTSD. Most of the relevant literature consists of case reports of Cannabis use by patients with PTSD.

Anxiety disorders.Patients frequently indicate that smoking Cannabis helps relieve their anxiety, although there is no replicated evidence based on double-blind RCTs to support this. However, in rat models CBD has been shown to facilitate extinction of conditioned fear via the endocannabinoid system.^54-56 The mechanism of action is not completely understood. CBD has been shown to have antagonistic action at CB₁ and CB₂ receptors. It may have similar effects on memory extinction and may be an adjunct to exposure therapies for anxiety disorders.

Das et al⁵⁷ studied the effects of CBD (32 mg) on extinction and consolidation of memory related to contextual fear in 48 individuals. They found that CBD can enhance extinction learning, and suggested it may have potential as an adjunct to extinction-based therapies for anxiety disorders.

Caveats: Adverse effects, lack of RCTs

Cannabis use causes impairment of learning, memory, attention, and working memory. Adolescents are particularly vulnerable to the effects of Cannabis on brain development at a time when synaptic pruning and increased myelination occur. Normal brain development could be disrupted. Some studies have linked Cannabis use to abnormalities in the amygdala, hippocampus, frontal lobe, and cerebellum. From 1995 to 2014, the potency of Cannabis (THC concentration) increased from 4% to 12%.⁵⁸ This has substantial implications for increased abuse among adolescents and the deleterious effects of Cannabis on the brain.

Heavy Cannabis use impairs motivation and could precipitate psychosis in vulnerable individuals. Cannabis use may be linked to the development of schizophrenia.⁵⁹

There are no well-conducted RCTs on the efficacy of MM, and adequate safety data are lacking. There is also lack of consensus among qualified experts. There is soft evidence that MM may be helpful in some medical conditions, including but not limited to CINV, neuropathic pain, epilepsy, and MS-related spasticity. Currently, the benefits of using MM do not appear to outweigh the risks.

Bottom Line

Limited evidence suggests medical marijuana (MM) may be beneficial for treating a few medical conditions, including neuropathic pain and chemotherapy-induced nausea and vomiting. There is no clear and convincing evidence MM is beneficial for psychiatric disorders, and Cannabis can impair cognition and attention and may precipitate psychosis. The risk of deleterious effects are greater in adolescents.

Related Resources

• Nguyen DH, Thant TM. Caring for medical marijuana patients who request controlled prescriptions. Current Psychiatry. 2017;16(8):50-51.
• National Institute on Drug Abuse. Marijuana as medicine. https://www.drugabuse.gov/publications/drugfacts/ marijuana-medicine.

Drug Brand Names

Alizapride • Litican, Superan
Chlorpromazine • Thorazine
Domperidone • Motilium
Dronabinol • Marinol, Syndros
Haloperidol • Haldol
Metoclopramide • Reglan
Nabilone • Cesamet
Nabiximols • Sativex
Ondansetron • Zofran, Zuplenz
Prochlorperazine • Compazine
Thiethylperazine • Torecan

Monoamine oxidase inhibitors (MAOIs) have well-established efficacy for treating depression, panic disorder, and social phobia. However, a lack of familiarity with these agents and misconceptions about the risks associated with their use have led to MAOIs being substantially underutilized. The goal of this 2-part guide to MAOIs is to educate clinicians about this often-overlooked class of medications. Part 1 (“A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A) described the pharmacology of MAOIs, the mechanism by which tyramine induces hypertension in patients taking MAOIs, and what to tell patients about dietary restrictions associated with these medications. Part 2 covers how to avoid potential drug interactions, including serotonin syndrome (SS) and pressor effects, that could affect patients receiving an MAOI; other factors to consider when starting a patient on an MAOI; and augmentation strategies for depressed patients who do not achieve remission from MAOI monotherapy.

MAOIs and potential drug interactions

One source of concern in patients receiving irreversible nonselective MAOIs is the development of excessive serotonergic neurotransmission resulting in SS. In the 1960s, researchers noted that administering large doses of tryptophan to MAOI-treated patients resulted in clonus and hyperactive reflexes without hypertensive events.¹ In 1991, Sternbach² provided an extensive case series and described the first set of criteria for SS. Features of SS include:

• mild symptoms: tremor, akathisia, inducible clonus
• moderate symptoms: spontaneous or sustained clonus, muscular hypertonicity
• severe symptoms: hyperthermia, diaphoresis.²

Although SS can be induced by significant exposure to individual agents that promote excess synaptic serotonin (eg, overdose of selective serotonin reuptake inhibitors [SSRIs]), the majority of fatal cases have occurred among patients taking MAOIs who were coadministered an agent that inhibited serotonin reuptake (Table 1³). Animal studies have determined that excessive stimulation of the 5HT2A receptor is primarily responsible for SS,⁴ and that 5HT2A antagonists, such as mirtazapine, can block the development of SS in a mouse coadministered fluoxetine and tranylcypromine.⁵ In addition to a patient’s medication history, the clinical hallmark of SS that helps distinguish it from neuroleptic malignant syndrome, delirium, and other acute syndromes is clonus, which becomes spontaneous and sustained as the severity increases.

Risk for SS. Most medications that promote serotonergic activity are well known for their use as antidepressants, but other agents that have 5HT reuptake properties (eg, the antihistamine chlorpheniramine) must be avoided. Although older literature suggests that the use of lower doses of certain tricyclic antidepressants concurrently with MAOIs may not be as dangerous as once believed,⁶ there are sufficient reports of serious outcomes that tricyclics should be avoided in patients taking MAOIs because of the risk of SS, and also because, in general, tricyclics are poorly tolerated.⁷

Desipramine, a potent norepinephrine transporter (NET) inhibitor, blocks the entry of tyramine into cells by NET, thereby preventing hypertensive events in animal models of tyramine overexposure. However, in some assays, the affinity for the serotonin transporter is not insignificant, so at higher doses desipramine may pose the same theoretical risk for SS as seen with other tricyclics.³

Lastly, rasagiline is an MAO-B selective inhibitor that has been available in the United States since 2008 for the treatment of Parkinson’s disease (PD). Although this drug lacks MAO-A antagonism, its package insert carries SS warnings; however, analysis of outcomes from a large multicenter rasagiline trial (N = 1,504) found no SS events in the 471 patients receiving rasagiline plus antidepressants (74.5% on SSRIs).⁸ Because depression is a common comorbidity in PD, clinicians who encounter rasagiline-treated patients who need antidepressant therapy should consult with the patient’s neurologist regarding their experience and comfort level with combining rasagiline and SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs).

Astute clinicians will recognize that antidepressants that lack 5HT reuptake (eg, bupropion, mirtazapine) are not on this list of agents that may increase SS risk when taken with an MAOI. Older papers often list mirtazapine, but as a 5HT2A antagonist, it does not possess a plausible mechanism by which it can induce 5HT toxicity.^9,10 Most atypical antipsychotics have significant 5HT2A antagonism and can be combined with MAOIs, but ziprasidone is an exception: as a moderate SNRI, it has been associated with SS when administered with an MAOI.¹¹

Pressor reactions. The only theoretical sources of concern for pressor effects are medications that act as norepinephrine releasers through interactions at the trace amine-associated receptor 1 (TAAR1) (for more information on TAAR1, see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A). Amphetamines are one such class, but a 2004 review did not find cases of hypertensive crises when amphetamines were combined with MAOIs,¹² nor did a recent article that described the combined use of lisdexamfetamine and transdermal selegiline.¹³ Presumably, the low level of intracellular exposure mitigates the risk of excessive TAAR1 agonism, but amphetamine derivatives should be approached cautiously and with careful blood pressure monitoring. On the other hand, methylphenidate is an inhibitor of dopamine reuptake with no affinity for TAAR1¹⁴ or the serotonin transporter,¹⁵ and does not induce a pressor response nor increase risk for SS when combined with MAOIs.³ Concerns about the use of α1-adrenergic agonists in patients taking MAOIs are not universal, as the deleterious effects on blood pressure are seen only in certain vulnerable patients, typically those with preexisting hypertension. Nonetheless, all patients should be cautioned about the use of phenylephrine and pseudoephedrine.¹⁶
 

Starting a patient on an MAOI

Contraindicated medications need to be tapered before beginning MAOI treatment. The duration of the washout period depends on the half-life of the medication and any active metabolites. Antidepressants with half-lives of approximately ≤24 hours should be tapered over 7 to 14 days (depending on the dose) to minimize the risk of withdrawal syndromes, while those with long half-lives (eg, fluoxetine, vortioxetine) can be stopped abruptly. After stopping a medication for 5 half-lives, 96.875% of the medication is removed, so adequate time must elapse after the last dose before starting an MAOI. Table 2^17-22 lists the half-lives of commonly used newer antidepressants and any active metabolites or isomers. Clinicians should always err on the side of caution before starting an MAOI, and give their patients a brief overview of SS symptoms; however, be mindful of not extending time the patient is without effective antidepressant levels.

Initiation of an MAOI is always based on whether the patient can reliably follow the basic dietary advice (see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A), and they agree to check with their clinician before starting new medications. Titration of MAOIs should be based on tolerability; orthostasis is the primary dose-limiting adverse effect associated with rapid titration or higher dosages. This may be especially true in older patients with poor vasomotor tone, or those on α1-adrenergic antagonists or other agents that may induce orthostatic effects. The rapid titration schedules present in certain package inserts (eg, phenelzine²³) should not be followed.

The orthostasis management strategy is similar to that employed for clozapine: minimize the use of concurrent α1-adrenergic antagonists, lower the doses of antihypertensives as much as possible, and encourage adequate fluid intake. For patients with ongoing orthostasis and without a history of congestive heart failure, consider using the potent mineralocorticoid fludrocortisone starting at 0.1 mg/d, and titrating every 10 to 14 days if needed to a maximum of 0.3 mg/d.²⁴ Older literature noted weight gain, peripheral edema, and sexual dysfunction as common adverse effects. Research on the most recently studied MAOI, selegiline transdermal, reported rates of these adverse effects as follows: weight gain: 2.1% for selegiline transdermal vs 2.4% for placebo; all forms of sexual dysfunction: 0 to 1% for selegiline transdermal vs 0 to 0.4% for placebo.²⁵

Augmentation options for patients taking MAOIs

For depressed patients who do not achieve remission of symptoms from MAOI therapy, augmentation options should be sought, as patients who respond but fail to remit are at increased risk of relapse.²⁶ Lithium augmentation is one of the more common strategies, with abundant data supporting its use.^27,28 Case reports dating back >12 years describe the concurrent use of bupropion and MAOIs.^12,29 A recent review of augmentation of MAOIs with second-generation antipsychotics found multiple positive reports for most agents, including aripiprazole, with the sole exception of ziprasidone, a moderate SNRI for which cases of SS have been reported.¹¹ As of November 2017, there are no case reports for asenapine, lurasidone, brexpiprazole, or cariprazine. Triiodothyronine is often a neglected strategy, but older case reports of combined treatment with MAOIs found no obvious concerns beyond those related to the use of thyroid hormone.^30,31

Monoamine oxidase inhibitors (MAOIs) have well-established efficacy for treating depression, panic disorder, and social phobia. However, a lack of familiarity with these agents and misconceptions about the risks associated with their use have led to MAOIs being substantially underutilized. The goal of this 2-part guide to MAOIs is to educate clinicians about this often-overlooked class of medications. Part 1 (“A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A) described the pharmacology of MAOIs, the mechanism by which tyramine induces hypertension in patients taking MAOIs, and what to tell patients about dietary restrictions associated with these medications. Part 2 covers how to avoid potential drug interactions, including serotonin syndrome (SS) and pressor effects, that could affect patients receiving an MAOI; other factors to consider when starting a patient on an MAOI; and augmentation strategies for depressed patients who do not achieve remission from MAOI monotherapy.

MAOIs and potential drug interactions

One source of concern in patients receiving irreversible nonselective MAOIs is the development of excessive serotonergic neurotransmission resulting in SS. In the 1960s, researchers noted that administering large doses of tryptophan to MAOI-treated patients resulted in clonus and hyperactive reflexes without hypertensive events.¹ In 1991, Sternbach² provided an extensive case series and described the first set of criteria for SS. Features of SS include:

• mild symptoms: tremor, akathisia, inducible clonus
• moderate symptoms: spontaneous or sustained clonus, muscular hypertonicity
• severe symptoms: hyperthermia, diaphoresis.²

Although SS can be induced by significant exposure to individual agents that promote excess synaptic serotonin (eg, overdose of selective serotonin reuptake inhibitors [SSRIs]), the majority of fatal cases have occurred among patients taking MAOIs who were coadministered an agent that inhibited serotonin reuptake (Table 1³). Animal studies have determined that excessive stimulation of the 5HT2A receptor is primarily responsible for SS,⁴ and that 5HT2A antagonists, such as mirtazapine, can block the development of SS in a mouse coadministered fluoxetine and tranylcypromine.⁵ In addition to a patient’s medication history, the clinical hallmark of SS that helps distinguish it from neuroleptic malignant syndrome, delirium, and other acute syndromes is clonus, which becomes spontaneous and sustained as the severity increases.

Risk for SS. Most medications that promote serotonergic activity are well known for their use as antidepressants, but other agents that have 5HT reuptake properties (eg, the antihistamine chlorpheniramine) must be avoided. Although older literature suggests that the use of lower doses of certain tricyclic antidepressants concurrently with MAOIs may not be as dangerous as once believed,⁶ there are sufficient reports of serious outcomes that tricyclics should be avoided in patients taking MAOIs because of the risk of SS, and also because, in general, tricyclics are poorly tolerated.⁷

Desipramine, a potent norepinephrine transporter (NET) inhibitor, blocks the entry of tyramine into cells by NET, thereby preventing hypertensive events in animal models of tyramine overexposure. However, in some assays, the affinity for the serotonin transporter is not insignificant, so at higher doses desipramine may pose the same theoretical risk for SS as seen with other tricyclics.³

Lastly, rasagiline is an MAO-B selective inhibitor that has been available in the United States since 2008 for the treatment of Parkinson’s disease (PD). Although this drug lacks MAO-A antagonism, its package insert carries SS warnings; however, analysis of outcomes from a large multicenter rasagiline trial (N = 1,504) found no SS events in the 471 patients receiving rasagiline plus antidepressants (74.5% on SSRIs).⁸ Because depression is a common comorbidity in PD, clinicians who encounter rasagiline-treated patients who need antidepressant therapy should consult with the patient’s neurologist regarding their experience and comfort level with combining rasagiline and SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs).

Astute clinicians will recognize that antidepressants that lack 5HT reuptake (eg, bupropion, mirtazapine) are not on this list of agents that may increase SS risk when taken with an MAOI. Older papers often list mirtazapine, but as a 5HT2A antagonist, it does not possess a plausible mechanism by which it can induce 5HT toxicity.^9,10 Most atypical antipsychotics have significant 5HT2A antagonism and can be combined with MAOIs, but ziprasidone is an exception: as a moderate SNRI, it has been associated with SS when administered with an MAOI.¹¹

Pressor reactions. The only theoretical sources of concern for pressor effects are medications that act as norepinephrine releasers through interactions at the trace amine-associated receptor 1 (TAAR1) (for more information on TAAR1, see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A). Amphetamines are one such class, but a 2004 review did not find cases of hypertensive crises when amphetamines were combined with MAOIs,¹² nor did a recent article that described the combined use of lisdexamfetamine and transdermal selegiline.¹³ Presumably, the low level of intracellular exposure mitigates the risk of excessive TAAR1 agonism, but amphetamine derivatives should be approached cautiously and with careful blood pressure monitoring. On the other hand, methylphenidate is an inhibitor of dopamine reuptake with no affinity for TAAR1¹⁴ or the serotonin transporter,¹⁵ and does not induce a pressor response nor increase risk for SS when combined with MAOIs.³ Concerns about the use of α1-adrenergic agonists in patients taking MAOIs are not universal, as the deleterious effects on blood pressure are seen only in certain vulnerable patients, typically those with preexisting hypertension. Nonetheless, all patients should be cautioned about the use of phenylephrine and pseudoephedrine.¹⁶
 

Starting a patient on an MAOI

Contraindicated medications need to be tapered before beginning MAOI treatment. The duration of the washout period depends on the half-life of the medication and any active metabolites. Antidepressants with half-lives of approximately ≤24 hours should be tapered over 7 to 14 days (depending on the dose) to minimize the risk of withdrawal syndromes, while those with long half-lives (eg, fluoxetine, vortioxetine) can be stopped abruptly. After stopping a medication for 5 half-lives, 96.875% of the medication is removed, so adequate time must elapse after the last dose before starting an MAOI. Table 2^17-22 lists the half-lives of commonly used newer antidepressants and any active metabolites or isomers. Clinicians should always err on the side of caution before starting an MAOI, and give their patients a brief overview of SS symptoms; however, be mindful of not extending time the patient is without effective antidepressant levels.

Initiation of an MAOI is always based on whether the patient can reliably follow the basic dietary advice (see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A), and they agree to check with their clinician before starting new medications. Titration of MAOIs should be based on tolerability; orthostasis is the primary dose-limiting adverse effect associated with rapid titration or higher dosages. This may be especially true in older patients with poor vasomotor tone, or those on α1-adrenergic antagonists or other agents that may induce orthostatic effects. The rapid titration schedules present in certain package inserts (eg, phenelzine²³) should not be followed.

The orthostasis management strategy is similar to that employed for clozapine: minimize the use of concurrent α1-adrenergic antagonists, lower the doses of antihypertensives as much as possible, and encourage adequate fluid intake. For patients with ongoing orthostasis and without a history of congestive heart failure, consider using the potent mineralocorticoid fludrocortisone starting at 0.1 mg/d, and titrating every 10 to 14 days if needed to a maximum of 0.3 mg/d.²⁴ Older literature noted weight gain, peripheral edema, and sexual dysfunction as common adverse effects. Research on the most recently studied MAOI, selegiline transdermal, reported rates of these adverse effects as follows: weight gain: 2.1% for selegiline transdermal vs 2.4% for placebo; all forms of sexual dysfunction: 0 to 1% for selegiline transdermal vs 0 to 0.4% for placebo.²⁵

Augmentation options for patients taking MAOIs

For depressed patients who do not achieve remission of symptoms from MAOI therapy, augmentation options should be sought, as patients who respond but fail to remit are at increased risk of relapse.²⁶ Lithium augmentation is one of the more common strategies, with abundant data supporting its use.^27,28 Case reports dating back >12 years describe the concurrent use of bupropion and MAOIs.^12,29 A recent review of augmentation of MAOIs with second-generation antipsychotics found multiple positive reports for most agents, including aripiprazole, with the sole exception of ziprasidone, a moderate SNRI for which cases of SS have been reported.¹¹ As of November 2017, there are no case reports for asenapine, lurasidone, brexpiprazole, or cariprazine. Triiodothyronine is often a neglected strategy, but older case reports of combined treatment with MAOIs found no obvious concerns beyond those related to the use of thyroid hormone.^30,31

Monoamine oxidase inhibitors (MAOIs) have well-established efficacy for treating depression, panic disorder, and social phobia. However, a lack of familiarity with these agents and misconceptions about the risks associated with their use have led to MAOIs being substantially underutilized. The goal of this 2-part guide to MAOIs is to educate clinicians about this often-overlooked class of medications. Part 1 (“A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A) described the pharmacology of MAOIs, the mechanism by which tyramine induces hypertension in patients taking MAOIs, and what to tell patients about dietary restrictions associated with these medications. Part 2 covers how to avoid potential drug interactions, including serotonin syndrome (SS) and pressor effects, that could affect patients receiving an MAOI; other factors to consider when starting a patient on an MAOI; and augmentation strategies for depressed patients who do not achieve remission from MAOI monotherapy.

MAOIs and potential drug interactions

One source of concern in patients receiving irreversible nonselective MAOIs is the development of excessive serotonergic neurotransmission resulting in SS. In the 1960s, researchers noted that administering large doses of tryptophan to MAOI-treated patients resulted in clonus and hyperactive reflexes without hypertensive events.¹ In 1991, Sternbach² provided an extensive case series and described the first set of criteria for SS. Features of SS include:

• mild symptoms: tremor, akathisia, inducible clonus
• moderate symptoms: spontaneous or sustained clonus, muscular hypertonicity
• severe symptoms: hyperthermia, diaphoresis.²

Although SS can be induced by significant exposure to individual agents that promote excess synaptic serotonin (eg, overdose of selective serotonin reuptake inhibitors [SSRIs]), the majority of fatal cases have occurred among patients taking MAOIs who were coadministered an agent that inhibited serotonin reuptake (Table 1³). Animal studies have determined that excessive stimulation of the 5HT2A receptor is primarily responsible for SS,⁴ and that 5HT2A antagonists, such as mirtazapine, can block the development of SS in a mouse coadministered fluoxetine and tranylcypromine.⁵ In addition to a patient’s medication history, the clinical hallmark of SS that helps distinguish it from neuroleptic malignant syndrome, delirium, and other acute syndromes is clonus, which becomes spontaneous and sustained as the severity increases.

Risk for SS. Most medications that promote serotonergic activity are well known for their use as antidepressants, but other agents that have 5HT reuptake properties (eg, the antihistamine chlorpheniramine) must be avoided. Although older literature suggests that the use of lower doses of certain tricyclic antidepressants concurrently with MAOIs may not be as dangerous as once believed,⁶ there are sufficient reports of serious outcomes that tricyclics should be avoided in patients taking MAOIs because of the risk of SS, and also because, in general, tricyclics are poorly tolerated.⁷

Desipramine, a potent norepinephrine transporter (NET) inhibitor, blocks the entry of tyramine into cells by NET, thereby preventing hypertensive events in animal models of tyramine overexposure. However, in some assays, the affinity for the serotonin transporter is not insignificant, so at higher doses desipramine may pose the same theoretical risk for SS as seen with other tricyclics.³

Lastly, rasagiline is an MAO-B selective inhibitor that has been available in the United States since 2008 for the treatment of Parkinson’s disease (PD). Although this drug lacks MAO-A antagonism, its package insert carries SS warnings; however, analysis of outcomes from a large multicenter rasagiline trial (N = 1,504) found no SS events in the 471 patients receiving rasagiline plus antidepressants (74.5% on SSRIs).⁸ Because depression is a common comorbidity in PD, clinicians who encounter rasagiline-treated patients who need antidepressant therapy should consult with the patient’s neurologist regarding their experience and comfort level with combining rasagiline and SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs).

Astute clinicians will recognize that antidepressants that lack 5HT reuptake (eg, bupropion, mirtazapine) are not on this list of agents that may increase SS risk when taken with an MAOI. Older papers often list mirtazapine, but as a 5HT2A antagonist, it does not possess a plausible mechanism by which it can induce 5HT toxicity.^9,10 Most atypical antipsychotics have significant 5HT2A antagonism and can be combined with MAOIs, but ziprasidone is an exception: as a moderate SNRI, it has been associated with SS when administered with an MAOI.¹¹

Pressor reactions. The only theoretical sources of concern for pressor effects are medications that act as norepinephrine releasers through interactions at the trace amine-associated receptor 1 (TAAR1) (for more information on TAAR1, see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A). Amphetamines are one such class, but a 2004 review did not find cases of hypertensive crises when amphetamines were combined with MAOIs,¹² nor did a recent article that described the combined use of lisdexamfetamine and transdermal selegiline.¹³ Presumably, the low level of intracellular exposure mitigates the risk of excessive TAAR1 agonism, but amphetamine derivatives should be approached cautiously and with careful blood pressure monitoring. On the other hand, methylphenidate is an inhibitor of dopamine reuptake with no affinity for TAAR1¹⁴ or the serotonin transporter,¹⁵ and does not induce a pressor response nor increase risk for SS when combined with MAOIs.³ Concerns about the use of α1-adrenergic agonists in patients taking MAOIs are not universal, as the deleterious effects on blood pressure are seen only in certain vulnerable patients, typically those with preexisting hypertension. Nonetheless, all patients should be cautioned about the use of phenylephrine and pseudoephedrine.¹⁶
 

Starting a patient on an MAOI

Contraindicated medications need to be tapered before beginning MAOI treatment. The duration of the washout period depends on the half-life of the medication and any active metabolites. Antidepressants with half-lives of approximately ≤24 hours should be tapered over 7 to 14 days (depending on the dose) to minimize the risk of withdrawal syndromes, while those with long half-lives (eg, fluoxetine, vortioxetine) can be stopped abruptly. After stopping a medication for 5 half-lives, 96.875% of the medication is removed, so adequate time must elapse after the last dose before starting an MAOI. Table 2^17-22 lists the half-lives of commonly used newer antidepressants and any active metabolites or isomers. Clinicians should always err on the side of caution before starting an MAOI, and give their patients a brief overview of SS symptoms; however, be mindful of not extending time the patient is without effective antidepressant levels.

Initiation of an MAOI is always based on whether the patient can reliably follow the basic dietary advice (see “A concise guide to monoamine inhibitors,” Current Psychiatry. December 2017, p. 14-23,47,A), and they agree to check with their clinician before starting new medications. Titration of MAOIs should be based on tolerability; orthostasis is the primary dose-limiting adverse effect associated with rapid titration or higher dosages. This may be especially true in older patients with poor vasomotor tone, or those on α1-adrenergic antagonists or other agents that may induce orthostatic effects. The rapid titration schedules present in certain package inserts (eg, phenelzine²³) should not be followed.

The orthostasis management strategy is similar to that employed for clozapine: minimize the use of concurrent α1-adrenergic antagonists, lower the doses of antihypertensives as much as possible, and encourage adequate fluid intake. For patients with ongoing orthostasis and without a history of congestive heart failure, consider using the potent mineralocorticoid fludrocortisone starting at 0.1 mg/d, and titrating every 10 to 14 days if needed to a maximum of 0.3 mg/d.²⁴ Older literature noted weight gain, peripheral edema, and sexual dysfunction as common adverse effects. Research on the most recently studied MAOI, selegiline transdermal, reported rates of these adverse effects as follows: weight gain: 2.1% for selegiline transdermal vs 2.4% for placebo; all forms of sexual dysfunction: 0 to 1% for selegiline transdermal vs 0 to 0.4% for placebo.²⁵

Augmentation options for patients taking MAOIs

For depressed patients who do not achieve remission of symptoms from MAOI therapy, augmentation options should be sought, as patients who respond but fail to remit are at increased risk of relapse.²⁶ Lithium augmentation is one of the more common strategies, with abundant data supporting its use.^27,28 Case reports dating back >12 years describe the concurrent use of bupropion and MAOIs.^12,29 A recent review of augmentation of MAOIs with second-generation antipsychotics found multiple positive reports for most agents, including aripiprazole, with the sole exception of ziprasidone, a moderate SNRI for which cases of SS have been reported.¹¹ As of November 2017, there are no case reports for asenapine, lurasidone, brexpiprazole, or cariprazine. Triiodothyronine is often a neglected strategy, but older case reports of combined treatment with MAOIs found no obvious concerns beyond those related to the use of thyroid hormone.^30,31

Being a psychiatrist today often entails long hours immersed in charts or on computers, a lack of fresh air, and eating meals in a hurry. Being on call, facing deadline pressures, and juggling multiple responsibilities can lead to fatigue, frustration, and a lack of adequate socialization. These circumstances can take their toll on us in unpleasant and unhealthy ways, resulting in exhaustion, illness, and isolation. After spending many hours caring for our patients, yoga can help restore and revitalize our own bodies and minds. Preliminary research indicates that yoga can have beneficial effects on one’s mental state, and may help treat depression, anxiety, and other conditions, although many studies of yoga have been small or poorly designed.^1,2

What is yoga?

Yoga is an ancient practice that originated in India thousands of years ago. It was introduced to the West in the 19th century. Yoga is a holistic lifestyle of well-being that includes physical and meditative practices. Today, the most popular forms of yoga typically incorporate a combination of physical postures, controlled breathing, deep relaxation, and/or meditation.²

How to begin yoga practice

Start slow and simple. Watching a beginner’s video at home or taking a beginner’s class in a yoga studio can be extremely helpful. Take time to learn how to mindfully move in and out of postures to avoid injury or strain. Yoga postures often represent animals, nature, and heroes that suggest unity with life, evolution, and universality. These postures can be done in any quiet setting; practicing out in nature may be particularly enjoyable for some. Practicing yoga postures can help you:

• develop balance, endurance, strength, flexibility, and coordination
• release chronic muscular tension
• rejuvenate the body.

Explore different schools. Over time, numerous schools of yoga have evolved. They vary from gentle to strenuous, with an emphasis on postures, breath work, meditation, singing, or a combination of these skills. Choose what feels good and safe based on your personal preference and physical ability.

Be mindful. Focusing solely on the present moment calms the mind and increases awareness. Meditative practice can sharpen clarity and focus. Meditation can involve focusing your attention on sounds, images, or inspirational words or phrases. Each of our movements can invite self-respect and further awareness of the daily toll that modern life places on our minds and bodies. Active breath work is believed to cultivate vitality. Calm breath work and meditative practices help still the mind and decrease physiologic overarousal.

Stay consistent. Regardless of your physical ability or level of mobility, consistent yoga practice is necessary to realize its benefits. Therefore, a weekly class may be a good way to start. Eventually, a good goal is to practice twice a day, at dawn and dusk.

Appreciate the experience. Immerse yourself in each moment of yoga practice. There is no need to rush. Enjoy your journey!

Being a psychiatrist today often entails long hours immersed in charts or on computers, a lack of fresh air, and eating meals in a hurry. Being on call, facing deadline pressures, and juggling multiple responsibilities can lead to fatigue, frustration, and a lack of adequate socialization. These circumstances can take their toll on us in unpleasant and unhealthy ways, resulting in exhaustion, illness, and isolation. After spending many hours caring for our patients, yoga can help restore and revitalize our own bodies and minds. Preliminary research indicates that yoga can have beneficial effects on one’s mental state, and may help treat depression, anxiety, and other conditions, although many studies of yoga have been small or poorly designed.^1,2

What is yoga?

Yoga is an ancient practice that originated in India thousands of years ago. It was introduced to the West in the 19th century. Yoga is a holistic lifestyle of well-being that includes physical and meditative practices. Today, the most popular forms of yoga typically incorporate a combination of physical postures, controlled breathing, deep relaxation, and/or meditation.²

How to begin yoga practice

Start slow and simple. Watching a beginner’s video at home or taking a beginner’s class in a yoga studio can be extremely helpful. Take time to learn how to mindfully move in and out of postures to avoid injury or strain. Yoga postures often represent animals, nature, and heroes that suggest unity with life, evolution, and universality. These postures can be done in any quiet setting; practicing out in nature may be particularly enjoyable for some. Practicing yoga postures can help you:

• develop balance, endurance, strength, flexibility, and coordination
• release chronic muscular tension
• rejuvenate the body.

Explore different schools. Over time, numerous schools of yoga have evolved. They vary from gentle to strenuous, with an emphasis on postures, breath work, meditation, singing, or a combination of these skills. Choose what feels good and safe based on your personal preference and physical ability.

Be mindful. Focusing solely on the present moment calms the mind and increases awareness. Meditative practice can sharpen clarity and focus. Meditation can involve focusing your attention on sounds, images, or inspirational words or phrases. Each of our movements can invite self-respect and further awareness of the daily toll that modern life places on our minds and bodies. Active breath work is believed to cultivate vitality. Calm breath work and meditative practices help still the mind and decrease physiologic overarousal.

Stay consistent. Regardless of your physical ability or level of mobility, consistent yoga practice is necessary to realize its benefits. Therefore, a weekly class may be a good way to start. Eventually, a good goal is to practice twice a day, at dawn and dusk.

Appreciate the experience. Immerse yourself in each moment of yoga practice. There is no need to rush. Enjoy your journey!

Being a psychiatrist today often entails long hours immersed in charts or on computers, a lack of fresh air, and eating meals in a hurry. Being on call, facing deadline pressures, and juggling multiple responsibilities can lead to fatigue, frustration, and a lack of adequate socialization. These circumstances can take their toll on us in unpleasant and unhealthy ways, resulting in exhaustion, illness, and isolation. After spending many hours caring for our patients, yoga can help restore and revitalize our own bodies and minds. Preliminary research indicates that yoga can have beneficial effects on one’s mental state, and may help treat depression, anxiety, and other conditions, although many studies of yoga have been small or poorly designed.^1,2

What is yoga?

Yoga is an ancient practice that originated in India thousands of years ago. It was introduced to the West in the 19th century. Yoga is a holistic lifestyle of well-being that includes physical and meditative practices. Today, the most popular forms of yoga typically incorporate a combination of physical postures, controlled breathing, deep relaxation, and/or meditation.²

How to begin yoga practice

Start slow and simple. Watching a beginner’s video at home or taking a beginner’s class in a yoga studio can be extremely helpful. Take time to learn how to mindfully move in and out of postures to avoid injury or strain. Yoga postures often represent animals, nature, and heroes that suggest unity with life, evolution, and universality. These postures can be done in any quiet setting; practicing out in nature may be particularly enjoyable for some. Practicing yoga postures can help you:

• develop balance, endurance, strength, flexibility, and coordination
• release chronic muscular tension
• rejuvenate the body.

Explore different schools. Over time, numerous schools of yoga have evolved. They vary from gentle to strenuous, with an emphasis on postures, breath work, meditation, singing, or a combination of these skills. Choose what feels good and safe based on your personal preference and physical ability.

Be mindful. Focusing solely on the present moment calms the mind and increases awareness. Meditative practice can sharpen clarity and focus. Meditation can involve focusing your attention on sounds, images, or inspirational words or phrases. Each of our movements can invite self-respect and further awareness of the daily toll that modern life places on our minds and bodies. Active breath work is believed to cultivate vitality. Calm breath work and meditative practices help still the mind and decrease physiologic overarousal.

Stay consistent. Regardless of your physical ability or level of mobility, consistent yoga practice is necessary to realize its benefits. Therefore, a weekly class may be a good way to start. Eventually, a good goal is to practice twice a day, at dawn and dusk.

Appreciate the experience. Immerse yourself in each moment of yoga practice. There is no need to rush. Enjoy your journey!

Attention-deficit/hyperactivity disorder (ADHD) affects 5% of children and adolescents worldwide.¹ Children with ADHD commonly have trouble with attention, hyperactivity, impulsivity, organization, and emotional reactivity, and these difficulties can result in behaviors that frustrate, worry, and overwhelm parents, teachers, and other caregivers.

Extensive evidence supports stimulants as a first-line treatment. However, nonpharmacologic interventions are important, yet often overlooked, adjuncts that can be helpful for children who have a partial response to stimulants or are not prescribed medication. Teaching caregivers to use the following interventions will allow them to help children better navigate situations that require managing their symptoms, such as in a classroom setting.²

Attention. Children with ADHD typically find it challenging to prioritize what to focus on, sustain that focus, and switch between tasks. Shouting instructions often is unproductive. Therefore, encourage parents and teachers to use clear and concise instructions with supplementary visual tools to aid these children. When providing instructions in classrooms, teachers should look directly at the student and call him (her) by name. It also can be helpful to have the student repeat the instructions. Seating students with ADHD near the front of the classroom, close to the teacher and away from other distracting students, can improve their focus and allow the teacher to more easily give nonverbal cues, such as tapping on the student’s desk if his attention is waning.

Hyperactivity. Children with ADHD are prone to excessive talkativeness and continuous motor movement; therefore, sitting still for long periods can be exceptionally difficult. Teachers and caregivers should keep assignments short. For students whose primary manifestation of ADHD is hyperactivity, sitting near the back of the classroom will allow them to stand and stretch without disrupting the class. Occasionally giving these students a time-limited, acceptable outlet for their urge to move may be beneficial.

Impulsivity. Children who exhibit this symptom are more focused on the present and have difficulty weighing the consequences of their actions. Allowing these children to take frequent breaks (eg, more play time) will let their brains rest and recharge so that they can take a step back to evaluate the outcomes of their actions. Instruct parents and teachers to give children with ADHD regular verbal or written feedback to monitor and modify behaviors over time. Consequences for not following the rules should be immediate and consistent.

Organization. School assignments require sequencing, planning, and time management. Therefore, having daily visual reminders of prioritized assignments and schedules is helpful for children with ADHD, both at school and at home. Teachers and parents can help children stay organized by checking and reviewing the child’s agenda with him several times a day; this will allow him more time to think about what he needs to do to complete assignments.Emotional reactivity. Children with ADHD become frustrated easily and often are particularly sensitive to disappointment because of the continuous redirection they receive. Normalizing their mistakes by reinforcing that everyone makes mistakes and teaching them to learn from their mistakes can help reduce their embarrassment.

It also can be helpful to identify triggers for emotional reactivity. Parents and teachers should minimize the amount of talking when a child is unable to control his emotions. Helping children label their emotions, developing strategies for when they become upset, and outlining clear consequences for unacceptable behaviors can help modify their reactions.

Attention-deficit/hyperactivity disorder (ADHD) affects 5% of children and adolescents worldwide.¹ Children with ADHD commonly have trouble with attention, hyperactivity, impulsivity, organization, and emotional reactivity, and these difficulties can result in behaviors that frustrate, worry, and overwhelm parents, teachers, and other caregivers.

Extensive evidence supports stimulants as a first-line treatment. However, nonpharmacologic interventions are important, yet often overlooked, adjuncts that can be helpful for children who have a partial response to stimulants or are not prescribed medication. Teaching caregivers to use the following interventions will allow them to help children better navigate situations that require managing their symptoms, such as in a classroom setting.²

Attention. Children with ADHD typically find it challenging to prioritize what to focus on, sustain that focus, and switch between tasks. Shouting instructions often is unproductive. Therefore, encourage parents and teachers to use clear and concise instructions with supplementary visual tools to aid these children. When providing instructions in classrooms, teachers should look directly at the student and call him (her) by name. It also can be helpful to have the student repeat the instructions. Seating students with ADHD near the front of the classroom, close to the teacher and away from other distracting students, can improve their focus and allow the teacher to more easily give nonverbal cues, such as tapping on the student’s desk if his attention is waning.

Hyperactivity. Children with ADHD are prone to excessive talkativeness and continuous motor movement; therefore, sitting still for long periods can be exceptionally difficult. Teachers and caregivers should keep assignments short. For students whose primary manifestation of ADHD is hyperactivity, sitting near the back of the classroom will allow them to stand and stretch without disrupting the class. Occasionally giving these students a time-limited, acceptable outlet for their urge to move may be beneficial.

Impulsivity. Children who exhibit this symptom are more focused on the present and have difficulty weighing the consequences of their actions. Allowing these children to take frequent breaks (eg, more play time) will let their brains rest and recharge so that they can take a step back to evaluate the outcomes of their actions. Instruct parents and teachers to give children with ADHD regular verbal or written feedback to monitor and modify behaviors over time. Consequences for not following the rules should be immediate and consistent.

Organization. School assignments require sequencing, planning, and time management. Therefore, having daily visual reminders of prioritized assignments and schedules is helpful for children with ADHD, both at school and at home. Teachers and parents can help children stay organized by checking and reviewing the child’s agenda with him several times a day; this will allow him more time to think about what he needs to do to complete assignments.Emotional reactivity. Children with ADHD become frustrated easily and often are particularly sensitive to disappointment because of the continuous redirection they receive. Normalizing their mistakes by reinforcing that everyone makes mistakes and teaching them to learn from their mistakes can help reduce their embarrassment.

It also can be helpful to identify triggers for emotional reactivity. Parents and teachers should minimize the amount of talking when a child is unable to control his emotions. Helping children label their emotions, developing strategies for when they become upset, and outlining clear consequences for unacceptable behaviors can help modify their reactions.

Attention-deficit/hyperactivity disorder (ADHD) affects 5% of children and adolescents worldwide.¹ Children with ADHD commonly have trouble with attention, hyperactivity, impulsivity, organization, and emotional reactivity, and these difficulties can result in behaviors that frustrate, worry, and overwhelm parents, teachers, and other caregivers.

Extensive evidence supports stimulants as a first-line treatment. However, nonpharmacologic interventions are important, yet often overlooked, adjuncts that can be helpful for children who have a partial response to stimulants or are not prescribed medication. Teaching caregivers to use the following interventions will allow them to help children better navigate situations that require managing their symptoms, such as in a classroom setting.²

Attention. Children with ADHD typically find it challenging to prioritize what to focus on, sustain that focus, and switch between tasks. Shouting instructions often is unproductive. Therefore, encourage parents and teachers to use clear and concise instructions with supplementary visual tools to aid these children. When providing instructions in classrooms, teachers should look directly at the student and call him (her) by name. It also can be helpful to have the student repeat the instructions. Seating students with ADHD near the front of the classroom, close to the teacher and away from other distracting students, can improve their focus and allow the teacher to more easily give nonverbal cues, such as tapping on the student’s desk if his attention is waning.

Hyperactivity. Children with ADHD are prone to excessive talkativeness and continuous motor movement; therefore, sitting still for long periods can be exceptionally difficult. Teachers and caregivers should keep assignments short. For students whose primary manifestation of ADHD is hyperactivity, sitting near the back of the classroom will allow them to stand and stretch without disrupting the class. Occasionally giving these students a time-limited, acceptable outlet for their urge to move may be beneficial.

Impulsivity. Children who exhibit this symptom are more focused on the present and have difficulty weighing the consequences of their actions. Allowing these children to take frequent breaks (eg, more play time) will let their brains rest and recharge so that they can take a step back to evaluate the outcomes of their actions. Instruct parents and teachers to give children with ADHD regular verbal or written feedback to monitor and modify behaviors over time. Consequences for not following the rules should be immediate and consistent.

Organization. School assignments require sequencing, planning, and time management. Therefore, having daily visual reminders of prioritized assignments and schedules is helpful for children with ADHD, both at school and at home. Teachers and parents can help children stay organized by checking and reviewing the child’s agenda with him several times a day; this will allow him more time to think about what he needs to do to complete assignments.Emotional reactivity. Children with ADHD become frustrated easily and often are particularly sensitive to disappointment because of the continuous redirection they receive. Normalizing their mistakes by reinforcing that everyone makes mistakes and teaching them to learn from their mistakes can help reduce their embarrassment.

It also can be helpful to identify triggers for emotional reactivity. Parents and teachers should minimize the amount of talking when a child is unable to control his emotions. Helping children label their emotions, developing strategies for when they become upset, and outlining clear consequences for unacceptable behaviors can help modify their reactions.

The epidemiology of hepatitis A virus (HAV) disease has changed. Since July 2016, there have been 5 large outbreaks of infection involving more than 1600 cases,¹ with affected states requiring assistance from the Centers for Disease Control and Prevention (CDC). Two of these outbreaks were foodborne, and 3 involved person-to-person transmission.¹

Before 2016, the number of outbreaks had been very low, and were predominantly associated with contaminated food, infected food handlers, and other food service-related exposures. Total annual cases of HAV infection had been declining steadily in all age groups since 1995 when HAV vaccine became available, from an estimated 271,000 cases resulting in 100 deaths² to an estimated 2800 cases (with 1390 reported) resulting in 67 deaths in 2015 (FIGURE).³

Extent of the outbreaks

The largest hepatitis A outbreak involving person-to-person transmission in the United States in the past 20 years is occurring now in California. Predominantly affected are the homeless and users of illicit drugs, whose risk of infection is compounded by exposure to fecally-contaminated environments. As of December 1, the largest number of cases were recorded in San Diego (567), Santa Cruz (76), and Los Angeles (11).⁴ Adding 18 cases from other locations, the total has reached 672, resulting in 430 hospitalizations (64%) and 21 deaths (3%).⁴ In San Diego, 20% of those infected also had chronic hepatitis C and 5% had chronic hepatitis B.¹

In southeastern Michigan, 555 cases have been reported, with 457 hospitalizations (82%) and 20 deaths (4%).⁵ In Utah, 91 cases and 53 hospitalizations (58%) have been documented.⁶ In these regions, the predominant risk factors have been homelessness and illicit drug use. And many of those infected have had chronic hepatitis C (27.5%), hepatitis B (13.2%), or both (9.9%).⁶ In 2 of the 3 states just described, the outbreaks have involved HAV genotype 1B.¹

In New York City, an outbreak starting in January 2017 resulted in 51 cases. The epidemiology of this outbreak has been different from the others, involving men who have sex with men (MSM) and the HAV genotype 1A that matches a strain circulating among MSM in Europe.⁷

Low adult immunity is behind the outbreaks

These outbreaks have occurred in an adult US population that has low levels of immunity to HAV. In 2012 only 12.2% of adults ages 19 to 49 years had received 2 doses of HAV vaccine⁸ and only 24.2% of adults had antibodies to HAV,⁹ showing that most adults had never been infected with the virus or vaccinated. The reduction in HAV incidence previously described is due to the introduction of targeted, and then universal, child HAV vaccination recommendations by the Advisory Committee on Immunization Practices.

As the incidence of HAV disease declined, fewer individuals became infected as children, leading later to a susceptible pool of adults who had not been infected as children and who did not receive the vaccine in adulthood. Most of these adults will not be exposed to HAV due to decreased rates of infection in children, which, historically, has been the predominant means of adult exposure. The high hospitalization and death rates encountered in the recent and ongoing large outbreaks are explained by the multiple comorbidities of those infected.

Who should be vaccinated against HAV

The CDC recommends giving HAV vaccine to all children at age one year, and to the following groups:^2,10,11

• residents of a community that has a high rate of hepatitis A infection
• household members or other close personal contacts (eg, regular babysitters) of adopted children newly arrived from countries with high or intermediate hepatitis A endemicity
• men who have sex with other men
• users of illicit injection and noninjection drugs
• workers in, or travelers to, countries with high rates of hepatitis A infection
• individuals with chronic liver disease
• individuals who work with HAV-infected animals or with HAV in a research setting.

Outbreak-specific vaccine recommendations

The CDC has additionally recommended that, during outbreaks, health care providers should consider taking the following 4 steps:^12,13

1. Increase the availability of HAV vaccine to the homeless and to those who use illicit drugs; to anyone who has ongoing, close contact with people who are homeless or who use injection and non-injection drugs; and as post-exposure prophylaxis for unvaccinated people who have been exposed to HAV in the previous 2 weeks.
2. Defer the second dose of HAV vaccine if it is in short supply.
3. Perform pre-vaccination serologic testing to identify those who are immune, thereby preserving vaccine and reducing costs.
4. Use TWINRIX if other HAV vaccines are unavailable, keeping in mind that a single dose of TWINRIX achieves 94% protection against HAV but only 31% against hepatitis B virus (HBV). Three doses of TWINRIX are needed for full protection against HBV.

Available vaccines

Three vaccines are available for protection against HAV (TABLE^2,14). Post-exposure prevention of HAV can be achieved with HAV vaccine or immune globulin.¹⁵ Vaccine is preferred for individuals up to age 40 years and can be used for older individuals if immune globulin is unavailable.

The CDC reports that the supply of adult HAV vaccine is being strained by these large outbreaks.¹⁶ Physicians will need to stay in touch with their local public health departments regarding vaccine availability in the community and any local recommendations being made regarding vaccine administration, as well as to the status of any local HAV outbreaks.

The epidemiology of hepatitis A virus (HAV) disease has changed. Since July 2016, there have been 5 large outbreaks of infection involving more than 1600 cases,¹ with affected states requiring assistance from the Centers for Disease Control and Prevention (CDC). Two of these outbreaks were foodborne, and 3 involved person-to-person transmission.¹

Before 2016, the number of outbreaks had been very low, and were predominantly associated with contaminated food, infected food handlers, and other food service-related exposures. Total annual cases of HAV infection had been declining steadily in all age groups since 1995 when HAV vaccine became available, from an estimated 271,000 cases resulting in 100 deaths² to an estimated 2800 cases (with 1390 reported) resulting in 67 deaths in 2015 (FIGURE).³

Extent of the outbreaks

The largest hepatitis A outbreak involving person-to-person transmission in the United States in the past 20 years is occurring now in California. Predominantly affected are the homeless and users of illicit drugs, whose risk of infection is compounded by exposure to fecally-contaminated environments. As of December 1, the largest number of cases were recorded in San Diego (567), Santa Cruz (76), and Los Angeles (11).⁴ Adding 18 cases from other locations, the total has reached 672, resulting in 430 hospitalizations (64%) and 21 deaths (3%).⁴ In San Diego, 20% of those infected also had chronic hepatitis C and 5% had chronic hepatitis B.¹

In southeastern Michigan, 555 cases have been reported, with 457 hospitalizations (82%) and 20 deaths (4%).⁵ In Utah, 91 cases and 53 hospitalizations (58%) have been documented.⁶ In these regions, the predominant risk factors have been homelessness and illicit drug use. And many of those infected have had chronic hepatitis C (27.5%), hepatitis B (13.2%), or both (9.9%).⁶ In 2 of the 3 states just described, the outbreaks have involved HAV genotype 1B.¹

In New York City, an outbreak starting in January 2017 resulted in 51 cases. The epidemiology of this outbreak has been different from the others, involving men who have sex with men (MSM) and the HAV genotype 1A that matches a strain circulating among MSM in Europe.⁷

Low adult immunity is behind the outbreaks

These outbreaks have occurred in an adult US population that has low levels of immunity to HAV. In 2012 only 12.2% of adults ages 19 to 49 years had received 2 doses of HAV vaccine⁸ and only 24.2% of adults had antibodies to HAV,⁹ showing that most adults had never been infected with the virus or vaccinated. The reduction in HAV incidence previously described is due to the introduction of targeted, and then universal, child HAV vaccination recommendations by the Advisory Committee on Immunization Practices.

As the incidence of HAV disease declined, fewer individuals became infected as children, leading later to a susceptible pool of adults who had not been infected as children and who did not receive the vaccine in adulthood. Most of these adults will not be exposed to HAV due to decreased rates of infection in children, which, historically, has been the predominant means of adult exposure. The high hospitalization and death rates encountered in the recent and ongoing large outbreaks are explained by the multiple comorbidities of those infected.

Who should be vaccinated against HAV

The CDC recommends giving HAV vaccine to all children at age one year, and to the following groups:^2,10,11

• residents of a community that has a high rate of hepatitis A infection
• household members or other close personal contacts (eg, regular babysitters) of adopted children newly arrived from countries with high or intermediate hepatitis A endemicity
• men who have sex with other men
• users of illicit injection and noninjection drugs
• workers in, or travelers to, countries with high rates of hepatitis A infection
• individuals with chronic liver disease
• individuals who work with HAV-infected animals or with HAV in a research setting.

Outbreak-specific vaccine recommendations

The CDC has additionally recommended that, during outbreaks, health care providers should consider taking the following 4 steps:^12,13

1. Increase the availability of HAV vaccine to the homeless and to those who use illicit drugs; to anyone who has ongoing, close contact with people who are homeless or who use injection and non-injection drugs; and as post-exposure prophylaxis for unvaccinated people who have been exposed to HAV in the previous 2 weeks.
2. Defer the second dose of HAV vaccine if it is in short supply.
3. Perform pre-vaccination serologic testing to identify those who are immune, thereby preserving vaccine and reducing costs.
4. Use TWINRIX if other HAV vaccines are unavailable, keeping in mind that a single dose of TWINRIX achieves 94% protection against HAV but only 31% against hepatitis B virus (HBV). Three doses of TWINRIX are needed for full protection against HBV.

Available vaccines

Three vaccines are available for protection against HAV (TABLE^2,14). Post-exposure prevention of HAV can be achieved with HAV vaccine or immune globulin.¹⁵ Vaccine is preferred for individuals up to age 40 years and can be used for older individuals if immune globulin is unavailable.

The CDC reports that the supply of adult HAV vaccine is being strained by these large outbreaks.¹⁶ Physicians will need to stay in touch with their local public health departments regarding vaccine availability in the community and any local recommendations being made regarding vaccine administration, as well as to the status of any local HAV outbreaks.

The epidemiology of hepatitis A virus (HAV) disease has changed. Since July 2016, there have been 5 large outbreaks of infection involving more than 1600 cases,¹ with affected states requiring assistance from the Centers for Disease Control and Prevention (CDC). Two of these outbreaks were foodborne, and 3 involved person-to-person transmission.¹

Before 2016, the number of outbreaks had been very low, and were predominantly associated with contaminated food, infected food handlers, and other food service-related exposures. Total annual cases of HAV infection had been declining steadily in all age groups since 1995 when HAV vaccine became available, from an estimated 271,000 cases resulting in 100 deaths² to an estimated 2800 cases (with 1390 reported) resulting in 67 deaths in 2015 (FIGURE).³

Extent of the outbreaks

The largest hepatitis A outbreak involving person-to-person transmission in the United States in the past 20 years is occurring now in California. Predominantly affected are the homeless and users of illicit drugs, whose risk of infection is compounded by exposure to fecally-contaminated environments. As of December 1, the largest number of cases were recorded in San Diego (567), Santa Cruz (76), and Los Angeles (11).⁴ Adding 18 cases from other locations, the total has reached 672, resulting in 430 hospitalizations (64%) and 21 deaths (3%).⁴ In San Diego, 20% of those infected also had chronic hepatitis C and 5% had chronic hepatitis B.¹

In southeastern Michigan, 555 cases have been reported, with 457 hospitalizations (82%) and 20 deaths (4%).⁵ In Utah, 91 cases and 53 hospitalizations (58%) have been documented.⁶ In these regions, the predominant risk factors have been homelessness and illicit drug use. And many of those infected have had chronic hepatitis C (27.5%), hepatitis B (13.2%), or both (9.9%).⁶ In 2 of the 3 states just described, the outbreaks have involved HAV genotype 1B.¹

In New York City, an outbreak starting in January 2017 resulted in 51 cases. The epidemiology of this outbreak has been different from the others, involving men who have sex with men (MSM) and the HAV genotype 1A that matches a strain circulating among MSM in Europe.⁷

Low adult immunity is behind the outbreaks

These outbreaks have occurred in an adult US population that has low levels of immunity to HAV. In 2012 only 12.2% of adults ages 19 to 49 years had received 2 doses of HAV vaccine⁸ and only 24.2% of adults had antibodies to HAV,⁹ showing that most adults had never been infected with the virus or vaccinated. The reduction in HAV incidence previously described is due to the introduction of targeted, and then universal, child HAV vaccination recommendations by the Advisory Committee on Immunization Practices.

As the incidence of HAV disease declined, fewer individuals became infected as children, leading later to a susceptible pool of adults who had not been infected as children and who did not receive the vaccine in adulthood. Most of these adults will not be exposed to HAV due to decreased rates of infection in children, which, historically, has been the predominant means of adult exposure. The high hospitalization and death rates encountered in the recent and ongoing large outbreaks are explained by the multiple comorbidities of those infected.

Who should be vaccinated against HAV

The CDC recommends giving HAV vaccine to all children at age one year, and to the following groups:^2,10,11

• residents of a community that has a high rate of hepatitis A infection
• household members or other close personal contacts (eg, regular babysitters) of adopted children newly arrived from countries with high or intermediate hepatitis A endemicity
• men who have sex with other men
• users of illicit injection and noninjection drugs
• workers in, or travelers to, countries with high rates of hepatitis A infection
• individuals with chronic liver disease
• individuals who work with HAV-infected animals or with HAV in a research setting.

Outbreak-specific vaccine recommendations

The CDC has additionally recommended that, during outbreaks, health care providers should consider taking the following 4 steps:^12,13

1. Increase the availability of HAV vaccine to the homeless and to those who use illicit drugs; to anyone who has ongoing, close contact with people who are homeless or who use injection and non-injection drugs; and as post-exposure prophylaxis for unvaccinated people who have been exposed to HAV in the previous 2 weeks.
2. Defer the second dose of HAV vaccine if it is in short supply.
3. Perform pre-vaccination serologic testing to identify those who are immune, thereby preserving vaccine and reducing costs.
4. Use TWINRIX if other HAV vaccines are unavailable, keeping in mind that a single dose of TWINRIX achieves 94% protection against HAV but only 31% against hepatitis B virus (HBV). Three doses of TWINRIX are needed for full protection against HBV.

Available vaccines

Three vaccines are available for protection against HAV (TABLE^2,14). Post-exposure prevention of HAV can be achieved with HAV vaccine or immune globulin.¹⁵ Vaccine is preferred for individuals up to age 40 years and can be used for older individuals if immune globulin is unavailable.

The CDC reports that the supply of adult HAV vaccine is being strained by these large outbreaks.¹⁶ Physicians will need to stay in touch with their local public health departments regarding vaccine availability in the community and any local recommendations being made regarding vaccine administration, as well as to the status of any local HAV outbreaks.

The last 2 decades have seen a dramatic rise in the use of medical imaging in general,^1,2 as well as in the diagnostic workup of pulmonary embolism (PE) more specifically, since the introduction of multidetector row computed tomography pulmonary angiography (CTPA) in 1998.³ From 1999 to 2010, the proportions of emergency department (ED) visits associated with a diagnosis of PE and admissions for PE have increased markedly in the United States, where the situation has been well documented.^4,5 A 14-fold increase in the use of CTPA was observed in health maintenance organizations from 2001 to 2008.³ A significant increase in the probability of having a diagnosis of PE in the ED was reported, likely because of increased access to CTPA, from 2001 to 2010.⁴ With a prevalence of 2% or less in the ED, diagnostic yields as low as 5% suggest a significant problem of overuse.^6,7

Strategies have been proposed to improve the appropriateness of imaging in the detection of PE, and these rely on the use of a validated clinical decision rule (CDR) to assess the pretest probability of the diagnosis. The purpose of this systematic review is to summarize the evidence associated with interventions aimed at reducing the overuse of imaging in the diagnostic workup of PE in the ED and hospital wards. Specifically, the types of interventions, their clinical effectiveness, as well as possible harms will be assessed. A secondary objective is to appraise the impact of these interventions on healthcare costs as well as the facilitators and barriers to their implementation.

Inclusion Criteria

Targeted settings were EDs and inpatient services of adult tertiary and quaternary care hospitals. The search addressed interventions aimed at reducing the overuse of imaging in the diagnostic workup for PE. The comparators were usual care or another type of related intervention. The main outcomes considered were the use of imaging, diagnostic yield, radiation dose, adherence to guidelines to a quality measure, safety, and costs; both experimental and observational studies were included.

Literature Search

A systematic literature search in the following electronic databases was performed: PubMed, MEDLINE, Embase, and EBM Reviews (Cochrane, ACP Journal Club, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Cochrane Health Technology Assessment, and the NHS Economic Evaluation Database). The reference period was from 1998 to March 28, 2017, and publications in English and French were searched. The detailed search strategy, adapted to each of the databases, appears in supplemental Appendix 1.

Study Selection and Data Extraction

One author (SD) reviewed the titles of the selected articles and excluded those that obviously did not satisfy the inclusion criteria. Then, 2 authors (SD and LL) independently reviewed the titles and abstracts of the remaining articles. They reviewed the full manuscript of potentially relevant articles for inclusion. Disagreements that could not be resolved by discussion would have been arbitrated by a third author (CCL); however, no such disagreement occurred.

Quality and Risk of Bias Assessment

For experimental or quasiexperimental studies that involved an intervention group and a control group, the criteria proposed by the Cochrane collaborative for the evaluation of bias were used.⁸ For studies using a before and after design, the following main biases associated with such designs were assessed: history effect, maturation bias, testing bias, regression to the mean, and conditioning bias.⁹

Data Extraction and Synthesis

Data pertaining to efficacy, safety, costs, and facilitators and barriers to the implementation of interventions were extracted from the studies. The research process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 checklist.¹⁰ In view of the heterogeneity of the studies, a narrative synthesis was produced in accordance with the methodology proposed by Popay et al.¹¹ The review protocol was registered in PROSPERO (this registry can be consulted at the following URL address: http://www.crd.york.ac.uk/PROSPERO/).

RESULTS

The search screened 2814 records after the removal of duplicates and studies published before 1998. The figure illustrates the literature selection process.¹² Seventeen studies were included in the review following appraisal. Most of the studies (15/17) evaluated interventions in the ED,^7,13-26 while the remaining studies (2/17) were conducted in clinical wards of acute care hospitals.^27,28 Thirteen studies were conducted in the United States, 3 in Australia, and 1 in Europe. Four types of interventions were identified in the selected studies: electronic clinical decision support (CDS) (8/17), educational interventions (7/17), performance feedback reports (PFRs) (1/17), and an institutional clinical pretest policy (1/17). In 10 of the studies, the proposed intervention was mandatory.

One systematic review and meta-analysis pertaining to the impact of CDRs on CTPA use and yield was identified.²⁹ Five of the studies it included were also included in the present review.^13,16,21-23 However, its focus is different than the present one, which aims at assessing the evidence associated with the interventions being implemented to promote the use of the CDRs.²⁹

The list of included studies appears in supplemental Appendix 2. The list of potentially relevant studies that were finally excluded is provided in supplemental Appendix 3.

Most studies (14/17) presented a before-after design, with data collection corresponding to periods preceding and following a specific intervention. Most of them are retrospective and assessed the efficacy and safety results. They were deemed of generally poor quality and were subject to many of the biases mentioned above as well as to an interaction between the intervention and its implementation context. The remaining 3 studies were experimental in design with a comparative control group.^13,14,27 In 2 of these studies, a comparison was made with traditional clinical practice (no intervention).^13,27 In the third, the intervention was compared with CDS only.¹⁴ The control group studies were of intermediate to very good quality and were subject to biases of performance, detection, selection, and attrition.

Table 1 summarizes the study characteristics of the included studies. The detailed methodological quality appraisal of the control group studies appears in supplemental Appendix 4.

Efficacy

CDS and PFRs

Eight of the studies appraised CDS interventions.^{13,16,17,19,21,22,24,28} They consisted of computer-based applications imbedded into the computerized physician order entry of the setting (ED or clinical ward of an acute care hospital), which are prompted when a physician orders an imaging exam or D-dimer test.

Educational Interventions and Policy

Seven of the interventions assessed in the included studies were educational in their essence, involving training sessions aimed at strengthening physician use of CDRs for the diagnosis of PE.^{15,18,20,23,25-27} Three studies observed a statistically significant impact on the

The impact of a policy fostering the use of a CDR and D-dimer was appraised in 1 study.⁷ This intervention translated into a significant reduction of CTPA use and a significant increase of CTPA diagnostic yield. However, only 4% of patient charts reported a clinical probability of PE, and in most cases, the type of CDR used was not mentioned.⁷

Safety

A minority of studies evaluated the safety of the interventions.^{13,18,19,23,25,27} Only 2 of these

The 2 studies involving a control group did not find significant differences between the intervention and the control groups with respect to mortality, complications because of thromboembolic and bleeding events, or any other adverse event during the 3-months’ follow-up.^13,27

Jiménez et al.¹⁹ reported less than 1% mortality following the implementation of a CDS (0.7%; 95% CI, 0.2%-1.1%). In their study assessing the impact of an educational intervention, Kline et al.²³ (2004) observed that none of the patients discharged with a fully negative Charlotte rule died suddenly and unexpectedly at 90-day follow-up. However, another educational intervention aimed at reducing ED patients’ radiation exposure observed a significant increase in the 90-day all-cause mortality of patients with negative CTPA, which was associated with a decline in the 90-day mortality of patients with negative ventilation/perfusion (V/Q) scanning.²⁵

Jiménez et al.¹⁹ observed an absolute decrease of 2.5% in the incidence of symptomatic VTE events after the intervention (95% CI, 0.9%-4.6%; P < .01). The occurrence of VTE events, including PE, reached 1% in Goergen et al.¹⁸ and 3.9% in Kline et al.²³ (2004) during follow-up.

Economic Aspects

Kline et al.¹³ (2014) found a significant decrease in charges and estimated costs for medical care within 90 days of initial ED presentation in the patients who were investigated with CTPA in the intervention group. The median costs of medical care within 30 days of the initial ED presentation were US $1274 in the control group and US $934 in the intervention group (P = .018).¹³ The median charges of medical care within 30 days of the initial ED presentation were US $7595 in the control group and US $6281 in the intervention group (P = .004).¹³

Facilitators and Barriers

Only 1 study appraised the reasons given by emergency physicians for not adhering to CDS recommendations.¹⁶ The reason most often given was the time needed to access and use the application, which was perceived as having a negative impact on productivity as well as a preference for intuitive clinical judgment.¹⁶ Though not the result of specific evaluation or data collection, some authors commented on the factors that may facilitate or impede the implementation of interventions to diminish the inappropriate use.^14,20 Kanaan et al.²⁰ proposed that factors other than the knowledge of current clinical guidelines may explain CTPA use. Booker and Johnson²⁶ suggested that the demand for rapid turnover in the ED may lead to “so-called ‘blanket ordering’, which attempts to reach diagnosis as quickly as possible despite cost and patient safety.” Raja et al.¹⁴ (2015) suggested that the unambiguous representation of guidelines based on validated, high-quality evidence in the CDS may have improved physician adoption in their study.

Efficacy

Baseline values for the use of imaging and diagnostic yield show important variation, especially when compared with the study performed in Europe.¹⁹ In general, only a modest impact is measured with regard to a decrease in the use of imaging, an increase in diagnostic use, and adherence to validated CDRs.

Among the interventions appraised, CDS was evaluated in the largest number of included studies, and its impact has been appraised with the largest number of indicators. Among the 6 studies that assessed the impact of this type of intervention on the use of imaging, 4 observed a significant decrease of CTPA use postintervention.^19,21,22,28 None of these studies involved a control group. The 2 with CDS that had no significant impact on CT use were conducted in US EDs and were based on dichotomous Wells scores.^16,17 Adherence to CDS recommendations was mandatory in 1 and voluntary in the other.^16,17 The variable impact of these interventions was at least partly attributable to contextual factors. However, because of the lack of data pertaining to these factors, it is not possible to draw conclusive remarks on their effect.

The impact of CDS on diagnostic yield was mixed because 3 studies observed an increase in diagnostic yield postintervention,^16,21,22 and 3 others monitored no significant impact.^19,24,28 Adherence to guidelines or a quality measure was assessed in 2 studies, which reported a significant increase in appropriate ordering.^17,24 Raja et al.²⁴ (2014) observed an 18.7% increase in appropriate ordering after the implementation of a CDS from 56.9% to 75.6% (P < .01). Geeting et al.¹⁷ observed a similar increase, with appropriate ordering increasing from 58% to 76% over the duration of the intervention. However, this increase in appropriate use was not associated with a variation in CTPA use or diagnostic yield, which leads the investigators to posit that the physicians gradually inflated the Wells score they keyed into the CDS despite that no threshold Wells score was required to perform a CTPA.¹⁷

Raja et al.¹⁴ (2015) demonstrated that the implementation of performance feedback reporting, in addition to a CDS, can significantly increase adherence to CDR for the evaluation of PE in the ED. Additional studies would help to better understand the potential impact of such reports on CTPA use in the diagnostic workup of PE. However, it suggests that a combination of interventions, including the implementation of a CDS, performance feedback reporting, and well-designed and specific educational interventions, may have a more significant impact than any of these types of interventions taken separately.

The impact of the educational interventions appraised in this review on the expected results is mixed, though it is difficult to compare the observed results and draw conclusive remarks, as the characteristics of the interventions and study designs are different from each other.

Safety

There is limited evidence on the safety of appraised interventions. Only 6 studies appraised venous thrombolic events or mortality.^{13,18,19,23,25,27} However, no adverse events were noted in those studies evaluating possible complications or missed diagnoses. Additional research is needed to confirm the safety of the interventions appraised in this systematic review.

Facilitators and Barriers

There are significant limitations with respect to the analysis of the factors that favor or impede the implementation of the interventions appraised in this review. However, 2 studies that did not meet the inclusion criteria appraised physicians’ perceptions and attitudes toward prescribing imaging tests in the diagnostic workup of PE.^31,32 One is Swiss³¹ and the other is Canadian.³² Both were conducted in the ED of academic hospitals. Rohacek et al.³¹ observed that defensive behaviors, such as “fear of missing PE,” were frequent and associated with a lower probability of a positive CTPA (OR = 0.36; 95% CI, 0.14-0.92). Ahn et al.³² concluded that, although ED physicians who participated in their survey possessed limited knowledge of radiation doses of CTPA and V/Q scans, they opted for V/Q scans that emit lower radiation doses in younger patients, especially females, which may reflect efforts done in the study setting to reduce patients’ radiation exposure.

There is not enough data to conclude on safety and the impact on healthcare costs.

Implications for Future Research

Future controlled studies of high methodological quality would help to better understand the effects associated with the implementation of the interventions aimed at reducing the inappropriate use of imaging in the diagnostic workup of PE. Efficacy results show that the success of the implementation of the various types of interventions is variable. This variation may be at least partly attributable to contextual factors, such as the external environment, the organizational leadership and culture, or the microsystem, such as differences in care patterns.^33-35 The impact of context factors on the effectiveness of the interventions should be assessed further with appropriate tools.^33,34,36

The joint use of CDS and PFRs appears more effective than the other types of intervention in reducing the inappropriate use of CTPA. However, an approach combining these with well-designed educational interventions as well as policies may be even more effective.

Future studies of high methodological quality would strengthen the evidence concerning the relative efficacy and safety of the interventions appraised, especially when various types are combined. Future research should also aim at bringing answers to the knowledge gaps related to the factors of success and barriers associated with the implementation of the interventions.

Disclosure

The authors report no conflict of interest.

The last 2 decades have seen a dramatic rise in the use of medical imaging in general,^1,2 as well as in the diagnostic workup of pulmonary embolism (PE) more specifically, since the introduction of multidetector row computed tomography pulmonary angiography (CTPA) in 1998.³ From 1999 to 2010, the proportions of emergency department (ED) visits associated with a diagnosis of PE and admissions for PE have increased markedly in the United States, where the situation has been well documented.^4,5 A 14-fold increase in the use of CTPA was observed in health maintenance organizations from 2001 to 2008.³ A significant increase in the probability of having a diagnosis of PE in the ED was reported, likely because of increased access to CTPA, from 2001 to 2010.⁴ With a prevalence of 2% or less in the ED, diagnostic yields as low as 5% suggest a significant problem of overuse.^6,7

Strategies have been proposed to improve the appropriateness of imaging in the detection of PE, and these rely on the use of a validated clinical decision rule (CDR) to assess the pretest probability of the diagnosis. The purpose of this systematic review is to summarize the evidence associated with interventions aimed at reducing the overuse of imaging in the diagnostic workup of PE in the ED and hospital wards. Specifically, the types of interventions, their clinical effectiveness, as well as possible harms will be assessed. A secondary objective is to appraise the impact of these interventions on healthcare costs as well as the facilitators and barriers to their implementation.

Inclusion Criteria

Targeted settings were EDs and inpatient services of adult tertiary and quaternary care hospitals. The search addressed interventions aimed at reducing the overuse of imaging in the diagnostic workup for PE. The comparators were usual care or another type of related intervention. The main outcomes considered were the use of imaging, diagnostic yield, radiation dose, adherence to guidelines to a quality measure, safety, and costs; both experimental and observational studies were included.

Literature Search

A systematic literature search in the following electronic databases was performed: PubMed, MEDLINE, Embase, and EBM Reviews (Cochrane, ACP Journal Club, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Cochrane Health Technology Assessment, and the NHS Economic Evaluation Database). The reference period was from 1998 to March 28, 2017, and publications in English and French were searched. The detailed search strategy, adapted to each of the databases, appears in supplemental Appendix 1.

Study Selection and Data Extraction

One author (SD) reviewed the titles of the selected articles and excluded those that obviously did not satisfy the inclusion criteria. Then, 2 authors (SD and LL) independently reviewed the titles and abstracts of the remaining articles. They reviewed the full manuscript of potentially relevant articles for inclusion. Disagreements that could not be resolved by discussion would have been arbitrated by a third author (CCL); however, no such disagreement occurred.

Quality and Risk of Bias Assessment

For experimental or quasiexperimental studies that involved an intervention group and a control group, the criteria proposed by the Cochrane collaborative for the evaluation of bias were used.⁸ For studies using a before and after design, the following main biases associated with such designs were assessed: history effect, maturation bias, testing bias, regression to the mean, and conditioning bias.⁹

Data Extraction and Synthesis

Data pertaining to efficacy, safety, costs, and facilitators and barriers to the implementation of interventions were extracted from the studies. The research process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 checklist.¹⁰ In view of the heterogeneity of the studies, a narrative synthesis was produced in accordance with the methodology proposed by Popay et al.¹¹ The review protocol was registered in PROSPERO (this registry can be consulted at the following URL address: http://www.crd.york.ac.uk/PROSPERO/).

RESULTS

The search screened 2814 records after the removal of duplicates and studies published before 1998. The figure illustrates the literature selection process.¹² Seventeen studies were included in the review following appraisal. Most of the studies (15/17) evaluated interventions in the ED,^7,13-26 while the remaining studies (2/17) were conducted in clinical wards of acute care hospitals.^27,28 Thirteen studies were conducted in the United States, 3 in Australia, and 1 in Europe. Four types of interventions were identified in the selected studies: electronic clinical decision support (CDS) (8/17), educational interventions (7/17), performance feedback reports (PFRs) (1/17), and an institutional clinical pretest policy (1/17). In 10 of the studies, the proposed intervention was mandatory.

One systematic review and meta-analysis pertaining to the impact of CDRs on CTPA use and yield was identified.²⁹ Five of the studies it included were also included in the present review.^13,16,21-23 However, its focus is different than the present one, which aims at assessing the evidence associated with the interventions being implemented to promote the use of the CDRs.²⁹

The list of included studies appears in supplemental Appendix 2. The list of potentially relevant studies that were finally excluded is provided in supplemental Appendix 3.

Most studies (14/17) presented a before-after design, with data collection corresponding to periods preceding and following a specific intervention. Most of them are retrospective and assessed the efficacy and safety results. They were deemed of generally poor quality and were subject to many of the biases mentioned above as well as to an interaction between the intervention and its implementation context. The remaining 3 studies were experimental in design with a comparative control group.^13,14,27 In 2 of these studies, a comparison was made with traditional clinical practice (no intervention).^13,27 In the third, the intervention was compared with CDS only.¹⁴ The control group studies were of intermediate to very good quality and were subject to biases of performance, detection, selection, and attrition.

Table 1 summarizes the study characteristics of the included studies. The detailed methodological quality appraisal of the control group studies appears in supplemental Appendix 4.

Efficacy

CDS and PFRs

Eight of the studies appraised CDS interventions.^{13,16,17,19,21,22,24,28} They consisted of computer-based applications imbedded into the computerized physician order entry of the setting (ED or clinical ward of an acute care hospital), which are prompted when a physician orders an imaging exam or D-dimer test.

Educational Interventions and Policy

Seven of the interventions assessed in the included studies were educational in their essence, involving training sessions aimed at strengthening physician use of CDRs for the diagnosis of PE.^{15,18,20,23,25-27} Three studies observed a statistically significant impact on the

The impact of a policy fostering the use of a CDR and D-dimer was appraised in 1 study.⁷ This intervention translated into a significant reduction of CTPA use and a significant increase of CTPA diagnostic yield. However, only 4% of patient charts reported a clinical probability of PE, and in most cases, the type of CDR used was not mentioned.⁷

Safety

A minority of studies evaluated the safety of the interventions.^{13,18,19,23,25,27} Only 2 of these

The 2 studies involving a control group did not find significant differences between the intervention and the control groups with respect to mortality, complications because of thromboembolic and bleeding events, or any other adverse event during the 3-months’ follow-up.^13,27

Jiménez et al.¹⁹ reported less than 1% mortality following the implementation of a CDS (0.7%; 95% CI, 0.2%-1.1%). In their study assessing the impact of an educational intervention, Kline et al.²³ (2004) observed that none of the patients discharged with a fully negative Charlotte rule died suddenly and unexpectedly at 90-day follow-up. However, another educational intervention aimed at reducing ED patients’ radiation exposure observed a significant increase in the 90-day all-cause mortality of patients with negative CTPA, which was associated with a decline in the 90-day mortality of patients with negative ventilation/perfusion (V/Q) scanning.²⁵

Jiménez et al.¹⁹ observed an absolute decrease of 2.5% in the incidence of symptomatic VTE events after the intervention (95% CI, 0.9%-4.6%; P < .01). The occurrence of VTE events, including PE, reached 1% in Goergen et al.¹⁸ and 3.9% in Kline et al.²³ (2004) during follow-up.

Economic Aspects

Kline et al.¹³ (2014) found a significant decrease in charges and estimated costs for medical care within 90 days of initial ED presentation in the patients who were investigated with CTPA in the intervention group. The median costs of medical care within 30 days of the initial ED presentation were US $1274 in the control group and US $934 in the intervention group (P = .018).¹³ The median charges of medical care within 30 days of the initial ED presentation were US $7595 in the control group and US $6281 in the intervention group (P = .004).¹³

Facilitators and Barriers

Only 1 study appraised the reasons given by emergency physicians for not adhering to CDS recommendations.¹⁶ The reason most often given was the time needed to access and use the application, which was perceived as having a negative impact on productivity as well as a preference for intuitive clinical judgment.¹⁶ Though not the result of specific evaluation or data collection, some authors commented on the factors that may facilitate or impede the implementation of interventions to diminish the inappropriate use.^14,20 Kanaan et al.²⁰ proposed that factors other than the knowledge of current clinical guidelines may explain CTPA use. Booker and Johnson²⁶ suggested that the demand for rapid turnover in the ED may lead to “so-called ‘blanket ordering’, which attempts to reach diagnosis as quickly as possible despite cost and patient safety.” Raja et al.¹⁴ (2015) suggested that the unambiguous representation of guidelines based on validated, high-quality evidence in the CDS may have improved physician adoption in their study.

Efficacy

Baseline values for the use of imaging and diagnostic yield show important variation, especially when compared with the study performed in Europe.¹⁹ In general, only a modest impact is measured with regard to a decrease in the use of imaging, an increase in diagnostic use, and adherence to validated CDRs.

Among the interventions appraised, CDS was evaluated in the largest number of included studies, and its impact has been appraised with the largest number of indicators. Among the 6 studies that assessed the impact of this type of intervention on the use of imaging, 4 observed a significant decrease of CTPA use postintervention.^19,21,22,28 None of these studies involved a control group. The 2 with CDS that had no significant impact on CT use were conducted in US EDs and were based on dichotomous Wells scores.^16,17 Adherence to CDS recommendations was mandatory in 1 and voluntary in the other.^16,17 The variable impact of these interventions was at least partly attributable to contextual factors. However, because of the lack of data pertaining to these factors, it is not possible to draw conclusive remarks on their effect.

The impact of CDS on diagnostic yield was mixed because 3 studies observed an increase in diagnostic yield postintervention,^16,21,22 and 3 others monitored no significant impact.^19,24,28 Adherence to guidelines or a quality measure was assessed in 2 studies, which reported a significant increase in appropriate ordering.^17,24 Raja et al.²⁴ (2014) observed an 18.7% increase in appropriate ordering after the implementation of a CDS from 56.9% to 75.6% (P < .01). Geeting et al.¹⁷ observed a similar increase, with appropriate ordering increasing from 58% to 76% over the duration of the intervention. However, this increase in appropriate use was not associated with a variation in CTPA use or diagnostic yield, which leads the investigators to posit that the physicians gradually inflated the Wells score they keyed into the CDS despite that no threshold Wells score was required to perform a CTPA.¹⁷

Raja et al.¹⁴ (2015) demonstrated that the implementation of performance feedback reporting, in addition to a CDS, can significantly increase adherence to CDR for the evaluation of PE in the ED. Additional studies would help to better understand the potential impact of such reports on CTPA use in the diagnostic workup of PE. However, it suggests that a combination of interventions, including the implementation of a CDS, performance feedback reporting, and well-designed and specific educational interventions, may have a more significant impact than any of these types of interventions taken separately.

The impact of the educational interventions appraised in this review on the expected results is mixed, though it is difficult to compare the observed results and draw conclusive remarks, as the characteristics of the interventions and study designs are different from each other.

Safety

There is limited evidence on the safety of appraised interventions. Only 6 studies appraised venous thrombolic events or mortality.^{13,18,19,23,25,27} However, no adverse events were noted in those studies evaluating possible complications or missed diagnoses. Additional research is needed to confirm the safety of the interventions appraised in this systematic review.

Facilitators and Barriers

There are significant limitations with respect to the analysis of the factors that favor or impede the implementation of the interventions appraised in this review. However, 2 studies that did not meet the inclusion criteria appraised physicians’ perceptions and attitudes toward prescribing imaging tests in the diagnostic workup of PE.^31,32 One is Swiss³¹ and the other is Canadian.³² Both were conducted in the ED of academic hospitals. Rohacek et al.³¹ observed that defensive behaviors, such as “fear of missing PE,” were frequent and associated with a lower probability of a positive CTPA (OR = 0.36; 95% CI, 0.14-0.92). Ahn et al.³² concluded that, although ED physicians who participated in their survey possessed limited knowledge of radiation doses of CTPA and V/Q scans, they opted for V/Q scans that emit lower radiation doses in younger patients, especially females, which may reflect efforts done in the study setting to reduce patients’ radiation exposure.

There is not enough data to conclude on safety and the impact on healthcare costs.

Implications for Future Research

Future controlled studies of high methodological quality would help to better understand the effects associated with the implementation of the interventions aimed at reducing the inappropriate use of imaging in the diagnostic workup of PE. Efficacy results show that the success of the implementation of the various types of interventions is variable. This variation may be at least partly attributable to contextual factors, such as the external environment, the organizational leadership and culture, or the microsystem, such as differences in care patterns.^33-35 The impact of context factors on the effectiveness of the interventions should be assessed further with appropriate tools.^33,34,36

The joint use of CDS and PFRs appears more effective than the other types of intervention in reducing the inappropriate use of CTPA. However, an approach combining these with well-designed educational interventions as well as policies may be even more effective.

Future studies of high methodological quality would strengthen the evidence concerning the relative efficacy and safety of the interventions appraised, especially when various types are combined. Future research should also aim at bringing answers to the knowledge gaps related to the factors of success and barriers associated with the implementation of the interventions.

Disclosure

The authors report no conflict of interest.

The last 2 decades have seen a dramatic rise in the use of medical imaging in general,^1,2 as well as in the diagnostic workup of pulmonary embolism (PE) more specifically, since the introduction of multidetector row computed tomography pulmonary angiography (CTPA) in 1998.³ From 1999 to 2010, the proportions of emergency department (ED) visits associated with a diagnosis of PE and admissions for PE have increased markedly in the United States, where the situation has been well documented.^4,5 A 14-fold increase in the use of CTPA was observed in health maintenance organizations from 2001 to 2008.³ A significant increase in the probability of having a diagnosis of PE in the ED was reported, likely because of increased access to CTPA, from 2001 to 2010.⁴ With a prevalence of 2% or less in the ED, diagnostic yields as low as 5% suggest a significant problem of overuse.^6,7

Strategies have been proposed to improve the appropriateness of imaging in the detection of PE, and these rely on the use of a validated clinical decision rule (CDR) to assess the pretest probability of the diagnosis. The purpose of this systematic review is to summarize the evidence associated with interventions aimed at reducing the overuse of imaging in the diagnostic workup of PE in the ED and hospital wards. Specifically, the types of interventions, their clinical effectiveness, as well as possible harms will be assessed. A secondary objective is to appraise the impact of these interventions on healthcare costs as well as the facilitators and barriers to their implementation.

Inclusion Criteria

Targeted settings were EDs and inpatient services of adult tertiary and quaternary care hospitals. The search addressed interventions aimed at reducing the overuse of imaging in the diagnostic workup for PE. The comparators were usual care or another type of related intervention. The main outcomes considered were the use of imaging, diagnostic yield, radiation dose, adherence to guidelines to a quality measure, safety, and costs; both experimental and observational studies were included.

Literature Search

A systematic literature search in the following electronic databases was performed: PubMed, MEDLINE, Embase, and EBM Reviews (Cochrane, ACP Journal Club, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, Cochrane Health Technology Assessment, and the NHS Economic Evaluation Database). The reference period was from 1998 to March 28, 2017, and publications in English and French were searched. The detailed search strategy, adapted to each of the databases, appears in supplemental Appendix 1.

Study Selection and Data Extraction

One author (SD) reviewed the titles of the selected articles and excluded those that obviously did not satisfy the inclusion criteria. Then, 2 authors (SD and LL) independently reviewed the titles and abstracts of the remaining articles. They reviewed the full manuscript of potentially relevant articles for inclusion. Disagreements that could not be resolved by discussion would have been arbitrated by a third author (CCL); however, no such disagreement occurred.

Quality and Risk of Bias Assessment

For experimental or quasiexperimental studies that involved an intervention group and a control group, the criteria proposed by the Cochrane collaborative for the evaluation of bias were used.⁸ For studies using a before and after design, the following main biases associated with such designs were assessed: history effect, maturation bias, testing bias, regression to the mean, and conditioning bias.⁹

Data Extraction and Synthesis

Data pertaining to efficacy, safety, costs, and facilitators and barriers to the implementation of interventions were extracted from the studies. The research process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 checklist.¹⁰ In view of the heterogeneity of the studies, a narrative synthesis was produced in accordance with the methodology proposed by Popay et al.¹¹ The review protocol was registered in PROSPERO (this registry can be consulted at the following URL address: http://www.crd.york.ac.uk/PROSPERO/).

RESULTS

The search screened 2814 records after the removal of duplicates and studies published before 1998. The figure illustrates the literature selection process.¹² Seventeen studies were included in the review following appraisal. Most of the studies (15/17) evaluated interventions in the ED,^7,13-26 while the remaining studies (2/17) were conducted in clinical wards of acute care hospitals.^27,28 Thirteen studies were conducted in the United States, 3 in Australia, and 1 in Europe. Four types of interventions were identified in the selected studies: electronic clinical decision support (CDS) (8/17), educational interventions (7/17), performance feedback reports (PFRs) (1/17), and an institutional clinical pretest policy (1/17). In 10 of the studies, the proposed intervention was mandatory.

One systematic review and meta-analysis pertaining to the impact of CDRs on CTPA use and yield was identified.²⁹ Five of the studies it included were also included in the present review.^13,16,21-23 However, its focus is different than the present one, which aims at assessing the evidence associated with the interventions being implemented to promote the use of the CDRs.²⁹

The list of included studies appears in supplemental Appendix 2. The list of potentially relevant studies that were finally excluded is provided in supplemental Appendix 3.

Most studies (14/17) presented a before-after design, with data collection corresponding to periods preceding and following a specific intervention. Most of them are retrospective and assessed the efficacy and safety results. They were deemed of generally poor quality and were subject to many of the biases mentioned above as well as to an interaction between the intervention and its implementation context. The remaining 3 studies were experimental in design with a comparative control group.^13,14,27 In 2 of these studies, a comparison was made with traditional clinical practice (no intervention).^13,27 In the third, the intervention was compared with CDS only.¹⁴ The control group studies were of intermediate to very good quality and were subject to biases of performance, detection, selection, and attrition.

Table 1 summarizes the study characteristics of the included studies. The detailed methodological quality appraisal of the control group studies appears in supplemental Appendix 4.

Efficacy

CDS and PFRs

Eight of the studies appraised CDS interventions.^{13,16,17,19,21,22,24,28} They consisted of computer-based applications imbedded into the computerized physician order entry of the setting (ED or clinical ward of an acute care hospital), which are prompted when a physician orders an imaging exam or D-dimer test.

Educational Interventions and Policy

Seven of the interventions assessed in the included studies were educational in their essence, involving training sessions aimed at strengthening physician use of CDRs for the diagnosis of PE.^{15,18,20,23,25-27} Three studies observed a statistically significant impact on the

The impact of a policy fostering the use of a CDR and D-dimer was appraised in 1 study.⁷ This intervention translated into a significant reduction of CTPA use and a significant increase of CTPA diagnostic yield. However, only 4% of patient charts reported a clinical probability of PE, and in most cases, the type of CDR used was not mentioned.⁷

Safety

A minority of studies evaluated the safety of the interventions.^{13,18,19,23,25,27} Only 2 of these

The 2 studies involving a control group did not find significant differences between the intervention and the control groups with respect to mortality, complications because of thromboembolic and bleeding events, or any other adverse event during the 3-months’ follow-up.^13,27

Jiménez et al.¹⁹ reported less than 1% mortality following the implementation of a CDS (0.7%; 95% CI, 0.2%-1.1%). In their study assessing the impact of an educational intervention, Kline et al.²³ (2004) observed that none of the patients discharged with a fully negative Charlotte rule died suddenly and unexpectedly at 90-day follow-up. However, another educational intervention aimed at reducing ED patients’ radiation exposure observed a significant increase in the 90-day all-cause mortality of patients with negative CTPA, which was associated with a decline in the 90-day mortality of patients with negative ventilation/perfusion (V/Q) scanning.²⁵

Jiménez et al.¹⁹ observed an absolute decrease of 2.5% in the incidence of symptomatic VTE events after the intervention (95% CI, 0.9%-4.6%; P < .01). The occurrence of VTE events, including PE, reached 1% in Goergen et al.¹⁸ and 3.9% in Kline et al.²³ (2004) during follow-up.

Economic Aspects

Kline et al.¹³ (2014) found a significant decrease in charges and estimated costs for medical care within 90 days of initial ED presentation in the patients who were investigated with CTPA in the intervention group. The median costs of medical care within 30 days of the initial ED presentation were US $1274 in the control group and US $934 in the intervention group (P = .018).¹³ The median charges of medical care within 30 days of the initial ED presentation were US $7595 in the control group and US $6281 in the intervention group (P = .004).¹³

Facilitators and Barriers

Only 1 study appraised the reasons given by emergency physicians for not adhering to CDS recommendations.¹⁶ The reason most often given was the time needed to access and use the application, which was perceived as having a negative impact on productivity as well as a preference for intuitive clinical judgment.¹⁶ Though not the result of specific evaluation or data collection, some authors commented on the factors that may facilitate or impede the implementation of interventions to diminish the inappropriate use.^14,20 Kanaan et al.²⁰ proposed that factors other than the knowledge of current clinical guidelines may explain CTPA use. Booker and Johnson²⁶ suggested that the demand for rapid turnover in the ED may lead to “so-called ‘blanket ordering’, which attempts to reach diagnosis as quickly as possible despite cost and patient safety.” Raja et al.¹⁴ (2015) suggested that the unambiguous representation of guidelines based on validated, high-quality evidence in the CDS may have improved physician adoption in their study.

Efficacy

Baseline values for the use of imaging and diagnostic yield show important variation, especially when compared with the study performed in Europe.¹⁹ In general, only a modest impact is measured with regard to a decrease in the use of imaging, an increase in diagnostic use, and adherence to validated CDRs.

Among the interventions appraised, CDS was evaluated in the largest number of included studies, and its impact has been appraised with the largest number of indicators. Among the 6 studies that assessed the impact of this type of intervention on the use of imaging, 4 observed a significant decrease of CTPA use postintervention.^19,21,22,28 None of these studies involved a control group. The 2 with CDS that had no significant impact on CT use were conducted in US EDs and were based on dichotomous Wells scores.^16,17 Adherence to CDS recommendations was mandatory in 1 and voluntary in the other.^16,17 The variable impact of these interventions was at least partly attributable to contextual factors. However, because of the lack of data pertaining to these factors, it is not possible to draw conclusive remarks on their effect.

The impact of CDS on diagnostic yield was mixed because 3 studies observed an increase in diagnostic yield postintervention,^16,21,22 and 3 others monitored no significant impact.^19,24,28 Adherence to guidelines or a quality measure was assessed in 2 studies, which reported a significant increase in appropriate ordering.^17,24 Raja et al.²⁴ (2014) observed an 18.7% increase in appropriate ordering after the implementation of a CDS from 56.9% to 75.6% (P < .01). Geeting et al.¹⁷ observed a similar increase, with appropriate ordering increasing from 58% to 76% over the duration of the intervention. However, this increase in appropriate use was not associated with a variation in CTPA use or diagnostic yield, which leads the investigators to posit that the physicians gradually inflated the Wells score they keyed into the CDS despite that no threshold Wells score was required to perform a CTPA.¹⁷

Raja et al.¹⁴ (2015) demonstrated that the implementation of performance feedback reporting, in addition to a CDS, can significantly increase adherence to CDR for the evaluation of PE in the ED. Additional studies would help to better understand the potential impact of such reports on CTPA use in the diagnostic workup of PE. However, it suggests that a combination of interventions, including the implementation of a CDS, performance feedback reporting, and well-designed and specific educational interventions, may have a more significant impact than any of these types of interventions taken separately.

The impact of the educational interventions appraised in this review on the expected results is mixed, though it is difficult to compare the observed results and draw conclusive remarks, as the characteristics of the interventions and study designs are different from each other.

Safety

There is limited evidence on the safety of appraised interventions. Only 6 studies appraised venous thrombolic events or mortality.^{13,18,19,23,25,27} However, no adverse events were noted in those studies evaluating possible complications or missed diagnoses. Additional research is needed to confirm the safety of the interventions appraised in this systematic review.

Facilitators and Barriers

There are significant limitations with respect to the analysis of the factors that favor or impede the implementation of the interventions appraised in this review. However, 2 studies that did not meet the inclusion criteria appraised physicians’ perceptions and attitudes toward prescribing imaging tests in the diagnostic workup of PE.^31,32 One is Swiss³¹ and the other is Canadian.³² Both were conducted in the ED of academic hospitals. Rohacek et al.³¹ observed that defensive behaviors, such as “fear of missing PE,” were frequent and associated with a lower probability of a positive CTPA (OR = 0.36; 95% CI, 0.14-0.92). Ahn et al.³² concluded that, although ED physicians who participated in their survey possessed limited knowledge of radiation doses of CTPA and V/Q scans, they opted for V/Q scans that emit lower radiation doses in younger patients, especially females, which may reflect efforts done in the study setting to reduce patients’ radiation exposure.

There is not enough data to conclude on safety and the impact on healthcare costs.

Implications for Future Research

Future controlled studies of high methodological quality would help to better understand the effects associated with the implementation of the interventions aimed at reducing the inappropriate use of imaging in the diagnostic workup of PE. Efficacy results show that the success of the implementation of the various types of interventions is variable. This variation may be at least partly attributable to contextual factors, such as the external environment, the organizational leadership and culture, or the microsystem, such as differences in care patterns.^33-35 The impact of context factors on the effectiveness of the interventions should be assessed further with appropriate tools.^33,34,36

The joint use of CDS and PFRs appears more effective than the other types of intervention in reducing the inappropriate use of CTPA. However, an approach combining these with well-designed educational interventions as well as policies may be even more effective.

Future studies of high methodological quality would strengthen the evidence concerning the relative efficacy and safety of the interventions appraised, especially when various types are combined. Future research should also aim at bringing answers to the knowledge gaps related to the factors of success and barriers associated with the implementation of the interventions.

Disclosure

The authors report no conflict of interest.

The aim of palliative care (PC) is to improve quality of life for patients facing serious, life-threatening illness and their families.¹ Due to insufficient numbers of PC specialists to meet the PC needs for every hospitalized patient,² all hospitalists should maintain basic PC skills as recognized by PC being a core competency for hospitalists.^3,4

We summarize and critique PC research articles published between January 1, 2016, and December 31, 2016, that have a high likelihood of impacting the practice of hospital medicine. We hand searched 15 journals and conducted a MEDLINE keyword search of PC terms (see Table). All titles and/or abstracts were reviewed and selected for full review based on the following factors: palliative medicine content, scientific rigor, impact on practice, and relevance to hospital medicine. Fifty-five articles were individually reviewed and scored by all authors according to rigor, impact, and relevance. Articles were ranked according to their mean scores, and 9 articles were chosen for inclusion through consensus discussion.

Antipsychotics Were Inferior to a Placebo in Treating Nonterminal Delirium

Agar MR, Lawlor PG, Quinn S, et al. Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial. JAMA Intern Med. 2017;177(1):34-42.

Background

Delirium is highly prevalent in PC and is associated with significant distress.⁵ Antipsychotics are widely used for symptoms of delirium, although current evidence does not support this practice in hospitalized adults.^6,7

Findings

This was a double-blind, parallel-arm, placebo randomized controlled trial (RCT) of 247 patients with delirium with an estimated life expectancy of ≥7 days in 11 PC or hospice units across Australia. Patients were randomized to receive risperidone, haloperidol, or a placebo in addition to nonpharmacological management of delirium. Delirium symptom scores after 3 days of treatment, the use of midazolam as a rescue medication, and the presence of extrapyramidal symptoms (EPS) were measured. The risperidone and haloperidol arms had significantly higher delirium symptom scores (P = .02 and P = .009, respectively), mean EPS symptoms (P < .001), and more use of rescue midazolam than the placebo arm. Mortality was higher for antipsychotics, with a hazard ratio of 1.73 for haloperidol (P = .003), 1.29 for risperidone (P = .14), and 1.47 for any antipsychotic (P = .01).

Cautions

The study population was elderly (mean age >70 years) with mild delirium scores. The use of antipsychotics was associated with more benzodiazepine use, which could itself worsen delirium. As patients with clinician-predicted life expectancy of <7 days were excluded, findings cannot be extrapolated to the treatment of terminal delirium, which can often be more symptomatic and difficult to treat.

Implications

Avoid scheduled antipsychotics in patients with nonterminal delirium, as they can increase risk of harm without advantages, over nonpharmacologic interventions.

Low-Dose Morphine Was Superior to Weak Opioids in the Treatment of Moderate Cancer Pain

Bandieri E, Romero M, Ripamonti CI, et al. Randomized trial of low-dose morphine versus weak opioids in moderate cancer pain. J Clin Oncol. 2016;34(5):436-442.

Background

The World Health Organization guidelines recommend the use of weak opioids (WOs), such as codeine or tramadol, as a sequential step in the management of cancer pain.⁸ This strategy has not been tested against low doses of stronger opioids.

Findings

In this multicenter, open-label RCT, 240 patients in Italy were randomized and stratified by age (<75 years or ≥75 years) to either the WO group or low-dose morphine (M) group. The primary outcome measure was a reduction in pain intensity by 20% or more. Secondary outcomes included an improvement in symptom scores, a ≥30% and ≥50% reduction in pain, increased opioid dosage, and adverse side effects. Compared with the WO group, the M group had more patients with a 20% reduction in pain (88.2% vs 54.7%; P < .001), more evidence of pain control in the first week (80.9% vs 43.6%; P < .001), more patients with a ≥30% and ≥50% reduction in pain, and less need to switch to a stronger opioid (15.5% vs 35.0%; P = .001) or require dose increases. Adverse effects were similar in both groups.

Cautions

Patients with chronic kidney disease (CKD) were excluded due to concerns about the accumulation of morphine metabolites. Additionally, this study was open label, increasing the risk of bias.

Implications

Low-dose morphine should be considered over the use of WOs to achieve better and more rapid pain control in patients without CKD.

The Use of Methadone as a Coanalgesic May Improve Moderate Cancer Pain

Courtemanche F, Dao D, Gagné F, et al. Methadone as a coanalgesic for palliative care cancer patients. J Palliat Med. 2016;19(9):972-978.

Background

Methadone is effective at treating cancer pain and is often utilized when patients have neuropathic pain, fail to respond to traditional opioids, or have renal failure.^9,10 However, its long half-life and many drug interactions make methadone challenging to use.

Findings

This cohort study looked at 153 inpatient or outpatient PC patients in Montreal who received methadone as a coanalgesic for cancer pain. The patients’ median morphine equivalent dose was 120 mg when initiating methadone. The median starting dose of methadone was 3 mg per day. Of patients, 49.3% had a significant response (≥30% pain reduction), with a median response time of 7 days, and 30.1% achieved a substantial response (≥50% pain reduction), with a median response time of 3 days. Patients with higher initial pain scores were more likely to respond to adjuvant methadone. Those who had not responded after a week of methadone were unlikely to respond despite dose escalations. Adverse effects included drowsiness (51.4%), confusion (27.4%), constipation (24.7%), nausea (19.9%), and myoclonia (16.4%).

Cautions

This was an observational study with retrospective data, leading to higher levels of missing data. A high rate of adverse side effects was reported (90.4%). Further study is needed to validate and reproduce the findings.

Implications

The use of adjuvant low-dose methadone may be considered in patients with moderate pain despite high-dose opioids. If a response is not seen within 7 days, then methadone use should be reconsidered.

Many Hospitalized Patients on Comfort Care Still Receive Antimicrobials

Merel SE, Meier CA, McKinney CM, Pottinger PS. Antimicrobial use in patients on a comfort care protocol: a retrospective cohort study. J Palliat Med. 2016;19(11):1210-1214.

Background

It is unknown how often patients who are hospitalized at the end of life continue to receive antimicrobials and what factors are associated with antimicrobial use.

Findings

This retrospective cohort study of 1881 hospitalized adults transitioned to a comfort care order (CCO) set at 2 academic medical centers found that 77% of these patients received antimicrobials during their hospital stay (62.4% at 24 hours prior to CCO). Of the 711 still alive at ≥24 hours after CCO, 111 (15.6%) were still on antimicrobials, with that proportion remaining stable for the remainder of hospitalization. In comparing those who did and did not receive antimicrobials after 24 hours of CCO, the presence of a documented infection was not significantly different after adjusting for age. Those with a cancer diagnosis (adjusted risk ratio [ARR] = 1.44: P = .04), a longer length of stay (≥7 days vs <7 days; ARR = 1.49; P = .05), and those discharged home (ARR 2.93; P < .001) or to a facility (ARR 3.63; P < .001) versus dying in the hospital were more likely to be on antimicrobials 24 hours after CCO. Compared with those on a medicine service, patients in the medical and surgical intensive care units (ICUs) were less likely to receive antimicrobials (medical ICU ARR = 0.32; P = .01; surgical ICU and/or neuro-ICU ARR = 0.32; P = .02). The most commonly administered antimicrobials were fluoroquinolones and vancomycin.

Cautions

Only 111 patients were still on antimicrobials at 24 hours, which limited analysis. Investigators relied on retrospective data for medication administration and diagnoses.

Implications

Further work is needed to understand and address the expectations of clinicians, patients, and families regarding the role of antimicrobials at the end of life.

Video Decision Aids Improved Rates of Advance Care Planning and Hospice Use and Decreased Costs

Volandes, AE, Paasche-Orlow MK, Davis AD et al. Use of video decision aids to promote advance care planning in Hilo, Hawai‘i. J Gen Intern Med. 2016;31(9):1035-1040.

Background

Advance care planning (ACP) can be enhanced with the use of video decision aids, which may help address scalability and cost.¹¹ The Hawaii Medical Service Association began an initiative to improve ACP rates, which included a financial incentive. Clinician training and patient access to ACP videos were implemented 1 year into this campaign, which was intended for patients with late-stage disease.

Findings

This study tested the impact of the video intervention on the rates of ACP documentation in Hilo, Hawaii, along with secondary outcomes of hospice use, hospital deaths, and costs. The intervention was sequentially rolled out to Hilo Medical Center (HMC), followed by hospice and primary care practices. Following the video introduction, the proportion of patients discharged from HMC with ACP documentation markedly increased (3.2% to 39.9%; P < .001). The percentage of hospital patients discharged to hospice increased from 5.7% to 13.8% (P < .001). Overall admissions to the Hospice of Hilo increased at a greater rate than in other parts of Hawaii. After the intervention in Hilo, the in-hospital death rate among patients >65 years old declined slightly (P = .14), while in the rest of the state, the rate remained essentially unchanged. ACP planning did not reduce healthcare costs at the end of life, but costs seemed to increase more slowly in Hilo after the intervention than they did in the rest of Hawaii (P < .05).

Cautions

This report relies on before-and-after comparisons, with potential confounding by a background pay-for-quality initiative; however, the timing of the changes in outcomes correlates well with the introduction of the videos. ACP videos have been studied in other settings, so the intervention is likely generalizable to other states.

Implications

A widespread distribution of ACP videos and training for physicians in their use may lead to significant increases in ACP documentation and other beneficial clinical outcomes for patients and health systems.

A Standardized Palliative Care-Led Intervention Did Not Improve Psychological Outcomes in Families of Patients with Chronic Critical Illness

Carson SS, Cox CE, Wallenstein S, et al. Effect of palliative care-led meetings for families of patients with chronic critical illness: a randomized clinical trial. JAMA. 2016;316(1):51-62.

Background

Chronic critical illness (CCI) occurs when a patient neither recovers nor dies for days to weeks after an acute illness requiring aggressive intensive care. CCI is associated with poor patient and family outcomes.¹² Does a protocol-driven support and information meeting led by PC providers improve these outcomes?

Findings

This multicenter RCT compared 130 CCI patients (184 surrogates) who received a structured intervention to 126 patients (181 surrogates) with usual care. The structured intervention was led by PC clinicians in order to provide supportive conversations and information about CCI and prognosis compared with the usual intensivist communication. The support and information team met with the families of patients in the intervention group after day 7 of mechanical ventilation (MV) and again 10 days later. Both the intervention and control groups received validated information about CCI, and all were eligible for specialty PC consultation, as indicated. The primary outcome of the study was the Hospital Anxiety and Depression Scale (HADS) at 90-day follow-up with the surrogates. Secondary endpoints included posttraumatic stress disorder (PTSD) assessment and other communication measures as well as patient outcomes (hospital mortality, 90-day survival, length of stay, and days of MV). At least 1 meeting took place for 89% of patients (82% of surrogates) in the intervention arm. Fewer patients in the intervention arm had nonstudy PC consultations (13% vs 22%). Ninety-day HADS results were similar in the 2 groups. PTSD symptoms, however, were higher in the intervention group (Impact of Event Scale-Revised score: 25.9 for intervention and 21.3 for control; intergroup difference 4.6 [95% confidence interval, 0.01-9.10]). There were no statistically significant differences among the patient-focused measures, including survival.

Cautions

Although the teams contained skilled clinicians led by PC practitioners, this was not an ordinary PC intervention. The intervention included information and emotional support meetings alone rather than support from a PC team driven by clinical considerations. This study included surrogates of patients with CCI but not other conditions.

Implications

Protocol-driven support and information meetings may not improve, and may slightly worsen, outcomes in families of patients with CCI. This study did not evaluate and should not be applied to clinically indicated, specialty PC consultation in the ICU.

Caregivers of Patients Surviving Prolonged Critical Illness Experience High and Persistent Rates of Depression

Cameron JI, Chu LM, Matte A, et al. One-year outcomes in caregivers of critically ill patients. N Engl J Med. 2016;374(19):1831-1841.

Background

More than half of patients with a CCI require caregiver support 1 year after hospitalization.¹³ Caregivers provide tremendous physical and psychosocial support to their loved ones, but that care is often associated with significant burden.¹⁴

Findings

This prospective parallel cohort study followed caregivers of surviving patients ventilated for at least 7 days from 10 academic hospitals in Canada. The prevalence of depression (Center for Epidemiologic Studies–Depression scale ≥16) in this cohort of 280 caregivers (70% were women) was 67%, 49%, 43%, and 43% at the survey intervals of 7 days, 3 months, 6 months, and 12 months after ICU discharge, respectively. Using latent-class linear mixed models, the investigators identified 2 groups of caregivers: those whose depressive symptoms decreased over time (84%) and those whose depressive symptoms persisted at a high level for the year (16%). Patient characteristics (such as age, comorbidity, sex, and functional status) were not associated with caregiver outcomes. Younger caregiver age, greater effect of patient care on other activities, less social support, less mastery (sense of control), and less personal growth were associated with worse caregiver mental health outcomes.

Cautions

Although this is a high-quality prospective study, causality of caregiving on the high rates of depressive symptoms cannot be confirmed without a control group or knowledge of the caregivers’ mental health status prior to the episode of prolonged critical illness.

Implications

Patient critical illness may have serious impacts on caregiver health and well-being. Hospitalists should be attentive to factors associated with caregiver vulnerability and offer support. Improving caregivers’ sense of control and social support may be targets for interventions.

People with Non-normative Sexuality or Gender Face Additional Barriers and Stressors with Partner Loss

Bristowe K, Marshall S, Harding R. The bereavement experiences of lesbian, gay, bisexual and/or trans* people who have lost a partner: A systematic review, thematic synthesis and modelling of the literature. Palliat Med. 2016;30(8):730-744.

Background

Grief and bereavement impact individuals differently as they adjust to a death. Increasingly, it is recognized that lesbian, gay, bisexual, and/or transgender (LGBT) communities may face additional barriers when interacting with the healthcare system. This review sought to identify and appraise the evidence of the bereavement experiences among LGBT communities.

Findings

This systematic review summarized quantitative and qualitative data from 23 articles (13 studies). The synthesis noted that the pain associated with the loss of a partner was a universal experience regardless of sexual identity or gender history. Additional barriers and stressors of bereavement were reported for LGBT people, including homophobia, failure to acknowledge the relationship, additional legal and financial issues, and the shadow of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS). LGBT people turned to additional resources for bereavement help: professional support, social and familial support, and societal and community support. Caregiver bereavement support experiences were shaped by whether the relationships were disclosed and accepted (acceptance-disclosure model).

Cautions

The quantitative data was mostly from the 1990s and described the context of HIV/AIDS. The qualitative studies, however, were done in the last decade. Very little research was available for transgender or bisexual caregivers.

Implications

People who identify as LGBT face additional barriers and stressors with the loss of a partner. The described acceptance-disclosure model may help providers be mindful of the additional barriers to LGBT bereavement support.

Physician Trainees Experience Significant Moral Distress with Futile Treatments

Dzeng E, Colaianni A, Roland M, et al. Moral distress amongst American physician trainees regarding futile treatments at the end of life: a qualitative study. J Gen Intern Med. 2016;31(1):93-99.

Background

Physician trainees are often faced with ethical challenges in providing end-of-life care. These ethical challenges can create confusion and conflict about the balance between the benefits and burdens experienced by patients.

Findings

The authors used semistructured, in-depth, qualitative interviews of 22 internal medicine trainees from 3 academic medical centers. An analysis of these interviews revealed several themes. Trainees reported moral distress when (1) many of the treatments provided in end-of-life care (ie, feeding tubes in advanced dementia) were perceived to be futile; (2) they felt obligated to provide end-of-life care that was not in the patient’s best interest, leading to “torture” or “suffering” for the patient; (3) they provided care they felt not to be in the patient’s best interest; (4) they perceived themselves to be powerless to affect change in these dilemmas; (5) they attributed some of their powerlessness to the hierarchy of their academic institutions; and (6) they feared that dehumanization and cynicism would be required to endure this distress.

Cautions

Resident recruitment occurred by solicitation, which may invite bias. Generalizability of qualitative studies to other settings can be limited.

Implications

Trainees may experience several dimensions of moral distress in end-of-life care. These findings challenge training programs to find ways to reduce the dehumanization, sense of powerlessness, and cynicism that this distress may cause.

Disclosure

The authors declare that they have no relevant financial conflicts of interest.

The aim of palliative care (PC) is to improve quality of life for patients facing serious, life-threatening illness and their families.¹ Due to insufficient numbers of PC specialists to meet the PC needs for every hospitalized patient,² all hospitalists should maintain basic PC skills as recognized by PC being a core competency for hospitalists.^3,4

We summarize and critique PC research articles published between January 1, 2016, and December 31, 2016, that have a high likelihood of impacting the practice of hospital medicine. We hand searched 15 journals and conducted a MEDLINE keyword search of PC terms (see Table). All titles and/or abstracts were reviewed and selected for full review based on the following factors: palliative medicine content, scientific rigor, impact on practice, and relevance to hospital medicine. Fifty-five articles were individually reviewed and scored by all authors according to rigor, impact, and relevance. Articles were ranked according to their mean scores, and 9 articles were chosen for inclusion through consensus discussion.

Antipsychotics Were Inferior to a Placebo in Treating Nonterminal Delirium

Agar MR, Lawlor PG, Quinn S, et al. Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial. JAMA Intern Med. 2017;177(1):34-42.

Background

Delirium is highly prevalent in PC and is associated with significant distress.⁵ Antipsychotics are widely used for symptoms of delirium, although current evidence does not support this practice in hospitalized adults.^6,7

Findings

This was a double-blind, parallel-arm, placebo randomized controlled trial (RCT) of 247 patients with delirium with an estimated life expectancy of ≥7 days in 11 PC or hospice units across Australia. Patients were randomized to receive risperidone, haloperidol, or a placebo in addition to nonpharmacological management of delirium. Delirium symptom scores after 3 days of treatment, the use of midazolam as a rescue medication, and the presence of extrapyramidal symptoms (EPS) were measured. The risperidone and haloperidol arms had significantly higher delirium symptom scores (P = .02 and P = .009, respectively), mean EPS symptoms (P < .001), and more use of rescue midazolam than the placebo arm. Mortality was higher for antipsychotics, with a hazard ratio of 1.73 for haloperidol (P = .003), 1.29 for risperidone (P = .14), and 1.47 for any antipsychotic (P = .01).

Cautions

The study population was elderly (mean age >70 years) with mild delirium scores. The use of antipsychotics was associated with more benzodiazepine use, which could itself worsen delirium. As patients with clinician-predicted life expectancy of <7 days were excluded, findings cannot be extrapolated to the treatment of terminal delirium, which can often be more symptomatic and difficult to treat.

Implications

Avoid scheduled antipsychotics in patients with nonterminal delirium, as they can increase risk of harm without advantages, over nonpharmacologic interventions.

Low-Dose Morphine Was Superior to Weak Opioids in the Treatment of Moderate Cancer Pain

Bandieri E, Romero M, Ripamonti CI, et al. Randomized trial of low-dose morphine versus weak opioids in moderate cancer pain. J Clin Oncol. 2016;34(5):436-442.

Background

The World Health Organization guidelines recommend the use of weak opioids (WOs), such as codeine or tramadol, as a sequential step in the management of cancer pain.⁸ This strategy has not been tested against low doses of stronger opioids.

Findings

In this multicenter, open-label RCT, 240 patients in Italy were randomized and stratified by age (<75 years or ≥75 years) to either the WO group or low-dose morphine (M) group. The primary outcome measure was a reduction in pain intensity by 20% or more. Secondary outcomes included an improvement in symptom scores, a ≥30% and ≥50% reduction in pain, increased opioid dosage, and adverse side effects. Compared with the WO group, the M group had more patients with a 20% reduction in pain (88.2% vs 54.7%; P < .001), more evidence of pain control in the first week (80.9% vs 43.6%; P < .001), more patients with a ≥30% and ≥50% reduction in pain, and less need to switch to a stronger opioid (15.5% vs 35.0%; P = .001) or require dose increases. Adverse effects were similar in both groups.

Cautions

Patients with chronic kidney disease (CKD) were excluded due to concerns about the accumulation of morphine metabolites. Additionally, this study was open label, increasing the risk of bias.

Implications

Low-dose morphine should be considered over the use of WOs to achieve better and more rapid pain control in patients without CKD.

The Use of Methadone as a Coanalgesic May Improve Moderate Cancer Pain

Courtemanche F, Dao D, Gagné F, et al. Methadone as a coanalgesic for palliative care cancer patients. J Palliat Med. 2016;19(9):972-978.

Background

Methadone is effective at treating cancer pain and is often utilized when patients have neuropathic pain, fail to respond to traditional opioids, or have renal failure.^9,10 However, its long half-life and many drug interactions make methadone challenging to use.

Findings

This cohort study looked at 153 inpatient or outpatient PC patients in Montreal who received methadone as a coanalgesic for cancer pain. The patients’ median morphine equivalent dose was 120 mg when initiating methadone. The median starting dose of methadone was 3 mg per day. Of patients, 49.3% had a significant response (≥30% pain reduction), with a median response time of 7 days, and 30.1% achieved a substantial response (≥50% pain reduction), with a median response time of 3 days. Patients with higher initial pain scores were more likely to respond to adjuvant methadone. Those who had not responded after a week of methadone were unlikely to respond despite dose escalations. Adverse effects included drowsiness (51.4%), confusion (27.4%), constipation (24.7%), nausea (19.9%), and myoclonia (16.4%).

Cautions

This was an observational study with retrospective data, leading to higher levels of missing data. A high rate of adverse side effects was reported (90.4%). Further study is needed to validate and reproduce the findings.

Implications

The use of adjuvant low-dose methadone may be considered in patients with moderate pain despite high-dose opioids. If a response is not seen within 7 days, then methadone use should be reconsidered.

Many Hospitalized Patients on Comfort Care Still Receive Antimicrobials

Merel SE, Meier CA, McKinney CM, Pottinger PS. Antimicrobial use in patients on a comfort care protocol: a retrospective cohort study. J Palliat Med. 2016;19(11):1210-1214.

Background

It is unknown how often patients who are hospitalized at the end of life continue to receive antimicrobials and what factors are associated with antimicrobial use.

Findings

This retrospective cohort study of 1881 hospitalized adults transitioned to a comfort care order (CCO) set at 2 academic medical centers found that 77% of these patients received antimicrobials during their hospital stay (62.4% at 24 hours prior to CCO). Of the 711 still alive at ≥24 hours after CCO, 111 (15.6%) were still on antimicrobials, with that proportion remaining stable for the remainder of hospitalization. In comparing those who did and did not receive antimicrobials after 24 hours of CCO, the presence of a documented infection was not significantly different after adjusting for age. Those with a cancer diagnosis (adjusted risk ratio [ARR] = 1.44: P = .04), a longer length of stay (≥7 days vs <7 days; ARR = 1.49; P = .05), and those discharged home (ARR 2.93; P < .001) or to a facility (ARR 3.63; P < .001) versus dying in the hospital were more likely to be on antimicrobials 24 hours after CCO. Compared with those on a medicine service, patients in the medical and surgical intensive care units (ICUs) were less likely to receive antimicrobials (medical ICU ARR = 0.32; P = .01; surgical ICU and/or neuro-ICU ARR = 0.32; P = .02). The most commonly administered antimicrobials were fluoroquinolones and vancomycin.

Cautions

Only 111 patients were still on antimicrobials at 24 hours, which limited analysis. Investigators relied on retrospective data for medication administration and diagnoses.

Implications

Further work is needed to understand and address the expectations of clinicians, patients, and families regarding the role of antimicrobials at the end of life.

Video Decision Aids Improved Rates of Advance Care Planning and Hospice Use and Decreased Costs

Volandes, AE, Paasche-Orlow MK, Davis AD et al. Use of video decision aids to promote advance care planning in Hilo, Hawai‘i. J Gen Intern Med. 2016;31(9):1035-1040.

Background

Advance care planning (ACP) can be enhanced with the use of video decision aids, which may help address scalability and cost.¹¹ The Hawaii Medical Service Association began an initiative to improve ACP rates, which included a financial incentive. Clinician training and patient access to ACP videos were implemented 1 year into this campaign, which was intended for patients with late-stage disease.

Findings

This study tested the impact of the video intervention on the rates of ACP documentation in Hilo, Hawaii, along with secondary outcomes of hospice use, hospital deaths, and costs. The intervention was sequentially rolled out to Hilo Medical Center (HMC), followed by hospice and primary care practices. Following the video introduction, the proportion of patients discharged from HMC with ACP documentation markedly increased (3.2% to 39.9%; P < .001). The percentage of hospital patients discharged to hospice increased from 5.7% to 13.8% (P < .001). Overall admissions to the Hospice of Hilo increased at a greater rate than in other parts of Hawaii. After the intervention in Hilo, the in-hospital death rate among patients >65 years old declined slightly (P = .14), while in the rest of the state, the rate remained essentially unchanged. ACP planning did not reduce healthcare costs at the end of life, but costs seemed to increase more slowly in Hilo after the intervention than they did in the rest of Hawaii (P < .05).

Cautions

This report relies on before-and-after comparisons, with potential confounding by a background pay-for-quality initiative; however, the timing of the changes in outcomes correlates well with the introduction of the videos. ACP videos have been studied in other settings, so the intervention is likely generalizable to other states.

Implications

A widespread distribution of ACP videos and training for physicians in their use may lead to significant increases in ACP documentation and other beneficial clinical outcomes for patients and health systems.

A Standardized Palliative Care-Led Intervention Did Not Improve Psychological Outcomes in Families of Patients with Chronic Critical Illness

Carson SS, Cox CE, Wallenstein S, et al. Effect of palliative care-led meetings for families of patients with chronic critical illness: a randomized clinical trial. JAMA. 2016;316(1):51-62.

Background

Chronic critical illness (CCI) occurs when a patient neither recovers nor dies for days to weeks after an acute illness requiring aggressive intensive care. CCI is associated with poor patient and family outcomes.¹² Does a protocol-driven support and information meeting led by PC providers improve these outcomes?

Findings

This multicenter RCT compared 130 CCI patients (184 surrogates) who received a structured intervention to 126 patients (181 surrogates) with usual care. The structured intervention was led by PC clinicians in order to provide supportive conversations and information about CCI and prognosis compared with the usual intensivist communication. The support and information team met with the families of patients in the intervention group after day 7 of mechanical ventilation (MV) and again 10 days later. Both the intervention and control groups received validated information about CCI, and all were eligible for specialty PC consultation, as indicated. The primary outcome of the study was the Hospital Anxiety and Depression Scale (HADS) at 90-day follow-up with the surrogates. Secondary endpoints included posttraumatic stress disorder (PTSD) assessment and other communication measures as well as patient outcomes (hospital mortality, 90-day survival, length of stay, and days of MV). At least 1 meeting took place for 89% of patients (82% of surrogates) in the intervention arm. Fewer patients in the intervention arm had nonstudy PC consultations (13% vs 22%). Ninety-day HADS results were similar in the 2 groups. PTSD symptoms, however, were higher in the intervention group (Impact of Event Scale-Revised score: 25.9 for intervention and 21.3 for control; intergroup difference 4.6 [95% confidence interval, 0.01-9.10]). There were no statistically significant differences among the patient-focused measures, including survival.

Cautions

Although the teams contained skilled clinicians led by PC practitioners, this was not an ordinary PC intervention. The intervention included information and emotional support meetings alone rather than support from a PC team driven by clinical considerations. This study included surrogates of patients with CCI but not other conditions.

Implications

Protocol-driven support and information meetings may not improve, and may slightly worsen, outcomes in families of patients with CCI. This study did not evaluate and should not be applied to clinically indicated, specialty PC consultation in the ICU.

Caregivers of Patients Surviving Prolonged Critical Illness Experience High and Persistent Rates of Depression

Cameron JI, Chu LM, Matte A, et al. One-year outcomes in caregivers of critically ill patients. N Engl J Med. 2016;374(19):1831-1841.

Background

More than half of patients with a CCI require caregiver support 1 year after hospitalization.¹³ Caregivers provide tremendous physical and psychosocial support to their loved ones, but that care is often associated with significant burden.¹⁴

Findings

This prospective parallel cohort study followed caregivers of surviving patients ventilated for at least 7 days from 10 academic hospitals in Canada. The prevalence of depression (Center for Epidemiologic Studies–Depression scale ≥16) in this cohort of 280 caregivers (70% were women) was 67%, 49%, 43%, and 43% at the survey intervals of 7 days, 3 months, 6 months, and 12 months after ICU discharge, respectively. Using latent-class linear mixed models, the investigators identified 2 groups of caregivers: those whose depressive symptoms decreased over time (84%) and those whose depressive symptoms persisted at a high level for the year (16%). Patient characteristics (such as age, comorbidity, sex, and functional status) were not associated with caregiver outcomes. Younger caregiver age, greater effect of patient care on other activities, less social support, less mastery (sense of control), and less personal growth were associated with worse caregiver mental health outcomes.

Cautions

Although this is a high-quality prospective study, causality of caregiving on the high rates of depressive symptoms cannot be confirmed without a control group or knowledge of the caregivers’ mental health status prior to the episode of prolonged critical illness.

Implications

Patient critical illness may have serious impacts on caregiver health and well-being. Hospitalists should be attentive to factors associated with caregiver vulnerability and offer support. Improving caregivers’ sense of control and social support may be targets for interventions.

People with Non-normative Sexuality or Gender Face Additional Barriers and Stressors with Partner Loss

Bristowe K, Marshall S, Harding R. The bereavement experiences of lesbian, gay, bisexual and/or trans* people who have lost a partner: A systematic review, thematic synthesis and modelling of the literature. Palliat Med. 2016;30(8):730-744.

Background

Grief and bereavement impact individuals differently as they adjust to a death. Increasingly, it is recognized that lesbian, gay, bisexual, and/or transgender (LGBT) communities may face additional barriers when interacting with the healthcare system. This review sought to identify and appraise the evidence of the bereavement experiences among LGBT communities.

Findings

This systematic review summarized quantitative and qualitative data from 23 articles (13 studies). The synthesis noted that the pain associated with the loss of a partner was a universal experience regardless of sexual identity or gender history. Additional barriers and stressors of bereavement were reported for LGBT people, including homophobia, failure to acknowledge the relationship, additional legal and financial issues, and the shadow of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS). LGBT people turned to additional resources for bereavement help: professional support, social and familial support, and societal and community support. Caregiver bereavement support experiences were shaped by whether the relationships were disclosed and accepted (acceptance-disclosure model).

Cautions

The quantitative data was mostly from the 1990s and described the context of HIV/AIDS. The qualitative studies, however, were done in the last decade. Very little research was available for transgender or bisexual caregivers.

Implications

People who identify as LGBT face additional barriers and stressors with the loss of a partner. The described acceptance-disclosure model may help providers be mindful of the additional barriers to LGBT bereavement support.

Physician Trainees Experience Significant Moral Distress with Futile Treatments

Dzeng E, Colaianni A, Roland M, et al. Moral distress amongst American physician trainees regarding futile treatments at the end of life: a qualitative study. J Gen Intern Med. 2016;31(1):93-99.

Background

Physician trainees are often faced with ethical challenges in providing end-of-life care. These ethical challenges can create confusion and conflict about the balance between the benefits and burdens experienced by patients.

Findings

The authors used semistructured, in-depth, qualitative interviews of 22 internal medicine trainees from 3 academic medical centers. An analysis of these interviews revealed several themes. Trainees reported moral distress when (1) many of the treatments provided in end-of-life care (ie, feeding tubes in advanced dementia) were perceived to be futile; (2) they felt obligated to provide end-of-life care that was not in the patient’s best interest, leading to “torture” or “suffering” for the patient; (3) they provided care they felt not to be in the patient’s best interest; (4) they perceived themselves to be powerless to affect change in these dilemmas; (5) they attributed some of their powerlessness to the hierarchy of their academic institutions; and (6) they feared that dehumanization and cynicism would be required to endure this distress.

Cautions

Resident recruitment occurred by solicitation, which may invite bias. Generalizability of qualitative studies to other settings can be limited.

Implications

Trainees may experience several dimensions of moral distress in end-of-life care. These findings challenge training programs to find ways to reduce the dehumanization, sense of powerlessness, and cynicism that this distress may cause.

Disclosure

The authors declare that they have no relevant financial conflicts of interest.

The aim of palliative care (PC) is to improve quality of life for patients facing serious, life-threatening illness and their families.¹ Due to insufficient numbers of PC specialists to meet the PC needs for every hospitalized patient,² all hospitalists should maintain basic PC skills as recognized by PC being a core competency for hospitalists.^3,4

We summarize and critique PC research articles published between January 1, 2016, and December 31, 2016, that have a high likelihood of impacting the practice of hospital medicine. We hand searched 15 journals and conducted a MEDLINE keyword search of PC terms (see Table). All titles and/or abstracts were reviewed and selected for full review based on the following factors: palliative medicine content, scientific rigor, impact on practice, and relevance to hospital medicine. Fifty-five articles were individually reviewed and scored by all authors according to rigor, impact, and relevance. Articles were ranked according to their mean scores, and 9 articles were chosen for inclusion through consensus discussion.

Antipsychotics Were Inferior to a Placebo in Treating Nonterminal Delirium

Agar MR, Lawlor PG, Quinn S, et al. Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial. JAMA Intern Med. 2017;177(1):34-42.

Background

Delirium is highly prevalent in PC and is associated with significant distress.⁵ Antipsychotics are widely used for symptoms of delirium, although current evidence does not support this practice in hospitalized adults.^6,7

Findings

This was a double-blind, parallel-arm, placebo randomized controlled trial (RCT) of 247 patients with delirium with an estimated life expectancy of ≥7 days in 11 PC or hospice units across Australia. Patients were randomized to receive risperidone, haloperidol, or a placebo in addition to nonpharmacological management of delirium. Delirium symptom scores after 3 days of treatment, the use of midazolam as a rescue medication, and the presence of extrapyramidal symptoms (EPS) were measured. The risperidone and haloperidol arms had significantly higher delirium symptom scores (P = .02 and P = .009, respectively), mean EPS symptoms (P < .001), and more use of rescue midazolam than the placebo arm. Mortality was higher for antipsychotics, with a hazard ratio of 1.73 for haloperidol (P = .003), 1.29 for risperidone (P = .14), and 1.47 for any antipsychotic (P = .01).

Cautions

The study population was elderly (mean age >70 years) with mild delirium scores. The use of antipsychotics was associated with more benzodiazepine use, which could itself worsen delirium. As patients with clinician-predicted life expectancy of <7 days were excluded, findings cannot be extrapolated to the treatment of terminal delirium, which can often be more symptomatic and difficult to treat.

Implications

Avoid scheduled antipsychotics in patients with nonterminal delirium, as they can increase risk of harm without advantages, over nonpharmacologic interventions.

Low-Dose Morphine Was Superior to Weak Opioids in the Treatment of Moderate Cancer Pain

Bandieri E, Romero M, Ripamonti CI, et al. Randomized trial of low-dose morphine versus weak opioids in moderate cancer pain. J Clin Oncol. 2016;34(5):436-442.

Background

The World Health Organization guidelines recommend the use of weak opioids (WOs), such as codeine or tramadol, as a sequential step in the management of cancer pain.⁸ This strategy has not been tested against low doses of stronger opioids.

Findings

In this multicenter, open-label RCT, 240 patients in Italy were randomized and stratified by age (<75 years or ≥75 years) to either the WO group or low-dose morphine (M) group. The primary outcome measure was a reduction in pain intensity by 20% or more. Secondary outcomes included an improvement in symptom scores, a ≥30% and ≥50% reduction in pain, increased opioid dosage, and adverse side effects. Compared with the WO group, the M group had more patients with a 20% reduction in pain (88.2% vs 54.7%; P < .001), more evidence of pain control in the first week (80.9% vs 43.6%; P < .001), more patients with a ≥30% and ≥50% reduction in pain, and less need to switch to a stronger opioid (15.5% vs 35.0%; P = .001) or require dose increases. Adverse effects were similar in both groups.

Cautions

Patients with chronic kidney disease (CKD) were excluded due to concerns about the accumulation of morphine metabolites. Additionally, this study was open label, increasing the risk of bias.

Implications

Low-dose morphine should be considered over the use of WOs to achieve better and more rapid pain control in patients without CKD.

The Use of Methadone as a Coanalgesic May Improve Moderate Cancer Pain

Courtemanche F, Dao D, Gagné F, et al. Methadone as a coanalgesic for palliative care cancer patients. J Palliat Med. 2016;19(9):972-978.

Background

Methadone is effective at treating cancer pain and is often utilized when patients have neuropathic pain, fail to respond to traditional opioids, or have renal failure.^9,10 However, its long half-life and many drug interactions make methadone challenging to use.

Findings

This cohort study looked at 153 inpatient or outpatient PC patients in Montreal who received methadone as a coanalgesic for cancer pain. The patients’ median morphine equivalent dose was 120 mg when initiating methadone. The median starting dose of methadone was 3 mg per day. Of patients, 49.3% had a significant response (≥30% pain reduction), with a median response time of 7 days, and 30.1% achieved a substantial response (≥50% pain reduction), with a median response time of 3 days. Patients with higher initial pain scores were more likely to respond to adjuvant methadone. Those who had not responded after a week of methadone were unlikely to respond despite dose escalations. Adverse effects included drowsiness (51.4%), confusion (27.4%), constipation (24.7%), nausea (19.9%), and myoclonia (16.4%).

Cautions

This was an observational study with retrospective data, leading to higher levels of missing data. A high rate of adverse side effects was reported (90.4%). Further study is needed to validate and reproduce the findings.

Implications

The use of adjuvant low-dose methadone may be considered in patients with moderate pain despite high-dose opioids. If a response is not seen within 7 days, then methadone use should be reconsidered.

Many Hospitalized Patients on Comfort Care Still Receive Antimicrobials

Merel SE, Meier CA, McKinney CM, Pottinger PS. Antimicrobial use in patients on a comfort care protocol: a retrospective cohort study. J Palliat Med. 2016;19(11):1210-1214.

Background

It is unknown how often patients who are hospitalized at the end of life continue to receive antimicrobials and what factors are associated with antimicrobial use.

Findings

This retrospective cohort study of 1881 hospitalized adults transitioned to a comfort care order (CCO) set at 2 academic medical centers found that 77% of these patients received antimicrobials during their hospital stay (62.4% at 24 hours prior to CCO). Of the 711 still alive at ≥24 hours after CCO, 111 (15.6%) were still on antimicrobials, with that proportion remaining stable for the remainder of hospitalization. In comparing those who did and did not receive antimicrobials after 24 hours of CCO, the presence of a documented infection was not significantly different after adjusting for age. Those with a cancer diagnosis (adjusted risk ratio [ARR] = 1.44: P = .04), a longer length of stay (≥7 days vs <7 days; ARR = 1.49; P = .05), and those discharged home (ARR 2.93; P < .001) or to a facility (ARR 3.63; P < .001) versus dying in the hospital were more likely to be on antimicrobials 24 hours after CCO. Compared with those on a medicine service, patients in the medical and surgical intensive care units (ICUs) were less likely to receive antimicrobials (medical ICU ARR = 0.32; P = .01; surgical ICU and/or neuro-ICU ARR = 0.32; P = .02). The most commonly administered antimicrobials were fluoroquinolones and vancomycin.

Cautions

Only 111 patients were still on antimicrobials at 24 hours, which limited analysis. Investigators relied on retrospective data for medication administration and diagnoses.

Implications

Further work is needed to understand and address the expectations of clinicians, patients, and families regarding the role of antimicrobials at the end of life.

Video Decision Aids Improved Rates of Advance Care Planning and Hospice Use and Decreased Costs

Volandes, AE, Paasche-Orlow MK, Davis AD et al. Use of video decision aids to promote advance care planning in Hilo, Hawai‘i. J Gen Intern Med. 2016;31(9):1035-1040.

Background

Advance care planning (ACP) can be enhanced with the use of video decision aids, which may help address scalability and cost.¹¹ The Hawaii Medical Service Association began an initiative to improve ACP rates, which included a financial incentive. Clinician training and patient access to ACP videos were implemented 1 year into this campaign, which was intended for patients with late-stage disease.

Findings

This study tested the impact of the video intervention on the rates of ACP documentation in Hilo, Hawaii, along with secondary outcomes of hospice use, hospital deaths, and costs. The intervention was sequentially rolled out to Hilo Medical Center (HMC), followed by hospice and primary care practices. Following the video introduction, the proportion of patients discharged from HMC with ACP documentation markedly increased (3.2% to 39.9%; P < .001). The percentage of hospital patients discharged to hospice increased from 5.7% to 13.8% (P < .001). Overall admissions to the Hospice of Hilo increased at a greater rate than in other parts of Hawaii. After the intervention in Hilo, the in-hospital death rate among patients >65 years old declined slightly (P = .14), while in the rest of the state, the rate remained essentially unchanged. ACP planning did not reduce healthcare costs at the end of life, but costs seemed to increase more slowly in Hilo after the intervention than they did in the rest of Hawaii (P < .05).

Cautions

This report relies on before-and-after comparisons, with potential confounding by a background pay-for-quality initiative; however, the timing of the changes in outcomes correlates well with the introduction of the videos. ACP videos have been studied in other settings, so the intervention is likely generalizable to other states.

Implications

A widespread distribution of ACP videos and training for physicians in their use may lead to significant increases in ACP documentation and other beneficial clinical outcomes for patients and health systems.

A Standardized Palliative Care-Led Intervention Did Not Improve Psychological Outcomes in Families of Patients with Chronic Critical Illness

Carson SS, Cox CE, Wallenstein S, et al. Effect of palliative care-led meetings for families of patients with chronic critical illness: a randomized clinical trial. JAMA. 2016;316(1):51-62.

Background

Chronic critical illness (CCI) occurs when a patient neither recovers nor dies for days to weeks after an acute illness requiring aggressive intensive care. CCI is associated with poor patient and family outcomes.¹² Does a protocol-driven support and information meeting led by PC providers improve these outcomes?

Findings

This multicenter RCT compared 130 CCI patients (184 surrogates) who received a structured intervention to 126 patients (181 surrogates) with usual care. The structured intervention was led by PC clinicians in order to provide supportive conversations and information about CCI and prognosis compared with the usual intensivist communication. The support and information team met with the families of patients in the intervention group after day 7 of mechanical ventilation (MV) and again 10 days later. Both the intervention and control groups received validated information about CCI, and all were eligible for specialty PC consultation, as indicated. The primary outcome of the study was the Hospital Anxiety and Depression Scale (HADS) at 90-day follow-up with the surrogates. Secondary endpoints included posttraumatic stress disorder (PTSD) assessment and other communication measures as well as patient outcomes (hospital mortality, 90-day survival, length of stay, and days of MV). At least 1 meeting took place for 89% of patients (82% of surrogates) in the intervention arm. Fewer patients in the intervention arm had nonstudy PC consultations (13% vs 22%). Ninety-day HADS results were similar in the 2 groups. PTSD symptoms, however, were higher in the intervention group (Impact of Event Scale-Revised score: 25.9 for intervention and 21.3 for control; intergroup difference 4.6 [95% confidence interval, 0.01-9.10]). There were no statistically significant differences among the patient-focused measures, including survival.

Cautions

Although the teams contained skilled clinicians led by PC practitioners, this was not an ordinary PC intervention. The intervention included information and emotional support meetings alone rather than support from a PC team driven by clinical considerations. This study included surrogates of patients with CCI but not other conditions.

Implications

Protocol-driven support and information meetings may not improve, and may slightly worsen, outcomes in families of patients with CCI. This study did not evaluate and should not be applied to clinically indicated, specialty PC consultation in the ICU.

Caregivers of Patients Surviving Prolonged Critical Illness Experience High and Persistent Rates of Depression

Cameron JI, Chu LM, Matte A, et al. One-year outcomes in caregivers of critically ill patients. N Engl J Med. 2016;374(19):1831-1841.

Background

More than half of patients with a CCI require caregiver support 1 year after hospitalization.¹³ Caregivers provide tremendous physical and psychosocial support to their loved ones, but that care is often associated with significant burden.¹⁴

Findings

This prospective parallel cohort study followed caregivers of surviving patients ventilated for at least 7 days from 10 academic hospitals in Canada. The prevalence of depression (Center for Epidemiologic Studies–Depression scale ≥16) in this cohort of 280 caregivers (70% were women) was 67%, 49%, 43%, and 43% at the survey intervals of 7 days, 3 months, 6 months, and 12 months after ICU discharge, respectively. Using latent-class linear mixed models, the investigators identified 2 groups of caregivers: those whose depressive symptoms decreased over time (84%) and those whose depressive symptoms persisted at a high level for the year (16%). Patient characteristics (such as age, comorbidity, sex, and functional status) were not associated with caregiver outcomes. Younger caregiver age, greater effect of patient care on other activities, less social support, less mastery (sense of control), and less personal growth were associated with worse caregiver mental health outcomes.

Cautions

Although this is a high-quality prospective study, causality of caregiving on the high rates of depressive symptoms cannot be confirmed without a control group or knowledge of the caregivers’ mental health status prior to the episode of prolonged critical illness.

Implications

Patient critical illness may have serious impacts on caregiver health and well-being. Hospitalists should be attentive to factors associated with caregiver vulnerability and offer support. Improving caregivers’ sense of control and social support may be targets for interventions.

People with Non-normative Sexuality or Gender Face Additional Barriers and Stressors with Partner Loss

Bristowe K, Marshall S, Harding R. The bereavement experiences of lesbian, gay, bisexual and/or trans* people who have lost a partner: A systematic review, thematic synthesis and modelling of the literature. Palliat Med. 2016;30(8):730-744.

Background

Grief and bereavement impact individuals differently as they adjust to a death. Increasingly, it is recognized that lesbian, gay, bisexual, and/or transgender (LGBT) communities may face additional barriers when interacting with the healthcare system. This review sought to identify and appraise the evidence of the bereavement experiences among LGBT communities.

Findings

This systematic review summarized quantitative and qualitative data from 23 articles (13 studies). The synthesis noted that the pain associated with the loss of a partner was a universal experience regardless of sexual identity or gender history. Additional barriers and stressors of bereavement were reported for LGBT people, including homophobia, failure to acknowledge the relationship, additional legal and financial issues, and the shadow of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS). LGBT people turned to additional resources for bereavement help: professional support, social and familial support, and societal and community support. Caregiver bereavement support experiences were shaped by whether the relationships were disclosed and accepted (acceptance-disclosure model).

Cautions

The quantitative data was mostly from the 1990s and described the context of HIV/AIDS. The qualitative studies, however, were done in the last decade. Very little research was available for transgender or bisexual caregivers.

Implications

People who identify as LGBT face additional barriers and stressors with the loss of a partner. The described acceptance-disclosure model may help providers be mindful of the additional barriers to LGBT bereavement support.

Physician Trainees Experience Significant Moral Distress with Futile Treatments

Dzeng E, Colaianni A, Roland M, et al. Moral distress amongst American physician trainees regarding futile treatments at the end of life: a qualitative study. J Gen Intern Med. 2016;31(1):93-99.

Background

Physician trainees are often faced with ethical challenges in providing end-of-life care. These ethical challenges can create confusion and conflict about the balance between the benefits and burdens experienced by patients.

Findings

The authors used semistructured, in-depth, qualitative interviews of 22 internal medicine trainees from 3 academic medical centers. An analysis of these interviews revealed several themes. Trainees reported moral distress when (1) many of the treatments provided in end-of-life care (ie, feeding tubes in advanced dementia) were perceived to be futile; (2) they felt obligated to provide end-of-life care that was not in the patient’s best interest, leading to “torture” or “suffering” for the patient; (3) they provided care they felt not to be in the patient’s best interest; (4) they perceived themselves to be powerless to affect change in these dilemmas; (5) they attributed some of their powerlessness to the hierarchy of their academic institutions; and (6) they feared that dehumanization and cynicism would be required to endure this distress.

Cautions

Resident recruitment occurred by solicitation, which may invite bias. Generalizability of qualitative studies to other settings can be limited.

Implications

Trainees may experience several dimensions of moral distress in end-of-life care. These findings challenge training programs to find ways to reduce the dehumanization, sense of powerlessness, and cynicism that this distress may cause.

Disclosure

The authors declare that they have no relevant financial conflicts of interest.

Engaging patients and their caregivers in care improves health outcomes^1-3 and is endorsed by leading healthcare organizations as essential to improving care quality and safety.^4-6 Patient engagement emphasizes that patients, caregivers, and healthcare providers work together to “promote and support active patient and public involvement in health and healthcare and to strengthen their influence on healthcare decisions.”⁷ Patient portals, web-based personal health records linked to electronic health record (EHR) data, are intended to promote engagement by providing patients and their caregivers with timely electronic access to their healthcare information and supporting communication through secure messaging with their healthcare team.⁸ The use of patient portals has also been suggested as a way for patients and/or caregivers to identify and intercept medical errors, thus having the potential to also improve patient safety.^8,9

As a requirement for meaningful use, access to health information through patient portals in the ambulatory setting has increased dramatically.¹⁰ Studies evaluating the use of these patient portals to promote patient-centered care are growing, but evidence supporting their impact on improved health outcomes is currently insufficient.^11-15 Although research and policy focus on the use of patient portals in the ambulatory setting, recent literature suggests that patient portals may be used to share inpatient clinical information to engage patients and their caregivers during their hospitalization.^16-18 Before the widespread use of patient portals in the inpatient setting is endorsed, systematic research is needed to understand optimal portal design requirements, if and how these portals are used, and whether their use provides value to the hospitalized patient and/or caregiver.⁸

Prior literature summarized early findings regarding the use of various technologies designed to engage hospitalized patients.^17,19,20 In this systematic review, we describe the emerging literature examining the design, use, and impact of inpatient portals for hospitalized patients and/or caregivers over the last 10 years. Inpatient portals are defined here as electronic patient portals tethered to EHRs that are designed to provide hospitalized patients and/or caregivers secure access to personalized, inpatient clinical information with the intent of engaging them in their hospital care. After analyzing and summarizing these data, we then identify knowledge gaps and potential future research directions.

Search Strategy, Study Selection, and Analysis

This systematic review included available, peer-reviewed, and grey literature published from January 1, 2006, to August 8, 2017, in PubMed, Web of Science (including the Institute of Electrical and Electronics Engineers Xplore), Cochrane, CINAHLPlus, and Scopus databases. Terms and phrases, including those found in the Medical Subject Heading (MeSH) index, were used to identify studies evaluating (1) patient portals (“health record, personal [MeSH],” “personal health record,” “patient portal,” “inpatient portal,” “ipad,” “tablet,” or “bedside information technology”), (2) engagement (“engagement,” “empowerment,” “participation,” “activation,” or “self-efficacy”), and (3) in the hospital (“inpatient [MeSH],” “hospital [MeSH],” “hospitalized patient [MeSH],” or “unit”). MeSH terms were used when applicable. Based on previous literature, free-text terms were also used when subject headings were not applied consistently, such as with terms related to engagement.^17,21 Studies were excluded if they were not written in English, if they evaluated portals exclusively in the emergency department or ambulatory setting, and/or if they described future study protocols. Studies describing general inpatient technology or evaluating portals used in the hospital but not tethered to inpatient EHR clinical data were also excluded.

By using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines,²² 2 researchers (M.K. and P.H.) completed the literature search and potential article screening. Results were aggregated and studies were screened and excluded from full review based on title and abstract information. Additional studies were included after reference list review. During a full review of included studies, 2 researchers independently extracted data, including the study objective, design, setting, sample, data collection instruments, outcomes, and a description of results. Guided by our study objective, findings were reconciled by consensus and analyzed and described according to the following 3 themes: (1) inpatient portal design, (2) inpatient portal use and usability, and (3) the impact of inpatient portal use on patient or caregiver and healthcare team outcomes as defined by retrieved studies.

The quality of studies was evaluated by the same 2 researchers independently by using the Downs and Black checklist for assessing the methodological quality of randomized and nonrandomized healthcare interventions.²³ Qualitative studies describing the development of portal prototypes and/or portal redesign efforts were excluded from these analyses. Discrepancies were resolved by consensus.Because of the wide variability in study designs, populations, and outcomes, a meta-analysis of pooled data was not performed.

Of the 731 studies identified through database searching and reference review, 36 were included for full-text review and 17 met inclusion criteria (Figure; Table 1). Studies excluded after full-text review described portal use outside of the inpatient setting, portals not linked to hospital EHR clinical data, portals not designed for inpatients, and/or inpatient technology in general. The inpatient portal platforms, hardware used, and functionalities varied within included studies (Table 2). The majority of studies used custom, web-based inpatient portal applications on tablet computers. Most provided information about the patients’ hospital medications, healthcare team, and education about their condition and/or a medical glossary. Many included the patient’s schedule, hospital problem list, discharge information, and a way to keep notes.

There has been a recent increase in inpatient portal study publication, with 9 studies published during or after 2016. Five were conducted in the pediatric setting and all but 1³⁰ with English-speaking participants. Twelve studies were qualitative, many of which were conducted in multiple phases by using semi-structured interviews and/or focus groups to develop or redesign inpatient portals. Of the remaining studies, 3 used a cross-sectional design, 1 used a before and after design without a control group, and 1 was a nonrandomized trial. Studies were rated as having medium-to-high risk of bias because of design flaws (Table 1 in supplementary Appendix). Because many studies were small pilot studies and all were single-centered studies, the generalizability of findings to different healthcare settings or patient populations is limited.

Inpatient Portal Design

Most included studies evaluated patient and/or caregiver information needs to design and/or enhance inpatient portals.^16,24-37 In 1 study, patients described an overall lack of information provided in the hospital and insufficient time to understand and remember information, which, when shared, was often presented by using medical terminology.³⁰ They wanted information to help them understand their daily hospital routine, confirm and compare medications and test results, learn about care, and prepare for discharge. Participants in multiple studies echoed these results, indicating the need for a schedule of upcoming clinical events (eg, medication administration, procedures, imaging), secure and timely clinical information (eg, list of diagnoses and medications, test results), personalized education, a medical glossary, discharge information, and a way to take notes and recognize and communicate with providers.

Patients also requested further information transparency,^34,37 including physicians’ notes, radiology results, operative reports, and billing information, along with general hospital information,¹⁶ meal ordering,³³ and video conferencing.²⁷ ln designing and refining an inpatient medication-tracking tool, participants identified the need for information about medication dosage, frequency, timing, administration method, criticality, alternative medications or forms, and education.^26,36 Patients and/or caregivers also indicated interest in communicating with inpatient providers by using the portal.^{16,27,28,30-37} In 1 study, patients highlighted the need to be involved in care plan development,²⁷ which led to portal refinement to allow for patient-generated data entry, including care goals and a way to communicate real-time concerns and feedback.²⁸

Studies also considered healthcare team perspectives to inform portal design.^{25,26,28,30,35,37} Although information needs usually overlapped, patient and healthcare team priorities differed in some areas. Although patients wanted to “know what was going to happen to them,” nurses in 1 study were more concerned about providing information to protect patients, such as safety and precaution materials.²⁵ Similarly, when designing a medication-tracking tool, patients sought information that helped them understand what to expect, while pharmacists focused on medication safety and providing information that fit their workflow (eg, abstract medication schedules).³⁶

Identified study data raised important portal interface design considerations. Results suggested clinical data should be presented by using simple displays,²⁸ accommodating real-time information. Participants recommended links^16,29 to personalized patient-friendly³⁷ education accessed with minimal steps.²⁶ Interfaces may be personalized for target users, such as patient or proxy and younger or older individuals. For example, older patients reported less familiarity with touch screens, internal keyboards, and handwriting recognition, favoring voice recognition for recording notes.²⁷ This raised questions about how portals can be designed to best maintain patient privacy.²⁵ Interface design, such as navigation, also relied heavily on hardware choice, such as tablet versus mobile phone.²⁸

Inpatient Portal Use and Usability

Most patient and/or caregiver participants in included studies were interested in using an inpatient portal, used it when offered, found it easy to use, useful, and/or were satisfied with it.^16,18,24-37 Most used and liked functionalities that provided healthcare team, test result, and medication information.^22,33,37 In the 1 identified controlled trial,¹⁸ researchers evaluated an inpatient portal given to adult inpatients that included a problem list, schedule, medication list, and healthcare team information. Of the intervention unit patients, 80% used the portal, 76% indicated it was easy to use, and 71% thought it provided useful information. When a portal was given to 239 adult patients and caregivers in another study, 66% sent a total of 291 messages to the healthcare team.³¹ Of these, 153 provided feedback, 76 expressed preferences, and 16 communicated concerns. In a pediatric study, an inpatient portal was given to 296 parents who sent a total of 36 messages and 176 requests.³³ Messages sent included information regarding caregiver needs, questions, updates, and/or positive endorsements of the healthcare team and/or care.

Impact of Inpatient Portal Use

Multiple studies evaluated the impact of inpatient portal use on patient and/or caregiver engagement, empowerment, activation, and/or knowledge, which had mixed results. Most adult patients interviewed in one study had positive experiences using a portal to answer their questions between physician visits and learn about, remember, and engage in care.³⁷ A majority of adult inpatient portal users in another study agreed that portal use helped them feel in control and understand their condition; however, they did not report having improved discharge timing knowledge.²⁹ In a pediatric study, most parent inpatient portal users agreed use improved their ability to monitor, understand, and make decisions about their child’s care.³³ In the controlled trial,¹⁸ a higher percentage of portal intervention patients could identify their physician or role; however, patient activation was not statistically different between intervention and control patients.

Results from included studies also evaluated the impact of portal use on communication. Some suggest inpatient portal use may replace and/or facilitate verbal communication between patients, caregivers, and providers.³⁵ In a pediatric study, 51% of parent portal users reported it gave them the information they needed, reducing the amount of questions they had for their healthcare team.³³ Similarly 43% of 14 adult inpatient portal users in another study thought the portal could replace at least some face-to-face communication.³⁷ Some providers indicated portal use enhanced rounding discussion quality.³⁵ Another study suggested that patient-provider communication via electronic messaging may provide benefits for some patients and not others.³⁷

Multiple studies evaluated patient, caregiver, and/or healthcare team perceptions of the impact of inpatient portal use on detection of errors and patient safety.^29,31,33,35 In adult inpatients, 6% agreed portal use could help them find errors.²⁹ In a pediatric study, 8% reported finding at least 1 medication error by using the portal, and 89% thought use reduced errors in their child’s care.³³ One patient in a qualitative study of adult inpatients cited an example of a dosing error discovered by using the portal.³⁷ Healthcare providers in another study also reported that use facilitated patient error identification.³⁵

Included studies evaluated the potential impact of portal use on patient anxiety, confusion, and/or worry, and the work of healthcare teams. In 1 study, nurses voiced concerns about giving information subject to change or that couldn’t always be achieved because of competing hospital priorities, such as discharge timing.²⁵ They also worried about giving medical information that would create cognitive overload for patients and/or require professional interpretation. Although providers in another study perceived little negative impact on their workflow after portal implementation, they worried about the potential of adding other information to the portal.³⁵ For example, they were concerned that the future release of abnormal test results or sensitive data would lead to confusion and more time spent answering patient questions. Physicians also worried that secure messaging could be overused by patients, would be used to inappropriately express acute concerns, or might adversely affect verbal communication. Providers in 2 studies expressed concerns about potential negative implications of portal use on their work before implementation, which were subsequently reduced after portal implementation.^29,38 Conversely, no parent portal users in another study thought portal information was confusing.³³ One parent participant noted portal use may actually decrease anxiety: “Access to their medical information gives patients and their caregivers perspective and insight into their hospital care and empowers them with knowledge about [what is going on], which reduces anxiety.”³⁷

We identified multiple studies evaluating the design, use, and impact of inpatient patient portals for hospitalized patients and caregivers. Based on the information needs identified by patients and healthcare team participants, multiple key content and design recommendations are suggested, including presenting (1) timely, personalized clinical and educational information in lay terms, (2) the care trajectory, including care plan and patient schedule, and (3) a way to recognize and communicate with the inpatient healthcare team. Design challenges still exist, such as translating medical terminology from EHRs into patient-friendly language, proxy access, and portal integration across transitions. Data from identified studies suggest hospitalized patients and caregivers are interested in and willing to use inpatient portals, but there is less information about the use of each functionality. Evidence supporting the role of inpatient portal use in improving patient and/or caregiver engagement, knowledge, communication, and the quality and safety of care is currently limited. Included studies indicate that healthcare team members had concerns about using portals to share clinical information and communicate electronically in the hospital. The extent to which these concerns translate to demonstrable problems remains to be seen.

Early studies focus on patient and caregiver information needs and portal interface design. Although the necessity for certain core functionalities and design requirements are becoming clear,²⁰ best practices regarding the amount and timing of information released (eg, physician notes, lab results), optimal hardware decisions (eg, large-screen displays, hospital-owned tablets, bring-your-own-device model), and details around secure-messaging implementation in the acute hospital setting are still lacking. Future work is needed to understand optimal patient-provider communication architectures that support improved synchronous and asynchronous messaging and privacy-preserving approaches to the design of these systems to handle patient-generated data as it becomes more commonplace. Although patient participants in these studies were generally satisfied using inpatient portals, many indicated the need for even more transparency, such as the release of results in real time and inclusion of physician notes (even if they could not be fully comprehended).³⁷ As the movement of sharing notes with patients in the ambulatory setting grows,³⁹ it will inevitably extend to the inpatient setting.⁴⁰ Further research is needed to understand the impact of increased transparency on health outcomes, patient anxiety, and inpatient healthcare team workload. Although the majority of studies described the design and/or use of custom portal platforms, EHR vendors are now developing inpatient portals that integrate into preexisting systems (eg, MyChart Bedside, Epic Systems). This will increase the likelihood of broad inpatient portal adoption and may facilitate multicenter trials evaluating the impact of their use.

The next steps will need to focus on the evaluation of specific inpatient portal functionalities and the impact of their use on objective process and outcome measures by using rigorous, experimental study designs. Akin to ambulatory portal research, measures of interest will include patient activation,^41,42 patient and/or caregiver satisfaction,⁴³ care processes (eg, length of stay, readmissions), and patient safety (eg, safety perceptions, adverse drug events, hospital-acquired conditions, and diagnostic errors). More than a mechanism for unidirectional sharing information from providers to the patient, inpatient portals will also provide a platform for the reciprocal exchange of information from the patient to the provider through patient-generated data, such as goal setting and feedback. Patients may play a larger role in reporting hospital satisfaction in real time, reconciling medications, contributing to the treatment plan, and identifying medical errors. As portals are integrated across the care continuum,²⁰ our understanding of their impact may become more clear.

In this review, only 5 studies were conducted in the pediatric hospital setting.^24,32-34,38 With hospitalized children experiencing 3 times more harm from medical errors than adults,⁴⁴ engaging parents in inpatient care to improve safety has become a national priority.⁴⁵ Giving patient portals, or “parent portals,” to parents of hospitalized children may provide a unique opportunity to share healthcare information and promote engagement, a direction for future study. There is also a research gap in evaluating adolescent inpatient portal use. Future portals may be designed to incentivize young children to learn about their hospitalization through games linked to health-related education.

Finally, as patients and caregivers begin using inpatient portals, there will almost certainly be consequences for healthcare teams. Understanding and anticipating human and work system factors influencing inpatient portal adoption and use from the perspectives of both patients and healthcare teams are needed.^46,47 Engaging healthcare team members as valuable stakeholders during implementation and measuring the impact of portal use on their workload is necessary, especially as portal use spreads beyond pilot units. The success of inpatient portals is dependent upon both the positive benefits for patients and their acceptance by healthcare teams.⁴⁸

Limitations exist in conducting a systematic literature review.⁴⁹ The conceptual definition of a portal for hospitalized patients and patient/caregiver engagement is evolving; therefore, our definition may not have captured all relevant studies. We intentionally did not include all inpatient technology, as we were interested in a narrow definition of portals designed for inpatients that provided clinical information from the inpatient EHR. Because of rapid technology changes, we also limited our search to studies published within the last 10 years; prior literature has been described elsewhere.¹⁷ We excluded non-English language studies, limiting our ability to capture the full scope of inpatient portal research. These patients already experience healthcare delivery disparities, widened by the inaccessibility of innovative health information technologies.⁵⁰ Future studies would be enhanced with the inclusion of these participants.

Inpatient portal research is in its infancy but growing rapidly. Studies to date are primarily focused on portal design and have small sample sizes. Early findings suggest that patients and caregivers are, in general, enthusiastic about using inpatient portals. Further research is needed, however, to determine the impact of inpatient portal use on patient engagement and hospital-care quality, safety, and cost.

Disclosure

This work was supported by a Department of Pediatrics Research and Development Grant at the University of Wisconsin School of Medicine and Public Health. This publication was also supported by the Clinical and Translational Science Award program through the National Center for Advancing Translational Sciences, grant UL1TR000427. Dr. Hoonakker’s involvement was also partially supported by the National Science Foundation, grant CMMI 1536987. Funding sources had no involvement in study design, analysis, or interpretation of data. The authors have no conflicts of interest to declare.

Engaging patients and their caregivers in care improves health outcomes^1-3 and is endorsed by leading healthcare organizations as essential to improving care quality and safety.^4-6 Patient engagement emphasizes that patients, caregivers, and healthcare providers work together to “promote and support active patient and public involvement in health and healthcare and to strengthen their influence on healthcare decisions.”⁷ Patient portals, web-based personal health records linked to electronic health record (EHR) data, are intended to promote engagement by providing patients and their caregivers with timely electronic access to their healthcare information and supporting communication through secure messaging with their healthcare team.⁸ The use of patient portals has also been suggested as a way for patients and/or caregivers to identify and intercept medical errors, thus having the potential to also improve patient safety.^8,9

As a requirement for meaningful use, access to health information through patient portals in the ambulatory setting has increased dramatically.¹⁰ Studies evaluating the use of these patient portals to promote patient-centered care are growing, but evidence supporting their impact on improved health outcomes is currently insufficient.^11-15 Although research and policy focus on the use of patient portals in the ambulatory setting, recent literature suggests that patient portals may be used to share inpatient clinical information to engage patients and their caregivers during their hospitalization.^16-18 Before the widespread use of patient portals in the inpatient setting is endorsed, systematic research is needed to understand optimal portal design requirements, if and how these portals are used, and whether their use provides value to the hospitalized patient and/or caregiver.⁸

Prior literature summarized early findings regarding the use of various technologies designed to engage hospitalized patients.^17,19,20 In this systematic review, we describe the emerging literature examining the design, use, and impact of inpatient portals for hospitalized patients and/or caregivers over the last 10 years. Inpatient portals are defined here as electronic patient portals tethered to EHRs that are designed to provide hospitalized patients and/or caregivers secure access to personalized, inpatient clinical information with the intent of engaging them in their hospital care. After analyzing and summarizing these data, we then identify knowledge gaps and potential future research directions.

Search Strategy, Study Selection, and Analysis

This systematic review included available, peer-reviewed, and grey literature published from January 1, 2006, to August 8, 2017, in PubMed, Web of Science (including the Institute of Electrical and Electronics Engineers Xplore), Cochrane, CINAHLPlus, and Scopus databases. Terms and phrases, including those found in the Medical Subject Heading (MeSH) index, were used to identify studies evaluating (1) patient portals (“health record, personal [MeSH],” “personal health record,” “patient portal,” “inpatient portal,” “ipad,” “tablet,” or “bedside information technology”), (2) engagement (“engagement,” “empowerment,” “participation,” “activation,” or “self-efficacy”), and (3) in the hospital (“inpatient [MeSH],” “hospital [MeSH],” “hospitalized patient [MeSH],” or “unit”). MeSH terms were used when applicable. Based on previous literature, free-text terms were also used when subject headings were not applied consistently, such as with terms related to engagement.^17,21 Studies were excluded if they were not written in English, if they evaluated portals exclusively in the emergency department or ambulatory setting, and/or if they described future study protocols. Studies describing general inpatient technology or evaluating portals used in the hospital but not tethered to inpatient EHR clinical data were also excluded.

By using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines,²² 2 researchers (M.K. and P.H.) completed the literature search and potential article screening. Results were aggregated and studies were screened and excluded from full review based on title and abstract information. Additional studies were included after reference list review. During a full review of included studies, 2 researchers independently extracted data, including the study objective, design, setting, sample, data collection instruments, outcomes, and a description of results. Guided by our study objective, findings were reconciled by consensus and analyzed and described according to the following 3 themes: (1) inpatient portal design, (2) inpatient portal use and usability, and (3) the impact of inpatient portal use on patient or caregiver and healthcare team outcomes as defined by retrieved studies.

The quality of studies was evaluated by the same 2 researchers independently by using the Downs and Black checklist for assessing the methodological quality of randomized and nonrandomized healthcare interventions.²³ Qualitative studies describing the development of portal prototypes and/or portal redesign efforts were excluded from these analyses. Discrepancies were resolved by consensus.Because of the wide variability in study designs, populations, and outcomes, a meta-analysis of pooled data was not performed.

Of the 731 studies identified through database searching and reference review, 36 were included for full-text review and 17 met inclusion criteria (Figure; Table 1). Studies excluded after full-text review described portal use outside of the inpatient setting, portals not linked to hospital EHR clinical data, portals not designed for inpatients, and/or inpatient technology in general. The inpatient portal platforms, hardware used, and functionalities varied within included studies (Table 2). The majority of studies used custom, web-based inpatient portal applications on tablet computers. Most provided information about the patients’ hospital medications, healthcare team, and education about their condition and/or a medical glossary. Many included the patient’s schedule, hospital problem list, discharge information, and a way to keep notes.

There has been a recent increase in inpatient portal study publication, with 9 studies published during or after 2016. Five were conducted in the pediatric setting and all but 1³⁰ with English-speaking participants. Twelve studies were qualitative, many of which were conducted in multiple phases by using semi-structured interviews and/or focus groups to develop or redesign inpatient portals. Of the remaining studies, 3 used a cross-sectional design, 1 used a before and after design without a control group, and 1 was a nonrandomized trial. Studies were rated as having medium-to-high risk of bias because of design flaws (Table 1 in supplementary Appendix). Because many studies were small pilot studies and all were single-centered studies, the generalizability of findings to different healthcare settings or patient populations is limited.

Inpatient Portal Design

Most included studies evaluated patient and/or caregiver information needs to design and/or enhance inpatient portals.^16,24-37 In 1 study, patients described an overall lack of information provided in the hospital and insufficient time to understand and remember information, which, when shared, was often presented by using medical terminology.³⁰ They wanted information to help them understand their daily hospital routine, confirm and compare medications and test results, learn about care, and prepare for discharge. Participants in multiple studies echoed these results, indicating the need for a schedule of upcoming clinical events (eg, medication administration, procedures, imaging), secure and timely clinical information (eg, list of diagnoses and medications, test results), personalized education, a medical glossary, discharge information, and a way to take notes and recognize and communicate with providers.

Patients also requested further information transparency,^34,37 including physicians’ notes, radiology results, operative reports, and billing information, along with general hospital information,¹⁶ meal ordering,³³ and video conferencing.²⁷ ln designing and refining an inpatient medication-tracking tool, participants identified the need for information about medication dosage, frequency, timing, administration method, criticality, alternative medications or forms, and education.^26,36 Patients and/or caregivers also indicated interest in communicating with inpatient providers by using the portal.^{16,27,28,30-37} In 1 study, patients highlighted the need to be involved in care plan development,²⁷ which led to portal refinement to allow for patient-generated data entry, including care goals and a way to communicate real-time concerns and feedback.²⁸

Studies also considered healthcare team perspectives to inform portal design.^{25,26,28,30,35,37} Although information needs usually overlapped, patient and healthcare team priorities differed in some areas. Although patients wanted to “know what was going to happen to them,” nurses in 1 study were more concerned about providing information to protect patients, such as safety and precaution materials.²⁵ Similarly, when designing a medication-tracking tool, patients sought information that helped them understand what to expect, while pharmacists focused on medication safety and providing information that fit their workflow (eg, abstract medication schedules).³⁶

Identified study data raised important portal interface design considerations. Results suggested clinical data should be presented by using simple displays,²⁸ accommodating real-time information. Participants recommended links^16,29 to personalized patient-friendly³⁷ education accessed with minimal steps.²⁶ Interfaces may be personalized for target users, such as patient or proxy and younger or older individuals. For example, older patients reported less familiarity with touch screens, internal keyboards, and handwriting recognition, favoring voice recognition for recording notes.²⁷ This raised questions about how portals can be designed to best maintain patient privacy.²⁵ Interface design, such as navigation, also relied heavily on hardware choice, such as tablet versus mobile phone.²⁸

Inpatient Portal Use and Usability

Most patient and/or caregiver participants in included studies were interested in using an inpatient portal, used it when offered, found it easy to use, useful, and/or were satisfied with it.^16,18,24-37 Most used and liked functionalities that provided healthcare team, test result, and medication information.^22,33,37 In the 1 identified controlled trial,¹⁸ researchers evaluated an inpatient portal given to adult inpatients that included a problem list, schedule, medication list, and healthcare team information. Of the intervention unit patients, 80% used the portal, 76% indicated it was easy to use, and 71% thought it provided useful information. When a portal was given to 239 adult patients and caregivers in another study, 66% sent a total of 291 messages to the healthcare team.³¹ Of these, 153 provided feedback, 76 expressed preferences, and 16 communicated concerns. In a pediatric study, an inpatient portal was given to 296 parents who sent a total of 36 messages and 176 requests.³³ Messages sent included information regarding caregiver needs, questions, updates, and/or positive endorsements of the healthcare team and/or care.

Impact of Inpatient Portal Use

Multiple studies evaluated the impact of inpatient portal use on patient and/or caregiver engagement, empowerment, activation, and/or knowledge, which had mixed results. Most adult patients interviewed in one study had positive experiences using a portal to answer their questions between physician visits and learn about, remember, and engage in care.³⁷ A majority of adult inpatient portal users in another study agreed that portal use helped them feel in control and understand their condition; however, they did not report having improved discharge timing knowledge.²⁹ In a pediatric study, most parent inpatient portal users agreed use improved their ability to monitor, understand, and make decisions about their child’s care.³³ In the controlled trial,¹⁸ a higher percentage of portal intervention patients could identify their physician or role; however, patient activation was not statistically different between intervention and control patients.

Results from included studies also evaluated the impact of portal use on communication. Some suggest inpatient portal use may replace and/or facilitate verbal communication between patients, caregivers, and providers.³⁵ In a pediatric study, 51% of parent portal users reported it gave them the information they needed, reducing the amount of questions they had for their healthcare team.³³ Similarly 43% of 14 adult inpatient portal users in another study thought the portal could replace at least some face-to-face communication.³⁷ Some providers indicated portal use enhanced rounding discussion quality.³⁵ Another study suggested that patient-provider communication via electronic messaging may provide benefits for some patients and not others.³⁷

Multiple studies evaluated patient, caregiver, and/or healthcare team perceptions of the impact of inpatient portal use on detection of errors and patient safety.^29,31,33,35 In adult inpatients, 6% agreed portal use could help them find errors.²⁹ In a pediatric study, 8% reported finding at least 1 medication error by using the portal, and 89% thought use reduced errors in their child’s care.³³ One patient in a qualitative study of adult inpatients cited an example of a dosing error discovered by using the portal.³⁷ Healthcare providers in another study also reported that use facilitated patient error identification.³⁵

Included studies evaluated the potential impact of portal use on patient anxiety, confusion, and/or worry, and the work of healthcare teams. In 1 study, nurses voiced concerns about giving information subject to change or that couldn’t always be achieved because of competing hospital priorities, such as discharge timing.²⁵ They also worried about giving medical information that would create cognitive overload for patients and/or require professional interpretation. Although providers in another study perceived little negative impact on their workflow after portal implementation, they worried about the potential of adding other information to the portal.³⁵ For example, they were concerned that the future release of abnormal test results or sensitive data would lead to confusion and more time spent answering patient questions. Physicians also worried that secure messaging could be overused by patients, would be used to inappropriately express acute concerns, or might adversely affect verbal communication. Providers in 2 studies expressed concerns about potential negative implications of portal use on their work before implementation, which were subsequently reduced after portal implementation.^29,38 Conversely, no parent portal users in another study thought portal information was confusing.³³ One parent participant noted portal use may actually decrease anxiety: “Access to their medical information gives patients and their caregivers perspective and insight into their hospital care and empowers them with knowledge about [what is going on], which reduces anxiety.”³⁷

We identified multiple studies evaluating the design, use, and impact of inpatient patient portals for hospitalized patients and caregivers. Based on the information needs identified by patients and healthcare team participants, multiple key content and design recommendations are suggested, including presenting (1) timely, personalized clinical and educational information in lay terms, (2) the care trajectory, including care plan and patient schedule, and (3) a way to recognize and communicate with the inpatient healthcare team. Design challenges still exist, such as translating medical terminology from EHRs into patient-friendly language, proxy access, and portal integration across transitions. Data from identified studies suggest hospitalized patients and caregivers are interested in and willing to use inpatient portals, but there is less information about the use of each functionality. Evidence supporting the role of inpatient portal use in improving patient and/or caregiver engagement, knowledge, communication, and the quality and safety of care is currently limited. Included studies indicate that healthcare team members had concerns about using portals to share clinical information and communicate electronically in the hospital. The extent to which these concerns translate to demonstrable problems remains to be seen.

Early studies focus on patient and caregiver information needs and portal interface design. Although the necessity for certain core functionalities and design requirements are becoming clear,²⁰ best practices regarding the amount and timing of information released (eg, physician notes, lab results), optimal hardware decisions (eg, large-screen displays, hospital-owned tablets, bring-your-own-device model), and details around secure-messaging implementation in the acute hospital setting are still lacking. Future work is needed to understand optimal patient-provider communication architectures that support improved synchronous and asynchronous messaging and privacy-preserving approaches to the design of these systems to handle patient-generated data as it becomes more commonplace. Although patient participants in these studies were generally satisfied using inpatient portals, many indicated the need for even more transparency, such as the release of results in real time and inclusion of physician notes (even if they could not be fully comprehended).³⁷ As the movement of sharing notes with patients in the ambulatory setting grows,³⁹ it will inevitably extend to the inpatient setting.⁴⁰ Further research is needed to understand the impact of increased transparency on health outcomes, patient anxiety, and inpatient healthcare team workload. Although the majority of studies described the design and/or use of custom portal platforms, EHR vendors are now developing inpatient portals that integrate into preexisting systems (eg, MyChart Bedside, Epic Systems). This will increase the likelihood of broad inpatient portal adoption and may facilitate multicenter trials evaluating the impact of their use.

The next steps will need to focus on the evaluation of specific inpatient portal functionalities and the impact of their use on objective process and outcome measures by using rigorous, experimental study designs. Akin to ambulatory portal research, measures of interest will include patient activation,^41,42 patient and/or caregiver satisfaction,⁴³ care processes (eg, length of stay, readmissions), and patient safety (eg, safety perceptions, adverse drug events, hospital-acquired conditions, and diagnostic errors). More than a mechanism for unidirectional sharing information from providers to the patient, inpatient portals will also provide a platform for the reciprocal exchange of information from the patient to the provider through patient-generated data, such as goal setting and feedback. Patients may play a larger role in reporting hospital satisfaction in real time, reconciling medications, contributing to the treatment plan, and identifying medical errors. As portals are integrated across the care continuum,²⁰ our understanding of their impact may become more clear.

In this review, only 5 studies were conducted in the pediatric hospital setting.^24,32-34,38 With hospitalized children experiencing 3 times more harm from medical errors than adults,⁴⁴ engaging parents in inpatient care to improve safety has become a national priority.⁴⁵ Giving patient portals, or “parent portals,” to parents of hospitalized children may provide a unique opportunity to share healthcare information and promote engagement, a direction for future study. There is also a research gap in evaluating adolescent inpatient portal use. Future portals may be designed to incentivize young children to learn about their hospitalization through games linked to health-related education.

Finally, as patients and caregivers begin using inpatient portals, there will almost certainly be consequences for healthcare teams. Understanding and anticipating human and work system factors influencing inpatient portal adoption and use from the perspectives of both patients and healthcare teams are needed.^46,47 Engaging healthcare team members as valuable stakeholders during implementation and measuring the impact of portal use on their workload is necessary, especially as portal use spreads beyond pilot units. The success of inpatient portals is dependent upon both the positive benefits for patients and their acceptance by healthcare teams.⁴⁸

Limitations exist in conducting a systematic literature review.⁴⁹ The conceptual definition of a portal for hospitalized patients and patient/caregiver engagement is evolving; therefore, our definition may not have captured all relevant studies. We intentionally did not include all inpatient technology, as we were interested in a narrow definition of portals designed for inpatients that provided clinical information from the inpatient EHR. Because of rapid technology changes, we also limited our search to studies published within the last 10 years; prior literature has been described elsewhere.¹⁷ We excluded non-English language studies, limiting our ability to capture the full scope of inpatient portal research. These patients already experience healthcare delivery disparities, widened by the inaccessibility of innovative health information technologies.⁵⁰ Future studies would be enhanced with the inclusion of these participants.

Inpatient portal research is in its infancy but growing rapidly. Studies to date are primarily focused on portal design and have small sample sizes. Early findings suggest that patients and caregivers are, in general, enthusiastic about using inpatient portals. Further research is needed, however, to determine the impact of inpatient portal use on patient engagement and hospital-care quality, safety, and cost.

Disclosure

This work was supported by a Department of Pediatrics Research and Development Grant at the University of Wisconsin School of Medicine and Public Health. This publication was also supported by the Clinical and Translational Science Award program through the National Center for Advancing Translational Sciences, grant UL1TR000427. Dr. Hoonakker’s involvement was also partially supported by the National Science Foundation, grant CMMI 1536987. Funding sources had no involvement in study design, analysis, or interpretation of data. The authors have no conflicts of interest to declare.

Engaging patients and their caregivers in care improves health outcomes^1-3 and is endorsed by leading healthcare organizations as essential to improving care quality and safety.^4-6 Patient engagement emphasizes that patients, caregivers, and healthcare providers work together to “promote and support active patient and public involvement in health and healthcare and to strengthen their influence on healthcare decisions.”⁷ Patient portals, web-based personal health records linked to electronic health record (EHR) data, are intended to promote engagement by providing patients and their caregivers with timely electronic access to their healthcare information and supporting communication through secure messaging with their healthcare team.⁸ The use of patient portals has also been suggested as a way for patients and/or caregivers to identify and intercept medical errors, thus having the potential to also improve patient safety.^8,9

As a requirement for meaningful use, access to health information through patient portals in the ambulatory setting has increased dramatically.¹⁰ Studies evaluating the use of these patient portals to promote patient-centered care are growing, but evidence supporting their impact on improved health outcomes is currently insufficient.^11-15 Although research and policy focus on the use of patient portals in the ambulatory setting, recent literature suggests that patient portals may be used to share inpatient clinical information to engage patients and their caregivers during their hospitalization.^16-18 Before the widespread use of patient portals in the inpatient setting is endorsed, systematic research is needed to understand optimal portal design requirements, if and how these portals are used, and whether their use provides value to the hospitalized patient and/or caregiver.⁸

Prior literature summarized early findings regarding the use of various technologies designed to engage hospitalized patients.^17,19,20 In this systematic review, we describe the emerging literature examining the design, use, and impact of inpatient portals for hospitalized patients and/or caregivers over the last 10 years. Inpatient portals are defined here as electronic patient portals tethered to EHRs that are designed to provide hospitalized patients and/or caregivers secure access to personalized, inpatient clinical information with the intent of engaging them in their hospital care. After analyzing and summarizing these data, we then identify knowledge gaps and potential future research directions.

Search Strategy, Study Selection, and Analysis

This systematic review included available, peer-reviewed, and grey literature published from January 1, 2006, to August 8, 2017, in PubMed, Web of Science (including the Institute of Electrical and Electronics Engineers Xplore), Cochrane, CINAHLPlus, and Scopus databases. Terms and phrases, including those found in the Medical Subject Heading (MeSH) index, were used to identify studies evaluating (1) patient portals (“health record, personal [MeSH],” “personal health record,” “patient portal,” “inpatient portal,” “ipad,” “tablet,” or “bedside information technology”), (2) engagement (“engagement,” “empowerment,” “participation,” “activation,” or “self-efficacy”), and (3) in the hospital (“inpatient [MeSH],” “hospital [MeSH],” “hospitalized patient [MeSH],” or “unit”). MeSH terms were used when applicable. Based on previous literature, free-text terms were also used when subject headings were not applied consistently, such as with terms related to engagement.^17,21 Studies were excluded if they were not written in English, if they evaluated portals exclusively in the emergency department or ambulatory setting, and/or if they described future study protocols. Studies describing general inpatient technology or evaluating portals used in the hospital but not tethered to inpatient EHR clinical data were also excluded.

By using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines,²² 2 researchers (M.K. and P.H.) completed the literature search and potential article screening. Results were aggregated and studies were screened and excluded from full review based on title and abstract information. Additional studies were included after reference list review. During a full review of included studies, 2 researchers independently extracted data, including the study objective, design, setting, sample, data collection instruments, outcomes, and a description of results. Guided by our study objective, findings were reconciled by consensus and analyzed and described according to the following 3 themes: (1) inpatient portal design, (2) inpatient portal use and usability, and (3) the impact of inpatient portal use on patient or caregiver and healthcare team outcomes as defined by retrieved studies.

The quality of studies was evaluated by the same 2 researchers independently by using the Downs and Black checklist for assessing the methodological quality of randomized and nonrandomized healthcare interventions.²³ Qualitative studies describing the development of portal prototypes and/or portal redesign efforts were excluded from these analyses. Discrepancies were resolved by consensus.Because of the wide variability in study designs, populations, and outcomes, a meta-analysis of pooled data was not performed.

Of the 731 studies identified through database searching and reference review, 36 were included for full-text review and 17 met inclusion criteria (Figure; Table 1). Studies excluded after full-text review described portal use outside of the inpatient setting, portals not linked to hospital EHR clinical data, portals not designed for inpatients, and/or inpatient technology in general. The inpatient portal platforms, hardware used, and functionalities varied within included studies (Table 2). The majority of studies used custom, web-based inpatient portal applications on tablet computers. Most provided information about the patients’ hospital medications, healthcare team, and education about their condition and/or a medical glossary. Many included the patient’s schedule, hospital problem list, discharge information, and a way to keep notes.

There has been a recent increase in inpatient portal study publication, with 9 studies published during or after 2016. Five were conducted in the pediatric setting and all but 1³⁰ with English-speaking participants. Twelve studies were qualitative, many of which were conducted in multiple phases by using semi-structured interviews and/or focus groups to develop or redesign inpatient portals. Of the remaining studies, 3 used a cross-sectional design, 1 used a before and after design without a control group, and 1 was a nonrandomized trial. Studies were rated as having medium-to-high risk of bias because of design flaws (Table 1 in supplementary Appendix). Because many studies were small pilot studies and all were single-centered studies, the generalizability of findings to different healthcare settings or patient populations is limited.

Inpatient Portal Design

Most included studies evaluated patient and/or caregiver information needs to design and/or enhance inpatient portals.^16,24-37 In 1 study, patients described an overall lack of information provided in the hospital and insufficient time to understand and remember information, which, when shared, was often presented by using medical terminology.³⁰ They wanted information to help them understand their daily hospital routine, confirm and compare medications and test results, learn about care, and prepare for discharge. Participants in multiple studies echoed these results, indicating the need for a schedule of upcoming clinical events (eg, medication administration, procedures, imaging), secure and timely clinical information (eg, list of diagnoses and medications, test results), personalized education, a medical glossary, discharge information, and a way to take notes and recognize and communicate with providers.

Patients also requested further information transparency,^34,37 including physicians’ notes, radiology results, operative reports, and billing information, along with general hospital information,¹⁶ meal ordering,³³ and video conferencing.²⁷ ln designing and refining an inpatient medication-tracking tool, participants identified the need for information about medication dosage, frequency, timing, administration method, criticality, alternative medications or forms, and education.^26,36 Patients and/or caregivers also indicated interest in communicating with inpatient providers by using the portal.^{16,27,28,30-37} In 1 study, patients highlighted the need to be involved in care plan development,²⁷ which led to portal refinement to allow for patient-generated data entry, including care goals and a way to communicate real-time concerns and feedback.²⁸

Studies also considered healthcare team perspectives to inform portal design.^{25,26,28,30,35,37} Although information needs usually overlapped, patient and healthcare team priorities differed in some areas. Although patients wanted to “know what was going to happen to them,” nurses in 1 study were more concerned about providing information to protect patients, such as safety and precaution materials.²⁵ Similarly, when designing a medication-tracking tool, patients sought information that helped them understand what to expect, while pharmacists focused on medication safety and providing information that fit their workflow (eg, abstract medication schedules).³⁶

Identified study data raised important portal interface design considerations. Results suggested clinical data should be presented by using simple displays,²⁸ accommodating real-time information. Participants recommended links^16,29 to personalized patient-friendly³⁷ education accessed with minimal steps.²⁶ Interfaces may be personalized for target users, such as patient or proxy and younger or older individuals. For example, older patients reported less familiarity with touch screens, internal keyboards, and handwriting recognition, favoring voice recognition for recording notes.²⁷ This raised questions about how portals can be designed to best maintain patient privacy.²⁵ Interface design, such as navigation, also relied heavily on hardware choice, such as tablet versus mobile phone.²⁸

Inpatient Portal Use and Usability

Most patient and/or caregiver participants in included studies were interested in using an inpatient portal, used it when offered, found it easy to use, useful, and/or were satisfied with it.^16,18,24-37 Most used and liked functionalities that provided healthcare team, test result, and medication information.^22,33,37 In the 1 identified controlled trial,¹⁸ researchers evaluated an inpatient portal given to adult inpatients that included a problem list, schedule, medication list, and healthcare team information. Of the intervention unit patients, 80% used the portal, 76% indicated it was easy to use, and 71% thought it provided useful information. When a portal was given to 239 adult patients and caregivers in another study, 66% sent a total of 291 messages to the healthcare team.³¹ Of these, 153 provided feedback, 76 expressed preferences, and 16 communicated concerns. In a pediatric study, an inpatient portal was given to 296 parents who sent a total of 36 messages and 176 requests.³³ Messages sent included information regarding caregiver needs, questions, updates, and/or positive endorsements of the healthcare team and/or care.

Impact of Inpatient Portal Use

Multiple studies evaluated the impact of inpatient portal use on patient and/or caregiver engagement, empowerment, activation, and/or knowledge, which had mixed results. Most adult patients interviewed in one study had positive experiences using a portal to answer their questions between physician visits and learn about, remember, and engage in care.³⁷ A majority of adult inpatient portal users in another study agreed that portal use helped them feel in control and understand their condition; however, they did not report having improved discharge timing knowledge.²⁹ In a pediatric study, most parent inpatient portal users agreed use improved their ability to monitor, understand, and make decisions about their child’s care.³³ In the controlled trial,¹⁸ a higher percentage of portal intervention patients could identify their physician or role; however, patient activation was not statistically different between intervention and control patients.

Results from included studies also evaluated the impact of portal use on communication. Some suggest inpatient portal use may replace and/or facilitate verbal communication between patients, caregivers, and providers.³⁵ In a pediatric study, 51% of parent portal users reported it gave them the information they needed, reducing the amount of questions they had for their healthcare team.³³ Similarly 43% of 14 adult inpatient portal users in another study thought the portal could replace at least some face-to-face communication.³⁷ Some providers indicated portal use enhanced rounding discussion quality.³⁵ Another study suggested that patient-provider communication via electronic messaging may provide benefits for some patients and not others.³⁷

Multiple studies evaluated patient, caregiver, and/or healthcare team perceptions of the impact of inpatient portal use on detection of errors and patient safety.^29,31,33,35 In adult inpatients, 6% agreed portal use could help them find errors.²⁹ In a pediatric study, 8% reported finding at least 1 medication error by using the portal, and 89% thought use reduced errors in their child’s care.³³ One patient in a qualitative study of adult inpatients cited an example of a dosing error discovered by using the portal.³⁷ Healthcare providers in another study also reported that use facilitated patient error identification.³⁵

Included studies evaluated the potential impact of portal use on patient anxiety, confusion, and/or worry, and the work of healthcare teams. In 1 study, nurses voiced concerns about giving information subject to change or that couldn’t always be achieved because of competing hospital priorities, such as discharge timing.²⁵ They also worried about giving medical information that would create cognitive overload for patients and/or require professional interpretation. Although providers in another study perceived little negative impact on their workflow after portal implementation, they worried about the potential of adding other information to the portal.³⁵ For example, they were concerned that the future release of abnormal test results or sensitive data would lead to confusion and more time spent answering patient questions. Physicians also worried that secure messaging could be overused by patients, would be used to inappropriately express acute concerns, or might adversely affect verbal communication. Providers in 2 studies expressed concerns about potential negative implications of portal use on their work before implementation, which were subsequently reduced after portal implementation.^29,38 Conversely, no parent portal users in another study thought portal information was confusing.³³ One parent participant noted portal use may actually decrease anxiety: “Access to their medical information gives patients and their caregivers perspective and insight into their hospital care and empowers them with knowledge about [what is going on], which reduces anxiety.”³⁷

We identified multiple studies evaluating the design, use, and impact of inpatient patient portals for hospitalized patients and caregivers. Based on the information needs identified by patients and healthcare team participants, multiple key content and design recommendations are suggested, including presenting (1) timely, personalized clinical and educational information in lay terms, (2) the care trajectory, including care plan and patient schedule, and (3) a way to recognize and communicate with the inpatient healthcare team. Design challenges still exist, such as translating medical terminology from EHRs into patient-friendly language, proxy access, and portal integration across transitions. Data from identified studies suggest hospitalized patients and caregivers are interested in and willing to use inpatient portals, but there is less information about the use of each functionality. Evidence supporting the role of inpatient portal use in improving patient and/or caregiver engagement, knowledge, communication, and the quality and safety of care is currently limited. Included studies indicate that healthcare team members had concerns about using portals to share clinical information and communicate electronically in the hospital. The extent to which these concerns translate to demonstrable problems remains to be seen.

Early studies focus on patient and caregiver information needs and portal interface design. Although the necessity for certain core functionalities and design requirements are becoming clear,²⁰ best practices regarding the amount and timing of information released (eg, physician notes, lab results), optimal hardware decisions (eg, large-screen displays, hospital-owned tablets, bring-your-own-device model), and details around secure-messaging implementation in the acute hospital setting are still lacking. Future work is needed to understand optimal patient-provider communication architectures that support improved synchronous and asynchronous messaging and privacy-preserving approaches to the design of these systems to handle patient-generated data as it becomes more commonplace. Although patient participants in these studies were generally satisfied using inpatient portals, many indicated the need for even more transparency, such as the release of results in real time and inclusion of physician notes (even if they could not be fully comprehended).³⁷ As the movement of sharing notes with patients in the ambulatory setting grows,³⁹ it will inevitably extend to the inpatient setting.⁴⁰ Further research is needed to understand the impact of increased transparency on health outcomes, patient anxiety, and inpatient healthcare team workload. Although the majority of studies described the design and/or use of custom portal platforms, EHR vendors are now developing inpatient portals that integrate into preexisting systems (eg, MyChart Bedside, Epic Systems). This will increase the likelihood of broad inpatient portal adoption and may facilitate multicenter trials evaluating the impact of their use.

The next steps will need to focus on the evaluation of specific inpatient portal functionalities and the impact of their use on objective process and outcome measures by using rigorous, experimental study designs. Akin to ambulatory portal research, measures of interest will include patient activation,^41,42 patient and/or caregiver satisfaction,⁴³ care processes (eg, length of stay, readmissions), and patient safety (eg, safety perceptions, adverse drug events, hospital-acquired conditions, and diagnostic errors). More than a mechanism for unidirectional sharing information from providers to the patient, inpatient portals will also provide a platform for the reciprocal exchange of information from the patient to the provider through patient-generated data, such as goal setting and feedback. Patients may play a larger role in reporting hospital satisfaction in real time, reconciling medications, contributing to the treatment plan, and identifying medical errors. As portals are integrated across the care continuum,²⁰ our understanding of their impact may become more clear.

In this review, only 5 studies were conducted in the pediatric hospital setting.^24,32-34,38 With hospitalized children experiencing 3 times more harm from medical errors than adults,⁴⁴ engaging parents in inpatient care to improve safety has become a national priority.⁴⁵ Giving patient portals, or “parent portals,” to parents of hospitalized children may provide a unique opportunity to share healthcare information and promote engagement, a direction for future study. There is also a research gap in evaluating adolescent inpatient portal use. Future portals may be designed to incentivize young children to learn about their hospitalization through games linked to health-related education.

Finally, as patients and caregivers begin using inpatient portals, there will almost certainly be consequences for healthcare teams. Understanding and anticipating human and work system factors influencing inpatient portal adoption and use from the perspectives of both patients and healthcare teams are needed.^46,47 Engaging healthcare team members as valuable stakeholders during implementation and measuring the impact of portal use on their workload is necessary, especially as portal use spreads beyond pilot units. The success of inpatient portals is dependent upon both the positive benefits for patients and their acceptance by healthcare teams.⁴⁸

Limitations exist in conducting a systematic literature review.⁴⁹ The conceptual definition of a portal for hospitalized patients and patient/caregiver engagement is evolving; therefore, our definition may not have captured all relevant studies. We intentionally did not include all inpatient technology, as we were interested in a narrow definition of portals designed for inpatients that provided clinical information from the inpatient EHR. Because of rapid technology changes, we also limited our search to studies published within the last 10 years; prior literature has been described elsewhere.¹⁷ We excluded non-English language studies, limiting our ability to capture the full scope of inpatient portal research. These patients already experience healthcare delivery disparities, widened by the inaccessibility of innovative health information technologies.⁵⁰ Future studies would be enhanced with the inclusion of these participants.

Inpatient portal research is in its infancy but growing rapidly. Studies to date are primarily focused on portal design and have small sample sizes. Early findings suggest that patients and caregivers are, in general, enthusiastic about using inpatient portals. Further research is needed, however, to determine the impact of inpatient portal use on patient engagement and hospital-care quality, safety, and cost.

Disclosure

This work was supported by a Department of Pediatrics Research and Development Grant at the University of Wisconsin School of Medicine and Public Health. This publication was also supported by the Clinical and Translational Science Award program through the National Center for Advancing Translational Sciences, grant UL1TR000427. Dr. Hoonakker’s involvement was also partially supported by the National Science Foundation, grant CMMI 1536987. Funding sources had no involvement in study design, analysis, or interpretation of data. The authors have no conflicts of interest to declare.

Hospitalists face complex questions about how to evaluate and treat the large number of individuals who are admitted on long-term opioid therapy (LTOT, defined as lasting 3 months or longer) for chronic noncancer pain. A recent study at one Veterans Affairs hospital, found 26% of medical inpatients were on LTOT.¹ Over the last 2 decades, use of LTOT has risen substantially in the United States, including among middle-aged and older adults.² Concurrently, inpatient hospitalizations related to the overuse of prescription opioids, including overdose, dependence, abuse, and adverse drug events, have increased by 153%.³ Individuals on LTOT can also be hospitalized for exacerbations of the opioid-treated chronic pain condition or unrelated conditions. In addition to affecting rates of hospitalization, use of LTOT is associated with higher rates of in-hospital adverse events, longer hospital stays, and higher readmission rates.^1,4,5

Physicians find managing chronic pain to be stressful, are often concerned about misuse and addiction, and believe their training in opioid prescribing is inadequate.⁶ Hospitalists report confidence in assessing and prescribing opioids for acute pain but limited success and satisfaction with treating exacerbations of chronic pain.⁷ Although half of all hospitalized patients receive opioids,⁵ little information is available to guide the care of hospitalized medical patients on LTOT for chronic noncancer pain.^8,9

Our multispecialty team sought to synthesize guideline recommendations and primary literature relevant to the assessment of medical inpatients on LTOT to assist practitioners balance effective pain treatment and opioid risk reduction. This article addresses obtaining a comprehensive pain history, identifying misuse and opioid use disorders, assessing the risk of overdose and adverse drug events, gauging the risk of withdrawal, and based on such findings, appraise indications for opioid therapy. Other authors have recently published narrative reviews on the management of acute pain in hospitalized patients with opioid dependence and the inpatient management of opioid use disorder.^10,11

To identify primary literature, we searched PubMed, EMBASE, The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Economic Evaluations Database, key meeting abstracts, and hand searches. To identify guidelines, we searched PubMed, National Guidelines Clearinghouse, specialty societies’ websites, the Centers for Disease Control and Prevention (CDC), the United Kingdom National Institute for Health and Care Excellence, the Canadian Medical Association, and the Australian Government National Health and Medical Research Council. Search terms related to opioids and chronic pain, which was last updated in October 2016.¹²

We selected English-language documents on opioids and chronic pain among adults, excluding pain in the setting of procedures, labor and delivery, life-limiting illness, or specific conditions. For primary literature, we considered intervention studies of any design that addressed pain management among hospitalized medical patients. We included guidelines and specialty society position statements published after January 1, 2009, that addressed pain in the hospital setting, acute pain in any setting, or chronic pain in the outpatient setting if published by a national body. Due to the paucity of documents specific to inpatient care, we used a narrative review format to synthesize information. Dual reviewers extracted guideline recommendations potentially relevant to medical inpatients on LTOT. We also summarize relevant assessment instruments, emphasizing very brief screening instruments, which may be more likely to be used by busy hospitalists.

Obtaining a Comprehensive Pain History

Hospitalists newly evaluating patients on LTOT often face a dual challenge: deciding if the patient has an immediate indication for additional opioids and if the current long-term opioid regimen should be altered or discontinued. In general, opioids are an accepted short-term treatment for moderate to severe acute pain but their role in chronic noncancer pain is controversial. Newly released guidelines by the CDC recommend initiating LTOT as a last resort, and the Departments of Veterans Affairs and Defense guidelines recommend against initiation of LTOT.^22,23

A key first step, therefore, is distinguishing between acute and chronic pain. Among patients on LTOT, pain can represent a new acute pain condition, an exacerbation of chronic pain, opioid-induced hyperalgesia, or opioid withdrawal. Acute pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in relation to such damage.²⁶ In contrast, chronic pain is a complex response that may not be related to actual or ongoing tissue damage, and is influenced by physiological, contextual, and psychological factors. Two acute pain guidelines and 1 chronic pain guideline recommend distinguishing acute and chronic pain,^9,16,21 3 chronic pain guidelines reinforce the importance of obtaining a pain history (including timing, intensity, frequency, onset, etc),^20,22,23 and 6 guidelines recommend ascertaining a history of prior pain-related treatments.^{9,13,14,16,20,22} Inquiring how the current pain compares with symptoms “on a good day,” what activities the patient can usually perform, and what the patient does outside the hospital to cope with pain can serve as entry into this conversation.

Identifying Misuse and Opioid Use Disorders

Nonmedical use of prescription opioids and opioid use disorders have more than doubled over the last decade.³⁵ Five guidelines, including 3 specific guidelines for acute pain or the hospital setting, recommend screening for opioid misuse.^{13,14,16,19,23} Many states mandate practitioners assess patients for substance use disorders before prescribing controlled substances.³⁶ Instruments to identify aberrant and risky use include the Current Opioid Misuse Measure,³⁷ Prescription Drug Use Questionnaire,³⁸ Addiction Behaviors Checklist,³⁹ Screening Tool for Abuse,⁴⁰ and the Self-Administered Single-Item Screening Question (Table 3).⁴¹ However, the evidence for these and other tools is limited and absent for the inpatient setting.^21,42

In addition to obtaining a history from the patient, 4 guidelines specific to hospital settings/acute pain and 4 chronic pain guidelines recommend practitioners access prescription drug monitoring programs (PDMPs).^{13-16,19,21-24} PDMPs exist in all states except Missouri, and about half of states mandate practitioners check the PDMP database in certain circumstances.³⁶ Studies examining the effects of PDMPs on prescribing are limited, but checking these databases can uncover concerning patterns including overlapping prescriptions or multiple prescribers.⁴³ PDMPs can also confirm reported medication doses, for which patient report may be less reliable.

Two hospital/acute pain guidelines and 5 chronic pain guidelines also recommend urine drug testing, although differing on when and whom to test, with some favoring universal screening.^11,20,23 Screening hospitalized patients may reveal substances not reported by patients, but medications administered in emergency departments can confound results. Furthermore, the commonly used immunoassay does not distinguish heroin from prescription opioids, nor detect hydrocodone, oxycodone, methadone, buprenorphine, or certain benzodiazepines. Chromatography/mass spectrometry assays can but are often not available from hospital laboratories. The differential for unexpected results includes substance use, self treatment of uncontrolled pain, diversion, or laboratory error.²⁰

If concerning opioid use is identified, 3 hospital setting/acute pain specific guidelines and the CDC guideline recommend sharing concerns with patients and assessing for a substance use disorder.^9,13,16,22 Determining whether patients have an opioid use disorder that meets the criteria in the Diagnostic and Statistical Manual, 5th Edition⁴⁴ can be challenging. Patients may minimize or deny symptoms or fear that the stigma of an opioid use disorder will lead to dismissive or subpar care. Additionally, substance use disorders are subject to federal confidentiality regulations, which can hamper acquisition of information from providers.⁴⁵ Thus, hospitalists may find specialty consultation helpful to confirm the diagnosis.

Assessing the Risk of Overdose and Adverse Drug Events

Oversedation, respiratory depression, and death can result from iatrogenic or self-administered opioid overdose in the hospital.5 Patient factors that increase this risk among outpatients include a prior history of overdose, preexisting substance use disorders, cognitive impairment, mood and personality disorders, chronic kidney disease, sleep apnea, obstructive lung disease, and recent abstinence from opioids.12 Medication factors include concomitant use of benzodiazepines and other central nervous system depressants, including alcohol; recent initiation of long-acting opioids; use of fentanyl patches, immediate-release fentanyl, or methadone; rapid titration; switching opioids without adequate dose reduction; pharmacokinetic drug–drug interactions; and, importantly, higher doses.12,22 Two guidelines specific to acute pain and hospital settings and 5 chronic pain guidelines recommend screening for use of benzodiazepines among patients on LTOT.13,14,16,18-20,22,21
The CDC guideline recommends careful assessment when doses exceed 50 mg of morphine equivalents per day and avoiding doses above 90 mg per day due to the heightened risk of overdose.²² In the hospital, 23% of patients receive doses at or above 100 mg of morphine equivalents per day,⁵ and concurrent use of central nervous system depressants is common. Changes in kidney and liver function during acute illness may impact opioid metabolism and contribute to overdose.

In addition to overdose, opioids are leading causes of adverse drug events during hospitalization.⁴⁶ Most studies have focused on surgical patients reporting common opioid-related events as nausea/vomiting, pruritus, rash, mental status changes, respiratory depression, ileus, and urinary retention.⁴⁷ Hospitalized patients may also exhibit chronic adverse effects due to LTOT. At least one-third of patients on LTOT eventually stop because of adverse effects, such as endocrinopathies, sleep disordered breathing, constipation, fractures, falls, and mental status changes.⁴⁸ Patients may lack awareness that their symptoms are attributable to opioids and are willing to reduce their opioid use once informed, especially when alternatives are offered to alleviate pain.

Gauging the Risk of Withdrawal

Sudden discontinuation of LTOT by patients, practitioners, or intercurrent events can have unanticipated and undesirable consequences. Withdrawal is not only distressing for patients; it can be dangerous because patients may resort to illicit use, diversion of opioids, or masking opioid withdrawal with other substances such as alcohol. The anxiety and distress associated with withdrawal, or anticipatory fear about withdrawal, can undermine therapeutic alliance and interfere with processes of care. Reviewed guidelines did not offer recommendations regarding withdrawal risk or specific strategies for avoidance. There is no specific prior dose threshold or degree of reduction in opioids that puts patients at risk for withdrawal, in part due to patients’ beliefs, expectations, and differences in response to opioid formulations. Symptoms of opioid withdrawal have been compared to a severe case of influenza, including stomach cramps, nausea and vomiting, diarrhea, tremor and muscle twitching, sweating, restlessness, yawning, tachycardia, anxiety and irritability, bone and joint aches, runny nose, tearing, and piloerection.⁴⁹ The Clinical Opiate Withdrawal Scale (COWS)⁴⁹ and the Clinical Institute Narcotic Assessment⁵¹ are clinician-administered tools to assess opioid withdrawal similar to the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised,⁵² to monitor for withdrawal in the inpatient setting.

Synthesizing and Appraising the Indications for Opioid Therapy

For medical inpatients who report adequate pain control and functional outcomes on current doses of LTOT, without evidence of misuse, the pragmatic approach is to continue the treatment plan established by the outpatient clinician rather than escalating or tapering the dose. If opioids are prescribed at discharge, 3 hospital setting/acute pain guidelines and the CDC guideline recommend prescribing the lowest effective dose of immediate release opioids for 3 to 7 days.^13,15,16,22

When patients exhibit evidence of an opioid use disorder, have a history of serious overdose, or are experiencing intolerable opioid-related adverse events, the hospitalist may conclude the harms of LTOT outweigh the benefits. For these patients, opioid treatment in the hospital can be aimed at preventing withdrawal, avoiding the perpetuation of inappropriate opioid use, managing other acute medical conditions, and communicating with outpatient prescribers. For patients with misuse, discontinuing opioids is potentially harmful and may be perceived as punitive. Hospitalists should consider consulting addiction or mental health specialists to assist with formulating a plan of care. However, such specialists may not be available in smaller or rural hospitals and referral at discharge can be challenging.⁵³

Beginning to taper opioids during the hospitalization can be appropriate when patients are motivated and can transition to an outpatient provider who will supervise the taper. In ambulatory settings, tapers of 10% to 30% every 2 to 5 days are generally well tolerated.⁵⁴ If patients started tapering opioids under supervision of an outpatient provider prior to hospitalization; ideally, the taper can be continued during hospitalization with close coordination with the outpatient clinician.

Unfortunately, many patients on LTOT are admitted with new sources of acute pain and or exacerbations of chronic pain, and some have concomitant substance use disorders; we plan to address the management of these complex situations in future work.

Despite the frequency with which patients on LTOT are hospitalized for nonsurgical stays and the challenges inherent in evaluating pain and assessing the possibility of substance use disorders, no formal guidelines or empirical research studies pertain to this population. Guidelines in this review were developed for hospital settings and acute pain in the absence of LTOT, and for outpatient care of patients on LTOT. We also included a nonsystematic synthesis of literature that varied in relevance to medical inpatients on LTOT.

Although inpatient assessment and treatment of patients with LTOT remains an underresearched area, we were able to extract and synthesize recommendations from 14 guideline statements and apply these to the assessment of patients with LTOT in the inpatient setting. Hospitalists frequently encounter patients on LTOT for chronic nonmalignant pain and are faced with complex decisions about the effectiveness and safety of LTOT; appropriate patient assessment is fundamental to making these decisions. Key guideline recommendations relevant to inpatient assessment include assessing both pain and functional status, differentiating acute from chronic pain, ascertaining preadmission pain treatment history, obtaining a psychosocial history, screening for mental health issues such as depression and anxiety, screening for substance use disorders, checking state prescription drug monitoring databases, ordering urine drug immunoassays, detecting use of sedative-hypnotics, identifying medical conditions associated with increased risk of overdose and adverse events, and appraising the potential benefits and harms of opioid therapy. Although approaches to assessing medical inpatients on LTOT can be extrapolated from outpatient guidelines, observational studies, and small studies in surgical populations, more work is needed to address these critical topics for inpatients on LTOT.

Disclosure

Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. The funding organization had no involvement in any aspect of the study, including design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. All other authors have no relevant conflicts of interest with the work.

Hospitalists face complex questions about how to evaluate and treat the large number of individuals who are admitted on long-term opioid therapy (LTOT, defined as lasting 3 months or longer) for chronic noncancer pain. A recent study at one Veterans Affairs hospital, found 26% of medical inpatients were on LTOT.¹ Over the last 2 decades, use of LTOT has risen substantially in the United States, including among middle-aged and older adults.² Concurrently, inpatient hospitalizations related to the overuse of prescription opioids, including overdose, dependence, abuse, and adverse drug events, have increased by 153%.³ Individuals on LTOT can also be hospitalized for exacerbations of the opioid-treated chronic pain condition or unrelated conditions. In addition to affecting rates of hospitalization, use of LTOT is associated with higher rates of in-hospital adverse events, longer hospital stays, and higher readmission rates.^1,4,5

Physicians find managing chronic pain to be stressful, are often concerned about misuse and addiction, and believe their training in opioid prescribing is inadequate.⁶ Hospitalists report confidence in assessing and prescribing opioids for acute pain but limited success and satisfaction with treating exacerbations of chronic pain.⁷ Although half of all hospitalized patients receive opioids,⁵ little information is available to guide the care of hospitalized medical patients on LTOT for chronic noncancer pain.^8,9

Our multispecialty team sought to synthesize guideline recommendations and primary literature relevant to the assessment of medical inpatients on LTOT to assist practitioners balance effective pain treatment and opioid risk reduction. This article addresses obtaining a comprehensive pain history, identifying misuse and opioid use disorders, assessing the risk of overdose and adverse drug events, gauging the risk of withdrawal, and based on such findings, appraise indications for opioid therapy. Other authors have recently published narrative reviews on the management of acute pain in hospitalized patients with opioid dependence and the inpatient management of opioid use disorder.^10,11

To identify primary literature, we searched PubMed, EMBASE, The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Economic Evaluations Database, key meeting abstracts, and hand searches. To identify guidelines, we searched PubMed, National Guidelines Clearinghouse, specialty societies’ websites, the Centers for Disease Control and Prevention (CDC), the United Kingdom National Institute for Health and Care Excellence, the Canadian Medical Association, and the Australian Government National Health and Medical Research Council. Search terms related to opioids and chronic pain, which was last updated in October 2016.¹²

We selected English-language documents on opioids and chronic pain among adults, excluding pain in the setting of procedures, labor and delivery, life-limiting illness, or specific conditions. For primary literature, we considered intervention studies of any design that addressed pain management among hospitalized medical patients. We included guidelines and specialty society position statements published after January 1, 2009, that addressed pain in the hospital setting, acute pain in any setting, or chronic pain in the outpatient setting if published by a national body. Due to the paucity of documents specific to inpatient care, we used a narrative review format to synthesize information. Dual reviewers extracted guideline recommendations potentially relevant to medical inpatients on LTOT. We also summarize relevant assessment instruments, emphasizing very brief screening instruments, which may be more likely to be used by busy hospitalists.

Obtaining a Comprehensive Pain History

Hospitalists newly evaluating patients on LTOT often face a dual challenge: deciding if the patient has an immediate indication for additional opioids and if the current long-term opioid regimen should be altered or discontinued. In general, opioids are an accepted short-term treatment for moderate to severe acute pain but their role in chronic noncancer pain is controversial. Newly released guidelines by the CDC recommend initiating LTOT as a last resort, and the Departments of Veterans Affairs and Defense guidelines recommend against initiation of LTOT.^22,23

A key first step, therefore, is distinguishing between acute and chronic pain. Among patients on LTOT, pain can represent a new acute pain condition, an exacerbation of chronic pain, opioid-induced hyperalgesia, or opioid withdrawal. Acute pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in relation to such damage.²⁶ In contrast, chronic pain is a complex response that may not be related to actual or ongoing tissue damage, and is influenced by physiological, contextual, and psychological factors. Two acute pain guidelines and 1 chronic pain guideline recommend distinguishing acute and chronic pain,^9,16,21 3 chronic pain guidelines reinforce the importance of obtaining a pain history (including timing, intensity, frequency, onset, etc),^20,22,23 and 6 guidelines recommend ascertaining a history of prior pain-related treatments.^{9,13,14,16,20,22} Inquiring how the current pain compares with symptoms “on a good day,” what activities the patient can usually perform, and what the patient does outside the hospital to cope with pain can serve as entry into this conversation.

Identifying Misuse and Opioid Use Disorders

Nonmedical use of prescription opioids and opioid use disorders have more than doubled over the last decade.³⁵ Five guidelines, including 3 specific guidelines for acute pain or the hospital setting, recommend screening for opioid misuse.^{13,14,16,19,23} Many states mandate practitioners assess patients for substance use disorders before prescribing controlled substances.³⁶ Instruments to identify aberrant and risky use include the Current Opioid Misuse Measure,³⁷ Prescription Drug Use Questionnaire,³⁸ Addiction Behaviors Checklist,³⁹ Screening Tool for Abuse,⁴⁰ and the Self-Administered Single-Item Screening Question (Table 3).⁴¹ However, the evidence for these and other tools is limited and absent for the inpatient setting.^21,42

In addition to obtaining a history from the patient, 4 guidelines specific to hospital settings/acute pain and 4 chronic pain guidelines recommend practitioners access prescription drug monitoring programs (PDMPs).^{13-16,19,21-24} PDMPs exist in all states except Missouri, and about half of states mandate practitioners check the PDMP database in certain circumstances.³⁶ Studies examining the effects of PDMPs on prescribing are limited, but checking these databases can uncover concerning patterns including overlapping prescriptions or multiple prescribers.⁴³ PDMPs can also confirm reported medication doses, for which patient report may be less reliable.

Two hospital/acute pain guidelines and 5 chronic pain guidelines also recommend urine drug testing, although differing on when and whom to test, with some favoring universal screening.^11,20,23 Screening hospitalized patients may reveal substances not reported by patients, but medications administered in emergency departments can confound results. Furthermore, the commonly used immunoassay does not distinguish heroin from prescription opioids, nor detect hydrocodone, oxycodone, methadone, buprenorphine, or certain benzodiazepines. Chromatography/mass spectrometry assays can but are often not available from hospital laboratories. The differential for unexpected results includes substance use, self treatment of uncontrolled pain, diversion, or laboratory error.²⁰

If concerning opioid use is identified, 3 hospital setting/acute pain specific guidelines and the CDC guideline recommend sharing concerns with patients and assessing for a substance use disorder.^9,13,16,22 Determining whether patients have an opioid use disorder that meets the criteria in the Diagnostic and Statistical Manual, 5th Edition⁴⁴ can be challenging. Patients may minimize or deny symptoms or fear that the stigma of an opioid use disorder will lead to dismissive or subpar care. Additionally, substance use disorders are subject to federal confidentiality regulations, which can hamper acquisition of information from providers.⁴⁵ Thus, hospitalists may find specialty consultation helpful to confirm the diagnosis.

Assessing the Risk of Overdose and Adverse Drug Events

Oversedation, respiratory depression, and death can result from iatrogenic or self-administered opioid overdose in the hospital.5 Patient factors that increase this risk among outpatients include a prior history of overdose, preexisting substance use disorders, cognitive impairment, mood and personality disorders, chronic kidney disease, sleep apnea, obstructive lung disease, and recent abstinence from opioids.12 Medication factors include concomitant use of benzodiazepines and other central nervous system depressants, including alcohol; recent initiation of long-acting opioids; use of fentanyl patches, immediate-release fentanyl, or methadone; rapid titration; switching opioids without adequate dose reduction; pharmacokinetic drug–drug interactions; and, importantly, higher doses.12,22 Two guidelines specific to acute pain and hospital settings and 5 chronic pain guidelines recommend screening for use of benzodiazepines among patients on LTOT.13,14,16,18-20,22,21
The CDC guideline recommends careful assessment when doses exceed 50 mg of morphine equivalents per day and avoiding doses above 90 mg per day due to the heightened risk of overdose.²² In the hospital, 23% of patients receive doses at or above 100 mg of morphine equivalents per day,⁵ and concurrent use of central nervous system depressants is common. Changes in kidney and liver function during acute illness may impact opioid metabolism and contribute to overdose.

In addition to overdose, opioids are leading causes of adverse drug events during hospitalization.⁴⁶ Most studies have focused on surgical patients reporting common opioid-related events as nausea/vomiting, pruritus, rash, mental status changes, respiratory depression, ileus, and urinary retention.⁴⁷ Hospitalized patients may also exhibit chronic adverse effects due to LTOT. At least one-third of patients on LTOT eventually stop because of adverse effects, such as endocrinopathies, sleep disordered breathing, constipation, fractures, falls, and mental status changes.⁴⁸ Patients may lack awareness that their symptoms are attributable to opioids and are willing to reduce their opioid use once informed, especially when alternatives are offered to alleviate pain.

Gauging the Risk of Withdrawal

Sudden discontinuation of LTOT by patients, practitioners, or intercurrent events can have unanticipated and undesirable consequences. Withdrawal is not only distressing for patients; it can be dangerous because patients may resort to illicit use, diversion of opioids, or masking opioid withdrawal with other substances such as alcohol. The anxiety and distress associated with withdrawal, or anticipatory fear about withdrawal, can undermine therapeutic alliance and interfere with processes of care. Reviewed guidelines did not offer recommendations regarding withdrawal risk or specific strategies for avoidance. There is no specific prior dose threshold or degree of reduction in opioids that puts patients at risk for withdrawal, in part due to patients’ beliefs, expectations, and differences in response to opioid formulations. Symptoms of opioid withdrawal have been compared to a severe case of influenza, including stomach cramps, nausea and vomiting, diarrhea, tremor and muscle twitching, sweating, restlessness, yawning, tachycardia, anxiety and irritability, bone and joint aches, runny nose, tearing, and piloerection.⁴⁹ The Clinical Opiate Withdrawal Scale (COWS)⁴⁹ and the Clinical Institute Narcotic Assessment⁵¹ are clinician-administered tools to assess opioid withdrawal similar to the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised,⁵² to monitor for withdrawal in the inpatient setting.

Synthesizing and Appraising the Indications for Opioid Therapy

For medical inpatients who report adequate pain control and functional outcomes on current doses of LTOT, without evidence of misuse, the pragmatic approach is to continue the treatment plan established by the outpatient clinician rather than escalating or tapering the dose. If opioids are prescribed at discharge, 3 hospital setting/acute pain guidelines and the CDC guideline recommend prescribing the lowest effective dose of immediate release opioids for 3 to 7 days.^13,15,16,22

When patients exhibit evidence of an opioid use disorder, have a history of serious overdose, or are experiencing intolerable opioid-related adverse events, the hospitalist may conclude the harms of LTOT outweigh the benefits. For these patients, opioid treatment in the hospital can be aimed at preventing withdrawal, avoiding the perpetuation of inappropriate opioid use, managing other acute medical conditions, and communicating with outpatient prescribers. For patients with misuse, discontinuing opioids is potentially harmful and may be perceived as punitive. Hospitalists should consider consulting addiction or mental health specialists to assist with formulating a plan of care. However, such specialists may not be available in smaller or rural hospitals and referral at discharge can be challenging.⁵³

Beginning to taper opioids during the hospitalization can be appropriate when patients are motivated and can transition to an outpatient provider who will supervise the taper. In ambulatory settings, tapers of 10% to 30% every 2 to 5 days are generally well tolerated.⁵⁴ If patients started tapering opioids under supervision of an outpatient provider prior to hospitalization; ideally, the taper can be continued during hospitalization with close coordination with the outpatient clinician.

Unfortunately, many patients on LTOT are admitted with new sources of acute pain and or exacerbations of chronic pain, and some have concomitant substance use disorders; we plan to address the management of these complex situations in future work.

Despite the frequency with which patients on LTOT are hospitalized for nonsurgical stays and the challenges inherent in evaluating pain and assessing the possibility of substance use disorders, no formal guidelines or empirical research studies pertain to this population. Guidelines in this review were developed for hospital settings and acute pain in the absence of LTOT, and for outpatient care of patients on LTOT. We also included a nonsystematic synthesis of literature that varied in relevance to medical inpatients on LTOT.

Although inpatient assessment and treatment of patients with LTOT remains an underresearched area, we were able to extract and synthesize recommendations from 14 guideline statements and apply these to the assessment of patients with LTOT in the inpatient setting. Hospitalists frequently encounter patients on LTOT for chronic nonmalignant pain and are faced with complex decisions about the effectiveness and safety of LTOT; appropriate patient assessment is fundamental to making these decisions. Key guideline recommendations relevant to inpatient assessment include assessing both pain and functional status, differentiating acute from chronic pain, ascertaining preadmission pain treatment history, obtaining a psychosocial history, screening for mental health issues such as depression and anxiety, screening for substance use disorders, checking state prescription drug monitoring databases, ordering urine drug immunoassays, detecting use of sedative-hypnotics, identifying medical conditions associated with increased risk of overdose and adverse events, and appraising the potential benefits and harms of opioid therapy. Although approaches to assessing medical inpatients on LTOT can be extrapolated from outpatient guidelines, observational studies, and small studies in surgical populations, more work is needed to address these critical topics for inpatients on LTOT.

Disclosure

Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. The funding organization had no involvement in any aspect of the study, including design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. All other authors have no relevant conflicts of interest with the work.

Hospitalists face complex questions about how to evaluate and treat the large number of individuals who are admitted on long-term opioid therapy (LTOT, defined as lasting 3 months or longer) for chronic noncancer pain. A recent study at one Veterans Affairs hospital, found 26% of medical inpatients were on LTOT.¹ Over the last 2 decades, use of LTOT has risen substantially in the United States, including among middle-aged and older adults.² Concurrently, inpatient hospitalizations related to the overuse of prescription opioids, including overdose, dependence, abuse, and adverse drug events, have increased by 153%.³ Individuals on LTOT can also be hospitalized for exacerbations of the opioid-treated chronic pain condition or unrelated conditions. In addition to affecting rates of hospitalization, use of LTOT is associated with higher rates of in-hospital adverse events, longer hospital stays, and higher readmission rates.^1,4,5

Physicians find managing chronic pain to be stressful, are often concerned about misuse and addiction, and believe their training in opioid prescribing is inadequate.⁶ Hospitalists report confidence in assessing and prescribing opioids for acute pain but limited success and satisfaction with treating exacerbations of chronic pain.⁷ Although half of all hospitalized patients receive opioids,⁵ little information is available to guide the care of hospitalized medical patients on LTOT for chronic noncancer pain.^8,9

Our multispecialty team sought to synthesize guideline recommendations and primary literature relevant to the assessment of medical inpatients on LTOT to assist practitioners balance effective pain treatment and opioid risk reduction. This article addresses obtaining a comprehensive pain history, identifying misuse and opioid use disorders, assessing the risk of overdose and adverse drug events, gauging the risk of withdrawal, and based on such findings, appraise indications for opioid therapy. Other authors have recently published narrative reviews on the management of acute pain in hospitalized patients with opioid dependence and the inpatient management of opioid use disorder.^10,11

To identify primary literature, we searched PubMed, EMBASE, The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Economic Evaluations Database, key meeting abstracts, and hand searches. To identify guidelines, we searched PubMed, National Guidelines Clearinghouse, specialty societies’ websites, the Centers for Disease Control and Prevention (CDC), the United Kingdom National Institute for Health and Care Excellence, the Canadian Medical Association, and the Australian Government National Health and Medical Research Council. Search terms related to opioids and chronic pain, which was last updated in October 2016.¹²

We selected English-language documents on opioids and chronic pain among adults, excluding pain in the setting of procedures, labor and delivery, life-limiting illness, or specific conditions. For primary literature, we considered intervention studies of any design that addressed pain management among hospitalized medical patients. We included guidelines and specialty society position statements published after January 1, 2009, that addressed pain in the hospital setting, acute pain in any setting, or chronic pain in the outpatient setting if published by a national body. Due to the paucity of documents specific to inpatient care, we used a narrative review format to synthesize information. Dual reviewers extracted guideline recommendations potentially relevant to medical inpatients on LTOT. We also summarize relevant assessment instruments, emphasizing very brief screening instruments, which may be more likely to be used by busy hospitalists.

Obtaining a Comprehensive Pain History

Hospitalists newly evaluating patients on LTOT often face a dual challenge: deciding if the patient has an immediate indication for additional opioids and if the current long-term opioid regimen should be altered or discontinued. In general, opioids are an accepted short-term treatment for moderate to severe acute pain but their role in chronic noncancer pain is controversial. Newly released guidelines by the CDC recommend initiating LTOT as a last resort, and the Departments of Veterans Affairs and Defense guidelines recommend against initiation of LTOT.^22,23

A key first step, therefore, is distinguishing between acute and chronic pain. Among patients on LTOT, pain can represent a new acute pain condition, an exacerbation of chronic pain, opioid-induced hyperalgesia, or opioid withdrawal. Acute pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in relation to such damage.²⁶ In contrast, chronic pain is a complex response that may not be related to actual or ongoing tissue damage, and is influenced by physiological, contextual, and psychological factors. Two acute pain guidelines and 1 chronic pain guideline recommend distinguishing acute and chronic pain,^9,16,21 3 chronic pain guidelines reinforce the importance of obtaining a pain history (including timing, intensity, frequency, onset, etc),^20,22,23 and 6 guidelines recommend ascertaining a history of prior pain-related treatments.^{9,13,14,16,20,22} Inquiring how the current pain compares with symptoms “on a good day,” what activities the patient can usually perform, and what the patient does outside the hospital to cope with pain can serve as entry into this conversation.

Identifying Misuse and Opioid Use Disorders

Nonmedical use of prescription opioids and opioid use disorders have more than doubled over the last decade.³⁵ Five guidelines, including 3 specific guidelines for acute pain or the hospital setting, recommend screening for opioid misuse.^{13,14,16,19,23} Many states mandate practitioners assess patients for substance use disorders before prescribing controlled substances.³⁶ Instruments to identify aberrant and risky use include the Current Opioid Misuse Measure,³⁷ Prescription Drug Use Questionnaire,³⁸ Addiction Behaviors Checklist,³⁹ Screening Tool for Abuse,⁴⁰ and the Self-Administered Single-Item Screening Question (Table 3).⁴¹ However, the evidence for these and other tools is limited and absent for the inpatient setting.^21,42

In addition to obtaining a history from the patient, 4 guidelines specific to hospital settings/acute pain and 4 chronic pain guidelines recommend practitioners access prescription drug monitoring programs (PDMPs).^{13-16,19,21-24} PDMPs exist in all states except Missouri, and about half of states mandate practitioners check the PDMP database in certain circumstances.³⁶ Studies examining the effects of PDMPs on prescribing are limited, but checking these databases can uncover concerning patterns including overlapping prescriptions or multiple prescribers.⁴³ PDMPs can also confirm reported medication doses, for which patient report may be less reliable.

Two hospital/acute pain guidelines and 5 chronic pain guidelines also recommend urine drug testing, although differing on when and whom to test, with some favoring universal screening.^11,20,23 Screening hospitalized patients may reveal substances not reported by patients, but medications administered in emergency departments can confound results. Furthermore, the commonly used immunoassay does not distinguish heroin from prescription opioids, nor detect hydrocodone, oxycodone, methadone, buprenorphine, or certain benzodiazepines. Chromatography/mass spectrometry assays can but are often not available from hospital laboratories. The differential for unexpected results includes substance use, self treatment of uncontrolled pain, diversion, or laboratory error.²⁰

If concerning opioid use is identified, 3 hospital setting/acute pain specific guidelines and the CDC guideline recommend sharing concerns with patients and assessing for a substance use disorder.^9,13,16,22 Determining whether patients have an opioid use disorder that meets the criteria in the Diagnostic and Statistical Manual, 5th Edition⁴⁴ can be challenging. Patients may minimize or deny symptoms or fear that the stigma of an opioid use disorder will lead to dismissive or subpar care. Additionally, substance use disorders are subject to federal confidentiality regulations, which can hamper acquisition of information from providers.⁴⁵ Thus, hospitalists may find specialty consultation helpful to confirm the diagnosis.

Assessing the Risk of Overdose and Adverse Drug Events

Oversedation, respiratory depression, and death can result from iatrogenic or self-administered opioid overdose in the hospital.5 Patient factors that increase this risk among outpatients include a prior history of overdose, preexisting substance use disorders, cognitive impairment, mood and personality disorders, chronic kidney disease, sleep apnea, obstructive lung disease, and recent abstinence from opioids.12 Medication factors include concomitant use of benzodiazepines and other central nervous system depressants, including alcohol; recent initiation of long-acting opioids; use of fentanyl patches, immediate-release fentanyl, or methadone; rapid titration; switching opioids without adequate dose reduction; pharmacokinetic drug–drug interactions; and, importantly, higher doses.12,22 Two guidelines specific to acute pain and hospital settings and 5 chronic pain guidelines recommend screening for use of benzodiazepines among patients on LTOT.13,14,16,18-20,22,21
The CDC guideline recommends careful assessment when doses exceed 50 mg of morphine equivalents per day and avoiding doses above 90 mg per day due to the heightened risk of overdose.²² In the hospital, 23% of patients receive doses at or above 100 mg of morphine equivalents per day,⁵ and concurrent use of central nervous system depressants is common. Changes in kidney and liver function during acute illness may impact opioid metabolism and contribute to overdose.

In addition to overdose, opioids are leading causes of adverse drug events during hospitalization.⁴⁶ Most studies have focused on surgical patients reporting common opioid-related events as nausea/vomiting, pruritus, rash, mental status changes, respiratory depression, ileus, and urinary retention.⁴⁷ Hospitalized patients may also exhibit chronic adverse effects due to LTOT. At least one-third of patients on LTOT eventually stop because of adverse effects, such as endocrinopathies, sleep disordered breathing, constipation, fractures, falls, and mental status changes.⁴⁸ Patients may lack awareness that their symptoms are attributable to opioids and are willing to reduce their opioid use once informed, especially when alternatives are offered to alleviate pain.

Gauging the Risk of Withdrawal

Sudden discontinuation of LTOT by patients, practitioners, or intercurrent events can have unanticipated and undesirable consequences. Withdrawal is not only distressing for patients; it can be dangerous because patients may resort to illicit use, diversion of opioids, or masking opioid withdrawal with other substances such as alcohol. The anxiety and distress associated with withdrawal, or anticipatory fear about withdrawal, can undermine therapeutic alliance and interfere with processes of care. Reviewed guidelines did not offer recommendations regarding withdrawal risk or specific strategies for avoidance. There is no specific prior dose threshold or degree of reduction in opioids that puts patients at risk for withdrawal, in part due to patients’ beliefs, expectations, and differences in response to opioid formulations. Symptoms of opioid withdrawal have been compared to a severe case of influenza, including stomach cramps, nausea and vomiting, diarrhea, tremor and muscle twitching, sweating, restlessness, yawning, tachycardia, anxiety and irritability, bone and joint aches, runny nose, tearing, and piloerection.⁴⁹ The Clinical Opiate Withdrawal Scale (COWS)⁴⁹ and the Clinical Institute Narcotic Assessment⁵¹ are clinician-administered tools to assess opioid withdrawal similar to the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised,⁵² to monitor for withdrawal in the inpatient setting.

Synthesizing and Appraising the Indications for Opioid Therapy

For medical inpatients who report adequate pain control and functional outcomes on current doses of LTOT, without evidence of misuse, the pragmatic approach is to continue the treatment plan established by the outpatient clinician rather than escalating or tapering the dose. If opioids are prescribed at discharge, 3 hospital setting/acute pain guidelines and the CDC guideline recommend prescribing the lowest effective dose of immediate release opioids for 3 to 7 days.^13,15,16,22

When patients exhibit evidence of an opioid use disorder, have a history of serious overdose, or are experiencing intolerable opioid-related adverse events, the hospitalist may conclude the harms of LTOT outweigh the benefits. For these patients, opioid treatment in the hospital can be aimed at preventing withdrawal, avoiding the perpetuation of inappropriate opioid use, managing other acute medical conditions, and communicating with outpatient prescribers. For patients with misuse, discontinuing opioids is potentially harmful and may be perceived as punitive. Hospitalists should consider consulting addiction or mental health specialists to assist with formulating a plan of care. However, such specialists may not be available in smaller or rural hospitals and referral at discharge can be challenging.⁵³

Beginning to taper opioids during the hospitalization can be appropriate when patients are motivated and can transition to an outpatient provider who will supervise the taper. In ambulatory settings, tapers of 10% to 30% every 2 to 5 days are generally well tolerated.⁵⁴ If patients started tapering opioids under supervision of an outpatient provider prior to hospitalization; ideally, the taper can be continued during hospitalization with close coordination with the outpatient clinician.

Unfortunately, many patients on LTOT are admitted with new sources of acute pain and or exacerbations of chronic pain, and some have concomitant substance use disorders; we plan to address the management of these complex situations in future work.

Despite the frequency with which patients on LTOT are hospitalized for nonsurgical stays and the challenges inherent in evaluating pain and assessing the possibility of substance use disorders, no formal guidelines or empirical research studies pertain to this population. Guidelines in this review were developed for hospital settings and acute pain in the absence of LTOT, and for outpatient care of patients on LTOT. We also included a nonsystematic synthesis of literature that varied in relevance to medical inpatients on LTOT.

Although inpatient assessment and treatment of patients with LTOT remains an underresearched area, we were able to extract and synthesize recommendations from 14 guideline statements and apply these to the assessment of patients with LTOT in the inpatient setting. Hospitalists frequently encounter patients on LTOT for chronic nonmalignant pain and are faced with complex decisions about the effectiveness and safety of LTOT; appropriate patient assessment is fundamental to making these decisions. Key guideline recommendations relevant to inpatient assessment include assessing both pain and functional status, differentiating acute from chronic pain, ascertaining preadmission pain treatment history, obtaining a psychosocial history, screening for mental health issues such as depression and anxiety, screening for substance use disorders, checking state prescription drug monitoring databases, ordering urine drug immunoassays, detecting use of sedative-hypnotics, identifying medical conditions associated with increased risk of overdose and adverse events, and appraising the potential benefits and harms of opioid therapy. Although approaches to assessing medical inpatients on LTOT can be extrapolated from outpatient guidelines, observational studies, and small studies in surgical populations, more work is needed to address these critical topics for inpatients on LTOT.

Disclosure

Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. The funding organization had no involvement in any aspect of the study, including design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. All other authors have no relevant conflicts of interest with the work.