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DIY nerve stimulation effective in episodic migraine
results from a phase 3 study show.
This is great news for headache patients who want to explore nondrug treatment options, said study investigator Deena E. Kuruvilla, MD, neurologist and headache specialist at the Westport Headache Institute, Connecticut.
She added that such devices “aren’t always part of the conversation when we’re discussing preventive and acute treatments with our patients. Making this a regular part of the conversation might be helpful to patients.”
The findings were presented at ANA 2021: 146th Annual Meeting of the American Neurological Association (ANA), which was held online.
A key therapeutic target
The randomized, double-blind trial compared E-TNS with sham stimulation for the acute treatment of migraine.
The E-TNS device (Verum Cefaly Abortive Program) stimulates the supraorbital nerve in the forehead. “This nerve is a branch of the trigeminal nerve, which is thought to be the key player in migraine pathophysiology,” Dr. Kuruvilla noted.
The device has been cleared by the U.S. Food and Drug Administration for acute and preventive treatment of migraine.
During a run-in period before randomization, patients were asked to keep a detailed headache diary and to become comfortable using the trial device to treat an acute migraine attack at home.
The study enrolled 538 adult patients at 10 centers. The patients were aged 18 to 65 years, and they had been having episodic migraines, with or without aura, for at least a year. The participants had to have received a migraine diagnosis before age 50, and they had to be experiencing an attack of migraine 2 to 8 days per month.
The patients used the device only for a migraine of at least moderate intensity that was accompanied by at least one migraine-associated symptom, such as photophobia, phonophobia, or nausea. They were asked not to take rescue medication prior to or during a therapy session.
Study participants applied either neurostimulation or sham stimulation for a continuous 2-hour period within 4 hours of a migraine attack over the 2-month study period.
The two primary endpoints were pain freedom and freedom from the most bothersome migraine-associated symptoms at 2 hours.
Compared to sham treatment, active stimulation was more effective in achieving pain freedom (P = .043) and freedom from the most bothersome migraine-associated symptom (P = .001) at 2 hours.
“So the study did meet both primary endpoints with statistical significance,” said Dr. Kuruvilla.
The five secondary endpoints included pain relief at 2 hours; absence of all migraine-associated symptoms at 2 hours; use of rescue medication within 24 hours; sustained pain freedom at 24 hours; and sustained pain relief at 24 hours.
All but one of these endpoints reached statistical significance, showing superiority for the active intervention. The only exception was in regard to use of rescue medication.
The most common adverse event (AE) was forehead paresthesia, discomfort, or burning, which was more common in the active-treatment group than in the sham-treatment group (P = .009). There were four cases of nausea or vomiting in the active-treatment group and none in the sham-treatment group. There were no serious AEs.
Available over the counter
Both moderators of the headache poster tour that featured this study – Justin C. McArthur, MBBS, from Johns Hopkins University, Baltimore, and Steven Galetta, MD, from NYU Grossman School of Medicine – praised the presentation.
Dr. Galetta questioned whether patients were receiving preventive therapies. Dr. Kuruvilla said that the patients were allowed to enter the trial while taking preventive therapies, including antiepileptic treatments, blood pressure medications, and antidepressants, but that they had to be receiving stable doses.
The investigators didn’t distinguish between participants who were taking preventive therapies and those who weren’t, she said. “The aim was really to look at acute treatment for migraine,” and patients taking such medication “had been stable on their regimen for a pretty prolonged period of time.”
Dr. McArthur asked about the origin of the nausea some patients experienced.
It was difficult to determine whether the nausea was an aspect of an individual patient’s migraine attack or was an effect of the stimulation, said Dr. Kuruvilla. She noted that some patients found the vibrating sensation from the device uncomfortable and that nausea could be associated with pain at the site.
The device costs $300 to $400 (U.S.) and is available over the counter.
Dr. Kuruvilla is a consultant for Cefaly, Neurolief, Theranica, Now What Media, and Kx Advisors. She is on the speakers bureau for AbbVie/Allergan, Amgen/Novartis, Lilly, the American Headache Society, Biohaven, and CME meeting, and she is on an advisory board at AbbVie/Allergan, Lilly, Theranica, and Amgen/Novartis. She is editor and associate editor of Healthline and is an author for WebMD/Medscape, Healthline.
A version of this article first appeared on Medscape.com.
results from a phase 3 study show.
This is great news for headache patients who want to explore nondrug treatment options, said study investigator Deena E. Kuruvilla, MD, neurologist and headache specialist at the Westport Headache Institute, Connecticut.
She added that such devices “aren’t always part of the conversation when we’re discussing preventive and acute treatments with our patients. Making this a regular part of the conversation might be helpful to patients.”
The findings were presented at ANA 2021: 146th Annual Meeting of the American Neurological Association (ANA), which was held online.
A key therapeutic target
The randomized, double-blind trial compared E-TNS with sham stimulation for the acute treatment of migraine.
The E-TNS device (Verum Cefaly Abortive Program) stimulates the supraorbital nerve in the forehead. “This nerve is a branch of the trigeminal nerve, which is thought to be the key player in migraine pathophysiology,” Dr. Kuruvilla noted.
The device has been cleared by the U.S. Food and Drug Administration for acute and preventive treatment of migraine.
During a run-in period before randomization, patients were asked to keep a detailed headache diary and to become comfortable using the trial device to treat an acute migraine attack at home.
The study enrolled 538 adult patients at 10 centers. The patients were aged 18 to 65 years, and they had been having episodic migraines, with or without aura, for at least a year. The participants had to have received a migraine diagnosis before age 50, and they had to be experiencing an attack of migraine 2 to 8 days per month.
The patients used the device only for a migraine of at least moderate intensity that was accompanied by at least one migraine-associated symptom, such as photophobia, phonophobia, or nausea. They were asked not to take rescue medication prior to or during a therapy session.
Study participants applied either neurostimulation or sham stimulation for a continuous 2-hour period within 4 hours of a migraine attack over the 2-month study period.
The two primary endpoints were pain freedom and freedom from the most bothersome migraine-associated symptoms at 2 hours.
Compared to sham treatment, active stimulation was more effective in achieving pain freedom (P = .043) and freedom from the most bothersome migraine-associated symptom (P = .001) at 2 hours.
“So the study did meet both primary endpoints with statistical significance,” said Dr. Kuruvilla.
The five secondary endpoints included pain relief at 2 hours; absence of all migraine-associated symptoms at 2 hours; use of rescue medication within 24 hours; sustained pain freedom at 24 hours; and sustained pain relief at 24 hours.
All but one of these endpoints reached statistical significance, showing superiority for the active intervention. The only exception was in regard to use of rescue medication.
The most common adverse event (AE) was forehead paresthesia, discomfort, or burning, which was more common in the active-treatment group than in the sham-treatment group (P = .009). There were four cases of nausea or vomiting in the active-treatment group and none in the sham-treatment group. There were no serious AEs.
Available over the counter
Both moderators of the headache poster tour that featured this study – Justin C. McArthur, MBBS, from Johns Hopkins University, Baltimore, and Steven Galetta, MD, from NYU Grossman School of Medicine – praised the presentation.
Dr. Galetta questioned whether patients were receiving preventive therapies. Dr. Kuruvilla said that the patients were allowed to enter the trial while taking preventive therapies, including antiepileptic treatments, blood pressure medications, and antidepressants, but that they had to be receiving stable doses.
The investigators didn’t distinguish between participants who were taking preventive therapies and those who weren’t, she said. “The aim was really to look at acute treatment for migraine,” and patients taking such medication “had been stable on their regimen for a pretty prolonged period of time.”
Dr. McArthur asked about the origin of the nausea some patients experienced.
It was difficult to determine whether the nausea was an aspect of an individual patient’s migraine attack or was an effect of the stimulation, said Dr. Kuruvilla. She noted that some patients found the vibrating sensation from the device uncomfortable and that nausea could be associated with pain at the site.
The device costs $300 to $400 (U.S.) and is available over the counter.
Dr. Kuruvilla is a consultant for Cefaly, Neurolief, Theranica, Now What Media, and Kx Advisors. She is on the speakers bureau for AbbVie/Allergan, Amgen/Novartis, Lilly, the American Headache Society, Biohaven, and CME meeting, and she is on an advisory board at AbbVie/Allergan, Lilly, Theranica, and Amgen/Novartis. She is editor and associate editor of Healthline and is an author for WebMD/Medscape, Healthline.
A version of this article first appeared on Medscape.com.
results from a phase 3 study show.
This is great news for headache patients who want to explore nondrug treatment options, said study investigator Deena E. Kuruvilla, MD, neurologist and headache specialist at the Westport Headache Institute, Connecticut.
She added that such devices “aren’t always part of the conversation when we’re discussing preventive and acute treatments with our patients. Making this a regular part of the conversation might be helpful to patients.”
The findings were presented at ANA 2021: 146th Annual Meeting of the American Neurological Association (ANA), which was held online.
A key therapeutic target
The randomized, double-blind trial compared E-TNS with sham stimulation for the acute treatment of migraine.
The E-TNS device (Verum Cefaly Abortive Program) stimulates the supraorbital nerve in the forehead. “This nerve is a branch of the trigeminal nerve, which is thought to be the key player in migraine pathophysiology,” Dr. Kuruvilla noted.
The device has been cleared by the U.S. Food and Drug Administration for acute and preventive treatment of migraine.
During a run-in period before randomization, patients were asked to keep a detailed headache diary and to become comfortable using the trial device to treat an acute migraine attack at home.
The study enrolled 538 adult patients at 10 centers. The patients were aged 18 to 65 years, and they had been having episodic migraines, with or without aura, for at least a year. The participants had to have received a migraine diagnosis before age 50, and they had to be experiencing an attack of migraine 2 to 8 days per month.
The patients used the device only for a migraine of at least moderate intensity that was accompanied by at least one migraine-associated symptom, such as photophobia, phonophobia, or nausea. They were asked not to take rescue medication prior to or during a therapy session.
Study participants applied either neurostimulation or sham stimulation for a continuous 2-hour period within 4 hours of a migraine attack over the 2-month study period.
The two primary endpoints were pain freedom and freedom from the most bothersome migraine-associated symptoms at 2 hours.
Compared to sham treatment, active stimulation was more effective in achieving pain freedom (P = .043) and freedom from the most bothersome migraine-associated symptom (P = .001) at 2 hours.
“So the study did meet both primary endpoints with statistical significance,” said Dr. Kuruvilla.
The five secondary endpoints included pain relief at 2 hours; absence of all migraine-associated symptoms at 2 hours; use of rescue medication within 24 hours; sustained pain freedom at 24 hours; and sustained pain relief at 24 hours.
All but one of these endpoints reached statistical significance, showing superiority for the active intervention. The only exception was in regard to use of rescue medication.
The most common adverse event (AE) was forehead paresthesia, discomfort, or burning, which was more common in the active-treatment group than in the sham-treatment group (P = .009). There were four cases of nausea or vomiting in the active-treatment group and none in the sham-treatment group. There were no serious AEs.
Available over the counter
Both moderators of the headache poster tour that featured this study – Justin C. McArthur, MBBS, from Johns Hopkins University, Baltimore, and Steven Galetta, MD, from NYU Grossman School of Medicine – praised the presentation.
Dr. Galetta questioned whether patients were receiving preventive therapies. Dr. Kuruvilla said that the patients were allowed to enter the trial while taking preventive therapies, including antiepileptic treatments, blood pressure medications, and antidepressants, but that they had to be receiving stable doses.
The investigators didn’t distinguish between participants who were taking preventive therapies and those who weren’t, she said. “The aim was really to look at acute treatment for migraine,” and patients taking such medication “had been stable on their regimen for a pretty prolonged period of time.”
Dr. McArthur asked about the origin of the nausea some patients experienced.
It was difficult to determine whether the nausea was an aspect of an individual patient’s migraine attack or was an effect of the stimulation, said Dr. Kuruvilla. She noted that some patients found the vibrating sensation from the device uncomfortable and that nausea could be associated with pain at the site.
The device costs $300 to $400 (U.S.) and is available over the counter.
Dr. Kuruvilla is a consultant for Cefaly, Neurolief, Theranica, Now What Media, and Kx Advisors. She is on the speakers bureau for AbbVie/Allergan, Amgen/Novartis, Lilly, the American Headache Society, Biohaven, and CME meeting, and she is on an advisory board at AbbVie/Allergan, Lilly, Theranica, and Amgen/Novartis. She is editor and associate editor of Healthline and is an author for WebMD/Medscape, Healthline.
A version of this article first appeared on Medscape.com.
FROM ANA
FDA approves combo pill for severe, acute pain
enough to require an opioid analgesic and for which alternative treatments fail to provide adequate pain relief.
Celecoxib is a nonsteroidal anti-inflammatory drug and tramadol is an opioid agonist. Seglentis contains 56 mg of celecoxib and 44 mg of tramadol.
“The unique co-crystal formulation of Seglentis provides effective pain relief via a multimodal approach,” Craig A. Sponseller, MD, chief medical officer of Kowa Pharmaceuticals America, said in a news release.
Esteve Pharmaceuticals has entered into an agreement with Kowa Pharmaceuticals America to commercialize the pain medicine in the United States, with a launch planned for early 2022.
“Seglentis uses four different and complementary mechanisms of analgesia and offers healthcare providers an important option to treat acute pain in adults that is severe enough to require opioid treatment and for which alternative treatments are inadequate,” Dr. Sponseller said.
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, the FDA will require a Risk Evaluation and Mitigation Strategy (REMS) for Seglentis.
The label states that the drug should be initiated as two tablets every 12 hours as needed and should be prescribed for the shortest duration consistent with individual patient treatment goals.
Patients should be monitored for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with Seglentis.
Prescribers should discuss naloxone (Narcan) with patients and consider prescribing the opioid antagonist naloxone based on the patient’s risk factors for overdose.
Full prescribing information is available online.
A version of this article was first published on Medscape.com.
enough to require an opioid analgesic and for which alternative treatments fail to provide adequate pain relief.
Celecoxib is a nonsteroidal anti-inflammatory drug and tramadol is an opioid agonist. Seglentis contains 56 mg of celecoxib and 44 mg of tramadol.
“The unique co-crystal formulation of Seglentis provides effective pain relief via a multimodal approach,” Craig A. Sponseller, MD, chief medical officer of Kowa Pharmaceuticals America, said in a news release.
Esteve Pharmaceuticals has entered into an agreement with Kowa Pharmaceuticals America to commercialize the pain medicine in the United States, with a launch planned for early 2022.
“Seglentis uses four different and complementary mechanisms of analgesia and offers healthcare providers an important option to treat acute pain in adults that is severe enough to require opioid treatment and for which alternative treatments are inadequate,” Dr. Sponseller said.
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, the FDA will require a Risk Evaluation and Mitigation Strategy (REMS) for Seglentis.
The label states that the drug should be initiated as two tablets every 12 hours as needed and should be prescribed for the shortest duration consistent with individual patient treatment goals.
Patients should be monitored for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with Seglentis.
Prescribers should discuss naloxone (Narcan) with patients and consider prescribing the opioid antagonist naloxone based on the patient’s risk factors for overdose.
Full prescribing information is available online.
A version of this article was first published on Medscape.com.
enough to require an opioid analgesic and for which alternative treatments fail to provide adequate pain relief.
Celecoxib is a nonsteroidal anti-inflammatory drug and tramadol is an opioid agonist. Seglentis contains 56 mg of celecoxib and 44 mg of tramadol.
“The unique co-crystal formulation of Seglentis provides effective pain relief via a multimodal approach,” Craig A. Sponseller, MD, chief medical officer of Kowa Pharmaceuticals America, said in a news release.
Esteve Pharmaceuticals has entered into an agreement with Kowa Pharmaceuticals America to commercialize the pain medicine in the United States, with a launch planned for early 2022.
“Seglentis uses four different and complementary mechanisms of analgesia and offers healthcare providers an important option to treat acute pain in adults that is severe enough to require opioid treatment and for which alternative treatments are inadequate,” Dr. Sponseller said.
Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, the FDA will require a Risk Evaluation and Mitigation Strategy (REMS) for Seglentis.
The label states that the drug should be initiated as two tablets every 12 hours as needed and should be prescribed for the shortest duration consistent with individual patient treatment goals.
Patients should be monitored for respiratory depression, especially within the first 24 to 72 hours of initiating therapy with Seglentis.
Prescribers should discuss naloxone (Narcan) with patients and consider prescribing the opioid antagonist naloxone based on the patient’s risk factors for overdose.
Full prescribing information is available online.
A version of this article was first published on Medscape.com.
Sleep apnea has many faces
Fortunately her problem stemmed from sleep apnea, and resolved with continuous positive airway pressure (CPAP) therapy.
Wallace and Bucks performed a meta analysis of 42 studies of memory in patients with sleep apnea and found sleep apnea patients were impaired when compared to healthy controls on verbal episodic memory (immediate recall, delayed recall, learning, and recognition) and visuospatial episodic memory (immediate and delayed recall).1 A meta-analysis by Olaithe and associates found an improvement in executive function in patients with sleep apnea who were treated with CPAP.2 I think this is worth considering especially in your patients who have subjective memory disturbances and do not appear to have a mild cognitive impairment or dementia.
About 15 years ago I saw a 74-year-old man for nocturia. He had seen two urologists and had a transurethral resection of the prostate (TURP) without any real change in his nocturia. I trialed him on all sorts of medications, and he seemed to improve temporarily a little on trazodone (went from seven episodes a night to four).
Eventually, after several years, I sent him for a sleep study. He had severe sleep apnea (Apnea Hypopnea Index, 65; O2 saturations as low as 60%). With treatment, his nocturia resolved. He went from seven episodes to two each night.
Zhou and colleagues performed a meta-analysis of 13 studies looking at the association of sleep apnea with nocturia.3 They found that men with sleep apnea have a high incidence of nocturia.
Miyazato and colleagues looked at the effect of CPAP treatment on nighttime urine production in patients with obstructive sleep apnea.4 In this small study of 40 patients, mean nighttime voiding episodes decreased from 2.1 to 1.2 (P < .01).
I have seen several patients with night sweats who ended up having sleep apnea. These patients have had a resolution of their night sweats with sleep apnea treatment.
Arnardottir and colleagues found that obstructive sleep apnea was associated with frequent nocturnal sweating.5 They found that 31% of men and 33% of women with OSA had nocturnal sweating, compared with about 10% of the general population.
When the OSA patients were treated with positive airway pressure, the prevalence of nocturnal sweating decreased to 11.5%, which is similar to general population numbers. Given how common both sleep apnea and night sweats are, this is an important consideration as you evaluate night sweats.
I have seen many patients who have had atrial fibrillation and sleep apnea. Shapira-Daniels and colleagues did a prospective study of 188 patients with atrial fibrillation without a history of sleep apnea who were referred for ablation.6 All patients had home sleep studies, and testing was consistent with sleep apnea in 82% of patients.
Kanagala and associates found that patients with untreated sleep apnea had a greater chance of recurrent atrial fibrillation after cardioversion.7 Recurrence of atrial fibrillation at 12 months was 82% in untreated OSA patients, higher than the 42% recurrence in the treated OSA group (P = .013) and the 53% recurrence in control patients.
I think sleep apnea evaluation should be strongly considered in patients with atrial fibrillation and should be done before referral for ablations.
Pearl: Consider sleep apnea as a possible cause of or contributing factor to the common primary care problems of cognitive concerns, nocturia, night sweats, and atrial fibrillation.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as 3rd-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.
References
1. Wallace A and Bucks RS. Memory and obstructive sleep apnea: a meta-analysis. Sleep. 2013;36(2):203. Epub 2013 Feb 1.
2. Olaithe M and Bucks RS. Executive dysfunction in OSA before and after treatment: a meta-analysis. Sleep. 2013;36(9):1297. Epub 2013 Sep 1.
3. Zhou J et al. Association between obstructive sleep apnea syndrome and nocturia: a meta-analysis. Sleep Breath. 2020 Dec;24(4):1293-8.
4. Miyauchi Y et al. Effect of the continuous positive airway pressure on the nocturnal urine volume or night-time frequency in patients with obstructive sleep apnea syndrome. Urology 2015;85:333.
5. Arnardottir ES et al. Nocturnal sweating–a common symptom of obstructive sleep apnoea: the Icelandic sleep apnoea cohort. BMJ Open. 2013 May 14;3(5):e002795. BMJ Open 2013;3:e002795
6. Shapira-Daniels A et al. Prevalence of undiagnosed sleep apnea in patients with atrial fibrillation and its impact on therapy. JACC Clin Electrophysiol. 2020;6(12):1499. Epub 2020 Aug 12.
7. Kanagala R et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107(20):2589. Epub 2003 May 12.
Fortunately her problem stemmed from sleep apnea, and resolved with continuous positive airway pressure (CPAP) therapy.
Wallace and Bucks performed a meta analysis of 42 studies of memory in patients with sleep apnea and found sleep apnea patients were impaired when compared to healthy controls on verbal episodic memory (immediate recall, delayed recall, learning, and recognition) and visuospatial episodic memory (immediate and delayed recall).1 A meta-analysis by Olaithe and associates found an improvement in executive function in patients with sleep apnea who were treated with CPAP.2 I think this is worth considering especially in your patients who have subjective memory disturbances and do not appear to have a mild cognitive impairment or dementia.
About 15 years ago I saw a 74-year-old man for nocturia. He had seen two urologists and had a transurethral resection of the prostate (TURP) without any real change in his nocturia. I trialed him on all sorts of medications, and he seemed to improve temporarily a little on trazodone (went from seven episodes a night to four).
Eventually, after several years, I sent him for a sleep study. He had severe sleep apnea (Apnea Hypopnea Index, 65; O2 saturations as low as 60%). With treatment, his nocturia resolved. He went from seven episodes to two each night.
Zhou and colleagues performed a meta-analysis of 13 studies looking at the association of sleep apnea with nocturia.3 They found that men with sleep apnea have a high incidence of nocturia.
Miyazato and colleagues looked at the effect of CPAP treatment on nighttime urine production in patients with obstructive sleep apnea.4 In this small study of 40 patients, mean nighttime voiding episodes decreased from 2.1 to 1.2 (P < .01).
I have seen several patients with night sweats who ended up having sleep apnea. These patients have had a resolution of their night sweats with sleep apnea treatment.
Arnardottir and colleagues found that obstructive sleep apnea was associated with frequent nocturnal sweating.5 They found that 31% of men and 33% of women with OSA had nocturnal sweating, compared with about 10% of the general population.
When the OSA patients were treated with positive airway pressure, the prevalence of nocturnal sweating decreased to 11.5%, which is similar to general population numbers. Given how common both sleep apnea and night sweats are, this is an important consideration as you evaluate night sweats.
I have seen many patients who have had atrial fibrillation and sleep apnea. Shapira-Daniels and colleagues did a prospective study of 188 patients with atrial fibrillation without a history of sleep apnea who were referred for ablation.6 All patients had home sleep studies, and testing was consistent with sleep apnea in 82% of patients.
Kanagala and associates found that patients with untreated sleep apnea had a greater chance of recurrent atrial fibrillation after cardioversion.7 Recurrence of atrial fibrillation at 12 months was 82% in untreated OSA patients, higher than the 42% recurrence in the treated OSA group (P = .013) and the 53% recurrence in control patients.
I think sleep apnea evaluation should be strongly considered in patients with atrial fibrillation and should be done before referral for ablations.
Pearl: Consider sleep apnea as a possible cause of or contributing factor to the common primary care problems of cognitive concerns, nocturia, night sweats, and atrial fibrillation.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as 3rd-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.
References
1. Wallace A and Bucks RS. Memory and obstructive sleep apnea: a meta-analysis. Sleep. 2013;36(2):203. Epub 2013 Feb 1.
2. Olaithe M and Bucks RS. Executive dysfunction in OSA before and after treatment: a meta-analysis. Sleep. 2013;36(9):1297. Epub 2013 Sep 1.
3. Zhou J et al. Association between obstructive sleep apnea syndrome and nocturia: a meta-analysis. Sleep Breath. 2020 Dec;24(4):1293-8.
4. Miyauchi Y et al. Effect of the continuous positive airway pressure on the nocturnal urine volume or night-time frequency in patients with obstructive sleep apnea syndrome. Urology 2015;85:333.
5. Arnardottir ES et al. Nocturnal sweating–a common symptom of obstructive sleep apnoea: the Icelandic sleep apnoea cohort. BMJ Open. 2013 May 14;3(5):e002795. BMJ Open 2013;3:e002795
6. Shapira-Daniels A et al. Prevalence of undiagnosed sleep apnea in patients with atrial fibrillation and its impact on therapy. JACC Clin Electrophysiol. 2020;6(12):1499. Epub 2020 Aug 12.
7. Kanagala R et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107(20):2589. Epub 2003 May 12.
Fortunately her problem stemmed from sleep apnea, and resolved with continuous positive airway pressure (CPAP) therapy.
Wallace and Bucks performed a meta analysis of 42 studies of memory in patients with sleep apnea and found sleep apnea patients were impaired when compared to healthy controls on verbal episodic memory (immediate recall, delayed recall, learning, and recognition) and visuospatial episodic memory (immediate and delayed recall).1 A meta-analysis by Olaithe and associates found an improvement in executive function in patients with sleep apnea who were treated with CPAP.2 I think this is worth considering especially in your patients who have subjective memory disturbances and do not appear to have a mild cognitive impairment or dementia.
About 15 years ago I saw a 74-year-old man for nocturia. He had seen two urologists and had a transurethral resection of the prostate (TURP) without any real change in his nocturia. I trialed him on all sorts of medications, and he seemed to improve temporarily a little on trazodone (went from seven episodes a night to four).
Eventually, after several years, I sent him for a sleep study. He had severe sleep apnea (Apnea Hypopnea Index, 65; O2 saturations as low as 60%). With treatment, his nocturia resolved. He went from seven episodes to two each night.
Zhou and colleagues performed a meta-analysis of 13 studies looking at the association of sleep apnea with nocturia.3 They found that men with sleep apnea have a high incidence of nocturia.
Miyazato and colleagues looked at the effect of CPAP treatment on nighttime urine production in patients with obstructive sleep apnea.4 In this small study of 40 patients, mean nighttime voiding episodes decreased from 2.1 to 1.2 (P < .01).
I have seen several patients with night sweats who ended up having sleep apnea. These patients have had a resolution of their night sweats with sleep apnea treatment.
Arnardottir and colleagues found that obstructive sleep apnea was associated with frequent nocturnal sweating.5 They found that 31% of men and 33% of women with OSA had nocturnal sweating, compared with about 10% of the general population.
When the OSA patients were treated with positive airway pressure, the prevalence of nocturnal sweating decreased to 11.5%, which is similar to general population numbers. Given how common both sleep apnea and night sweats are, this is an important consideration as you evaluate night sweats.
I have seen many patients who have had atrial fibrillation and sleep apnea. Shapira-Daniels and colleagues did a prospective study of 188 patients with atrial fibrillation without a history of sleep apnea who were referred for ablation.6 All patients had home sleep studies, and testing was consistent with sleep apnea in 82% of patients.
Kanagala and associates found that patients with untreated sleep apnea had a greater chance of recurrent atrial fibrillation after cardioversion.7 Recurrence of atrial fibrillation at 12 months was 82% in untreated OSA patients, higher than the 42% recurrence in the treated OSA group (P = .013) and the 53% recurrence in control patients.
I think sleep apnea evaluation should be strongly considered in patients with atrial fibrillation and should be done before referral for ablations.
Pearl: Consider sleep apnea as a possible cause of or contributing factor to the common primary care problems of cognitive concerns, nocturia, night sweats, and atrial fibrillation.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as 3rd-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.
References
1. Wallace A and Bucks RS. Memory and obstructive sleep apnea: a meta-analysis. Sleep. 2013;36(2):203. Epub 2013 Feb 1.
2. Olaithe M and Bucks RS. Executive dysfunction in OSA before and after treatment: a meta-analysis. Sleep. 2013;36(9):1297. Epub 2013 Sep 1.
3. Zhou J et al. Association between obstructive sleep apnea syndrome and nocturia: a meta-analysis. Sleep Breath. 2020 Dec;24(4):1293-8.
4. Miyauchi Y et al. Effect of the continuous positive airway pressure on the nocturnal urine volume or night-time frequency in patients with obstructive sleep apnea syndrome. Urology 2015;85:333.
5. Arnardottir ES et al. Nocturnal sweating–a common symptom of obstructive sleep apnoea: the Icelandic sleep apnoea cohort. BMJ Open. 2013 May 14;3(5):e002795. BMJ Open 2013;3:e002795
6. Shapira-Daniels A et al. Prevalence of undiagnosed sleep apnea in patients with atrial fibrillation and its impact on therapy. JACC Clin Electrophysiol. 2020;6(12):1499. Epub 2020 Aug 12.
7. Kanagala R et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107(20):2589. Epub 2003 May 12.
What I will and won’t miss
Someday I plan to retire.
Hopefully it’s not coming up anytime soon, but I’m sure it’s sooner than I realize. I’ve been in practice for 23 years, so I’m well past the halfway point of an average medical career.
I will miss a lot. There will be many things I won’t miss, but the job has far more good than bad, even today.
I’ve spent a lot of time at this huge desk, which my dad bought for his solo law practice in 1967. Although I won’t miss the lack of sleep, I will miss the silence of getting to the office before first light, making tea, and getting started for the day. It’s a peaceful daily start in a less-then-predictable job.
I’ll miss my patients. Not all of them, but most. The majority are decent people, and it’s an honor to be able to help them. Doing that has been the driving force that started me on this path a long time ago and still keeps me moving forward.
In some respects I’ll feel bad about retiring and leaving them. Some have been with me since residency. It will bother me that they’ll have to start over with a new neurologist. Hopefully that person will give them care as good, if not better, than I have.
I’ll really miss my staff. I’ve been lucky. They’re awesome, and have stayed with me for this crazy ride. My MA has been here since 1999, my secretary since 2004. At work they’re my family. Away from work they’re a part of my family. The three of us have survived my hospital call, good economic times, bad economic times, moving the office, my MA moving to the boondocks, the antics and events of our kids, and, as of now, a pandemic. They make the day fun. I’ll feel bad that they’ll need to change jobs if they’re still working then.
What I won’t miss are more concrete things – the endless forms, time spent on the phone and online to get medications and tests approved, the difficult (personality wise) patients who think being nasty and mean is going to get them better care, and having to practice CYA defensive medicine.
It’s good to look back after 23 years, and still have, overall, no regrets about choosing this ride.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Someday I plan to retire.
Hopefully it’s not coming up anytime soon, but I’m sure it’s sooner than I realize. I’ve been in practice for 23 years, so I’m well past the halfway point of an average medical career.
I will miss a lot. There will be many things I won’t miss, but the job has far more good than bad, even today.
I’ve spent a lot of time at this huge desk, which my dad bought for his solo law practice in 1967. Although I won’t miss the lack of sleep, I will miss the silence of getting to the office before first light, making tea, and getting started for the day. It’s a peaceful daily start in a less-then-predictable job.
I’ll miss my patients. Not all of them, but most. The majority are decent people, and it’s an honor to be able to help them. Doing that has been the driving force that started me on this path a long time ago and still keeps me moving forward.
In some respects I’ll feel bad about retiring and leaving them. Some have been with me since residency. It will bother me that they’ll have to start over with a new neurologist. Hopefully that person will give them care as good, if not better, than I have.
I’ll really miss my staff. I’ve been lucky. They’re awesome, and have stayed with me for this crazy ride. My MA has been here since 1999, my secretary since 2004. At work they’re my family. Away from work they’re a part of my family. The three of us have survived my hospital call, good economic times, bad economic times, moving the office, my MA moving to the boondocks, the antics and events of our kids, and, as of now, a pandemic. They make the day fun. I’ll feel bad that they’ll need to change jobs if they’re still working then.
What I won’t miss are more concrete things – the endless forms, time spent on the phone and online to get medications and tests approved, the difficult (personality wise) patients who think being nasty and mean is going to get them better care, and having to practice CYA defensive medicine.
It’s good to look back after 23 years, and still have, overall, no regrets about choosing this ride.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Someday I plan to retire.
Hopefully it’s not coming up anytime soon, but I’m sure it’s sooner than I realize. I’ve been in practice for 23 years, so I’m well past the halfway point of an average medical career.
I will miss a lot. There will be many things I won’t miss, but the job has far more good than bad, even today.
I’ve spent a lot of time at this huge desk, which my dad bought for his solo law practice in 1967. Although I won’t miss the lack of sleep, I will miss the silence of getting to the office before first light, making tea, and getting started for the day. It’s a peaceful daily start in a less-then-predictable job.
I’ll miss my patients. Not all of them, but most. The majority are decent people, and it’s an honor to be able to help them. Doing that has been the driving force that started me on this path a long time ago and still keeps me moving forward.
In some respects I’ll feel bad about retiring and leaving them. Some have been with me since residency. It will bother me that they’ll have to start over with a new neurologist. Hopefully that person will give them care as good, if not better, than I have.
I’ll really miss my staff. I’ve been lucky. They’re awesome, and have stayed with me for this crazy ride. My MA has been here since 1999, my secretary since 2004. At work they’re my family. Away from work they’re a part of my family. The three of us have survived my hospital call, good economic times, bad economic times, moving the office, my MA moving to the boondocks, the antics and events of our kids, and, as of now, a pandemic. They make the day fun. I’ll feel bad that they’ll need to change jobs if they’re still working then.
What I won’t miss are more concrete things – the endless forms, time spent on the phone and online to get medications and tests approved, the difficult (personality wise) patients who think being nasty and mean is going to get them better care, and having to practice CYA defensive medicine.
It’s good to look back after 23 years, and still have, overall, no regrets about choosing this ride.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Tramadol linked to higher risk of mortality, compared with codeine
Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.
Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.
However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.
“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.
Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”
The paper was published Oct. 19 in JAMA.
Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.
In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.
But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.
In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.
They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.
After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.
The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)
Higher risk of adverse outcomes
As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).
A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
Potential for confounding
Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.
“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”
For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.
“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”
But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”
Perceived safety
In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”
“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.
Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.
The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
A version of this article first appeared on Medscape.com.
Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.
Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.
However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.
“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.
Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”
The paper was published Oct. 19 in JAMA.
Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.
In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.
But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.
In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.
They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.
After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.
The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)
Higher risk of adverse outcomes
As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).
A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
Potential for confounding
Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.
“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”
For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.
“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”
But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”
Perceived safety
In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”
“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.
Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.
The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
A version of this article first appeared on Medscape.com.
Tramadol is increasingly used to manage chronic noncancer pain, but as compared with opioids, it appears to be linked to a higher risk for adverse outcomes, according to new data.
Among a cohort of patients who received a prescription for either tramadol or codeine for orthopedic-related pain, tramadol was significantly associated with a higher risk of mortality, cardiovascular events, and fractures.
However, there was no significant difference in the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders between the two drugs.
“However, this is a retrospective cohort study, and despite it providing information that would otherwise be impossible to gather – such as from randomized controlled trials – clinicians should not solely base their decision on this study,” cautioned lead author Carlen Reyes, MD, PhD, of the Institut Universitari d’Investigació en Atenció Primària (IDIAP Jordi Gol), Barcelona.
Dr. Reyes noted that the intake of tramadol and codeine was analyzed using the number of “packages” that were dispensed, as an approximation of the real intake. “Logically we could think that the more packages dispensed of one drug, the more dose the patient is taking, but this is not always true given the availability of different doses commercialized of tramadol and different doses prescribed,” she said. “Given that we did not account for the real dose prescribed, we can only suspect an increased risk of these outcomes and reinforce the need for further prospective studies with more specific dose-response analysis comparing tramadol and codeine.”
The paper was published Oct. 19 in JAMA.
Tramadol has been considered to be a relatively safe opioid and was even strongly recommended by the American Academy of Orthopaedic Surgeons for patients experiencing symptomatic knee osteoarthritis. The authors point out that studies looking at opioid use from 2019 to 2020 show that tramadol was the most prescribed opioid in England, the Netherlands, and Spain.
In the United States, the age-adjusted rate of drug overdose deaths from synthetic opioids rose from 1.0 per 100 000 in 2013 to 11.4 in 2019. Most of these deaths were attributable to fentanyl but some were also related to tramadol.
But despite its wide use in managing chronic noncancer pain, results of recent studies suggest adverse outcomes as compared with other agents. Last year, one study found that older patients who received tramadol had a significant increase in the risk of hip fracture vs. those using NSAIDs or codeine. Another study, also published in 2020, showed that patients with osteoarthritis who were treated with tramadol had a 20%-50% higher risk of dying during the first year of treatment than did patients who were treated with NSAIDs.
In the current paper, Dr. Reyes and colleagues evaluated the association of tramadol with mortality and other adverse clinical outcomes in outpatient settings, compared with codeine.
They conducted a retrospective, population-based, propensity score–matched cohort study using a primary care database that routinely collects medical records and pharmacy dispensations for more than 80% of the population of Catalonia, Spain. The cohort included people 18 years or older who had been prescribed tramadol or codeine from 2007 to 2017 and were followed up to Dec. 31, 2017.
After propensity score matching, the final analysis included 368,960 participants: 184,480 in the tramadol arm and 184,480 in the codeine arm.
The mean age of patients was 52.7 years in the tramadol arm and 53.5 years in the codeine arm, and the prevalence of cancer was 3.2% and 3.3%, respectively. The most common diagnoses in this cohort were back pain (47.5% vs. 48.5%), neck/shoulder pain (28.6% vs. 29.5%), and osteoarthritis (15.3% vs. 15.5%). The most commonly used drugs were ibuprofen (34.4% vs. 34.3%) and paracetamol/acetaminophen (37.1% vs. 36.8%)
Higher risk of adverse outcomes
As compared with codeine, tramadol use was significantly associated with a higher risk of mortality (13.00 vs. 5.61 per 1,000 person-years; hazard ratio, 2.31; 95% confidence interval, 2.08-2.56); absolute rate differences (7.37 per 1,000 person-years; 95% CI, 6.09-8.78), cardiovascular events (10.03 vs. 8.67 per 1,000 person-years; HR, 1.15; 95% CI, 1.05-1.27; ARD, 1.36 per 1,000 person-years; 95% CI, 0.45-2.36), and fractures (12.26 vs. 8.13 per 1,000 person-years; HR, 1.50; 95% CI, 1.37-1.65; ARD, 4.10 per 1,000 person-years; 95% CI, 3.02-5.29).
A subgroup and sensitivity analysis showed that the increased mortality risk associated with tramadol was significantly higher in younger persons vs. older ones (HR, 3.14; 95% CI, 1.82-5.41 vs. 2.39; 95% CI, 2.20-2.60]; P < .001 for interaction). In addition, women had a significantly greater risk of cardiovascular events versus men (HR, 1.32; 95% CI, 1.19-1.46] vs. 1.03; 95% CI, 0.9-1.13]; P < .001 for interaction).
Potential for confounding
Weighing in on the data, Daniel Solomon, MD, MPH, chief of clinical sciences, division of rheumatology, Brigham and Women’s Hospital, and professor of medicine, Harvard Medical School, Boston, noted that because it is extremely unlikely that anyone will ever conduct a large, head-to-head safety trial comparing different opioids, the results of this paper are important to consider.
“However, as the authors appropriately caution, this type of analysis is limited by the strong potential for residual confounding,” he said. “In other words, even though the authors used state-of-the-art methods to limit imbalances between the patients initiating tramadol versus codeine, there is strong reason to believe that imbalances that may account for the differences in adverse events exist.”
For example, he noted that if one looks at the distribution of comorbid conditions in the before-matching group, tramadol initiators demonstrate a higher frequency of chronic kidney disease, diabetes, and overall chronic comorbid diseases. “This suggests to me that prescribers apply selection criteria when choosing who to prescribe which opioid,” Dr. Solomon explained.
“While the authors’ use of propensity score matching limits confounding, it only can improve balance for measured confounders,” he said. “Other factors not measured in this type of data set – blood pressure, pain, physical activity, tobacco use, body mass index – may still demonstrate imbalances even after matching.”
But after these limitations are taken into consideration, the results remain concerning, Dr. Solomon emphasized, particularly the all-cause mortality excess of tramadol versus codeine users. “This study did not include cause of death, which would help the reader understand why users of tramadol were dying more frequently,” he added. “It also might help in understanding whether this is a true biologic effect or residual confounding.”
Perceived safety
In an accompanying editorial, Howard S. Kim, MD, MS, and colleagues from Northwestern University, Chicago, write that the greatest risk of tramadol may involve the perception that it is “inherently safer than other opioids.”
“In actuality, the mechanisms of action and variable metabolism of tramadol in a given population create considerable therapeutic uncertainty and introduce additional risk exposure,” they say, as demonstrated in the current study.
Therefore, when clinicians determine that an opioid is needed for pain relief, it may be a better option to select a pure opioid agonist that has a more predictable therapeutic effect and known adverse effect profile, such as morphine or hydrocodone. “This would allow clinicians and patients to more properly weigh the risks and benefits of initiating opioid therapy through shared decision-making and prompt the level of counseling on safe use, storage, and disposal practices that all opioids deserve,” write the editorialists.
The study was funded by the Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina. The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Reyes has disclosed no relevant financial relationships. Dr. Solomon disclosed salary support from research contracts to his hospital from Amgen, AbbVie, Moderna, the Rheumatology Research Foundation, and National Institutes of Health; and royalties from UpToDate. Dr. Kim reported unrelated grant support from the Agency for Healthcare Research and Quality.
A version of this article first appeared on Medscape.com.
MS and (non-COVID) vaccinations: consensus recommendations
by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN).
The document, announced at the annual ECTRIMS meeting, proposes a standard for vaccination in patients with MS, including a global vaccination strategy for the general MS patient population and selected subpopulations.
The document does not include any recommendations regarding vaccination against COVID-19, which is the subject of a separate report, announced at the annual meeting.
The main conclusions in the new report are as follows:
- Vaccinations in general are considered safe for patients with MS and do not modify disease activity/progression.
- Live attenuated vaccines, however, are contraindicated with immunosuppressants.
- Inactivated vaccines can be used safely, but their efficacy may be decreased with immunosuppressants.
- Vaccinations should be considered early in MS management before using immunosuppressants whenever possible.
Presenting the vaccination consensus document, Susana Otero-Romero, MD, from the Multiple Sclerosis Center of Catalonia, Spain, explained that vaccination has become an important part of the risk management strategy in patients with MS treated with highly active drugs but that questions remain as to when and whether to introduce a particular vaccine and which disease-modifying treatments affect vaccine response.
“The current reference tool has been developed to help professionals to decide on the best vaccination strategy for their patients,” she said.
The consensus document recommends that, in general, vaccination should be performed at the time of diagnosis of MS or in the early stages of the disease to prevent future delays in starting therapies.
“Ideally, vaccination should take place before the onset of disease-modifying treatment,” Dr. Otero-Romero said. The consensus document recommends inactivated vaccines to be given 2-3 weeks before immunosuppressive therapy is started, and live attenuated vaccines at least 4 weeks beforehand.
In the case of relapse, vaccination should be delayed until clinical resolution or stabilization if possible, the consensus statement recommends.
Serological testing for vaccine-induced antibody titers can be performed 1-2 months after the last dose of the vaccine (suggested for hepatitis B, measles, mumps, and varicella). For attenuated live vaccines, serological tests should be done before starting immunosuppressive therapy. In the case of insufficient response, consideration should be given to administering a booster dose of the vaccine, except for hepatitis B, in which a complete revaccination is recommended, according to the document.
As for vaccination during immunosuppressive therapy, this is considered safe for patients on interferon or glatiramer acetate when indicated, the report says.
Vaccination should ideally be avoided in patients on dimethyl fumarate, teriflunomide (Aubagio) or natalizumab (Tysabri), although it can be considered in exceptional cases when the potential risk of acquiring the infection is greater than the risk of developing vaccine-related infections (unless the absolute lymphocyte count is below 800/mm3), it adds.
Vaccination should be avoided in patients on S1P modulators (for example, fingolimod [Gilenya]), anti-CD20 therapies, and before immune restoration for cladribine (Leustatin) and alemtuzumab (Lemtrada).
In the case of patients stopping immunosuppressive therapy, inactivated vaccines can be given any time after the discontinuation of therapy but preferably after immune restoration. Live attenuated vaccines should only be administered after a safety interval ensures immune restoration has been met.
Which vaccines?
On which vaccines are needed in patients with MS, the consensus document recommends the same routine vaccination schedule as for the general population. In addition, it advises influenza and pneumococcal vaccination if patients are immunosuppressed or have significant disability.
It also recommends human papillomavirus vaccine in women and men independent of their age if they are to be treated with alemtuzumab, fingolimod, cladribine, or anti-CD20 drugs. Hepatitis B vaccination is also advised in patients treated with anti-CD20 drugs.
Special populations: pregnancy/elderly
In patients with MS who are pregnant, inactivated flu vaccine can be given in any trimester at the start of the flu season, and vaccination against diphtheria, tetanus, and pertussis can be given during the third trimester, the report says. Live attenuated vaccines should be completed at least 1 month before pregnancy or after delivery and 4-6 weeks prior to the initiation of immunosuppressive therapy.
Elderly patients with MS should receive flu and pneumococcal vaccines annually and would also benefit from the inactivated herpes zoster vaccine.
Travel vaccines
On vaccinations needed for travel, the report recommends that patients with MS consult a specialized travel clinic or vaccination expert and start immunizations 2-3 months before departure. Patients with MS with or without immunosuppressive therapy can receive hepatitis A, rabies, Japanese encephalitis, tic-borne encephalitis, polio, and inactivated typhoid vaccine. But yellow fever and oral typhoid are contraindicated in patients on immunosuppressive therapies.
A version of this article first appeared on Medscape.com.
by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN).
The document, announced at the annual ECTRIMS meeting, proposes a standard for vaccination in patients with MS, including a global vaccination strategy for the general MS patient population and selected subpopulations.
The document does not include any recommendations regarding vaccination against COVID-19, which is the subject of a separate report, announced at the annual meeting.
The main conclusions in the new report are as follows:
- Vaccinations in general are considered safe for patients with MS and do not modify disease activity/progression.
- Live attenuated vaccines, however, are contraindicated with immunosuppressants.
- Inactivated vaccines can be used safely, but their efficacy may be decreased with immunosuppressants.
- Vaccinations should be considered early in MS management before using immunosuppressants whenever possible.
Presenting the vaccination consensus document, Susana Otero-Romero, MD, from the Multiple Sclerosis Center of Catalonia, Spain, explained that vaccination has become an important part of the risk management strategy in patients with MS treated with highly active drugs but that questions remain as to when and whether to introduce a particular vaccine and which disease-modifying treatments affect vaccine response.
“The current reference tool has been developed to help professionals to decide on the best vaccination strategy for their patients,” she said.
The consensus document recommends that, in general, vaccination should be performed at the time of diagnosis of MS or in the early stages of the disease to prevent future delays in starting therapies.
“Ideally, vaccination should take place before the onset of disease-modifying treatment,” Dr. Otero-Romero said. The consensus document recommends inactivated vaccines to be given 2-3 weeks before immunosuppressive therapy is started, and live attenuated vaccines at least 4 weeks beforehand.
In the case of relapse, vaccination should be delayed until clinical resolution or stabilization if possible, the consensus statement recommends.
Serological testing for vaccine-induced antibody titers can be performed 1-2 months after the last dose of the vaccine (suggested for hepatitis B, measles, mumps, and varicella). For attenuated live vaccines, serological tests should be done before starting immunosuppressive therapy. In the case of insufficient response, consideration should be given to administering a booster dose of the vaccine, except for hepatitis B, in which a complete revaccination is recommended, according to the document.
As for vaccination during immunosuppressive therapy, this is considered safe for patients on interferon or glatiramer acetate when indicated, the report says.
Vaccination should ideally be avoided in patients on dimethyl fumarate, teriflunomide (Aubagio) or natalizumab (Tysabri), although it can be considered in exceptional cases when the potential risk of acquiring the infection is greater than the risk of developing vaccine-related infections (unless the absolute lymphocyte count is below 800/mm3), it adds.
Vaccination should be avoided in patients on S1P modulators (for example, fingolimod [Gilenya]), anti-CD20 therapies, and before immune restoration for cladribine (Leustatin) and alemtuzumab (Lemtrada).
In the case of patients stopping immunosuppressive therapy, inactivated vaccines can be given any time after the discontinuation of therapy but preferably after immune restoration. Live attenuated vaccines should only be administered after a safety interval ensures immune restoration has been met.
Which vaccines?
On which vaccines are needed in patients with MS, the consensus document recommends the same routine vaccination schedule as for the general population. In addition, it advises influenza and pneumococcal vaccination if patients are immunosuppressed or have significant disability.
It also recommends human papillomavirus vaccine in women and men independent of their age if they are to be treated with alemtuzumab, fingolimod, cladribine, or anti-CD20 drugs. Hepatitis B vaccination is also advised in patients treated with anti-CD20 drugs.
Special populations: pregnancy/elderly
In patients with MS who are pregnant, inactivated flu vaccine can be given in any trimester at the start of the flu season, and vaccination against diphtheria, tetanus, and pertussis can be given during the third trimester, the report says. Live attenuated vaccines should be completed at least 1 month before pregnancy or after delivery and 4-6 weeks prior to the initiation of immunosuppressive therapy.
Elderly patients with MS should receive flu and pneumococcal vaccines annually and would also benefit from the inactivated herpes zoster vaccine.
Travel vaccines
On vaccinations needed for travel, the report recommends that patients with MS consult a specialized travel clinic or vaccination expert and start immunizations 2-3 months before departure. Patients with MS with or without immunosuppressive therapy can receive hepatitis A, rabies, Japanese encephalitis, tic-borne encephalitis, polio, and inactivated typhoid vaccine. But yellow fever and oral typhoid are contraindicated in patients on immunosuppressive therapies.
A version of this article first appeared on Medscape.com.
by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN).
The document, announced at the annual ECTRIMS meeting, proposes a standard for vaccination in patients with MS, including a global vaccination strategy for the general MS patient population and selected subpopulations.
The document does not include any recommendations regarding vaccination against COVID-19, which is the subject of a separate report, announced at the annual meeting.
The main conclusions in the new report are as follows:
- Vaccinations in general are considered safe for patients with MS and do not modify disease activity/progression.
- Live attenuated vaccines, however, are contraindicated with immunosuppressants.
- Inactivated vaccines can be used safely, but their efficacy may be decreased with immunosuppressants.
- Vaccinations should be considered early in MS management before using immunosuppressants whenever possible.
Presenting the vaccination consensus document, Susana Otero-Romero, MD, from the Multiple Sclerosis Center of Catalonia, Spain, explained that vaccination has become an important part of the risk management strategy in patients with MS treated with highly active drugs but that questions remain as to when and whether to introduce a particular vaccine and which disease-modifying treatments affect vaccine response.
“The current reference tool has been developed to help professionals to decide on the best vaccination strategy for their patients,” she said.
The consensus document recommends that, in general, vaccination should be performed at the time of diagnosis of MS or in the early stages of the disease to prevent future delays in starting therapies.
“Ideally, vaccination should take place before the onset of disease-modifying treatment,” Dr. Otero-Romero said. The consensus document recommends inactivated vaccines to be given 2-3 weeks before immunosuppressive therapy is started, and live attenuated vaccines at least 4 weeks beforehand.
In the case of relapse, vaccination should be delayed until clinical resolution or stabilization if possible, the consensus statement recommends.
Serological testing for vaccine-induced antibody titers can be performed 1-2 months after the last dose of the vaccine (suggested for hepatitis B, measles, mumps, and varicella). For attenuated live vaccines, serological tests should be done before starting immunosuppressive therapy. In the case of insufficient response, consideration should be given to administering a booster dose of the vaccine, except for hepatitis B, in which a complete revaccination is recommended, according to the document.
As for vaccination during immunosuppressive therapy, this is considered safe for patients on interferon or glatiramer acetate when indicated, the report says.
Vaccination should ideally be avoided in patients on dimethyl fumarate, teriflunomide (Aubagio) or natalizumab (Tysabri), although it can be considered in exceptional cases when the potential risk of acquiring the infection is greater than the risk of developing vaccine-related infections (unless the absolute lymphocyte count is below 800/mm3), it adds.
Vaccination should be avoided in patients on S1P modulators (for example, fingolimod [Gilenya]), anti-CD20 therapies, and before immune restoration for cladribine (Leustatin) and alemtuzumab (Lemtrada).
In the case of patients stopping immunosuppressive therapy, inactivated vaccines can be given any time after the discontinuation of therapy but preferably after immune restoration. Live attenuated vaccines should only be administered after a safety interval ensures immune restoration has been met.
Which vaccines?
On which vaccines are needed in patients with MS, the consensus document recommends the same routine vaccination schedule as for the general population. In addition, it advises influenza and pneumococcal vaccination if patients are immunosuppressed or have significant disability.
It also recommends human papillomavirus vaccine in women and men independent of their age if they are to be treated with alemtuzumab, fingolimod, cladribine, or anti-CD20 drugs. Hepatitis B vaccination is also advised in patients treated with anti-CD20 drugs.
Special populations: pregnancy/elderly
In patients with MS who are pregnant, inactivated flu vaccine can be given in any trimester at the start of the flu season, and vaccination against diphtheria, tetanus, and pertussis can be given during the third trimester, the report says. Live attenuated vaccines should be completed at least 1 month before pregnancy or after delivery and 4-6 weeks prior to the initiation of immunosuppressive therapy.
Elderly patients with MS should receive flu and pneumococcal vaccines annually and would also benefit from the inactivated herpes zoster vaccine.
Travel vaccines
On vaccinations needed for travel, the report recommends that patients with MS consult a specialized travel clinic or vaccination expert and start immunizations 2-3 months before departure. Patients with MS with or without immunosuppressive therapy can receive hepatitis A, rabies, Japanese encephalitis, tic-borne encephalitis, polio, and inactivated typhoid vaccine. But yellow fever and oral typhoid are contraindicated in patients on immunosuppressive therapies.
A version of this article first appeared on Medscape.com.
From ECTRIMS 2021
Rituximab more effective than other MS treatments?
, according to new research.
The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.
The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”
He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
COMBAT-MS study
Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.
They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.
The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
Rituximab reduced relapses
The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.
Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.
For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.
In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.
But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.
The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.
Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
‘The uncertainty continues’
“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.
Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.
“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”
The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.
The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.
Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”
But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.
“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”
The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.
A version of this article first appeared on Medscape.com.
, according to new research.
The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.
The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”
He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
COMBAT-MS study
Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.
They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.
The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
Rituximab reduced relapses
The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.
Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.
For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.
In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.
But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.
The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.
Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
‘The uncertainty continues’
“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.
Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.
“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”
The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.
The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.
Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”
But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.
“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”
The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.
A version of this article first appeared on Medscape.com.
, according to new research.
The risk for a first relapse was 6 times higher in patients receiving interferon beta or glatiramer acetate, compared with those receiving rituximab. But the level of disability at 3 years was only marginally different between the drugs studied.
The small differences in Expanded Disability Status Scale (EDSS) score are surprising, said investigator Peter Alping, a clinical assistant and doctoral student in the Department of Clinical Neuroscience at the Karolinska Institutet, Stockholm, as he presented the data. “It could be that we have too-short follow-up, so that EDSS doesn’t have time to diverge between therapies.”
He presented the findings at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
COMBAT-MS study
Direct comparisons of disease-modifying therapies (DMTs) for MS can help neurologists choose the most appropriate treatment for a given patient. To compare the effectiveness of the most common initial DMTs administered in Sweden, the researchers examined data from the COMBAT-MS study.
They identified all patients who initiated an injectable therapy (interferon beta or glatiramer acetate), dimethyl fumarate, natalizumab, or rituximab as a first treatment between Jan. 1, 2011, and Dec. 14, 2020. Eligible participants had prospectively recorded outcome data in the Swedish MS Register. Follow-up for a participant continued even if the participant stopped receiving therapy.
The investigators replaced missing data using multiple imputation. They adjusted for potential confounders using stabilized inverse probability of treatment weighting with baseline variables. These variables included age, sex, disease duration, geographical region, EDSS score, and relapses.
Rituximab reduced relapses
The researchers included 1,938 first-ever treatment episodes in their analysis. Of this group, 858 were associated with injectables, 339 with dimethyl fumarate, 269 with natalizumab, and 472 with rituximab.
Participants’ baseline characteristics differed by the DMT that they used. Patients who initiated natalizumab were the youngest, had the shortest disease duration, and had the most previous relapses.
For each outcome, the investigators compared all other therapies with rituximab. After they adjusted the data, they found that the hazard ratio for first relapse was 6.0 for injectables, 2.9 for dimethyl fumarate, and 1.8 for natalizumab.
In the adjusted model, the MRI lesion rate ratio for injectables, compared with rituximab, was 4.5. The rate ratio was 4.8 for dimethyl fumarate and 1.9 for natalizumab.
But differences in EDSS score at 3 years from treatment initiation were small. EDSS score in patients who received injectables was 0.24 points higher, compared with those receiving rituximab. EDSS score was 0.05 points higher in patients receiving dimethyl fumarate and 0.01 points lower in patients receiving natalizumab.
The risk for treatment discontinuation, however, differed significantly between therapies. The HR for treatment discontinuation was 32.7 for injectables, 20.3 for dimethyl fumarate, and 16.3 for natalizumab, compared with rituximab.
Among patients receiving dimethyl fumarate and injectables, the main reasons for discontinuing therapy were inadequate effect and adverse events. The main reason for discontinuation among patients receiving natalizumab was categorized as “other reason,” which mostly reflected John Cunningham virus positivity and concern for developing progressive multifocal leukoencephalopathy.
‘The uncertainty continues’
“These differences that we see in the effectiveness can be somewhat surprising, especially when it comes to natalizumab,” which is considered very effective, said Mr. Alping. The vulnerable period that occurs after switching from natalizumab may partly explain the difference. “This is something to keep in mind when starting patients on natalizumab treatment in the clinic,” Mr. Alping added.
Although rituximab is not indicated for MS, many clinics are using it in this population, said Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research at the Neurological Institute of Cleveland Clinic, both in Cleveland, Ohio. Dr. Fox was not involved in the study.
“Assessing the generalizability of the study outside Sweden will be important,” he added, “but I would be surprised if their findings did not hold up to external validation.”
The way that the researchers addressed missing data could affect the interpretation of the findings. “Depending upon how much data was missing, their imputation methods may have a high level of uncertainty,” said Dr. Fox.
The researchers’ adjustments for baseline differences also raise questions. “Even though MRI was an outcome, it doesn’t appear they adjusted for baseline differences in MRI between the groups,” Dr. Fox observed.
Moreover, the study was conducted over a long period of time. “We know there are time effects in MS, with a very different disease activity expected from patients over time,” said Dr. Fox. For example, relapse rates in placebo groups of MS trials tend to decline over time. “This time effect likely impacted their results.”
But the disability findings may be the most important part of the study, according to Dr. Fox. The lack of significant difference in disability progression between therapies “highlights that a couple relapses or lesions on MRI may be too small to translate into long-term differences in disability progression,” he said.
“The long-term implications of small differences in relapse and MRI outcomes may be very small,” Dr. Fox went on. “Thus, the uncertainty continues around escalation treatment versus initial highly effective treatment paradigms.”
The Patient-Centered Outcomes Research Institute, the Swedish Research Council, and NEURO Sweden funded this study. Mr. Alping disclosed no relevant financial relationships. Dr. Fox receives consulting fees from the companies that manufacture all the therapies analyzed in the study.
A version of this article first appeared on Medscape.com.
From ECTRIMS 2021
Sleep problems in mental illness highly pervasive
An inpatient psychiatric diagnosis at some point over a lifetime is significantly associated with a range of sleep problems, results from the largest study of its kind show.
A prior diagnosis of major depression, schizophrenia, anxiety, or bipolar disorder was associated with a later bedtime, earlier waking time, and significantly poorer sleep quality that included frequent awakenings during the night and shorter sleep bouts.
“We were struck by the pervasiveness of sleep problems across all the diagnoses of mental illness and sleep parameters we looked at,” study investigator Michael Wainberg, PhD, a postdoctoral fellow at the Krembil Centre for Neuroinformatics at the Center for Addiction and Mental Health (CAMH), Toronto, told this news organization. “This suggests there may need to be even more of an emphasis on sleep in these patients than there already is.”
The study, which includes data from nearly 90,000 adults in the United Kingdom, was published online October 12 in PLoS Medicine.
Trove of data
Data for the analysis comes from the UK Biobank, a large-scale biomedical database launched in 2006 that has collected biological and medical data on more than 500,000 individuals who consented to provide blood, urine, and saliva samples and detailed lifestyle information that is matched to their medical records.
Between 2013 and 2015, more than 103,000 of these participants agreed to wear accelerometers on their wrists for 24 hours a day for 7 days, collecting a trove of data for researchers to mine.
“This allows us to get at objectively derived sleep measures and to measure them in greater numbers of people who have experienced mental illness,” said senior author Shreejoy Tripathy, PhD, assistant professor at the University of Toronto and independent scientist for CAMH. “You can study multiple disorders at once and the influence of other variables that might not be possible in the context of other studies.”
The research is the first known large-scale transdiagnostic study of objectively measured sleep and mental health. Insomnia and other sleep disorders are common among people with mental illness, as shown in prior research, including at least one study that used the same dataset the team employed for this project.
The new findings add to that body of work, Dr. Wainberg said, and look beyond just how long a person sleeps to the quality of the sleep they get.
“We found that the metrics of sleep quality seem to be affected more than mere sleep duration,” he said.
Unexpected finding
After excluding participants with faulty accelerometers and those who didn’t wear them for the entire 7-day study period, data from 89,205 participants (aged 43-79, 56% female, 97% self-reported White) was included. Lifetime inpatient psychiatric diagnoses were reported in 2.5% of the entire cohort.
Researchers looked at 10 sleep measures: bedtime, wake-up time, sleep duration, wake after sleep onset, sleep efficiency, number of awakenings, duration of longest sleep bout, number of naps, and variability in bedtime and sleep duration.
Although the effect sizes were small, having any psychiatric diagnosis was associated with significantly lower scores on every sleep measure except sleep duration.
Compared with those with no inpatient psychiatric diagnosis, those with any psychiatric diagnosis were significantly more likely to:
- have a later bedtime (beta = 0.07; 95% confidence interval, 0.06-0.09)
- have later wake-up time (beta = 0.10; 95% CI, 0.09-0.11)
- wake after sleep onset (beta = 0.10; 95% CI, 0.09-0.12)
- have poorer sleep efficiency (beta = –0.12; 95% CI, −0.14 to −0.11)
- have more awakenings (beta = 0.10; 95% CI, 0.09-0.11)
- have shorter duration of their longest sleep bout (beta = –0.09; 95% CI, −0.11 to −0.08)
- take more naps (beta = 0.11; 95% CI, 0.09-0.12)
- have greater variability in their bedtime (beta = 0.08; 95% CI, 0.06-0.09)
- have greater variability in their sleep duration (beta = 0.10; 95% CI, 0.09-0.12)
The only significant differences in sleep duration were found in those with lifetime major depressive disorder, who slept significantly less (beta = −0.02; P = .003), and in those with lifetime schizophrenia, who slept significantly longer (beta = 0.02; P = .0008).
Researchers found similar results when they examined patient-reported sleep measures collected when participants enrolled in the biobank, long before they agreed to wear an accelerometer.
“Everyone with a lifetime mental illness diagnosis trended toward worse sleep quality, regardless of their diagnosis,” Dr. Tripathy said. “We didn’t expect to see that.”
Limitations of the biobank data prohibited analysis by age and past or current use of psychiatric medications. In addition, investigators were unable to determine whether mental illness was active or controlled at the time of the study. Information on these, and other factors, is needed to truly begin to understand the real-world status of sleep patterns in people with mental illness, the researchers note.
However, the biobank data demonstrates how this type of information can be collected, helping Dr. Tripathy and others to design a new study that will launch next year with patients at CAMH. This effort is part of the BrainHealth Databank, a project that aims to develop a patient data bank similar to the one in the UK that was used for this study.
“We’ve shown that you can use wearable devices to measure correlates of sleep and derive insights about the objective measurements of sleep and associate them with mental illness diagnosis,” Dr. Tripathy said.
The study received no outside funding. Dr. Wainberg and Dr. Tripathy report receiving funding from Kavli Foundation, Krembil Foundation, CAMH Discovery Fund, the McLaughlin Foundation, NSERC, and CIHR. Disclosures for other authors are fully listed in the original article.
A version of this article first appeared on Medscape.com.
An inpatient psychiatric diagnosis at some point over a lifetime is significantly associated with a range of sleep problems, results from the largest study of its kind show.
A prior diagnosis of major depression, schizophrenia, anxiety, or bipolar disorder was associated with a later bedtime, earlier waking time, and significantly poorer sleep quality that included frequent awakenings during the night and shorter sleep bouts.
“We were struck by the pervasiveness of sleep problems across all the diagnoses of mental illness and sleep parameters we looked at,” study investigator Michael Wainberg, PhD, a postdoctoral fellow at the Krembil Centre for Neuroinformatics at the Center for Addiction and Mental Health (CAMH), Toronto, told this news organization. “This suggests there may need to be even more of an emphasis on sleep in these patients than there already is.”
The study, which includes data from nearly 90,000 adults in the United Kingdom, was published online October 12 in PLoS Medicine.
Trove of data
Data for the analysis comes from the UK Biobank, a large-scale biomedical database launched in 2006 that has collected biological and medical data on more than 500,000 individuals who consented to provide blood, urine, and saliva samples and detailed lifestyle information that is matched to their medical records.
Between 2013 and 2015, more than 103,000 of these participants agreed to wear accelerometers on their wrists for 24 hours a day for 7 days, collecting a trove of data for researchers to mine.
“This allows us to get at objectively derived sleep measures and to measure them in greater numbers of people who have experienced mental illness,” said senior author Shreejoy Tripathy, PhD, assistant professor at the University of Toronto and independent scientist for CAMH. “You can study multiple disorders at once and the influence of other variables that might not be possible in the context of other studies.”
The research is the first known large-scale transdiagnostic study of objectively measured sleep and mental health. Insomnia and other sleep disorders are common among people with mental illness, as shown in prior research, including at least one study that used the same dataset the team employed for this project.
The new findings add to that body of work, Dr. Wainberg said, and look beyond just how long a person sleeps to the quality of the sleep they get.
“We found that the metrics of sleep quality seem to be affected more than mere sleep duration,” he said.
Unexpected finding
After excluding participants with faulty accelerometers and those who didn’t wear them for the entire 7-day study period, data from 89,205 participants (aged 43-79, 56% female, 97% self-reported White) was included. Lifetime inpatient psychiatric diagnoses were reported in 2.5% of the entire cohort.
Researchers looked at 10 sleep measures: bedtime, wake-up time, sleep duration, wake after sleep onset, sleep efficiency, number of awakenings, duration of longest sleep bout, number of naps, and variability in bedtime and sleep duration.
Although the effect sizes were small, having any psychiatric diagnosis was associated with significantly lower scores on every sleep measure except sleep duration.
Compared with those with no inpatient psychiatric diagnosis, those with any psychiatric diagnosis were significantly more likely to:
- have a later bedtime (beta = 0.07; 95% confidence interval, 0.06-0.09)
- have later wake-up time (beta = 0.10; 95% CI, 0.09-0.11)
- wake after sleep onset (beta = 0.10; 95% CI, 0.09-0.12)
- have poorer sleep efficiency (beta = –0.12; 95% CI, −0.14 to −0.11)
- have more awakenings (beta = 0.10; 95% CI, 0.09-0.11)
- have shorter duration of their longest sleep bout (beta = –0.09; 95% CI, −0.11 to −0.08)
- take more naps (beta = 0.11; 95% CI, 0.09-0.12)
- have greater variability in their bedtime (beta = 0.08; 95% CI, 0.06-0.09)
- have greater variability in their sleep duration (beta = 0.10; 95% CI, 0.09-0.12)
The only significant differences in sleep duration were found in those with lifetime major depressive disorder, who slept significantly less (beta = −0.02; P = .003), and in those with lifetime schizophrenia, who slept significantly longer (beta = 0.02; P = .0008).
Researchers found similar results when they examined patient-reported sleep measures collected when participants enrolled in the biobank, long before they agreed to wear an accelerometer.
“Everyone with a lifetime mental illness diagnosis trended toward worse sleep quality, regardless of their diagnosis,” Dr. Tripathy said. “We didn’t expect to see that.”
Limitations of the biobank data prohibited analysis by age and past or current use of psychiatric medications. In addition, investigators were unable to determine whether mental illness was active or controlled at the time of the study. Information on these, and other factors, is needed to truly begin to understand the real-world status of sleep patterns in people with mental illness, the researchers note.
However, the biobank data demonstrates how this type of information can be collected, helping Dr. Tripathy and others to design a new study that will launch next year with patients at CAMH. This effort is part of the BrainHealth Databank, a project that aims to develop a patient data bank similar to the one in the UK that was used for this study.
“We’ve shown that you can use wearable devices to measure correlates of sleep and derive insights about the objective measurements of sleep and associate them with mental illness diagnosis,” Dr. Tripathy said.
The study received no outside funding. Dr. Wainberg and Dr. Tripathy report receiving funding from Kavli Foundation, Krembil Foundation, CAMH Discovery Fund, the McLaughlin Foundation, NSERC, and CIHR. Disclosures for other authors are fully listed in the original article.
A version of this article first appeared on Medscape.com.
An inpatient psychiatric diagnosis at some point over a lifetime is significantly associated with a range of sleep problems, results from the largest study of its kind show.
A prior diagnosis of major depression, schizophrenia, anxiety, or bipolar disorder was associated with a later bedtime, earlier waking time, and significantly poorer sleep quality that included frequent awakenings during the night and shorter sleep bouts.
“We were struck by the pervasiveness of sleep problems across all the diagnoses of mental illness and sleep parameters we looked at,” study investigator Michael Wainberg, PhD, a postdoctoral fellow at the Krembil Centre for Neuroinformatics at the Center for Addiction and Mental Health (CAMH), Toronto, told this news organization. “This suggests there may need to be even more of an emphasis on sleep in these patients than there already is.”
The study, which includes data from nearly 90,000 adults in the United Kingdom, was published online October 12 in PLoS Medicine.
Trove of data
Data for the analysis comes from the UK Biobank, a large-scale biomedical database launched in 2006 that has collected biological and medical data on more than 500,000 individuals who consented to provide blood, urine, and saliva samples and detailed lifestyle information that is matched to their medical records.
Between 2013 and 2015, more than 103,000 of these participants agreed to wear accelerometers on their wrists for 24 hours a day for 7 days, collecting a trove of data for researchers to mine.
“This allows us to get at objectively derived sleep measures and to measure them in greater numbers of people who have experienced mental illness,” said senior author Shreejoy Tripathy, PhD, assistant professor at the University of Toronto and independent scientist for CAMH. “You can study multiple disorders at once and the influence of other variables that might not be possible in the context of other studies.”
The research is the first known large-scale transdiagnostic study of objectively measured sleep and mental health. Insomnia and other sleep disorders are common among people with mental illness, as shown in prior research, including at least one study that used the same dataset the team employed for this project.
The new findings add to that body of work, Dr. Wainberg said, and look beyond just how long a person sleeps to the quality of the sleep they get.
“We found that the metrics of sleep quality seem to be affected more than mere sleep duration,” he said.
Unexpected finding
After excluding participants with faulty accelerometers and those who didn’t wear them for the entire 7-day study period, data from 89,205 participants (aged 43-79, 56% female, 97% self-reported White) was included. Lifetime inpatient psychiatric diagnoses were reported in 2.5% of the entire cohort.
Researchers looked at 10 sleep measures: bedtime, wake-up time, sleep duration, wake after sleep onset, sleep efficiency, number of awakenings, duration of longest sleep bout, number of naps, and variability in bedtime and sleep duration.
Although the effect sizes were small, having any psychiatric diagnosis was associated with significantly lower scores on every sleep measure except sleep duration.
Compared with those with no inpatient psychiatric diagnosis, those with any psychiatric diagnosis were significantly more likely to:
- have a later bedtime (beta = 0.07; 95% confidence interval, 0.06-0.09)
- have later wake-up time (beta = 0.10; 95% CI, 0.09-0.11)
- wake after sleep onset (beta = 0.10; 95% CI, 0.09-0.12)
- have poorer sleep efficiency (beta = –0.12; 95% CI, −0.14 to −0.11)
- have more awakenings (beta = 0.10; 95% CI, 0.09-0.11)
- have shorter duration of their longest sleep bout (beta = –0.09; 95% CI, −0.11 to −0.08)
- take more naps (beta = 0.11; 95% CI, 0.09-0.12)
- have greater variability in their bedtime (beta = 0.08; 95% CI, 0.06-0.09)
- have greater variability in their sleep duration (beta = 0.10; 95% CI, 0.09-0.12)
The only significant differences in sleep duration were found in those with lifetime major depressive disorder, who slept significantly less (beta = −0.02; P = .003), and in those with lifetime schizophrenia, who slept significantly longer (beta = 0.02; P = .0008).
Researchers found similar results when they examined patient-reported sleep measures collected when participants enrolled in the biobank, long before they agreed to wear an accelerometer.
“Everyone with a lifetime mental illness diagnosis trended toward worse sleep quality, regardless of their diagnosis,” Dr. Tripathy said. “We didn’t expect to see that.”
Limitations of the biobank data prohibited analysis by age and past or current use of psychiatric medications. In addition, investigators were unable to determine whether mental illness was active or controlled at the time of the study. Information on these, and other factors, is needed to truly begin to understand the real-world status of sleep patterns in people with mental illness, the researchers note.
However, the biobank data demonstrates how this type of information can be collected, helping Dr. Tripathy and others to design a new study that will launch next year with patients at CAMH. This effort is part of the BrainHealth Databank, a project that aims to develop a patient data bank similar to the one in the UK that was used for this study.
“We’ve shown that you can use wearable devices to measure correlates of sleep and derive insights about the objective measurements of sleep and associate them with mental illness diagnosis,” Dr. Tripathy said.
The study received no outside funding. Dr. Wainberg and Dr. Tripathy report receiving funding from Kavli Foundation, Krembil Foundation, CAMH Discovery Fund, the McLaughlin Foundation, NSERC, and CIHR. Disclosures for other authors are fully listed in the original article.
A version of this article first appeared on Medscape.com.
Art therapy linked to slowed Parkinson’s progression
Adding art therapy to standard drug treatment in Parkinson’s disease (PD) not only improves severity of both motor and nonmotor symptoms, but also slows rates of disease progression, new research suggests.
Fifty PD patients were randomly assigned to receive either art therapy, including sculpting and drawing, plus drug therapy or drug therapy alone, and followed up over 12 months.
Patients receiving combined therapy experienced improvements in symptoms, depression, and cognitive scores, and had reduced tremor and daytime sleepiness. They were also substantially less likely to experience disease progression.
“The use of art therapy can reduce the severity of motor and nonmotor manifestations of Parkinson’s disease,” said study investigator Iryna Khubetova, MD, PhD, head of the neurology department, Odessa (Ukraine) Regional Clinical Hospital.
she added.
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
A promising approach
Dr. Khubetova told this news organization that offering art therapy to PD patients was “very affordable,” especially as professional artists “provided materials for painting and other art supplies free of charge.”
“We hope this approach is very promising and would be widely adopted.”
She suggested the positive effect of art therapy could be related to “activating the brain’s reward neural network.”
This may be via improved visual attention acting on visuospatial mechanisms and emotional drive, with “activation of the medial orbitofrontal cortex, ventral striatum, and other structures.”
The researchers note PD, a “multisystem progressive neurodegenerative disease,” is among the three most common neurological disorders, with an incidence of 100-150 cases per 100,000 people.
They also note that nonpharmacologic approaches are “widely used” as an adjunct to drug therapy and as part of an “integrated approach” to disease management.
To examine the clinical efficacy of art therapy, the team recruited patients with PD who had preserved facility for independent movement, defined as stages 1-2.5 on the Hoehn and Yahr scale.
Patients were randomly assigned to art therapy sessions alongside standard drug therapy or to standard drug therapy alone. The art therapy included sculpting, free drawing, and coloring patterns.
Multiple benefits
Participants were assessed at baseline and at 6 and 12 months with the Unified Parkinson Disease Rating Scale (UPDRS), the Beck Depression Inventory, the Montreal Cognitive Assessment, and the Pegboard Test of finger dexterity.
Fifty patients were included in the study, with 30 assigned to standard drug therapy alone and 20 to the combined intervention. Participants had a mean age of 57.8 years, and 46% were women.
Over the study period, investigators found patients assigned to art therapy plus drug treatment had improved mood, as well as decreased daytime sleeping, reduced tremor, and a decrease in anxiety and fear intensity.
Between baseline and the 6- and 12-month assessments, patients in the combined therapy group showed improvements in scores on all of the questionnaires, and on the Pegboard Test. In contrast, scores were either stable or worsened in the standard drug therapy–alone group.
The team notes that there was also a marked difference in rates of disease progression, defined as a change on the Hoehn and Yahr scale of at least 0.5 points, between the two groups.
Only two (10%) patients in the combined drug and art therapy progressed over the study period, compared with 10 (33%) in the control group (P = .05).
The findings complement those of a recent study conducted by Alberto Cucca, MD, of the Fresco Institute for Parkinson’s and Movement Disorders, New York University, and colleagues.
Eighteen patients took part in the prospective, open-label trial. They were assessed before and after 20 sessions of art therapy on a range of measures.
Results revealed that following the art therapy, patients had improvements in the Navon Test (which assesses visual neglect, eye tracking, and UPDRS scores), as well as significantly increased functional connectivity levels in the visual cortex on resting-state functional MRI.
Many benefits, no side effects
Rebecca Gilbert, MD, PhD, vice president and chief scientific officer of the American Parkinson Disease Association, who was not involved in either study, told this news organization that the idea of art therapy for patients with Parkinson’s is “very reasonable.”
She highlighted that “people with Parkinson’s have many issues with their visuospatial abilities,” as well as their depth and distance perception, and so “enhancing that aspect could potentially be very beneficial.”
“So I’m hopeful that it’s a really good avenue to explore, and the preliminary data are very exciting.”
Dr. Gilbert also highlighted that the “wonderful” aspect of art therapy is that there are “so many benefits and not really any side effects.” Patients can “take the meds … and then enhance that with various therapies, and this would be an additional option.”
Another notable aspect of art therapy is the “social element” and the sense of “camaraderie,” although that has “to be teased out from the benefits you would get from the actual art therapy.”
Finally, Dr. Gilbert pointed out that the difference between the current trial and Dr. Cucca’s trial is the presence of a control group.
“Of course, it’s not blinded, because you know whether you got therapy or not … but that extra element of being able to compare with a group that didn’t get the treatment gives it a little more weight in terms of the field.”
No funding was declared. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Adding art therapy to standard drug treatment in Parkinson’s disease (PD) not only improves severity of both motor and nonmotor symptoms, but also slows rates of disease progression, new research suggests.
Fifty PD patients were randomly assigned to receive either art therapy, including sculpting and drawing, plus drug therapy or drug therapy alone, and followed up over 12 months.
Patients receiving combined therapy experienced improvements in symptoms, depression, and cognitive scores, and had reduced tremor and daytime sleepiness. They were also substantially less likely to experience disease progression.
“The use of art therapy can reduce the severity of motor and nonmotor manifestations of Parkinson’s disease,” said study investigator Iryna Khubetova, MD, PhD, head of the neurology department, Odessa (Ukraine) Regional Clinical Hospital.
she added.
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
A promising approach
Dr. Khubetova told this news organization that offering art therapy to PD patients was “very affordable,” especially as professional artists “provided materials for painting and other art supplies free of charge.”
“We hope this approach is very promising and would be widely adopted.”
She suggested the positive effect of art therapy could be related to “activating the brain’s reward neural network.”
This may be via improved visual attention acting on visuospatial mechanisms and emotional drive, with “activation of the medial orbitofrontal cortex, ventral striatum, and other structures.”
The researchers note PD, a “multisystem progressive neurodegenerative disease,” is among the three most common neurological disorders, with an incidence of 100-150 cases per 100,000 people.
They also note that nonpharmacologic approaches are “widely used” as an adjunct to drug therapy and as part of an “integrated approach” to disease management.
To examine the clinical efficacy of art therapy, the team recruited patients with PD who had preserved facility for independent movement, defined as stages 1-2.5 on the Hoehn and Yahr scale.
Patients were randomly assigned to art therapy sessions alongside standard drug therapy or to standard drug therapy alone. The art therapy included sculpting, free drawing, and coloring patterns.
Multiple benefits
Participants were assessed at baseline and at 6 and 12 months with the Unified Parkinson Disease Rating Scale (UPDRS), the Beck Depression Inventory, the Montreal Cognitive Assessment, and the Pegboard Test of finger dexterity.
Fifty patients were included in the study, with 30 assigned to standard drug therapy alone and 20 to the combined intervention. Participants had a mean age of 57.8 years, and 46% were women.
Over the study period, investigators found patients assigned to art therapy plus drug treatment had improved mood, as well as decreased daytime sleeping, reduced tremor, and a decrease in anxiety and fear intensity.
Between baseline and the 6- and 12-month assessments, patients in the combined therapy group showed improvements in scores on all of the questionnaires, and on the Pegboard Test. In contrast, scores were either stable or worsened in the standard drug therapy–alone group.
The team notes that there was also a marked difference in rates of disease progression, defined as a change on the Hoehn and Yahr scale of at least 0.5 points, between the two groups.
Only two (10%) patients in the combined drug and art therapy progressed over the study period, compared with 10 (33%) in the control group (P = .05).
The findings complement those of a recent study conducted by Alberto Cucca, MD, of the Fresco Institute for Parkinson’s and Movement Disorders, New York University, and colleagues.
Eighteen patients took part in the prospective, open-label trial. They were assessed before and after 20 sessions of art therapy on a range of measures.
Results revealed that following the art therapy, patients had improvements in the Navon Test (which assesses visual neglect, eye tracking, and UPDRS scores), as well as significantly increased functional connectivity levels in the visual cortex on resting-state functional MRI.
Many benefits, no side effects
Rebecca Gilbert, MD, PhD, vice president and chief scientific officer of the American Parkinson Disease Association, who was not involved in either study, told this news organization that the idea of art therapy for patients with Parkinson’s is “very reasonable.”
She highlighted that “people with Parkinson’s have many issues with their visuospatial abilities,” as well as their depth and distance perception, and so “enhancing that aspect could potentially be very beneficial.”
“So I’m hopeful that it’s a really good avenue to explore, and the preliminary data are very exciting.”
Dr. Gilbert also highlighted that the “wonderful” aspect of art therapy is that there are “so many benefits and not really any side effects.” Patients can “take the meds … and then enhance that with various therapies, and this would be an additional option.”
Another notable aspect of art therapy is the “social element” and the sense of “camaraderie,” although that has “to be teased out from the benefits you would get from the actual art therapy.”
Finally, Dr. Gilbert pointed out that the difference between the current trial and Dr. Cucca’s trial is the presence of a control group.
“Of course, it’s not blinded, because you know whether you got therapy or not … but that extra element of being able to compare with a group that didn’t get the treatment gives it a little more weight in terms of the field.”
No funding was declared. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Adding art therapy to standard drug treatment in Parkinson’s disease (PD) not only improves severity of both motor and nonmotor symptoms, but also slows rates of disease progression, new research suggests.
Fifty PD patients were randomly assigned to receive either art therapy, including sculpting and drawing, plus drug therapy or drug therapy alone, and followed up over 12 months.
Patients receiving combined therapy experienced improvements in symptoms, depression, and cognitive scores, and had reduced tremor and daytime sleepiness. They were also substantially less likely to experience disease progression.
“The use of art therapy can reduce the severity of motor and nonmotor manifestations of Parkinson’s disease,” said study investigator Iryna Khubetova, MD, PhD, head of the neurology department, Odessa (Ukraine) Regional Clinical Hospital.
she added.
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
A promising approach
Dr. Khubetova told this news organization that offering art therapy to PD patients was “very affordable,” especially as professional artists “provided materials for painting and other art supplies free of charge.”
“We hope this approach is very promising and would be widely adopted.”
She suggested the positive effect of art therapy could be related to “activating the brain’s reward neural network.”
This may be via improved visual attention acting on visuospatial mechanisms and emotional drive, with “activation of the medial orbitofrontal cortex, ventral striatum, and other structures.”
The researchers note PD, a “multisystem progressive neurodegenerative disease,” is among the three most common neurological disorders, with an incidence of 100-150 cases per 100,000 people.
They also note that nonpharmacologic approaches are “widely used” as an adjunct to drug therapy and as part of an “integrated approach” to disease management.
To examine the clinical efficacy of art therapy, the team recruited patients with PD who had preserved facility for independent movement, defined as stages 1-2.5 on the Hoehn and Yahr scale.
Patients were randomly assigned to art therapy sessions alongside standard drug therapy or to standard drug therapy alone. The art therapy included sculpting, free drawing, and coloring patterns.
Multiple benefits
Participants were assessed at baseline and at 6 and 12 months with the Unified Parkinson Disease Rating Scale (UPDRS), the Beck Depression Inventory, the Montreal Cognitive Assessment, and the Pegboard Test of finger dexterity.
Fifty patients were included in the study, with 30 assigned to standard drug therapy alone and 20 to the combined intervention. Participants had a mean age of 57.8 years, and 46% were women.
Over the study period, investigators found patients assigned to art therapy plus drug treatment had improved mood, as well as decreased daytime sleeping, reduced tremor, and a decrease in anxiety and fear intensity.
Between baseline and the 6- and 12-month assessments, patients in the combined therapy group showed improvements in scores on all of the questionnaires, and on the Pegboard Test. In contrast, scores were either stable or worsened in the standard drug therapy–alone group.
The team notes that there was also a marked difference in rates of disease progression, defined as a change on the Hoehn and Yahr scale of at least 0.5 points, between the two groups.
Only two (10%) patients in the combined drug and art therapy progressed over the study period, compared with 10 (33%) in the control group (P = .05).
The findings complement those of a recent study conducted by Alberto Cucca, MD, of the Fresco Institute for Parkinson’s and Movement Disorders, New York University, and colleagues.
Eighteen patients took part in the prospective, open-label trial. They were assessed before and after 20 sessions of art therapy on a range of measures.
Results revealed that following the art therapy, patients had improvements in the Navon Test (which assesses visual neglect, eye tracking, and UPDRS scores), as well as significantly increased functional connectivity levels in the visual cortex on resting-state functional MRI.
Many benefits, no side effects
Rebecca Gilbert, MD, PhD, vice president and chief scientific officer of the American Parkinson Disease Association, who was not involved in either study, told this news organization that the idea of art therapy for patients with Parkinson’s is “very reasonable.”
She highlighted that “people with Parkinson’s have many issues with their visuospatial abilities,” as well as their depth and distance perception, and so “enhancing that aspect could potentially be very beneficial.”
“So I’m hopeful that it’s a really good avenue to explore, and the preliminary data are very exciting.”
Dr. Gilbert also highlighted that the “wonderful” aspect of art therapy is that there are “so many benefits and not really any side effects.” Patients can “take the meds … and then enhance that with various therapies, and this would be an additional option.”
Another notable aspect of art therapy is the “social element” and the sense of “camaraderie,” although that has “to be teased out from the benefits you would get from the actual art therapy.”
Finally, Dr. Gilbert pointed out that the difference between the current trial and Dr. Cucca’s trial is the presence of a control group.
“Of course, it’s not blinded, because you know whether you got therapy or not … but that extra element of being able to compare with a group that didn’t get the treatment gives it a little more weight in terms of the field.”
No funding was declared. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ECNP 2021
FDA OKs new high-dose naloxone product for opioid overdose
ZIMHI from Adamis Pharmaceuticals is administered using a single-dose, prefilled syringe that delivers 5 mg of naloxone hydrochloride solution through intramuscular or subcutaneous injection.
Naloxone is an opioid antagonist that works by blocking or reversing the effects of the opioid, including extreme drowsiness, slowed breathing, or loss of consciousness.
Opioid-related overdose deaths — driven partly by prescription drug overdoses — remain a leading cause of death in the United States.
ZIMHI “provides an additional option in the treatment of opioid overdoses,” the FDA said in a statement announcing approval.
In a statement from Adamis Pharmaceuticals, Jeffrey Galinkin, MD, an anesthesiologist and former member of the FDA advisory committee for analgesics and addiction products, said he is “pleased to see this much-needed, high-dose naloxone product will become part of the treatment tool kit as a countermeasure to the continued surge in fentanyl related deaths.”
“The higher intramuscular doses of naloxone in ZIMHI should result in more rapid and higher levels of naloxone in the systemic circulation, which in turn, should result in more successful resuscitations,” Dr. Galinkin said.
Last spring the FDA approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of opioid overdose.
Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.
The FDA approved ZIMHI (and Kloxxado) through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.
The company plans to launch ZIMHI in the first quarter of 2022.
A version of this article first appeared on Medscape.com.
ZIMHI from Adamis Pharmaceuticals is administered using a single-dose, prefilled syringe that delivers 5 mg of naloxone hydrochloride solution through intramuscular or subcutaneous injection.
Naloxone is an opioid antagonist that works by blocking or reversing the effects of the opioid, including extreme drowsiness, slowed breathing, or loss of consciousness.
Opioid-related overdose deaths — driven partly by prescription drug overdoses — remain a leading cause of death in the United States.
ZIMHI “provides an additional option in the treatment of opioid overdoses,” the FDA said in a statement announcing approval.
In a statement from Adamis Pharmaceuticals, Jeffrey Galinkin, MD, an anesthesiologist and former member of the FDA advisory committee for analgesics and addiction products, said he is “pleased to see this much-needed, high-dose naloxone product will become part of the treatment tool kit as a countermeasure to the continued surge in fentanyl related deaths.”
“The higher intramuscular doses of naloxone in ZIMHI should result in more rapid and higher levels of naloxone in the systemic circulation, which in turn, should result in more successful resuscitations,” Dr. Galinkin said.
Last spring the FDA approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of opioid overdose.
Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.
The FDA approved ZIMHI (and Kloxxado) through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.
The company plans to launch ZIMHI in the first quarter of 2022.
A version of this article first appeared on Medscape.com.
ZIMHI from Adamis Pharmaceuticals is administered using a single-dose, prefilled syringe that delivers 5 mg of naloxone hydrochloride solution through intramuscular or subcutaneous injection.
Naloxone is an opioid antagonist that works by blocking or reversing the effects of the opioid, including extreme drowsiness, slowed breathing, or loss of consciousness.
Opioid-related overdose deaths — driven partly by prescription drug overdoses — remain a leading cause of death in the United States.
ZIMHI “provides an additional option in the treatment of opioid overdoses,” the FDA said in a statement announcing approval.
In a statement from Adamis Pharmaceuticals, Jeffrey Galinkin, MD, an anesthesiologist and former member of the FDA advisory committee for analgesics and addiction products, said he is “pleased to see this much-needed, high-dose naloxone product will become part of the treatment tool kit as a countermeasure to the continued surge in fentanyl related deaths.”
“The higher intramuscular doses of naloxone in ZIMHI should result in more rapid and higher levels of naloxone in the systemic circulation, which in turn, should result in more successful resuscitations,” Dr. Galinkin said.
Last spring the FDA approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of opioid overdose.
Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.
The FDA approved ZIMHI (and Kloxxado) through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.
The company plans to launch ZIMHI in the first quarter of 2022.
A version of this article first appeared on Medscape.com.