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Virus-specific T-cell infusion may resolve progressive multifocal leukoencephalopathy
, according to investigators from the University of Texas MD Anderson Cancer Center, Houston.
The infusion cleared JC virus from the cerebrospinal fluid (CSF) of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of MD Anderson’s department of stem cell transplantation and cellular therapy and colleagues. One of the patients completely recovered and returned to work.
“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators wrote in the New England Journal of Medicine. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions.
“Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators wrote. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”
This hypothesis proved accurate. The investigators infused three PML patients with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib (Jakafi) therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.
T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees: The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about 8 months later.
No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within 4 weeks of treatment. Still, the investigators were optimistic about future potential.
“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”
The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.
SOURCE: Muftuoglu M et al. N Engl J Med. 2018 Oct 11;379:1443-51
This article was updated 3/22/19.
, according to investigators from the University of Texas MD Anderson Cancer Center, Houston.
The infusion cleared JC virus from the cerebrospinal fluid (CSF) of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of MD Anderson’s department of stem cell transplantation and cellular therapy and colleagues. One of the patients completely recovered and returned to work.
“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators wrote in the New England Journal of Medicine. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions.
“Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators wrote. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”
This hypothesis proved accurate. The investigators infused three PML patients with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib (Jakafi) therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.
T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees: The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about 8 months later.
No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within 4 weeks of treatment. Still, the investigators were optimistic about future potential.
“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”
The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.
SOURCE: Muftuoglu M et al. N Engl J Med. 2018 Oct 11;379:1443-51
This article was updated 3/22/19.
, according to investigators from the University of Texas MD Anderson Cancer Center, Houston.
The infusion cleared JC virus from the cerebrospinal fluid (CSF) of two patients and reduced viral load in the third, reported lead author Muharrem Muftuoglu, MD, of MD Anderson’s department of stem cell transplantation and cellular therapy and colleagues. One of the patients completely recovered and returned to work.
“Several approaches for the treatment of PML, including the use of antiviral medications and mirtazapine, have been tested, with poor results,” the investigators wrote in the New England Journal of Medicine. Although virus-specific T-cell infusion is a novel approach to treating PML, this method has been used for other conditions.
“Several groups, including ours, have successfully used viral-specific T cells to treat BK virus infection after stem-cell transplantation,” the investigators wrote. “Because BK virus and JC virus are genetically similar to one another and share a number of immunogenic proteins with a substantial degree of sequence homology ... we hypothesized that T cells developed against BK virus may also be effective against JC virus infection.”
This hypothesis proved accurate. The investigators infused three PML patients with “cryopreserved, third-party–produced, viral-specific T cells that had been designed for the treatment of patients with BK virus infection after stem-cell transplantation.” Each patient presented with a different condition and PML-precipitating therapy. The first patient was a 32-year-old woman with high-risk acute myeloid leukemia who had received a cord-blood transplantation, the second a 73-year-old woman with JAK2-positive myeloproliferative neoplasia on ruxolitinib (Jakafi) therapy, and the third a 35-year-old man with HIV who had received highly active antiretroviral therapy.
T-cell infusions cleared JC virus from the CSF of the woman with leukemia (three infusions) and the man with HIV (four infusions). These patients recovered to different degrees: The woman had full resolution of symptoms, while the man had slurred speech and walked with a cane. Treatment reduced JC viral load in the elderly woman with myeloproliferative neoplasia (two infusions), but she did not clear the virus and died about 8 months later.
No adverse events occurred, but two patients developed immune reconstitution inflammatory syndrome. This was likely caused by the T-cell infusion, since absolute T-cell counts remained steady and white matter enhancement was detected on MRI within 4 weeks of treatment. Still, the investigators were optimistic about future potential.
“Third-party–produced, ‘off-the-shelf,’ partially HLA-matched, BK virus–specific T cells may serve as therapy for PML,” the investigators concluded. “Further study in a larger group of patients is required to determine the success rate, durability, and longer-term adverse events associated with this treatment.”
The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.
SOURCE: Muftuoglu M et al. N Engl J Med. 2018 Oct 11;379:1443-51
This article was updated 3/22/19.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Infusion of allogeneic BK virus-specific T cells may be an effective treatment for patients with PML.
Major finding: Two of three patients cleared JC virus from cerebrospinal fluid after infusion.
Study details: A case series involving three patients with PML.
Disclosures: The study was funded by the MD Anderson Cancer Center Moon Shots Program and the National Institutes of Health.
Source: Muftuoglu M et al. N Engl J Med. 2018 Oct 11;379:1443-51.
Snake bite detox, kidney stone coaster cure, soporific speakers
At least opioids don’t bite
Remember that song about the old lady who “swallowed” a fly? Well, what if the fly were actually a poisonous snake? And what if she didn’t really swallow it? And what if we stopped asking so many questions? A 33-year-old Indian man who was addicted to alcohol, tobacco, and opioids in the form of raw opium and “puppy husk” (we’re thinking it’s poppy husk, but the case report clearly said “puppy”) heard about something new: letting a poisonous snake bite you on the tongue.
He found some nomadic snake charmers to provide the snake (possibly a cobra, but he’s not sure), and the snake’s bite provides him with an hour of jerky body movements, blurred vision, and unresponsiveness, followed by 3-4 weeks of heightened arousal and a sense of well-being that is “more intense tha[n] the state of high experienced … with any dose of alcohol or opioids,” according to the Indian Journal of Psychological Medicine (2018;40[3]:269-71). Plus, he doesn’t use nearly as much alcohol and opium. (Yes, he has done this more than once. You’re rude to ask.)
The old lady in the song, of course, dies after “swallowing” a horse. Fortunately for this guy, there’s no such thing as a poisonous horse.
Ride out the kidney stones
Disney World, the happiest place on earth – unless you’re a kidney stone. A professor from the College of Osteopathic Medicine at Michigan State University, East Lansing, was inspired when one of his patients told him a recent trip to the Magic Kingdom had successfully dislodged a kidney stone. Armed with a silicone model of the renal system, David Wartinger, DO, spent many grueling hours atop various theme park rides. And, one can only assume, many more grueling hours exploring Cinderella’s Castle.
Dr. Wartinger discovered that the Big Thunder Mountain Railroad was more effective than Space Mountain or the Rock ‘n’ Roller Coaster at rattling around the rider and thus shaking out those kidney stones.
The brave professor’s tireless work has earned him one of 2018’s Ig Nobel prizes. We salute you.
In Russia, bear cures YOU
They do things a bit differently in Russia. Who else but a group of Russians would stare a freshly caught and presumably very angry Siberian brown bear in the mouth and think, “Hmm, yes – the perfect source for new and exciting antibiotics!”
Somehow, they managed to make it work. In an article published in Proceedings of the National Academy of Sciences, Russian scientists demonstrated a new technology that rapidly tests the microbiota within bear saliva for potential antibiotics to use against antibiotic-resistant infections such as Staphylococcus aureus. In one of the thousands of samples taken, all introduced S. aureus bacteria had been eliminated, and further analysis showed the presence of amicoumacin, a previously known antibiotic.
And this is just one bear. Who knows what new and exciting goodies lie in the mouths of other bears? Now, we feel it’s important to note that the saliva of any sufficiently wild animal would have sufficed. But when in Russia, if you can think of an excuse to catch a bear, then by God you had better go catch a bear. Anything less would be an insult to the Motherland!
I need a hug
Don’t we all. A new study from the department of psychology at Carnegie Mellon University in Pittsburgh examined whether hugs actually do anything to improve a bad mood. Unverified rumors purport that the study was commissioned by a cuddly red monster named Elmo.
Researchers concluded that consensual hugs are beneficial after some sort of conflict or negative event during the day and that they positively affect the hug-receiver. Researchers also concluded that hugs given by teddy bears or red pandas are the most beneficial, but human hugs will do if those aren’t available. Despite their bactericidal qualities, hugs from Russian bears aren’t encouraged.
Next slide, pleazzzzzzz
Picture a world in which your smartwatch counted backward. In which the room WiFi is a black hole. In which space-time’s zipper seems hopelessly stuck, with a loose string – or, in fact, PowerPoint slide #14 – wedged into its interlocking teeth. That’s right: You’re in a session at a medical conference.
Now, one meeting attendee has boldly researched what many an attendee has wondered before: Do boring speakers really talk for longer? Taking one for all humanity, that intrepid time traveler endured an inhumane, institutional review board–unapproved study design of 50 12-minute meeting sessions. After 4 minutes, he determined whether the speaker was, scientifically speaking, “boring” or “not boring.” He then clocked the time each speaker took to wrap it up.
Spoiler alert: “Not boring” also meant “done sooner” – in a mean time of 11 minutes and 42 seconds versus 13 minutes and 12 seconds for those oscillating in the dullness duality’s boring state. So, if the 4-minute marker heralds a soporific session? There’s more schwag and better WiFi in the exhibit hall.
At least opioids don’t bite
Remember that song about the old lady who “swallowed” a fly? Well, what if the fly were actually a poisonous snake? And what if she didn’t really swallow it? And what if we stopped asking so many questions? A 33-year-old Indian man who was addicted to alcohol, tobacco, and opioids in the form of raw opium and “puppy husk” (we’re thinking it’s poppy husk, but the case report clearly said “puppy”) heard about something new: letting a poisonous snake bite you on the tongue.
He found some nomadic snake charmers to provide the snake (possibly a cobra, but he’s not sure), and the snake’s bite provides him with an hour of jerky body movements, blurred vision, and unresponsiveness, followed by 3-4 weeks of heightened arousal and a sense of well-being that is “more intense tha[n] the state of high experienced … with any dose of alcohol or opioids,” according to the Indian Journal of Psychological Medicine (2018;40[3]:269-71). Plus, he doesn’t use nearly as much alcohol and opium. (Yes, he has done this more than once. You’re rude to ask.)
The old lady in the song, of course, dies after “swallowing” a horse. Fortunately for this guy, there’s no such thing as a poisonous horse.
Ride out the kidney stones
Disney World, the happiest place on earth – unless you’re a kidney stone. A professor from the College of Osteopathic Medicine at Michigan State University, East Lansing, was inspired when one of his patients told him a recent trip to the Magic Kingdom had successfully dislodged a kidney stone. Armed with a silicone model of the renal system, David Wartinger, DO, spent many grueling hours atop various theme park rides. And, one can only assume, many more grueling hours exploring Cinderella’s Castle.
Dr. Wartinger discovered that the Big Thunder Mountain Railroad was more effective than Space Mountain or the Rock ‘n’ Roller Coaster at rattling around the rider and thus shaking out those kidney stones.
The brave professor’s tireless work has earned him one of 2018’s Ig Nobel prizes. We salute you.
In Russia, bear cures YOU
They do things a bit differently in Russia. Who else but a group of Russians would stare a freshly caught and presumably very angry Siberian brown bear in the mouth and think, “Hmm, yes – the perfect source for new and exciting antibiotics!”
Somehow, they managed to make it work. In an article published in Proceedings of the National Academy of Sciences, Russian scientists demonstrated a new technology that rapidly tests the microbiota within bear saliva for potential antibiotics to use against antibiotic-resistant infections such as Staphylococcus aureus. In one of the thousands of samples taken, all introduced S. aureus bacteria had been eliminated, and further analysis showed the presence of amicoumacin, a previously known antibiotic.
And this is just one bear. Who knows what new and exciting goodies lie in the mouths of other bears? Now, we feel it’s important to note that the saliva of any sufficiently wild animal would have sufficed. But when in Russia, if you can think of an excuse to catch a bear, then by God you had better go catch a bear. Anything less would be an insult to the Motherland!
I need a hug
Don’t we all. A new study from the department of psychology at Carnegie Mellon University in Pittsburgh examined whether hugs actually do anything to improve a bad mood. Unverified rumors purport that the study was commissioned by a cuddly red monster named Elmo.
Researchers concluded that consensual hugs are beneficial after some sort of conflict or negative event during the day and that they positively affect the hug-receiver. Researchers also concluded that hugs given by teddy bears or red pandas are the most beneficial, but human hugs will do if those aren’t available. Despite their bactericidal qualities, hugs from Russian bears aren’t encouraged.
Next slide, pleazzzzzzz
Picture a world in which your smartwatch counted backward. In which the room WiFi is a black hole. In which space-time’s zipper seems hopelessly stuck, with a loose string – or, in fact, PowerPoint slide #14 – wedged into its interlocking teeth. That’s right: You’re in a session at a medical conference.
Now, one meeting attendee has boldly researched what many an attendee has wondered before: Do boring speakers really talk for longer? Taking one for all humanity, that intrepid time traveler endured an inhumane, institutional review board–unapproved study design of 50 12-minute meeting sessions. After 4 minutes, he determined whether the speaker was, scientifically speaking, “boring” or “not boring.” He then clocked the time each speaker took to wrap it up.
Spoiler alert: “Not boring” also meant “done sooner” – in a mean time of 11 minutes and 42 seconds versus 13 minutes and 12 seconds for those oscillating in the dullness duality’s boring state. So, if the 4-minute marker heralds a soporific session? There’s more schwag and better WiFi in the exhibit hall.
At least opioids don’t bite
Remember that song about the old lady who “swallowed” a fly? Well, what if the fly were actually a poisonous snake? And what if she didn’t really swallow it? And what if we stopped asking so many questions? A 33-year-old Indian man who was addicted to alcohol, tobacco, and opioids in the form of raw opium and “puppy husk” (we’re thinking it’s poppy husk, but the case report clearly said “puppy”) heard about something new: letting a poisonous snake bite you on the tongue.
He found some nomadic snake charmers to provide the snake (possibly a cobra, but he’s not sure), and the snake’s bite provides him with an hour of jerky body movements, blurred vision, and unresponsiveness, followed by 3-4 weeks of heightened arousal and a sense of well-being that is “more intense tha[n] the state of high experienced … with any dose of alcohol or opioids,” according to the Indian Journal of Psychological Medicine (2018;40[3]:269-71). Plus, he doesn’t use nearly as much alcohol and opium. (Yes, he has done this more than once. You’re rude to ask.)
The old lady in the song, of course, dies after “swallowing” a horse. Fortunately for this guy, there’s no such thing as a poisonous horse.
Ride out the kidney stones
Disney World, the happiest place on earth – unless you’re a kidney stone. A professor from the College of Osteopathic Medicine at Michigan State University, East Lansing, was inspired when one of his patients told him a recent trip to the Magic Kingdom had successfully dislodged a kidney stone. Armed with a silicone model of the renal system, David Wartinger, DO, spent many grueling hours atop various theme park rides. And, one can only assume, many more grueling hours exploring Cinderella’s Castle.
Dr. Wartinger discovered that the Big Thunder Mountain Railroad was more effective than Space Mountain or the Rock ‘n’ Roller Coaster at rattling around the rider and thus shaking out those kidney stones.
The brave professor’s tireless work has earned him one of 2018’s Ig Nobel prizes. We salute you.
In Russia, bear cures YOU
They do things a bit differently in Russia. Who else but a group of Russians would stare a freshly caught and presumably very angry Siberian brown bear in the mouth and think, “Hmm, yes – the perfect source for new and exciting antibiotics!”
Somehow, they managed to make it work. In an article published in Proceedings of the National Academy of Sciences, Russian scientists demonstrated a new technology that rapidly tests the microbiota within bear saliva for potential antibiotics to use against antibiotic-resistant infections such as Staphylococcus aureus. In one of the thousands of samples taken, all introduced S. aureus bacteria had been eliminated, and further analysis showed the presence of amicoumacin, a previously known antibiotic.
And this is just one bear. Who knows what new and exciting goodies lie in the mouths of other bears? Now, we feel it’s important to note that the saliva of any sufficiently wild animal would have sufficed. But when in Russia, if you can think of an excuse to catch a bear, then by God you had better go catch a bear. Anything less would be an insult to the Motherland!
I need a hug
Don’t we all. A new study from the department of psychology at Carnegie Mellon University in Pittsburgh examined whether hugs actually do anything to improve a bad mood. Unverified rumors purport that the study was commissioned by a cuddly red monster named Elmo.
Researchers concluded that consensual hugs are beneficial after some sort of conflict or negative event during the day and that they positively affect the hug-receiver. Researchers also concluded that hugs given by teddy bears or red pandas are the most beneficial, but human hugs will do if those aren’t available. Despite their bactericidal qualities, hugs from Russian bears aren’t encouraged.
Next slide, pleazzzzzzz
Picture a world in which your smartwatch counted backward. In which the room WiFi is a black hole. In which space-time’s zipper seems hopelessly stuck, with a loose string – or, in fact, PowerPoint slide #14 – wedged into its interlocking teeth. That’s right: You’re in a session at a medical conference.
Now, one meeting attendee has boldly researched what many an attendee has wondered before: Do boring speakers really talk for longer? Taking one for all humanity, that intrepid time traveler endured an inhumane, institutional review board–unapproved study design of 50 12-minute meeting sessions. After 4 minutes, he determined whether the speaker was, scientifically speaking, “boring” or “not boring.” He then clocked the time each speaker took to wrap it up.
Spoiler alert: “Not boring” also meant “done sooner” – in a mean time of 11 minutes and 42 seconds versus 13 minutes and 12 seconds for those oscillating in the dullness duality’s boring state. So, if the 4-minute marker heralds a soporific session? There’s more schwag and better WiFi in the exhibit hall.
Genomic profiling predicts outcomes in patients with MPN
Genomic characteristics of patients with myeloproliferative neoplasms (MPN) can predict clinical outcomes, a recent study found.
Eight genomic subgroups of MPN were recognized, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts, according to Jacob Grinfeld, MD, of the Wellcome-MRC Cambridge (England) Stem Cell Institute and Cambridge Institute for Medical Research and his colleagues.
“Current classification schemes distinguish among the subtypes of myeloproliferative neoplasms according to clinical and laboratory features, but uncertainty clouds where and how to draw dividing lines among them,” the investigators wrote in the New England Journal of Medicine. “In blood cancers, a progressive shift is under way, from clinical and morphologic classification schemes to those that are based on genomics.”
MPNs are often driven by mutations in CALR, MPL, or JAK2 genes, but classification is not confined to just three genomic types; many patients have additional driver mutations throughout a variety of cancer genes, and it is these additional mutations that are responsible for the wide range of disease phenotypes and clinical outcomes.
This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other MPN diagnoses. The investigators performed targeted sequencing for the full coding sequence of 69 genes and genomewide copy-number information in 1,887 patients. Another 148 patients underwent whole-exome sequencing.
By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across a population of patients with MPNs and identify mutation-associated clinical outcomes.
The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations. In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.
Further analysis identified eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations. For example, one subgroup included patients with TP53 mutations; these individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia (AML), compared with the JAK2-heterozygous subgroup (P less than .001).
Because prognosis is “a key determinant of the treatment of patients with MPNs,” genomic subgrouping may one day guide clinical decision making, the investigators concluded.
To further this cause, the investigators have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.
The study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.
SOURCE: Grinfeld J et al. N Engl J Med. 2018;379:1416-30.
Genomic characteristics of patients with myeloproliferative neoplasms (MPN) can predict clinical outcomes, a recent study found.
Eight genomic subgroups of MPN were recognized, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts, according to Jacob Grinfeld, MD, of the Wellcome-MRC Cambridge (England) Stem Cell Institute and Cambridge Institute for Medical Research and his colleagues.
“Current classification schemes distinguish among the subtypes of myeloproliferative neoplasms according to clinical and laboratory features, but uncertainty clouds where and how to draw dividing lines among them,” the investigators wrote in the New England Journal of Medicine. “In blood cancers, a progressive shift is under way, from clinical and morphologic classification schemes to those that are based on genomics.”
MPNs are often driven by mutations in CALR, MPL, or JAK2 genes, but classification is not confined to just three genomic types; many patients have additional driver mutations throughout a variety of cancer genes, and it is these additional mutations that are responsible for the wide range of disease phenotypes and clinical outcomes.
This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other MPN diagnoses. The investigators performed targeted sequencing for the full coding sequence of 69 genes and genomewide copy-number information in 1,887 patients. Another 148 patients underwent whole-exome sequencing.
By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across a population of patients with MPNs and identify mutation-associated clinical outcomes.
The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations. In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.
Further analysis identified eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations. For example, one subgroup included patients with TP53 mutations; these individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia (AML), compared with the JAK2-heterozygous subgroup (P less than .001).
Because prognosis is “a key determinant of the treatment of patients with MPNs,” genomic subgrouping may one day guide clinical decision making, the investigators concluded.
To further this cause, the investigators have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.
The study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.
SOURCE: Grinfeld J et al. N Engl J Med. 2018;379:1416-30.
Genomic characteristics of patients with myeloproliferative neoplasms (MPN) can predict clinical outcomes, a recent study found.
Eight genomic subgroups of MPN were recognized, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts, according to Jacob Grinfeld, MD, of the Wellcome-MRC Cambridge (England) Stem Cell Institute and Cambridge Institute for Medical Research and his colleagues.
“Current classification schemes distinguish among the subtypes of myeloproliferative neoplasms according to clinical and laboratory features, but uncertainty clouds where and how to draw dividing lines among them,” the investigators wrote in the New England Journal of Medicine. “In blood cancers, a progressive shift is under way, from clinical and morphologic classification schemes to those that are based on genomics.”
MPNs are often driven by mutations in CALR, MPL, or JAK2 genes, but classification is not confined to just three genomic types; many patients have additional driver mutations throughout a variety of cancer genes, and it is these additional mutations that are responsible for the wide range of disease phenotypes and clinical outcomes.
This study included 2,035 patients with MPNs, including essential thrombocythemia, polycythemia vera, myelofibrosis, and other MPN diagnoses. The investigators performed targeted sequencing for the full coding sequence of 69 genes and genomewide copy-number information in 1,887 patients. Another 148 patients underwent whole-exome sequencing.
By sequencing coding exons from 69 myeloid cancer genes, the investigators were able to survey the diversity of mutations across a population of patients with MPNs and identify mutation-associated clinical outcomes.
The results showed that slightly less than half (45%) of the patients had a solitary abnormality in CALR, MPL, or JAK2, while the remaining patients had additional driver mutations. In some instances, additional mutations were numerous, particularly in older patients with advanced disease. In at least five cases, 33 genes had driver mutations.
Further analysis identified eight genomic subgroups that could predict clinical outcomes based on shared chromosomal abnormalities and mutations. For example, one subgroup included patients with TP53 mutations; these individuals had a “dismal prognosis” and were 15.5 times more likely to transform to acute myeloid leukemia (AML), compared with the JAK2-heterozygous subgroup (P less than .001).
Because prognosis is “a key determinant of the treatment of patients with MPNs,” genomic subgrouping may one day guide clinical decision making, the investigators concluded.
To further this cause, the investigators have made available an online calculator of individualized patient outcomes, which can be accessed at https://cancer.sanger.ac.uk/mpn-multistage/.
The study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.
SOURCE: Grinfeld J et al. N Engl J Med. 2018;379:1416-30.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Eight genomic subgroups of MPN were recognized, each with distinct clinical features, including event-free survival, risk of leukemic transformation, and blood counts.
Study details: A gene sequencing study involving 2,035 patients with MPN.
Disclosures: The study was funded by the Wellcome Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cancer Research UK, and others. Some study authors reported fees from Celgene, Novartis, Gilead, Shire, and others outside of the study.
Source: Grinfeld J et al. N Engl J Med. 2018;379:1416-30.
Some dubious of proposal on e-cigarettes; World Mental Health Day takes spotlight
Traditional cigarettes are addictive, and they kill. Now it appears that e-cigarettes, which electronically deliver nicotine in the absence of the lung-damaging smoke, might be a healthier alternative.
The American Cancer Society noted in June that, although the long-term effects of e-cigarettes are “not known,” they are “markedly less harmful” than traditional smoking. Sensing the changing tide, tobacco companies are going all in on e-cigarettes. And, as reported on CBS Sunday Morning, Dr. Gottlieb points out that in light of the impact of nicotine on the developing brain, a “strong regulatory process” is needed that puts new products “through an appropriate series of regulatory gates.”
Still, however, some people are dubious. The tobacco companies that are leading the transition are the same companies that once espoused the healthy benefits of smoking and suppressed counter information. Seeking greater profits, some products are marketed with enticing colors and flavors, with the goal of appealing to consumers – including teens. San Francisco has banned the sale of such products.
Dr. Gottlieb and others are quick to point out that what might be helpful for adults looking to quit also is enticing to teenagers. Using e-cigarettes would seem to be better than cigarette smoking. However, whether e-cigarettes are benign remains unknown.
Mental health takes center stage
An article in The Guardian by Tedros Adhanom Ghebreyesus, PhD, director general of the World Health Organization, and Lady Gaga, musician and cofounder of Born This Way Foundation, cited some sobering facts: 800,000 people kill themselves every year, a rate of six people every minute. Some are famous (Kate Spade and Anthony Bourdain). Others are not. But all leave people who love them and are often devastated by the passing.
For the 25% of people who will experience mental health issues during their lives, admitting their need for help risks being stigmatized, and gaining that help is difficult. This is changing; however, according to the article, funding for mental health constitutes less than 1% of global aid funding.
But there is cause for optimism. WHO is working with countries on a global action plan on mental health. Community-based mental health care initiatives are providing help for those in need. The authors cite the success of the HIV/AIDS efforts as an example of what can be achieved. “That movement helped save millions of lives and is an illustration of the potential for collective human action to tackle seemingly insurmountable problems,” they wrote on the eve of World Mental Health Day, which is Oct. 10.
“The two of us have taken different paths in life. But both of us have seen how political leadership, funding, innovation, and individual acts of bravery and compassion can change the world. It is time to do the same for mental health.”
Navigating the pain of stillbirth
The impending birth of a child can be a time of happy anticipation and planning. But when the pregnancy ends in stillbirth, a person’s world is shattered. The experience is not rare – in the United Kingdom, for example, about nine babies are stillborn every day. When this horror happened to BBC journalist Fiona Crack, she channeled her grief into a chronicle of her journey and those of five other women with some hope and optimism.
“My arms ached. I thought I had a blood clot, but the doctors told me it was normal – a biological response to the shock that there was no living child for me to hold. I sobbed. My milk came through, marking my T-shirt, and I was too exhausted to be embarrassed,” Ms. Crack wrote.
There came a year of first events that would never be shared with her child, Willow – Christmas, Mother’s Day, and the dreaded first birthday. Slowly she mustered resolve. She also connected with five women around the United Kingdom who had faced the same horror.
Some solace has been found. But the scar will always remain. “Over the past year, my need to remember and memorialize Willow has jostled with my need for self-preservation. A year on, grief can still occasionally floor me, slicing behind my knees, but I can feel it coming and I can prepare, knowing I can survive its brief but powerful kick. Willow’s birth made me a Mum and Tim a Dad. My arms no longer ache like those first hours, but they are still empty. I am a mother without a baby,” Ms. Crack writes.
In the United States, about 24,000 stillbirths are reported each year, research shows. Mindfulness therapies have been shown to reduce posttraumatic stress symptoms among women after experiencing stillbirth.
Polygraph tests and employment
Jobs are not always easy to find. Once employed, there can be fear that job security is transient, as well as pressure to please the employer. How far is too far in efforts to gain this pleasure? An article on the BBC website explores the issue.
In some countries, including the United States, the issue is theoretical, since polygraph testing of employees is illegal. But elsewhere, such as in South Africa, there is no legal protection. And polygraph testing has been used in Kenya for prospective politicians. According to polygraph expert Doug Williams, polygraph testing is fallible and is mainly used as a means of intimidation.
“It’s a psychological billy club that coerces and intimidates a person into a confession. It scares the hell out of people. I would never work for a company that requires polygraphs because they’re starting the entire relationship off as an adversarial proceeding,” Mr. Williams said in an interview. The presumption of distrust can be toxic to a workplace.
“If most employees agree to take a lie detection test, then there would naturally come to be some suspicion of those who refuse to take it,” says Nick Bostrom, PhD, ethics professor at the University of Oxford (England). “Refusal would send a bad signal – it suggests you have something to hide.”
In a world where personal information can be just a few mouse clicks away, the issue is worth thinking about.
Music as a healing force
The first album from musician Cat Power (stage name of Chan Marshall) comes after a hiatus of 6 years. The intervening time has been spent as a mom and in other pursuits. The album, “Wanderer,” reflects the stabilizing influence of being a parent and the need to keep striving in life.
“I think I’ve found what I never thought I would have. I’ve found what I never thought I would see, which is becoming a parent. There are no words for what I have now in my heart. But I’m still myself. The psychospiritual parts of me are always looking for truth, always looking for beauty in all that truth,” Ms. Power said in an interview with NPR.
Music also is a way to deal with a life that included a parent who had substance abuse problems and her own bouts of depression. “There’s so much pain that people carry and try to avoid. … That’s why music is so incredible,” she said.
Ms. Power hopes that people who listen to her album will realize that they are not alone. “We’re all on this ball of mud, this tiny speck, a ball of mud together,” she said. “We all feel all the same things. Maybe we don’t know how to communicate well. Maybe we’re learning. Maybe this lifetime, for all of us, is just a learning spell.”
Traditional cigarettes are addictive, and they kill. Now it appears that e-cigarettes, which electronically deliver nicotine in the absence of the lung-damaging smoke, might be a healthier alternative.
The American Cancer Society noted in June that, although the long-term effects of e-cigarettes are “not known,” they are “markedly less harmful” than traditional smoking. Sensing the changing tide, tobacco companies are going all in on e-cigarettes. And, as reported on CBS Sunday Morning, Dr. Gottlieb points out that in light of the impact of nicotine on the developing brain, a “strong regulatory process” is needed that puts new products “through an appropriate series of regulatory gates.”
Still, however, some people are dubious. The tobacco companies that are leading the transition are the same companies that once espoused the healthy benefits of smoking and suppressed counter information. Seeking greater profits, some products are marketed with enticing colors and flavors, with the goal of appealing to consumers – including teens. San Francisco has banned the sale of such products.
Dr. Gottlieb and others are quick to point out that what might be helpful for adults looking to quit also is enticing to teenagers. Using e-cigarettes would seem to be better than cigarette smoking. However, whether e-cigarettes are benign remains unknown.
Mental health takes center stage
An article in The Guardian by Tedros Adhanom Ghebreyesus, PhD, director general of the World Health Organization, and Lady Gaga, musician and cofounder of Born This Way Foundation, cited some sobering facts: 800,000 people kill themselves every year, a rate of six people every minute. Some are famous (Kate Spade and Anthony Bourdain). Others are not. But all leave people who love them and are often devastated by the passing.
For the 25% of people who will experience mental health issues during their lives, admitting their need for help risks being stigmatized, and gaining that help is difficult. This is changing; however, according to the article, funding for mental health constitutes less than 1% of global aid funding.
But there is cause for optimism. WHO is working with countries on a global action plan on mental health. Community-based mental health care initiatives are providing help for those in need. The authors cite the success of the HIV/AIDS efforts as an example of what can be achieved. “That movement helped save millions of lives and is an illustration of the potential for collective human action to tackle seemingly insurmountable problems,” they wrote on the eve of World Mental Health Day, which is Oct. 10.
“The two of us have taken different paths in life. But both of us have seen how political leadership, funding, innovation, and individual acts of bravery and compassion can change the world. It is time to do the same for mental health.”
Navigating the pain of stillbirth
The impending birth of a child can be a time of happy anticipation and planning. But when the pregnancy ends in stillbirth, a person’s world is shattered. The experience is not rare – in the United Kingdom, for example, about nine babies are stillborn every day. When this horror happened to BBC journalist Fiona Crack, she channeled her grief into a chronicle of her journey and those of five other women with some hope and optimism.
“My arms ached. I thought I had a blood clot, but the doctors told me it was normal – a biological response to the shock that there was no living child for me to hold. I sobbed. My milk came through, marking my T-shirt, and I was too exhausted to be embarrassed,” Ms. Crack wrote.
There came a year of first events that would never be shared with her child, Willow – Christmas, Mother’s Day, and the dreaded first birthday. Slowly she mustered resolve. She also connected with five women around the United Kingdom who had faced the same horror.
Some solace has been found. But the scar will always remain. “Over the past year, my need to remember and memorialize Willow has jostled with my need for self-preservation. A year on, grief can still occasionally floor me, slicing behind my knees, but I can feel it coming and I can prepare, knowing I can survive its brief but powerful kick. Willow’s birth made me a Mum and Tim a Dad. My arms no longer ache like those first hours, but they are still empty. I am a mother without a baby,” Ms. Crack writes.
In the United States, about 24,000 stillbirths are reported each year, research shows. Mindfulness therapies have been shown to reduce posttraumatic stress symptoms among women after experiencing stillbirth.
Polygraph tests and employment
Jobs are not always easy to find. Once employed, there can be fear that job security is transient, as well as pressure to please the employer. How far is too far in efforts to gain this pleasure? An article on the BBC website explores the issue.
In some countries, including the United States, the issue is theoretical, since polygraph testing of employees is illegal. But elsewhere, such as in South Africa, there is no legal protection. And polygraph testing has been used in Kenya for prospective politicians. According to polygraph expert Doug Williams, polygraph testing is fallible and is mainly used as a means of intimidation.
“It’s a psychological billy club that coerces and intimidates a person into a confession. It scares the hell out of people. I would never work for a company that requires polygraphs because they’re starting the entire relationship off as an adversarial proceeding,” Mr. Williams said in an interview. The presumption of distrust can be toxic to a workplace.
“If most employees agree to take a lie detection test, then there would naturally come to be some suspicion of those who refuse to take it,” says Nick Bostrom, PhD, ethics professor at the University of Oxford (England). “Refusal would send a bad signal – it suggests you have something to hide.”
In a world where personal information can be just a few mouse clicks away, the issue is worth thinking about.
Music as a healing force
The first album from musician Cat Power (stage name of Chan Marshall) comes after a hiatus of 6 years. The intervening time has been spent as a mom and in other pursuits. The album, “Wanderer,” reflects the stabilizing influence of being a parent and the need to keep striving in life.
“I think I’ve found what I never thought I would have. I’ve found what I never thought I would see, which is becoming a parent. There are no words for what I have now in my heart. But I’m still myself. The psychospiritual parts of me are always looking for truth, always looking for beauty in all that truth,” Ms. Power said in an interview with NPR.
Music also is a way to deal with a life that included a parent who had substance abuse problems and her own bouts of depression. “There’s so much pain that people carry and try to avoid. … That’s why music is so incredible,” she said.
Ms. Power hopes that people who listen to her album will realize that they are not alone. “We’re all on this ball of mud, this tiny speck, a ball of mud together,” she said. “We all feel all the same things. Maybe we don’t know how to communicate well. Maybe we’re learning. Maybe this lifetime, for all of us, is just a learning spell.”
Traditional cigarettes are addictive, and they kill. Now it appears that e-cigarettes, which electronically deliver nicotine in the absence of the lung-damaging smoke, might be a healthier alternative.
The American Cancer Society noted in June that, although the long-term effects of e-cigarettes are “not known,” they are “markedly less harmful” than traditional smoking. Sensing the changing tide, tobacco companies are going all in on e-cigarettes. And, as reported on CBS Sunday Morning, Dr. Gottlieb points out that in light of the impact of nicotine on the developing brain, a “strong regulatory process” is needed that puts new products “through an appropriate series of regulatory gates.”
Still, however, some people are dubious. The tobacco companies that are leading the transition are the same companies that once espoused the healthy benefits of smoking and suppressed counter information. Seeking greater profits, some products are marketed with enticing colors and flavors, with the goal of appealing to consumers – including teens. San Francisco has banned the sale of such products.
Dr. Gottlieb and others are quick to point out that what might be helpful for adults looking to quit also is enticing to teenagers. Using e-cigarettes would seem to be better than cigarette smoking. However, whether e-cigarettes are benign remains unknown.
Mental health takes center stage
An article in The Guardian by Tedros Adhanom Ghebreyesus, PhD, director general of the World Health Organization, and Lady Gaga, musician and cofounder of Born This Way Foundation, cited some sobering facts: 800,000 people kill themselves every year, a rate of six people every minute. Some are famous (Kate Spade and Anthony Bourdain). Others are not. But all leave people who love them and are often devastated by the passing.
For the 25% of people who will experience mental health issues during their lives, admitting their need for help risks being stigmatized, and gaining that help is difficult. This is changing; however, according to the article, funding for mental health constitutes less than 1% of global aid funding.
But there is cause for optimism. WHO is working with countries on a global action plan on mental health. Community-based mental health care initiatives are providing help for those in need. The authors cite the success of the HIV/AIDS efforts as an example of what can be achieved. “That movement helped save millions of lives and is an illustration of the potential for collective human action to tackle seemingly insurmountable problems,” they wrote on the eve of World Mental Health Day, which is Oct. 10.
“The two of us have taken different paths in life. But both of us have seen how political leadership, funding, innovation, and individual acts of bravery and compassion can change the world. It is time to do the same for mental health.”
Navigating the pain of stillbirth
The impending birth of a child can be a time of happy anticipation and planning. But when the pregnancy ends in stillbirth, a person’s world is shattered. The experience is not rare – in the United Kingdom, for example, about nine babies are stillborn every day. When this horror happened to BBC journalist Fiona Crack, she channeled her grief into a chronicle of her journey and those of five other women with some hope and optimism.
“My arms ached. I thought I had a blood clot, but the doctors told me it was normal – a biological response to the shock that there was no living child for me to hold. I sobbed. My milk came through, marking my T-shirt, and I was too exhausted to be embarrassed,” Ms. Crack wrote.
There came a year of first events that would never be shared with her child, Willow – Christmas, Mother’s Day, and the dreaded first birthday. Slowly she mustered resolve. She also connected with five women around the United Kingdom who had faced the same horror.
Some solace has been found. But the scar will always remain. “Over the past year, my need to remember and memorialize Willow has jostled with my need for self-preservation. A year on, grief can still occasionally floor me, slicing behind my knees, but I can feel it coming and I can prepare, knowing I can survive its brief but powerful kick. Willow’s birth made me a Mum and Tim a Dad. My arms no longer ache like those first hours, but they are still empty. I am a mother without a baby,” Ms. Crack writes.
In the United States, about 24,000 stillbirths are reported each year, research shows. Mindfulness therapies have been shown to reduce posttraumatic stress symptoms among women after experiencing stillbirth.
Polygraph tests and employment
Jobs are not always easy to find. Once employed, there can be fear that job security is transient, as well as pressure to please the employer. How far is too far in efforts to gain this pleasure? An article on the BBC website explores the issue.
In some countries, including the United States, the issue is theoretical, since polygraph testing of employees is illegal. But elsewhere, such as in South Africa, there is no legal protection. And polygraph testing has been used in Kenya for prospective politicians. According to polygraph expert Doug Williams, polygraph testing is fallible and is mainly used as a means of intimidation.
“It’s a psychological billy club that coerces and intimidates a person into a confession. It scares the hell out of people. I would never work for a company that requires polygraphs because they’re starting the entire relationship off as an adversarial proceeding,” Mr. Williams said in an interview. The presumption of distrust can be toxic to a workplace.
“If most employees agree to take a lie detection test, then there would naturally come to be some suspicion of those who refuse to take it,” says Nick Bostrom, PhD, ethics professor at the University of Oxford (England). “Refusal would send a bad signal – it suggests you have something to hide.”
In a world where personal information can be just a few mouse clicks away, the issue is worth thinking about.
Music as a healing force
The first album from musician Cat Power (stage name of Chan Marshall) comes after a hiatus of 6 years. The intervening time has been spent as a mom and in other pursuits. The album, “Wanderer,” reflects the stabilizing influence of being a parent and the need to keep striving in life.
“I think I’ve found what I never thought I would have. I’ve found what I never thought I would see, which is becoming a parent. There are no words for what I have now in my heart. But I’m still myself. The psychospiritual parts of me are always looking for truth, always looking for beauty in all that truth,” Ms. Power said in an interview with NPR.
Music also is a way to deal with a life that included a parent who had substance abuse problems and her own bouts of depression. “There’s so much pain that people carry and try to avoid. … That’s why music is so incredible,” she said.
Ms. Power hopes that people who listen to her album will realize that they are not alone. “We’re all on this ball of mud, this tiny speck, a ball of mud together,” she said. “We all feel all the same things. Maybe we don’t know how to communicate well. Maybe we’re learning. Maybe this lifetime, for all of us, is just a learning spell.”
Review finds some therapies show promise in managing prurigo nodularis
FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
Recent success in the use of (PN) suggests that safer and more effective systemic therapies that provide relief and management of this debilitating chronic skin condition are possible, reported Azam A. Qureshi, BA, of the department of dermatology, George Washington University, Washington, and his coauthors.
Their report was published in the Journal of the American Academy of Dermatology.
They conducted a systematic review of 35 clinical studies of different therapies for PN, published between Jan. 1, 1990, and March 22, 2018, using PubMed and Scopus databases. Their goal was twofold: to provide a summary of current evidence-based therapies and their corresponding level of evidence ratings, and to help researchers “identify gaps in PN treatment development and study.”
From 706 studies, the authors selected 35 clinical studies of treatment strategies for PN, for which the pathogenesis is virtually unknown, they noted. The studies included 15 prospective cohort studies, 11 retrospective reviews, 8 randomized controlled trials (with 10-127 patients), and 1 case series. Studies that failed to report treatment outcomes and those with fewer than five patients were excluded from the review.
Treatment modalities included topical agents, phototherapy and photochemotherapy, thalidomide, systemic immunomodulatory drugs, antiepileptics and antidepressants, and emerging treatment approaches. Many of the treatments evaluated in the review were found to offer limited promise for clinical application as a result of low efficacy or frequent side effects. The authors attributed the overall lack of success with treatments to the “heterogeneous nature of the etiology of chronic pruritus.”
Thalidomide was found to have limited use given its poor safety profile; lenalidomide achieved better outcomes, but treatment in one case was stopped because of possible drug-induced neuropathy or myopathy, they wrote. The systemic immunomodulatory agents methotrexate and cyclosporine exhibited successful treatment but also were found to have poor safety profiles. Greater promise was seen with antiepileptics and antidepressants, which were associated with fewer side effects. “Antidepressants, such as mirtazapine and amitriptyline, and antiepileptics, such as gabapentin and pregabalin, can offer significant relief to a good number of patients, though success is variable and as we found in our study, the evidence available is limited,” senior author Adam Friedman, MD, professor of dermatology at George Washington University, said in an interview.
Among the most positive outcomes achieved were those in which promising newer treatments, including targeting IL-31 signaling and opioid receptor modulation, were used. In particular, the authors cited nemolizumab, an IL-31 receptor A antagonist, which is currently in a phase 2 trial of PN. Beneficial effects of extended release nalbuphine, an opioid k-receptor agonist and mu-receptor antagonist, were found in an unpublished multicenter, double-blind randomized controlled trial, with no serious adverse effects attributed to treatment.
Among the emerging treatments are the neurokinin-1 receptor antagonists, which include serlopitant, which showed beneficial effects compared with placebo in an 8-week randomized controlled study, they wrote. The neurokinin-1 receptor “is a target of substance P, a mediator of itch and a probable pathogenic agent in PN,” they wrote. “Binding by these agents likely disrupts substance P signaling, thereby halting PN pathogenesis,” they added.
“Antidepressants such as mirtazapine and amitriptyline and antiepileptics such as gabapentin and pregabalin can offer significant relief to a good number of patients, though success is variable and as we found in our study, the evidence available is limited,” Dr. Friedman said in the interview.
Mr. Qureshi had no relevant financial disclosures. Dr. Friedman has received honoraria for participation in advisory boards for Menlo Therapeutics, and serves as an investigator for Kiniksa Pharmaceuticals. A third author received honoraria for participation in advisory boards for Menlo, and several other companies, and received grant/research support as an investigator from Menlo, Kiniksa, and several other companies.
SOURCE: Qureshi AA et al. J Am Acad Dermatol. 2018. doi: 10.1016/j.jaad.2018.09.020.
FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
Recent success in the use of (PN) suggests that safer and more effective systemic therapies that provide relief and management of this debilitating chronic skin condition are possible, reported Azam A. Qureshi, BA, of the department of dermatology, George Washington University, Washington, and his coauthors.
Their report was published in the Journal of the American Academy of Dermatology.
They conducted a systematic review of 35 clinical studies of different therapies for PN, published between Jan. 1, 1990, and March 22, 2018, using PubMed and Scopus databases. Their goal was twofold: to provide a summary of current evidence-based therapies and their corresponding level of evidence ratings, and to help researchers “identify gaps in PN treatment development and study.”
From 706 studies, the authors selected 35 clinical studies of treatment strategies for PN, for which the pathogenesis is virtually unknown, they noted. The studies included 15 prospective cohort studies, 11 retrospective reviews, 8 randomized controlled trials (with 10-127 patients), and 1 case series. Studies that failed to report treatment outcomes and those with fewer than five patients were excluded from the review.
Treatment modalities included topical agents, phototherapy and photochemotherapy, thalidomide, systemic immunomodulatory drugs, antiepileptics and antidepressants, and emerging treatment approaches. Many of the treatments evaluated in the review were found to offer limited promise for clinical application as a result of low efficacy or frequent side effects. The authors attributed the overall lack of success with treatments to the “heterogeneous nature of the etiology of chronic pruritus.”
Thalidomide was found to have limited use given its poor safety profile; lenalidomide achieved better outcomes, but treatment in one case was stopped because of possible drug-induced neuropathy or myopathy, they wrote. The systemic immunomodulatory agents methotrexate and cyclosporine exhibited successful treatment but also were found to have poor safety profiles. Greater promise was seen with antiepileptics and antidepressants, which were associated with fewer side effects. “Antidepressants, such as mirtazapine and amitriptyline, and antiepileptics, such as gabapentin and pregabalin, can offer significant relief to a good number of patients, though success is variable and as we found in our study, the evidence available is limited,” senior author Adam Friedman, MD, professor of dermatology at George Washington University, said in an interview.
Among the most positive outcomes achieved were those in which promising newer treatments, including targeting IL-31 signaling and opioid receptor modulation, were used. In particular, the authors cited nemolizumab, an IL-31 receptor A antagonist, which is currently in a phase 2 trial of PN. Beneficial effects of extended release nalbuphine, an opioid k-receptor agonist and mu-receptor antagonist, were found in an unpublished multicenter, double-blind randomized controlled trial, with no serious adverse effects attributed to treatment.
Among the emerging treatments are the neurokinin-1 receptor antagonists, which include serlopitant, which showed beneficial effects compared with placebo in an 8-week randomized controlled study, they wrote. The neurokinin-1 receptor “is a target of substance P, a mediator of itch and a probable pathogenic agent in PN,” they wrote. “Binding by these agents likely disrupts substance P signaling, thereby halting PN pathogenesis,” they added.
“Antidepressants such as mirtazapine and amitriptyline and antiepileptics such as gabapentin and pregabalin can offer significant relief to a good number of patients, though success is variable and as we found in our study, the evidence available is limited,” Dr. Friedman said in the interview.
Mr. Qureshi had no relevant financial disclosures. Dr. Friedman has received honoraria for participation in advisory boards for Menlo Therapeutics, and serves as an investigator for Kiniksa Pharmaceuticals. A third author received honoraria for participation in advisory boards for Menlo, and several other companies, and received grant/research support as an investigator from Menlo, Kiniksa, and several other companies.
SOURCE: Qureshi AA et al. J Am Acad Dermatol. 2018. doi: 10.1016/j.jaad.2018.09.020.
FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
Recent success in the use of (PN) suggests that safer and more effective systemic therapies that provide relief and management of this debilitating chronic skin condition are possible, reported Azam A. Qureshi, BA, of the department of dermatology, George Washington University, Washington, and his coauthors.
Their report was published in the Journal of the American Academy of Dermatology.
They conducted a systematic review of 35 clinical studies of different therapies for PN, published between Jan. 1, 1990, and March 22, 2018, using PubMed and Scopus databases. Their goal was twofold: to provide a summary of current evidence-based therapies and their corresponding level of evidence ratings, and to help researchers “identify gaps in PN treatment development and study.”
From 706 studies, the authors selected 35 clinical studies of treatment strategies for PN, for which the pathogenesis is virtually unknown, they noted. The studies included 15 prospective cohort studies, 11 retrospective reviews, 8 randomized controlled trials (with 10-127 patients), and 1 case series. Studies that failed to report treatment outcomes and those with fewer than five patients were excluded from the review.
Treatment modalities included topical agents, phototherapy and photochemotherapy, thalidomide, systemic immunomodulatory drugs, antiepileptics and antidepressants, and emerging treatment approaches. Many of the treatments evaluated in the review were found to offer limited promise for clinical application as a result of low efficacy or frequent side effects. The authors attributed the overall lack of success with treatments to the “heterogeneous nature of the etiology of chronic pruritus.”
Thalidomide was found to have limited use given its poor safety profile; lenalidomide achieved better outcomes, but treatment in one case was stopped because of possible drug-induced neuropathy or myopathy, they wrote. The systemic immunomodulatory agents methotrexate and cyclosporine exhibited successful treatment but also were found to have poor safety profiles. Greater promise was seen with antiepileptics and antidepressants, which were associated with fewer side effects. “Antidepressants, such as mirtazapine and amitriptyline, and antiepileptics, such as gabapentin and pregabalin, can offer significant relief to a good number of patients, though success is variable and as we found in our study, the evidence available is limited,” senior author Adam Friedman, MD, professor of dermatology at George Washington University, said in an interview.
Among the most positive outcomes achieved were those in which promising newer treatments, including targeting IL-31 signaling and opioid receptor modulation, were used. In particular, the authors cited nemolizumab, an IL-31 receptor A antagonist, which is currently in a phase 2 trial of PN. Beneficial effects of extended release nalbuphine, an opioid k-receptor agonist and mu-receptor antagonist, were found in an unpublished multicenter, double-blind randomized controlled trial, with no serious adverse effects attributed to treatment.
Among the emerging treatments are the neurokinin-1 receptor antagonists, which include serlopitant, which showed beneficial effects compared with placebo in an 8-week randomized controlled study, they wrote. The neurokinin-1 receptor “is a target of substance P, a mediator of itch and a probable pathogenic agent in PN,” they wrote. “Binding by these agents likely disrupts substance P signaling, thereby halting PN pathogenesis,” they added.
“Antidepressants such as mirtazapine and amitriptyline and antiepileptics such as gabapentin and pregabalin can offer significant relief to a good number of patients, though success is variable and as we found in our study, the evidence available is limited,” Dr. Friedman said in the interview.
Mr. Qureshi had no relevant financial disclosures. Dr. Friedman has received honoraria for participation in advisory boards for Menlo Therapeutics, and serves as an investigator for Kiniksa Pharmaceuticals. A third author received honoraria for participation in advisory boards for Menlo, and several other companies, and received grant/research support as an investigator from Menlo, Kiniksa, and several other companies.
SOURCE: Qureshi AA et al. J Am Acad Dermatol. 2018. doi: 10.1016/j.jaad.2018.09.020.
Key clinical point: Additional research is needed to develop more individualized treatment strategies, but data for some treatments are promising.
Major finding: Treatments identified as having beneficial effects in the review included nemolizumab, an IL-31 receptor A antagonist; nalbuphine, an opioid k-receptor agonist and mu-receptor antagonist, and serlopitant, a neurokinin-1 receptor antagonist.
Study details: A systematic review of 35 studies evaluating treatments for PN, published between Jan. 1, 1990, and March 22, 2018.
Disclosures: Mr. Qureshi had no relevant financial disclosures. Dr. Friedman has received honoraria for participation in advisory boards for Menlo Therapeutics, and serves as an investigator for Kiniksa Pharmaceuticals. A third author received honoraria for participation in advisory boards for Menlo, and several other companies, and received grant/research support as an investigator from Menlo, Kiniksa, and several other companies.
Source: Qureshi AA et al. J Am Acad Dermatol. 2018. doi: 10.1016/j.jaad.2018.09.020.
Increased incidence of GI, colorectal cancers seen in young, obese patients
PHILADELPHIA – Researchers have identified a link between obesity and an increased incidence rate of gastrointestinal (GI) cancers in younger patients as well as an increased rate of colorectal, esophageal, and pancreatic cancer resections in obese patients of various ages, according to an award-winning presentation at the annual meeting of the American College of Gastroenterology.
“These findings strengthen a contributing role of obesity in etiology as well as increasing incidence of these cancers, and call for more efforts targeting obesity,” Hisham Hussan, MD, assistant professor at The Ohio State University Wexner Medical Center in Columbus, stated in his presentation.
The abstract, presented by Dr. Hussan, received an American College of Gastroenterology Category Award in the subject of obesity. He noted in his presentation that the obesity rate in U.S. adults exceeded 37% in 2014. In addition, the temporal changes of obesity-related GI cancers with regard to age-specific groups are not known, he said.
“There’s sufficient evidence linking obesity to certain [GI cancers], such as esophagus, colon, pancreas, and gastric,” Dr. Hussan said. “However, the impact of rising obesity prevalence on the incidence of these obesity-related GI cancers is unknown.”
Dr. Hussan and his colleagues sought to investigate the incidence of obesity-related GI cancers by age group as well as whether there was an association between obesity-related GI cancers in both obese and nonobese patients.
“Our hypothesis is that the incidence of some obesity-related GI cancers is rising in some age groups, and we suspect that this corresponds with increasing rates of obese patients undergoing these cancerous resections,” he said in his presentation.
The researchers evaluated cancer incidence trends in the Surveillance, Epidemiology and End Results (SEER) database between 2002 and 2013 as well as obesity trends from 91,116 obese patients (7.16%) and 1,181,127 nonobese patients (92.84%) in the National Inpatient Sample (NIS) database who underwent cancer resection surgeries. Of these, 93.1% of patients underwent colorectal and 4.4% of patients underwent gastric cancer resections. Patients were considered obese if they had a body mass index of at least 30 kg/m2. The researchers examined annual trends for incidence rates of obesity-related GI cancers by age group and obesity-related GI cancer resection by age and obesity, using a joinpoint regression analysis to determine the percentage change per year.
In patients aged between 20 and 49 years, the incidence of colorectal cancer increased by 1.5% compared with a decrease of 1.5% in patients aged between 50 and 64 years old, a 3.8% decrease in patients aged 65-74 years, and a 3.9% decrease in patients who were a minimum of 75 years old. Gastric cancer incidence also increased by 0.7% in patients aged between 20 and 49 years compared with a 0.5%, 1.1%, and 1.8% decrease among patients who were aged 50-64 years, 65-74 years, and at least 75 years, respectively. There was an increased cancer incidence among patients in the 20- to 49-year-old age group (0.8%), 50- to 64-year-old age group (1.0%), 65- to 74-year-old age group (0.7%), and the 75-and-older group (1.0%). Esophageal cancer was associated with a decreased incidence in the 20- to 49-year-old group (1.8%), 50- to 64-year-old group (1.1%), 65- to 74-year-old age group (1.2%), and the 75-and-older group (0.7%)
For obese patients who underwent colorectal cancer resection, there was a 13.1% increase in the 18- to 49-year-old group, a 10.3% increase in the 50- to 64-year-old group, an 11.3% increase in the 65- to 74-year-old group, and a 12.8% increase in the 75-year-or-older group, compared with an overall decreased incidence in the nonobese group. There was an increased rate of pancreatic cancer resections for obese patients in the 50-to 64-year-old group (26.9%) and 65- to 74-year-old group (27.6%), compared with nonobese patients. Patients in the 18- to 49-year-old group (11.2%), 50- to 64-year-old group (14.6%), and 65- to 74-year-old group (25.7%) also had a higher incidence of esophageal cancer resections.
The limitations of the study included defining BMI at the time of surgery, which does not account for weight loss due to cachexia, and relying on ICD-9 codes for obesity, which “may not be reliable in some cases.
“However, we [saw] an increase in obese patients who come for resection, so it could have probably been more pronounced if we had accounted for obesity at the earlier age before diagnosis,” he added.
Dr. Hussan reports no relevant conflicts of interest.
SOURCE: Hussan H. ACG 2018, Presentation 34.
PHILADELPHIA – Researchers have identified a link between obesity and an increased incidence rate of gastrointestinal (GI) cancers in younger patients as well as an increased rate of colorectal, esophageal, and pancreatic cancer resections in obese patients of various ages, according to an award-winning presentation at the annual meeting of the American College of Gastroenterology.
“These findings strengthen a contributing role of obesity in etiology as well as increasing incidence of these cancers, and call for more efforts targeting obesity,” Hisham Hussan, MD, assistant professor at The Ohio State University Wexner Medical Center in Columbus, stated in his presentation.
The abstract, presented by Dr. Hussan, received an American College of Gastroenterology Category Award in the subject of obesity. He noted in his presentation that the obesity rate in U.S. adults exceeded 37% in 2014. In addition, the temporal changes of obesity-related GI cancers with regard to age-specific groups are not known, he said.
“There’s sufficient evidence linking obesity to certain [GI cancers], such as esophagus, colon, pancreas, and gastric,” Dr. Hussan said. “However, the impact of rising obesity prevalence on the incidence of these obesity-related GI cancers is unknown.”
Dr. Hussan and his colleagues sought to investigate the incidence of obesity-related GI cancers by age group as well as whether there was an association between obesity-related GI cancers in both obese and nonobese patients.
“Our hypothesis is that the incidence of some obesity-related GI cancers is rising in some age groups, and we suspect that this corresponds with increasing rates of obese patients undergoing these cancerous resections,” he said in his presentation.
The researchers evaluated cancer incidence trends in the Surveillance, Epidemiology and End Results (SEER) database between 2002 and 2013 as well as obesity trends from 91,116 obese patients (7.16%) and 1,181,127 nonobese patients (92.84%) in the National Inpatient Sample (NIS) database who underwent cancer resection surgeries. Of these, 93.1% of patients underwent colorectal and 4.4% of patients underwent gastric cancer resections. Patients were considered obese if they had a body mass index of at least 30 kg/m2. The researchers examined annual trends for incidence rates of obesity-related GI cancers by age group and obesity-related GI cancer resection by age and obesity, using a joinpoint regression analysis to determine the percentage change per year.
In patients aged between 20 and 49 years, the incidence of colorectal cancer increased by 1.5% compared with a decrease of 1.5% in patients aged between 50 and 64 years old, a 3.8% decrease in patients aged 65-74 years, and a 3.9% decrease in patients who were a minimum of 75 years old. Gastric cancer incidence also increased by 0.7% in patients aged between 20 and 49 years compared with a 0.5%, 1.1%, and 1.8% decrease among patients who were aged 50-64 years, 65-74 years, and at least 75 years, respectively. There was an increased cancer incidence among patients in the 20- to 49-year-old age group (0.8%), 50- to 64-year-old age group (1.0%), 65- to 74-year-old age group (0.7%), and the 75-and-older group (1.0%). Esophageal cancer was associated with a decreased incidence in the 20- to 49-year-old group (1.8%), 50- to 64-year-old group (1.1%), 65- to 74-year-old age group (1.2%), and the 75-and-older group (0.7%)
For obese patients who underwent colorectal cancer resection, there was a 13.1% increase in the 18- to 49-year-old group, a 10.3% increase in the 50- to 64-year-old group, an 11.3% increase in the 65- to 74-year-old group, and a 12.8% increase in the 75-year-or-older group, compared with an overall decreased incidence in the nonobese group. There was an increased rate of pancreatic cancer resections for obese patients in the 50-to 64-year-old group (26.9%) and 65- to 74-year-old group (27.6%), compared with nonobese patients. Patients in the 18- to 49-year-old group (11.2%), 50- to 64-year-old group (14.6%), and 65- to 74-year-old group (25.7%) also had a higher incidence of esophageal cancer resections.
The limitations of the study included defining BMI at the time of surgery, which does not account for weight loss due to cachexia, and relying on ICD-9 codes for obesity, which “may not be reliable in some cases.
“However, we [saw] an increase in obese patients who come for resection, so it could have probably been more pronounced if we had accounted for obesity at the earlier age before diagnosis,” he added.
Dr. Hussan reports no relevant conflicts of interest.
SOURCE: Hussan H. ACG 2018, Presentation 34.
PHILADELPHIA – Researchers have identified a link between obesity and an increased incidence rate of gastrointestinal (GI) cancers in younger patients as well as an increased rate of colorectal, esophageal, and pancreatic cancer resections in obese patients of various ages, according to an award-winning presentation at the annual meeting of the American College of Gastroenterology.
“These findings strengthen a contributing role of obesity in etiology as well as increasing incidence of these cancers, and call for more efforts targeting obesity,” Hisham Hussan, MD, assistant professor at The Ohio State University Wexner Medical Center in Columbus, stated in his presentation.
The abstract, presented by Dr. Hussan, received an American College of Gastroenterology Category Award in the subject of obesity. He noted in his presentation that the obesity rate in U.S. adults exceeded 37% in 2014. In addition, the temporal changes of obesity-related GI cancers with regard to age-specific groups are not known, he said.
“There’s sufficient evidence linking obesity to certain [GI cancers], such as esophagus, colon, pancreas, and gastric,” Dr. Hussan said. “However, the impact of rising obesity prevalence on the incidence of these obesity-related GI cancers is unknown.”
Dr. Hussan and his colleagues sought to investigate the incidence of obesity-related GI cancers by age group as well as whether there was an association between obesity-related GI cancers in both obese and nonobese patients.
“Our hypothesis is that the incidence of some obesity-related GI cancers is rising in some age groups, and we suspect that this corresponds with increasing rates of obese patients undergoing these cancerous resections,” he said in his presentation.
The researchers evaluated cancer incidence trends in the Surveillance, Epidemiology and End Results (SEER) database between 2002 and 2013 as well as obesity trends from 91,116 obese patients (7.16%) and 1,181,127 nonobese patients (92.84%) in the National Inpatient Sample (NIS) database who underwent cancer resection surgeries. Of these, 93.1% of patients underwent colorectal and 4.4% of patients underwent gastric cancer resections. Patients were considered obese if they had a body mass index of at least 30 kg/m2. The researchers examined annual trends for incidence rates of obesity-related GI cancers by age group and obesity-related GI cancer resection by age and obesity, using a joinpoint regression analysis to determine the percentage change per year.
In patients aged between 20 and 49 years, the incidence of colorectal cancer increased by 1.5% compared with a decrease of 1.5% in patients aged between 50 and 64 years old, a 3.8% decrease in patients aged 65-74 years, and a 3.9% decrease in patients who were a minimum of 75 years old. Gastric cancer incidence also increased by 0.7% in patients aged between 20 and 49 years compared with a 0.5%, 1.1%, and 1.8% decrease among patients who were aged 50-64 years, 65-74 years, and at least 75 years, respectively. There was an increased cancer incidence among patients in the 20- to 49-year-old age group (0.8%), 50- to 64-year-old age group (1.0%), 65- to 74-year-old age group (0.7%), and the 75-and-older group (1.0%). Esophageal cancer was associated with a decreased incidence in the 20- to 49-year-old group (1.8%), 50- to 64-year-old group (1.1%), 65- to 74-year-old age group (1.2%), and the 75-and-older group (0.7%)
For obese patients who underwent colorectal cancer resection, there was a 13.1% increase in the 18- to 49-year-old group, a 10.3% increase in the 50- to 64-year-old group, an 11.3% increase in the 65- to 74-year-old group, and a 12.8% increase in the 75-year-or-older group, compared with an overall decreased incidence in the nonobese group. There was an increased rate of pancreatic cancer resections for obese patients in the 50-to 64-year-old group (26.9%) and 65- to 74-year-old group (27.6%), compared with nonobese patients. Patients in the 18- to 49-year-old group (11.2%), 50- to 64-year-old group (14.6%), and 65- to 74-year-old group (25.7%) also had a higher incidence of esophageal cancer resections.
The limitations of the study included defining BMI at the time of surgery, which does not account for weight loss due to cachexia, and relying on ICD-9 codes for obesity, which “may not be reliable in some cases.
“However, we [saw] an increase in obese patients who come for resection, so it could have probably been more pronounced if we had accounted for obesity at the earlier age before diagnosis,” he added.
Dr. Hussan reports no relevant conflicts of interest.
SOURCE: Hussan H. ACG 2018, Presentation 34.
REPORTING FROM ACG 2018
Key clinical point: There is a higher incidence of colorectal and gastric cancer among obese patients under 50 years old.
Major finding: Obese patients of all age ranges had a higher rate of colorectal cancer resections, obese patients 75 and younger had a significantly higher incidence of esophageal cancer resections, and obese patients aged between 50 and 74 years had a higher rate of pancreatic resections, compared with nonobese patients.
Study details: A database analysis of cancer incidence trends in the Surveillance, Epidemiology, and End Results database and patient cancer incidence and obesity trends in the National Inpatient Sample database between 2002 and 2013.
Disclosures: Dr. Hussan reports no conflicts of interest.
Source: Hussan H. ACG 2018, Presentation 34.
GARFIELD-AF registry: DOACs cut mortality 19%
MUNICH – Treatment of real-world patients newly diagnosed with atrial fibrillation using a direct oral anticoagulant led to benefits that tracked the advantages previously seen in randomized, controlled trials of these drugs, based on findings from more than 26,000 patients enrolled in a global registry.
Atrial fibrillation patients enrolled in the GARFIELD-AF(Global Anticoagulant Registry in the Field) study who started treatment with a direct oral anticoagulant (DOAC) had a 19% relative risk reduction in all-cause mortality during 2 years of follow-up, compared with patients on an oral vitamin K antagonist (VKA) regimen (such as warfarin), a statistically significant difference after adjustment for 30 demographic, clinical, and registry variables, A. John Camm, MD, said at the annual congress of the European Society of Cardiology. The analysis also showed trends toward lower rates of stroke or systemic thrombosis as well as major bleeding events when patients received a DOAC, compared with those on VKA, but these differences were not statistically significant, reported Dr. Camm, a professor of clinical cardiology at St. George’s University of London.
The analyses run by Dr. Camm and his associates also confirmed the superiority of oral anticoagulation. There was an adjusted 17% relative risk reduction in all-cause mortality during 2-year follow-up in patients on any form of oral anticoagulation, compared with patients who did not receive anticoagulation, a statistically significant difference. The comparison of patients on any oral anticoagulant with those not on treatment also showed a significant lowering of stroke or systemic embolism, as well as a 36% relative increase in the risk for a major bleeding episode that was close to statistical significance.
These findings in a registry of patients undergoing routine care “suggest that the effectiveness of oral anticoagulants in randomized clinical trials can be translated to the broad cross section of patients treated in everyday practice,” Dr. Camm said. However, he highlighted two important qualifications to the findings.
First, the analysis focused on the type of anticoagulation patients received at the time they entered the GARFIELD-AF registry and did not account for possible changes in treatment after that. Second, the analysis did not adjust for additional potential confounding variables, which Dr. Camm was certain existed and affected the findings.
“I’m concerned that a confounder we have not been able to account for is the quality of medical care that patients received,” he noted. “The substantial reduction in mortality [using a DOAC, compared with a VKA] is not simply due to reductions in stroke or major bleeding. We must look at other explanations, such as differences in quality of care and access to care.”
The analyses have also not yet looked at outcomes based on the specific DOAC a patient received – apixaban, dabigatran, edoxaban, or rivaroxaban – something that Dr. Camm said is in the works.
GARFIELD-AF enrolled nearly 35,000 patients with newly diagnosed atrial fibrillation and at least one stroke risk factor in 35 countries from April 2013 to September 2016. The analysis winnowed this down to 26,742 patients who also had a CHA2DS2-VASc score of at least 2 (which identifies patients with a high thrombotic risk) and had complete enrollment and follow-up data.
GARFIELD-AF was funded in part by Bayer. Dr. Camm reported being an adviser to Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer/Bristol-Myers Squibb.
MUNICH – Treatment of real-world patients newly diagnosed with atrial fibrillation using a direct oral anticoagulant led to benefits that tracked the advantages previously seen in randomized, controlled trials of these drugs, based on findings from more than 26,000 patients enrolled in a global registry.
Atrial fibrillation patients enrolled in the GARFIELD-AF(Global Anticoagulant Registry in the Field) study who started treatment with a direct oral anticoagulant (DOAC) had a 19% relative risk reduction in all-cause mortality during 2 years of follow-up, compared with patients on an oral vitamin K antagonist (VKA) regimen (such as warfarin), a statistically significant difference after adjustment for 30 demographic, clinical, and registry variables, A. John Camm, MD, said at the annual congress of the European Society of Cardiology. The analysis also showed trends toward lower rates of stroke or systemic thrombosis as well as major bleeding events when patients received a DOAC, compared with those on VKA, but these differences were not statistically significant, reported Dr. Camm, a professor of clinical cardiology at St. George’s University of London.
The analyses run by Dr. Camm and his associates also confirmed the superiority of oral anticoagulation. There was an adjusted 17% relative risk reduction in all-cause mortality during 2-year follow-up in patients on any form of oral anticoagulation, compared with patients who did not receive anticoagulation, a statistically significant difference. The comparison of patients on any oral anticoagulant with those not on treatment also showed a significant lowering of stroke or systemic embolism, as well as a 36% relative increase in the risk for a major bleeding episode that was close to statistical significance.
These findings in a registry of patients undergoing routine care “suggest that the effectiveness of oral anticoagulants in randomized clinical trials can be translated to the broad cross section of patients treated in everyday practice,” Dr. Camm said. However, he highlighted two important qualifications to the findings.
First, the analysis focused on the type of anticoagulation patients received at the time they entered the GARFIELD-AF registry and did not account for possible changes in treatment after that. Second, the analysis did not adjust for additional potential confounding variables, which Dr. Camm was certain existed and affected the findings.
“I’m concerned that a confounder we have not been able to account for is the quality of medical care that patients received,” he noted. “The substantial reduction in mortality [using a DOAC, compared with a VKA] is not simply due to reductions in stroke or major bleeding. We must look at other explanations, such as differences in quality of care and access to care.”
The analyses have also not yet looked at outcomes based on the specific DOAC a patient received – apixaban, dabigatran, edoxaban, or rivaroxaban – something that Dr. Camm said is in the works.
GARFIELD-AF enrolled nearly 35,000 patients with newly diagnosed atrial fibrillation and at least one stroke risk factor in 35 countries from April 2013 to September 2016. The analysis winnowed this down to 26,742 patients who also had a CHA2DS2-VASc score of at least 2 (which identifies patients with a high thrombotic risk) and had complete enrollment and follow-up data.
GARFIELD-AF was funded in part by Bayer. Dr. Camm reported being an adviser to Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer/Bristol-Myers Squibb.
MUNICH – Treatment of real-world patients newly diagnosed with atrial fibrillation using a direct oral anticoagulant led to benefits that tracked the advantages previously seen in randomized, controlled trials of these drugs, based on findings from more than 26,000 patients enrolled in a global registry.
Atrial fibrillation patients enrolled in the GARFIELD-AF(Global Anticoagulant Registry in the Field) study who started treatment with a direct oral anticoagulant (DOAC) had a 19% relative risk reduction in all-cause mortality during 2 years of follow-up, compared with patients on an oral vitamin K antagonist (VKA) regimen (such as warfarin), a statistically significant difference after adjustment for 30 demographic, clinical, and registry variables, A. John Camm, MD, said at the annual congress of the European Society of Cardiology. The analysis also showed trends toward lower rates of stroke or systemic thrombosis as well as major bleeding events when patients received a DOAC, compared with those on VKA, but these differences were not statistically significant, reported Dr. Camm, a professor of clinical cardiology at St. George’s University of London.
The analyses run by Dr. Camm and his associates also confirmed the superiority of oral anticoagulation. There was an adjusted 17% relative risk reduction in all-cause mortality during 2-year follow-up in patients on any form of oral anticoagulation, compared with patients who did not receive anticoagulation, a statistically significant difference. The comparison of patients on any oral anticoagulant with those not on treatment also showed a significant lowering of stroke or systemic embolism, as well as a 36% relative increase in the risk for a major bleeding episode that was close to statistical significance.
These findings in a registry of patients undergoing routine care “suggest that the effectiveness of oral anticoagulants in randomized clinical trials can be translated to the broad cross section of patients treated in everyday practice,” Dr. Camm said. However, he highlighted two important qualifications to the findings.
First, the analysis focused on the type of anticoagulation patients received at the time they entered the GARFIELD-AF registry and did not account for possible changes in treatment after that. Second, the analysis did not adjust for additional potential confounding variables, which Dr. Camm was certain existed and affected the findings.
“I’m concerned that a confounder we have not been able to account for is the quality of medical care that patients received,” he noted. “The substantial reduction in mortality [using a DOAC, compared with a VKA] is not simply due to reductions in stroke or major bleeding. We must look at other explanations, such as differences in quality of care and access to care.”
The analyses have also not yet looked at outcomes based on the specific DOAC a patient received – apixaban, dabigatran, edoxaban, or rivaroxaban – something that Dr. Camm said is in the works.
GARFIELD-AF enrolled nearly 35,000 patients with newly diagnosed atrial fibrillation and at least one stroke risk factor in 35 countries from April 2013 to September 2016. The analysis winnowed this down to 26,742 patients who also had a CHA2DS2-VASc score of at least 2 (which identifies patients with a high thrombotic risk) and had complete enrollment and follow-up data.
GARFIELD-AF was funded in part by Bayer. Dr. Camm reported being an adviser to Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer/Bristol-Myers Squibb.
REPORTING FROM THE ESC CONGRESS 2018
Key clinical point:
Major finding: Direct oral anticoagulant–treated patients had a 19% relative reduction in all-cause death, compared with patients on a vitamin K antagonist.
Study details: The GARFIELD-AF registry, which included 26,742 patients with newly diagnosed atrial fibrillation.
Disclosures: GARFIELD-AF was funded in part by Bayer. Dr. Camm has been an adviser to Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Pfizer/Bristol-Myers Squibb.
MCL treatment choices depend partly on age
CHICAGO – Treatment for mantle cell lymphoma (MCL) depends at least in part on patient age, with some important differences in those aged 65 years or younger versus those over age 65, according to Kristie A. Blum, MD.
“For the [younger] early-stage patients I’ll think about radiation and maybe observation, although I think [observation] is pretty uncommon,” Dr. Blum, acting hematology and medical oncology professor at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
For advanced-stage patients, a number of options, including observation, can be considered, she said.
Observation
Observation is acceptable in highly selected advanced stage cases. In a 2009 study of 97 mantle cell patients, 31 were observed for more than 3 months before treatment was initiated (median time to treatment, 12 months), and at median follow-up of 55 months, overall survival (OS) was significantly better in the observation group (not reached vs. 64 months in treated patients), she said (J Clin Oncol. 2009 Mar 10;27[8]:1209-13).
Observed patients had better performance status and lower-risk standard International Prognostic Index scores, compared with treated patients, and the authors concluded that a “watch-and-wait” approach is acceptable in select patients.
“In addition, if you looked at their overall survival from the time of first treatment, there was no difference in the groups, suggesting you really weren’t hurting people by delaying their therapy,” Dr. Blum said.
In a more recent series of 440 favorable-risk MCL patients, 17% were observed for at least 3 months (median time to treatment, 35 months), 80% were observed for at least 12 months, and 13% were observed for 5 years.
Again, median OS was better for observed patients than for those treated initially, at 72 months vs. 52.5 months (Ann Oncol. 2017;28[10]:2489-95).
“So I do think there is a subset of patients that can safely be observed with mantle cell [lymphoma],” she said.
Transplant-based approaches
Transplant-based approaches in younger patients with advanced disease include the Nordic regimen plus autologous stem cell transplant (ASCT), R-CHOP/R-DHAP plus ASCT, and R-bendamustine/R-cytarabine – all with post-ASCT maintenance rituximab, Dr. Blum said.
Cytarabine-containing induction was established as the pretransplant standard of care by the 474-patient MCL Younger trial, which demonstrated significantly prolonged time to treatment failure (9.1 vs. 3.9 years), with alternating pretransplant R-CHOP/R-DHAP versus R-CHOP for six cycles, though this was associated with increased toxicity. (Lancet. 2016 Aug 6;388[10044]:565-75).
For example, grade 3-4 thrombocytopenia occurred in 73% vs. 9% of patients, she noted.
The Nordic MCL2 trial showed that an intensive regimen involving alternating Maxi-CHOP and AraC followed by transplant results in median OS of about 12 years and PFS of about 8 years.
“I do want to highlight, though, that again, the high-risk patients don’t do very well,” she said, noting that median PFS even with this intensive approach was only 2.5 years in those at high risk based on MCL International Prognostic Index (MIPI) score, compared with 12.7 years for patients with a low-risk MIPI score.
Newer induction regimens also show some promise and appear feasible in younger patients based on early data, she said, noting that the SWOG S1106 trial comparing R-bendamustine and R-HyperCVAD showed a minimal residual disease (MRD) negativity rate of 78% in the R-bendamustine group. Another study evaluating R-bendamustine followed by AraC showed a 96% complete remission and PFS at 13 months of 96%, with MRD-negativity of 93% (Br J Haematol. 2016 Apr;173[1]:89-95).
Transplant also is an option in advanced stage patients aged 66-70 years who are fit and willing, Dr. Blum said.
“I spend a long time talking to these patients about whether they want a transplant or not,” she said.
For induction in those patients who choose transplant, Dr. Blum said she prefers bendamustine-based regimens, “because these have been published in patients up to the age of 70.”
Transplant timing is usually at the first complete remission.
Data show that 5-year OS after such early ASCT in patients with no more than two prior lines of chemotherapy is about 60%, compared with about 44% with late ASCT. For reduced intensity conditioning allogeneic stem cell transplant in that study, the 5-year OS was 62% for early transplant and 31% for late transplant (J Clin Oncol. 2014 Feb 1;32[4]:273-81).
R-HyperCVAD
R-HyperCVAD is another option in younger patients, and is usually given for eight cycles, followed by transplant only in those who aren’t in complete remission, Dr. Blum said.
Median failure-free survival among patients aged 65 years and younger in one study of this regimen was 6.5 years and OS was 13.4 years. In those over age 65, median failure-free survival was about 3 years (Br J Haematol. 2016 Jan;172[1]:80-88).
The SWOG 0213 study looked at this in a multicenter fashion, she said, noting that 39% of patients – 48% of whom were aged 65 and older – could not complete all eight cycles.
“Again, there was a high rate of this sort of infectious toxicity,” she said.
Median PFS was about 5 years in this study as well, and OS was nearly 7 years. For those over age 65, median PFS was just 1.6 years.
“So I don’t typically recommend this for the 65- to 70-year-olds,” she said.
Older nontransplant candidates
When treating patients who are unfit for transplant, Dr. Blum pointed to the results of the StiL and BRIGHT studies, which both showed that R-bendamustine was noninferior to R-CHOP as first-line treatment.
In addition, recent data on combined bendamustine and cytarabine (R-BAC500) showed that in 57 patients with a median age of 71 years, 95% received at least four cycles, and 67% completed six cycles. CR was 91% , and 2-year OS and PFS were 86% and 81%, respectively.
However, grade 3-4 neutropenia and thrombocytopenia occurred in 49% and 52% of patients, respectively (Lancet Haematol. 2017 Jan 1;4[1]:e15-e23).
The bortezomib-containing regimen VR-CAP has also been shown to be of benefit for older MCL patients not eligible for transplant, she said.
Median PFS with VR-CAP in a study of 487 newly diagnosed MCL patients was about 25 months vs. 14 months with R-CHOP (N Engl J Med. 2015 Mar 5;372:944-53).
“R-lenalidomide has activity in the front-line setting as well,” Dr. Blum said, citing a multicenter phase 2 study of 38 patients with a mean age of 65 years. The intention-to-treat analysis showed an overall response rate of 87%, CR rate of 61%, and 2-year PFS of 85% (N Engl J Med. 2015;373:1835-44).
Maintenance therapy
As for maintenance therapy in younger patients, a phase 3 study of 299 patients showed that rituximab maintenance was associated with significantly better 4-year PFS (83% vs. 64% with observation), and 4-year OS (89% vs. 80% with observation), she said (N Engl J Med. 2017 Sep 28;377:1250-60).
“I do think that rituximab maintenance is the standard of care now, based on this study,” Dr. Blum said, adding that there is also a role for rituximab maintenance in older patients.
A European Mantle Cell Network study of patients aged 60 and older (median age of 70) showed an OS of 62% with R-CHOP vs. 47% with R-FC (rituximab, fludarabine, and cyclophosphamide), and – among those then randomized to maintenance rituximab or interferon alpha – 4-year PFS of 58% vs. 29%, respectively (N Engl J Med. 2012;367:520-31).
“Now I will tell you that most of these patients are getting bendamustine. We don’t really know the role for rituximab maintenance after bendamustine-based induction, but at this point I think it’s reasonable to consider adding it,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
CHICAGO – Treatment for mantle cell lymphoma (MCL) depends at least in part on patient age, with some important differences in those aged 65 years or younger versus those over age 65, according to Kristie A. Blum, MD.
“For the [younger] early-stage patients I’ll think about radiation and maybe observation, although I think [observation] is pretty uncommon,” Dr. Blum, acting hematology and medical oncology professor at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
For advanced-stage patients, a number of options, including observation, can be considered, she said.
Observation
Observation is acceptable in highly selected advanced stage cases. In a 2009 study of 97 mantle cell patients, 31 were observed for more than 3 months before treatment was initiated (median time to treatment, 12 months), and at median follow-up of 55 months, overall survival (OS) was significantly better in the observation group (not reached vs. 64 months in treated patients), she said (J Clin Oncol. 2009 Mar 10;27[8]:1209-13).
Observed patients had better performance status and lower-risk standard International Prognostic Index scores, compared with treated patients, and the authors concluded that a “watch-and-wait” approach is acceptable in select patients.
“In addition, if you looked at their overall survival from the time of first treatment, there was no difference in the groups, suggesting you really weren’t hurting people by delaying their therapy,” Dr. Blum said.
In a more recent series of 440 favorable-risk MCL patients, 17% were observed for at least 3 months (median time to treatment, 35 months), 80% were observed for at least 12 months, and 13% were observed for 5 years.
Again, median OS was better for observed patients than for those treated initially, at 72 months vs. 52.5 months (Ann Oncol. 2017;28[10]:2489-95).
“So I do think there is a subset of patients that can safely be observed with mantle cell [lymphoma],” she said.
Transplant-based approaches
Transplant-based approaches in younger patients with advanced disease include the Nordic regimen plus autologous stem cell transplant (ASCT), R-CHOP/R-DHAP plus ASCT, and R-bendamustine/R-cytarabine – all with post-ASCT maintenance rituximab, Dr. Blum said.
Cytarabine-containing induction was established as the pretransplant standard of care by the 474-patient MCL Younger trial, which demonstrated significantly prolonged time to treatment failure (9.1 vs. 3.9 years), with alternating pretransplant R-CHOP/R-DHAP versus R-CHOP for six cycles, though this was associated with increased toxicity. (Lancet. 2016 Aug 6;388[10044]:565-75).
For example, grade 3-4 thrombocytopenia occurred in 73% vs. 9% of patients, she noted.
The Nordic MCL2 trial showed that an intensive regimen involving alternating Maxi-CHOP and AraC followed by transplant results in median OS of about 12 years and PFS of about 8 years.
“I do want to highlight, though, that again, the high-risk patients don’t do very well,” she said, noting that median PFS even with this intensive approach was only 2.5 years in those at high risk based on MCL International Prognostic Index (MIPI) score, compared with 12.7 years for patients with a low-risk MIPI score.
Newer induction regimens also show some promise and appear feasible in younger patients based on early data, she said, noting that the SWOG S1106 trial comparing R-bendamustine and R-HyperCVAD showed a minimal residual disease (MRD) negativity rate of 78% in the R-bendamustine group. Another study evaluating R-bendamustine followed by AraC showed a 96% complete remission and PFS at 13 months of 96%, with MRD-negativity of 93% (Br J Haematol. 2016 Apr;173[1]:89-95).
Transplant also is an option in advanced stage patients aged 66-70 years who are fit and willing, Dr. Blum said.
“I spend a long time talking to these patients about whether they want a transplant or not,” she said.
For induction in those patients who choose transplant, Dr. Blum said she prefers bendamustine-based regimens, “because these have been published in patients up to the age of 70.”
Transplant timing is usually at the first complete remission.
Data show that 5-year OS after such early ASCT in patients with no more than two prior lines of chemotherapy is about 60%, compared with about 44% with late ASCT. For reduced intensity conditioning allogeneic stem cell transplant in that study, the 5-year OS was 62% for early transplant and 31% for late transplant (J Clin Oncol. 2014 Feb 1;32[4]:273-81).
R-HyperCVAD
R-HyperCVAD is another option in younger patients, and is usually given for eight cycles, followed by transplant only in those who aren’t in complete remission, Dr. Blum said.
Median failure-free survival among patients aged 65 years and younger in one study of this regimen was 6.5 years and OS was 13.4 years. In those over age 65, median failure-free survival was about 3 years (Br J Haematol. 2016 Jan;172[1]:80-88).
The SWOG 0213 study looked at this in a multicenter fashion, she said, noting that 39% of patients – 48% of whom were aged 65 and older – could not complete all eight cycles.
“Again, there was a high rate of this sort of infectious toxicity,” she said.
Median PFS was about 5 years in this study as well, and OS was nearly 7 years. For those over age 65, median PFS was just 1.6 years.
“So I don’t typically recommend this for the 65- to 70-year-olds,” she said.
Older nontransplant candidates
When treating patients who are unfit for transplant, Dr. Blum pointed to the results of the StiL and BRIGHT studies, which both showed that R-bendamustine was noninferior to R-CHOP as first-line treatment.
In addition, recent data on combined bendamustine and cytarabine (R-BAC500) showed that in 57 patients with a median age of 71 years, 95% received at least four cycles, and 67% completed six cycles. CR was 91% , and 2-year OS and PFS were 86% and 81%, respectively.
However, grade 3-4 neutropenia and thrombocytopenia occurred in 49% and 52% of patients, respectively (Lancet Haematol. 2017 Jan 1;4[1]:e15-e23).
The bortezomib-containing regimen VR-CAP has also been shown to be of benefit for older MCL patients not eligible for transplant, she said.
Median PFS with VR-CAP in a study of 487 newly diagnosed MCL patients was about 25 months vs. 14 months with R-CHOP (N Engl J Med. 2015 Mar 5;372:944-53).
“R-lenalidomide has activity in the front-line setting as well,” Dr. Blum said, citing a multicenter phase 2 study of 38 patients with a mean age of 65 years. The intention-to-treat analysis showed an overall response rate of 87%, CR rate of 61%, and 2-year PFS of 85% (N Engl J Med. 2015;373:1835-44).
Maintenance therapy
As for maintenance therapy in younger patients, a phase 3 study of 299 patients showed that rituximab maintenance was associated with significantly better 4-year PFS (83% vs. 64% with observation), and 4-year OS (89% vs. 80% with observation), she said (N Engl J Med. 2017 Sep 28;377:1250-60).
“I do think that rituximab maintenance is the standard of care now, based on this study,” Dr. Blum said, adding that there is also a role for rituximab maintenance in older patients.
A European Mantle Cell Network study of patients aged 60 and older (median age of 70) showed an OS of 62% with R-CHOP vs. 47% with R-FC (rituximab, fludarabine, and cyclophosphamide), and – among those then randomized to maintenance rituximab or interferon alpha – 4-year PFS of 58% vs. 29%, respectively (N Engl J Med. 2012;367:520-31).
“Now I will tell you that most of these patients are getting bendamustine. We don’t really know the role for rituximab maintenance after bendamustine-based induction, but at this point I think it’s reasonable to consider adding it,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
CHICAGO – Treatment for mantle cell lymphoma (MCL) depends at least in part on patient age, with some important differences in those aged 65 years or younger versus those over age 65, according to Kristie A. Blum, MD.
“For the [younger] early-stage patients I’ll think about radiation and maybe observation, although I think [observation] is pretty uncommon,” Dr. Blum, acting hematology and medical oncology professor at Emory University in Atlanta, said at the American Society of Hematology Meeting on Hematologic Malignancies.
For advanced-stage patients, a number of options, including observation, can be considered, she said.
Observation
Observation is acceptable in highly selected advanced stage cases. In a 2009 study of 97 mantle cell patients, 31 were observed for more than 3 months before treatment was initiated (median time to treatment, 12 months), and at median follow-up of 55 months, overall survival (OS) was significantly better in the observation group (not reached vs. 64 months in treated patients), she said (J Clin Oncol. 2009 Mar 10;27[8]:1209-13).
Observed patients had better performance status and lower-risk standard International Prognostic Index scores, compared with treated patients, and the authors concluded that a “watch-and-wait” approach is acceptable in select patients.
“In addition, if you looked at their overall survival from the time of first treatment, there was no difference in the groups, suggesting you really weren’t hurting people by delaying their therapy,” Dr. Blum said.
In a more recent series of 440 favorable-risk MCL patients, 17% were observed for at least 3 months (median time to treatment, 35 months), 80% were observed for at least 12 months, and 13% were observed for 5 years.
Again, median OS was better for observed patients than for those treated initially, at 72 months vs. 52.5 months (Ann Oncol. 2017;28[10]:2489-95).
“So I do think there is a subset of patients that can safely be observed with mantle cell [lymphoma],” she said.
Transplant-based approaches
Transplant-based approaches in younger patients with advanced disease include the Nordic regimen plus autologous stem cell transplant (ASCT), R-CHOP/R-DHAP plus ASCT, and R-bendamustine/R-cytarabine – all with post-ASCT maintenance rituximab, Dr. Blum said.
Cytarabine-containing induction was established as the pretransplant standard of care by the 474-patient MCL Younger trial, which demonstrated significantly prolonged time to treatment failure (9.1 vs. 3.9 years), with alternating pretransplant R-CHOP/R-DHAP versus R-CHOP for six cycles, though this was associated with increased toxicity. (Lancet. 2016 Aug 6;388[10044]:565-75).
For example, grade 3-4 thrombocytopenia occurred in 73% vs. 9% of patients, she noted.
The Nordic MCL2 trial showed that an intensive regimen involving alternating Maxi-CHOP and AraC followed by transplant results in median OS of about 12 years and PFS of about 8 years.
“I do want to highlight, though, that again, the high-risk patients don’t do very well,” she said, noting that median PFS even with this intensive approach was only 2.5 years in those at high risk based on MCL International Prognostic Index (MIPI) score, compared with 12.7 years for patients with a low-risk MIPI score.
Newer induction regimens also show some promise and appear feasible in younger patients based on early data, she said, noting that the SWOG S1106 trial comparing R-bendamustine and R-HyperCVAD showed a minimal residual disease (MRD) negativity rate of 78% in the R-bendamustine group. Another study evaluating R-bendamustine followed by AraC showed a 96% complete remission and PFS at 13 months of 96%, with MRD-negativity of 93% (Br J Haematol. 2016 Apr;173[1]:89-95).
Transplant also is an option in advanced stage patients aged 66-70 years who are fit and willing, Dr. Blum said.
“I spend a long time talking to these patients about whether they want a transplant or not,” she said.
For induction in those patients who choose transplant, Dr. Blum said she prefers bendamustine-based regimens, “because these have been published in patients up to the age of 70.”
Transplant timing is usually at the first complete remission.
Data show that 5-year OS after such early ASCT in patients with no more than two prior lines of chemotherapy is about 60%, compared with about 44% with late ASCT. For reduced intensity conditioning allogeneic stem cell transplant in that study, the 5-year OS was 62% for early transplant and 31% for late transplant (J Clin Oncol. 2014 Feb 1;32[4]:273-81).
R-HyperCVAD
R-HyperCVAD is another option in younger patients, and is usually given for eight cycles, followed by transplant only in those who aren’t in complete remission, Dr. Blum said.
Median failure-free survival among patients aged 65 years and younger in one study of this regimen was 6.5 years and OS was 13.4 years. In those over age 65, median failure-free survival was about 3 years (Br J Haematol. 2016 Jan;172[1]:80-88).
The SWOG 0213 study looked at this in a multicenter fashion, she said, noting that 39% of patients – 48% of whom were aged 65 and older – could not complete all eight cycles.
“Again, there was a high rate of this sort of infectious toxicity,” she said.
Median PFS was about 5 years in this study as well, and OS was nearly 7 years. For those over age 65, median PFS was just 1.6 years.
“So I don’t typically recommend this for the 65- to 70-year-olds,” she said.
Older nontransplant candidates
When treating patients who are unfit for transplant, Dr. Blum pointed to the results of the StiL and BRIGHT studies, which both showed that R-bendamustine was noninferior to R-CHOP as first-line treatment.
In addition, recent data on combined bendamustine and cytarabine (R-BAC500) showed that in 57 patients with a median age of 71 years, 95% received at least four cycles, and 67% completed six cycles. CR was 91% , and 2-year OS and PFS were 86% and 81%, respectively.
However, grade 3-4 neutropenia and thrombocytopenia occurred in 49% and 52% of patients, respectively (Lancet Haematol. 2017 Jan 1;4[1]:e15-e23).
The bortezomib-containing regimen VR-CAP has also been shown to be of benefit for older MCL patients not eligible for transplant, she said.
Median PFS with VR-CAP in a study of 487 newly diagnosed MCL patients was about 25 months vs. 14 months with R-CHOP (N Engl J Med. 2015 Mar 5;372:944-53).
“R-lenalidomide has activity in the front-line setting as well,” Dr. Blum said, citing a multicenter phase 2 study of 38 patients with a mean age of 65 years. The intention-to-treat analysis showed an overall response rate of 87%, CR rate of 61%, and 2-year PFS of 85% (N Engl J Med. 2015;373:1835-44).
Maintenance therapy
As for maintenance therapy in younger patients, a phase 3 study of 299 patients showed that rituximab maintenance was associated with significantly better 4-year PFS (83% vs. 64% with observation), and 4-year OS (89% vs. 80% with observation), she said (N Engl J Med. 2017 Sep 28;377:1250-60).
“I do think that rituximab maintenance is the standard of care now, based on this study,” Dr. Blum said, adding that there is also a role for rituximab maintenance in older patients.
A European Mantle Cell Network study of patients aged 60 and older (median age of 70) showed an OS of 62% with R-CHOP vs. 47% with R-FC (rituximab, fludarabine, and cyclophosphamide), and – among those then randomized to maintenance rituximab or interferon alpha – 4-year PFS of 58% vs. 29%, respectively (N Engl J Med. 2012;367:520-31).
“Now I will tell you that most of these patients are getting bendamustine. We don’t really know the role for rituximab maintenance after bendamustine-based induction, but at this point I think it’s reasonable to consider adding it,” she said.
Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.
EXPERT ANALYSIS FROM MHM 2018
Brain mapping takes next step toward precision psychiatry
Brain mapping patterns varied with clinical mental health diagnoses in a study of 218 patients with schizophrenia spectrum disorders.
“Psychiatry is now the last area of medicine in which diseases are diagnosed solely on the basis of symptoms, and biomarkers to assist treatment remain to be developed,” wrote Thomas Wolfers of Radboud University, Nijmegen, the Netherlands, and his colleagues. They also said schizophrenia and bipolar disorder “are excellent examples of highly heterogeneous mental disorders.”
To explore brain structure homogeneity, the researchers used brain scans and mapping models to compare results in 218 adults aged 18-65 years with schizophrenia disorders (163 with schizophrenia and 190 with bipolar disorder) and 256 healthy controls. Demographics were similar between the groups.
The MRI data showed that the same abnormalities in more than 2% of patients with the same disorder occurred in very few loci. Schizophrenia patients showed significantly reduced gray matter in the frontal, cerebellar, and temporal regions; most bipolar patients showed changes in the cerebellar region.
The researchers identified extreme deviations across patients and controls in gray and white matter.
In gray matter, schizophrenia patients had a significantly higher percentage of extreme negative deviations across voxels (0.9% of voxels), compared with both bipolar patients and healthy controls (0.24% and 0.23%, respectively).
In white matter, a similar pattern emerged; schizophrenia patients had a significantly higher percentage of extreme negative deviations (0.62%), compared with healthy controls and bipolar patients (0.25% and 0.41%, respectively). In addition, extreme positive deviations were significantly higher among the controls (1.14% of voxels), compared with schizophrenia and bipolar patients (0.83% for both).
The findings support data from previous studies suggesting reduced cortical volume in schizophrenia patients, compared with healthy controls and bipolar disorder patients, the researchers noted.
“In this study, patients with schizophrenia and bipolar disorder differed extremely on an individual level; the lack of substantial overlap among patients in terms of extreme deviations from the normative model is evidence of the high degree of biological heterogeneity in both disorders,” wrote Mr. Wolfers and his colleagues.
The main limitations of the study were the inability to control for confounding variables and to make conclusions about causality, the researchers said. However, the absence of overlap in patients with the same disorder supports the use of brain mapping to study individual pathophysiologic signatures in schizophrenia and bipolar disorder patients, they concluded.
Mr. Wolfers had no financial conflicts to disclose. The study was supported by grants from multiple organizations, including the Netherlands Organisation for Scientific Research and the Wellcome Trust U.K. Strategic Award.
SOURCE: Wolfers T et al. JAMA Psychiatry. 2018. doi: 10.1001/jamapsychiatry.2018.2467.
A growing body of evidence suggests that “conventional psychiatric diagnoses of serious mental illness (SMI), when tested, do not show a common biology,” wrote Carol A. Tamminga, MD, and Elena I. Ivleva, MD, PhD, in an accompanying editorial. The editorialists noted the work of the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium to identify subtype disease clusters.
However, they wrote: “We question whether these biotype structures represent disease groups as opposed to mere brain biomarker clusters. Dr. Tamminga and Dr. Ivleva also expressed concern about whether biologically based subgroups would be clinically useful and questioned what evidence would be needed to accept such subtypes as disease subgroups.
Their ideas for further exploration included identifying a characteristic genetic fingerprint to help determine a common pathophysiology. In addition, “a disorder clustered by biological features might also show a distinctive pharmacological profile,” they wrote.
Next steps include making severe mental illness into a condition diagnosable based on biomarkers that also can serve as a foundation for treatment, which would be “a revolution in our ability to understand and treat complex brain disorders,” they noted (JAMA Psychiatry. 2018 Oct. doi: 10.1001/jamapsychiatry.2018.2451).
Dr. Tamminga and Dr. Ivleva are affiliated with the University of Texas, Dallas. Both of them serve as researchers with the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium and reported funding from the National Institute for Mental Health.
A growing body of evidence suggests that “conventional psychiatric diagnoses of serious mental illness (SMI), when tested, do not show a common biology,” wrote Carol A. Tamminga, MD, and Elena I. Ivleva, MD, PhD, in an accompanying editorial. The editorialists noted the work of the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium to identify subtype disease clusters.
However, they wrote: “We question whether these biotype structures represent disease groups as opposed to mere brain biomarker clusters. Dr. Tamminga and Dr. Ivleva also expressed concern about whether biologically based subgroups would be clinically useful and questioned what evidence would be needed to accept such subtypes as disease subgroups.
Their ideas for further exploration included identifying a characteristic genetic fingerprint to help determine a common pathophysiology. In addition, “a disorder clustered by biological features might also show a distinctive pharmacological profile,” they wrote.
Next steps include making severe mental illness into a condition diagnosable based on biomarkers that also can serve as a foundation for treatment, which would be “a revolution in our ability to understand and treat complex brain disorders,” they noted (JAMA Psychiatry. 2018 Oct. doi: 10.1001/jamapsychiatry.2018.2451).
Dr. Tamminga and Dr. Ivleva are affiliated with the University of Texas, Dallas. Both of them serve as researchers with the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium and reported funding from the National Institute for Mental Health.
A growing body of evidence suggests that “conventional psychiatric diagnoses of serious mental illness (SMI), when tested, do not show a common biology,” wrote Carol A. Tamminga, MD, and Elena I. Ivleva, MD, PhD, in an accompanying editorial. The editorialists noted the work of the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium to identify subtype disease clusters.
However, they wrote: “We question whether these biotype structures represent disease groups as opposed to mere brain biomarker clusters. Dr. Tamminga and Dr. Ivleva also expressed concern about whether biologically based subgroups would be clinically useful and questioned what evidence would be needed to accept such subtypes as disease subgroups.
Their ideas for further exploration included identifying a characteristic genetic fingerprint to help determine a common pathophysiology. In addition, “a disorder clustered by biological features might also show a distinctive pharmacological profile,” they wrote.
Next steps include making severe mental illness into a condition diagnosable based on biomarkers that also can serve as a foundation for treatment, which would be “a revolution in our ability to understand and treat complex brain disorders,” they noted (JAMA Psychiatry. 2018 Oct. doi: 10.1001/jamapsychiatry.2018.2451).
Dr. Tamminga and Dr. Ivleva are affiliated with the University of Texas, Dallas. Both of them serve as researchers with the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium and reported funding from the National Institute for Mental Health.
Brain mapping patterns varied with clinical mental health diagnoses in a study of 218 patients with schizophrenia spectrum disorders.
“Psychiatry is now the last area of medicine in which diseases are diagnosed solely on the basis of symptoms, and biomarkers to assist treatment remain to be developed,” wrote Thomas Wolfers of Radboud University, Nijmegen, the Netherlands, and his colleagues. They also said schizophrenia and bipolar disorder “are excellent examples of highly heterogeneous mental disorders.”
To explore brain structure homogeneity, the researchers used brain scans and mapping models to compare results in 218 adults aged 18-65 years with schizophrenia disorders (163 with schizophrenia and 190 with bipolar disorder) and 256 healthy controls. Demographics were similar between the groups.
The MRI data showed that the same abnormalities in more than 2% of patients with the same disorder occurred in very few loci. Schizophrenia patients showed significantly reduced gray matter in the frontal, cerebellar, and temporal regions; most bipolar patients showed changes in the cerebellar region.
The researchers identified extreme deviations across patients and controls in gray and white matter.
In gray matter, schizophrenia patients had a significantly higher percentage of extreme negative deviations across voxels (0.9% of voxels), compared with both bipolar patients and healthy controls (0.24% and 0.23%, respectively).
In white matter, a similar pattern emerged; schizophrenia patients had a significantly higher percentage of extreme negative deviations (0.62%), compared with healthy controls and bipolar patients (0.25% and 0.41%, respectively). In addition, extreme positive deviations were significantly higher among the controls (1.14% of voxels), compared with schizophrenia and bipolar patients (0.83% for both).
The findings support data from previous studies suggesting reduced cortical volume in schizophrenia patients, compared with healthy controls and bipolar disorder patients, the researchers noted.
“In this study, patients with schizophrenia and bipolar disorder differed extremely on an individual level; the lack of substantial overlap among patients in terms of extreme deviations from the normative model is evidence of the high degree of biological heterogeneity in both disorders,” wrote Mr. Wolfers and his colleagues.
The main limitations of the study were the inability to control for confounding variables and to make conclusions about causality, the researchers said. However, the absence of overlap in patients with the same disorder supports the use of brain mapping to study individual pathophysiologic signatures in schizophrenia and bipolar disorder patients, they concluded.
Mr. Wolfers had no financial conflicts to disclose. The study was supported by grants from multiple organizations, including the Netherlands Organisation for Scientific Research and the Wellcome Trust U.K. Strategic Award.
SOURCE: Wolfers T et al. JAMA Psychiatry. 2018. doi: 10.1001/jamapsychiatry.2018.2467.
Brain mapping patterns varied with clinical mental health diagnoses in a study of 218 patients with schizophrenia spectrum disorders.
“Psychiatry is now the last area of medicine in which diseases are diagnosed solely on the basis of symptoms, and biomarkers to assist treatment remain to be developed,” wrote Thomas Wolfers of Radboud University, Nijmegen, the Netherlands, and his colleagues. They also said schizophrenia and bipolar disorder “are excellent examples of highly heterogeneous mental disorders.”
To explore brain structure homogeneity, the researchers used brain scans and mapping models to compare results in 218 adults aged 18-65 years with schizophrenia disorders (163 with schizophrenia and 190 with bipolar disorder) and 256 healthy controls. Demographics were similar between the groups.
The MRI data showed that the same abnormalities in more than 2% of patients with the same disorder occurred in very few loci. Schizophrenia patients showed significantly reduced gray matter in the frontal, cerebellar, and temporal regions; most bipolar patients showed changes in the cerebellar region.
The researchers identified extreme deviations across patients and controls in gray and white matter.
In gray matter, schizophrenia patients had a significantly higher percentage of extreme negative deviations across voxels (0.9% of voxels), compared with both bipolar patients and healthy controls (0.24% and 0.23%, respectively).
In white matter, a similar pattern emerged; schizophrenia patients had a significantly higher percentage of extreme negative deviations (0.62%), compared with healthy controls and bipolar patients (0.25% and 0.41%, respectively). In addition, extreme positive deviations were significantly higher among the controls (1.14% of voxels), compared with schizophrenia and bipolar patients (0.83% for both).
The findings support data from previous studies suggesting reduced cortical volume in schizophrenia patients, compared with healthy controls and bipolar disorder patients, the researchers noted.
“In this study, patients with schizophrenia and bipolar disorder differed extremely on an individual level; the lack of substantial overlap among patients in terms of extreme deviations from the normative model is evidence of the high degree of biological heterogeneity in both disorders,” wrote Mr. Wolfers and his colleagues.
The main limitations of the study were the inability to control for confounding variables and to make conclusions about causality, the researchers said. However, the absence of overlap in patients with the same disorder supports the use of brain mapping to study individual pathophysiologic signatures in schizophrenia and bipolar disorder patients, they concluded.
Mr. Wolfers had no financial conflicts to disclose. The study was supported by grants from multiple organizations, including the Netherlands Organisation for Scientific Research and the Wellcome Trust U.K. Strategic Award.
SOURCE: Wolfers T et al. JAMA Psychiatry. 2018. doi: 10.1001/jamapsychiatry.2018.2467.
FROM JAMA PSYCHIATRY
Key clinical point: Technology that allows for brain mapping offers a framework for greater use of precision medicine in psychiatry.
Major finding: Few brain loci showed extreme deviations in more than 2% of patients with schizophrenia disorders in a brain mapping model.
Study details: The data come from MRI scans of 218 patients with schizophrenia or bipolar disorder and 256 healthy controls.
Disclosures: Mr. Wolfers had no financial conflicts to disclose. The study was supported by grants from multiple organizations, including the Netherlands Organisation for Scientific Research and the Wellcome Trust U.K. Strategic Award.
Source: Wolfers T et al. JAMA Psychiatry. 2018. doi: 10.1001/jamapsychiatry.2018.2467.
Beyond the opioids
The drug epidemic of early initiation, frequent use, and a polydrug reality
The national opioid epidemic is one of the most important public health challenges facing the United States today. This crisis has resulted in death, disability, and increased infectious and other comorbid diseases.
Public attention has been focused on the medical management of pain, patterns of opioid prescriptions, and use of heroin and fentanyl. But the opioid crisis is, in fact, part of a far larger drug epidemic. The foundation on which the opioid epidemic is built is recreational pharmacology – the widespread use of aggressively marketed chemicals that seductively superstimulate brain-reward producing alterations in consciousness and pleasure, often mislabeled “self-medication.”
Drugs of abuse are unique chemicals that stimulate their own taking by producing an intense reinforcement in the human brain, which tells users that they have done something monumentally good. Instead of preserving the species, this chemical stimulation of brain reward begins the process of retraining the brain and reward system to respond quickly to drugs of abuse and drug-promoting cues. Drugs of abuse do not come from one class or chemical structure, but, rather, from disparate chemical classes that have in common the stimulation of brain reward. This bad learning is accelerated to addiction when drugs of abuse are smoked, snorted, vaped, or injected, as these routes of administration produce rapidly rising and falling blood levels.
Thanks to the science of animal models, we understand drug self-administration and abstinence. However, in animals, we cannot approximate addiction beyond the mechanical because of the cultural complexity of human behavior. Most animal models are good at predicting what treatments will work for drug addiction in animals. They are less predictive when it comes to humans. Animal models are good for understanding withdrawal reversal and identifying self-administration reductions and even changes in place preference. Animal models have consistently shown that drugs of abuse raise the brain’s reward threshold and cause epigenetic changes, and that many of these changes are persistent, if not permanent. In animal models, clonidine or opioid detoxification followed by naltrexone is a cure for opioid use disorder. Again, in animal models, this protocol is tied to no relapses – just a cure. We know that this is not the case for humans suffering from opioid addiction, where relapses define the disorder.
A closer look at opioid overdoses
Opioid overdose deaths are skyrocketing in the United States. The number of deaths tied to opioid overdoses quadrupled between 1999 and 2015 (in this 15-year period, that is more than 500,000 deaths). Then, between 2015 and 2016, they further increased dramatically to more than 60,000 and in 2017 topped 72,000. This increase was driven partly by a sevenfold increase in overdose deaths involving synthetic opioids (excluding methadone): from 3,105 in 2013 to about 20,000 in 2016.
Illicitly manufactured fentanyl, a synthetic opioid 50-100 times more potent than morphine, is primarily responsible for this rapid increase. In addition, fentanyl analogs such as acetyl fentanyl, furanyl fentanyl, and carfentanil are being detected increasingly in overdose deaths and the illicit opioid drug supply. Drug overdose is the leading cause of accidental death in the United States, with opioids implicated in more than half of these deaths. Moreover, drug overdose is now the leading cause of death of all Americans under age 50. As if these data were not bad enough, recent analyses suggest that the number of opioid overdose deaths might be significantly undercounted. Without intervention, we would expect 235,000 opioid-related deaths (85,000 from prescription opioids and 150,000 from heroin) from 2016 to 2020; and 510,000 opioid-related deaths (170,000 from prescription opioids and 340,000 from heroin) from 2016 to 2025.1 In these opioid overdose deaths, rarely is the opioid the only drug present. Data from the Florida Drug-Related Outcomes Surveillance & Tracking System show that, in that state, more than 90% of opioid overdose deaths in 2016 showed other drugs of abuse present at death, an average of 2 to 4 – but as many as 11.2
It is well-accepted that medicine – in particular the overprescribing of opioids for pain and downplaying the risks of prescription opioid use – has played a fundamental role in the exponential rise in addiction and overdose death. The prescribing of other controlled substances, especially stimulants and benzodiazepines, also is a factor in overdose deaths.
To say that the country has an opioid problem would be a simplistic understatement. Drug sellers are innovative, consistently adding new chemicals to the menu of available drugs. The user market keeps adding potential customers who already have trained their brains and dopamine systems to respond vigorously to drug-promoting cues and drugs. We are a nation of polydrug users without drug or brand loyalty, engaging in “recreational pharmacology.” Framing the national drug problem around opioids misses the bigger target. The future of the national drug problem is more drugs used by more drug users – not simply prescription misuse or even opioids but instead globally produced illegal synthetic drugs as is now common in Hong Kong and Southeast Asia. A focus exclusively on opioid use disorders might yield great progress in new treatment developments that are specific to opioids. But few people addicted to opioids do not also use many other drugs in other drug classes. The opioid treatments (for example, buprenorphine, methadone, naltrexone) are irrelevant to these other addictive and problem-generating drugs.
Finally, as a very recent report found, the national opioid epidemic has had profound second- and third-hand effects on those with opioid use disorders, their families, and communities, costing about $80 billion yearly in lost productivity, treatment (including emergency, medical, psychiatric, and addiction-specific care), and criminal justice involvement.1 Worse yet, missing from current discussion is the simple fact that drug users in the United States spend $100 billion on drugs each year. The entire annual cost of all treatment – both public and private – for alcohol and other substance use disorders is $34 billion a year. Drug users could pay for all of the treatment in the country with one-third of the money they now spend on drugs.
How much do drug users themselves spend on addiction treatment? Close to zero. The costs of both treatment and prevention are almost all carried by nondrug users. While many drug policy discussions call for “more treatment,” as important as that objective is, overlooked is the fact that 95% of people with substance use disorders do not think they have a drug problem and do not want treatment. What actions are needed now?
Control drug supply
Illicit drug supply used to be centrally controlled and reasonably well understood by law enforcement. Today, the illegal supply of addicting chemicals is global, innovative, massive, and decentralized. More drugs, including opioids, are now manufactured and delivered to users in higher potency, at lower prices, and with greater convenience than ever before. At the same time, illegal drug suppliers are moving away from agriculturally produced drugs such as marijuana, cocaine, and heroin to purely synthetic drugs such as synthetic cannabis, methamphetamine, and fentanyl. These synthetics do not require growing fields that are difficult to conceal, nor do they require farmers, or complex, clandestine, and vulnerable modes of transportation.
Instead, these new drugs can be synthesized in small and mobile laboratories located in any part of the globe and delivered anonymously, often by mail, to the users’ addresses. In addition, there remains ample illegal access to the older addicting agricultural chemicals and access to the many addicting legal chemicals that are widely used in the practice of medicine (for example, prescription drugs, including opioids). These abundant and varied sources make addicting drugs widely available to millions of Americans. Strong supply reduction efforts are needed. We must use the Drug Enforcement Administration to increase the cost of doing business in the illegal drug supply chain, and decrease access to drugs by bolstering interdiction and reducing precursor access. We can work to screen packages for drugs sent by U.S. mail or other express services.
It is gratifying to see so many of the missing pieces identified in the classic report3 published in 2012 by Columbia University in New York. Health care providers and professionals-in-training are being taught addiction medicine principles and practices. The Surgeon General has helped mobilize the public response to this crisis, and rightly suggested4 that everyone learn how to use and carry naloxone. Researchers are refocused on more than supply reduction.5 In addition, the Substance Abuse and Mental Health Services Administration and the National Institute on Drug Abuse (NIDA) are working on delivery service improvements, developing nonopioid pain medications, and new treatments for addiction.
Increase access to naloxone
Increasing access to the opioid reversal medication is critical. Because of the surge in opioid overdose–related mortality, considerable resources have been devoted to emergency response and the widespread dissemination of the mu-opioid receptor antagonist naloxone.6
Naloxone should be readily available without prescription and at a price that makes access practical for emergency technicians and any concerned citizen. Administering naloxone should be analogous to CPR or cardioversion. They are similar, in that they are life-saving actions, but the target within the patient is the brain, rather than the heart. CPR education and cardioversion training efforts and access have been promoted well across the United States and can be done for naloxone.
Another comparison has been made between naloxone and giving an EpiPen to an allergic person in an anaphylaxis emergency or crisis. We need and want to rescue, resuscitate, and revive the overdosed patient and give the person another chance to make a change. We want to administer naloxone and get the patient evaluated and into long-term treatment. Now, rapid return to drug use is common after overdose reversal. We need to use overdose reversal as a path to treatment and see that it is sustained to long-term abstinence from drug use. The most recent report on the high cost of drug use correctly points out that none of the current treatment and policy proposals can reduce substantially the number of overdose deaths.1 Among 11 interventions analyzed by those researchers, making naloxone more available resulted in the greatest number of addiction deaths prevented.
Learn from physician health model of care
An assessment is needed of the 5-year recovery outcomes of all interventions for substance use disorder, including treatments that use and do not use medications, and harm-reduction interventions such as naloxone, needle exchange, and safe injection sites. A few years ago, researchers reported on a sample of 904 physicians consecutively admitted to 16 state Physician Health Programs (PHPs) that was monitored for 5 years or longer.7
This study characterized the outcomes of this episode of care and explored the elements of those programs that could improve the care routinely given to physicians but not to other addicted populations. PHPs were abstinence based and required physicians to abstain from any use of alcohol or other drugs of abuse as assessed by frequent random tests typically lasting for 5 years. Random tests rapidly identified any return to substance use, leading to swift and significant consequences.
Remarkably, 78% of participants had no positive test for either alcohol or drugs over the 5-year period of intensive monitoring. At posttreatment follow-up, 72% of the physicians were continuing to practice medicine. A key to the PHPs’ success is the 5 years of close monitoring with immediate consequences for any use and rapid, vigorous intervention upon any relapse to alcohol or drugs.
The unique PHP care management included close links to the 12-step fellowships of Alcoholics Anonymous (AA), Narcotics Anonymous, and other intensive recovery support for the entire 5 years of care management. The PHPs used relatively brief residential and outpatient treatment programs. Given the remarkable long-term outcomes of the PHPs, this model of care management should inspire new approaches to integrated and sustained care management of addiction in health care generally. The 5-year recovery standard should be applied to all addiction treatments to judge their value.8
Re-energize prevention efforts
The country must integrate addiction care into all of health care in the model of other chronic disease management: from prevention to intervention, treatment, monitoring, and intervention for any relapse. For prevention, we must retarget the health goal for youth under age 21 of no use of alcohol, nicotine, marijuana, or other drugs. Substance use disorders, including opioid use disorders, can be traced to adolescent use of alcohol and other drugs. The younger the age of a person initiating the use of any addicting substance – and the more chronic that use – the greater the likelihood of subsequent substance use problems persisting, or reigniting, later in life.
This later addiction risk resulting from adolescent drug use is no surprise, given the unique vulnerability of the adolescent brain, a brain that is especially vulnerable to addicting chemicals and that is not fully developed until about age 25. Effective addiction prevention – for example, helping youth grow up drug free – can improve dramatically public health by reducing the lifetime prevalence of substance use disorders, including opioid addiction.
Youth prevention efforts today vary tremendously in message and scope. Often, prevention messages for youth are limited to specific drugs (for example, nonmedical use of prescription drugs or tobacco) to specific situations (e.g., drunk driving), or to specific amounts of drug use (for example, binge drinking) when all substance use among youth is linked and all drug use poses health risks during adolescence and beyond. Among youth aged 12-17, the use of any one of the three most widely used and available drugs – alcohol, nicotine, and marijuana – increases the likelihood of using the other two drugs, as well as other illicit drugs.9 Similarly, no use of alcohol, nicotine, or marijuana decreases the likelihood of using the others, or of using other illicit drugs.
A recent clinical report and policy statement issued by the American Academy of Pediatrics affirms that it is in the best interests of young patients to not use any substances.10 The screening recommendations issued by the AAP further encourage pediatricians and adolescent medicine physicians to help guide their patients to this fundamental and easily-understood health goal.
A new and better vision for addiction prevention must focus on the single, clear goal of no use of alcohol, nicotine, marijuana, or other drugs for health by youth under age 21.11 Some good news for prevention is that, for the past 3 decades, there has been a slow but steadily increasing percentage of American high school seniors reporting abstinence from any use of alcohol, cigarettes, marijuana, and other illicit drugs.12 In 2014, 25.5% of high school seniors reported lifetime abstinence, and fully 50% reported past-month abstinence from all substances. Those figures are dramatic, compared with abstinence rates during the nation’s peak years of youth drug use. In 1978, among high school seniors, 4.4% reported lifetime abstinence from any use of alcohol, cigarettes, marijuana, and other illicit drugs and 21% reported past-month abstinence. Notably, similar increasing rates of abstinence have been recorded among eighth- and 10th-graders. This encouraging and largely overlooked reality demonstrates that the no-use prevention goal for youth is both realistic and attainable.
Expand drug and alcohol courts
We need to rehabilitate the role of the criminal justice system in a public health–oriented policy to achieve two essential goals: 1) to improve supply reduction as described above, and 2) to reshape the criminal justice system as an engine of recovery as it is now for alcohol addiction.
The landmark report, “Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs and Health,” called for a continuum of health care extending from prevention to early identification and treatment of substance use disorders and long-term health care management with the goal of sustained recovery.13 A growing number of pioneering programs within the criminal justice system (for example, Hawaii’s HOPE Probation, South Dakota’s 24/7 Sobriety Project, and drug courts) are using innovative monitoring strategies for individuals with substance use problems, including providing substance use disorder treatment, with results showing reduced substance use, reduced recidivism, and reduced incarceration.14
In HOPE, drug-involved offenders are subject to frequent random drug testing, rather than the typical drug testing done on standard probation, only at the time of scheduled meetings with probation officers. Failure to abstain from drugs or failure to show up for random drug testing always results in a brief jail sanction, usually 2-15 days, depending on the nature and severity of the offense. Upon placement in HOPE at a warning hearing, probationers are encouraged to succeed, and are fully informed of the length of the jail sanctions that will be imposed for each type of violation. They are assured of the certainty and speed with which the sanctions will be applied.
Sanctions are applied consistently and impartially to ensure fairness for all. Substance abuse treatment is available to all offenders who want it and to those who demonstrate a need for treatment through “behavioral triage.” Offenders who test positive for drugs two or more times in short order with jail sanctions are referred for a substance abuse assessment and instructed to follow any recommended treatment. For this reason, offenders in HOPE succeed in treatment – because they are the offenders in most need and are supported by the leverage provided by the court to help them complete treatment.
A randomized, controlled trial compared offenders assigned to HOPE Probation and a control group assigned to probation as usual. Compared with offenders on probation as usual, at 1-year follow-up, HOPE offenders were:
• 55% less likely to be arrested for a new crime.
• 72% less likely to test positive for illegal drugs.
• 61% less likely to skip appointments with their supervisory officer.
• 53% less likely to have their probation revoked.
There also is a growing potential to harness the latent but enormous strength of the families who have confronted and are continuing to confront addiction in a family member. Families and those with addictions can be engaged in alcohol or drug courts, which can act like the PHP for addicted individuals in the criminal justice system.
Implications for treatment
The diversion of medications that are prescribed and intended for patients in pain is just one part of the far larger drug use and overdose problem. An addicted person with a hijacked brain is not the same as a nonaddicted pain patient. Taking medication as prescribed for pain can produce physical dependence, but importantly, this is not addiction. The person who is using drugs – whether or not prescribed – to produce euphoria is a different person from the person in that same body who is abstinent and not using. Talking with a person in active addiction often is frustrating and futile. That addicted user’s brain wants to use drugs.
The PHP system of care management demonstrates that individuals with substance use disorders can refrain from any substance use for extended periods of time with a carrot and stick approach; permitting a physician to earn a livelihood as a physician is the carrot. In medication-assisted treatment (MAT), the carrot is provided by agonist drugs and the comfort-fit they provide in the brain. They protect the patient from anxiety, and reduce stress and craving responsivity. The stick is an environment that is intolerant of continued nonmedical or addicting drug use. This can be the family, an employer, the criminal justice system, or others in a position to insist on abstinence.
PHP care management shows the way to improve all treatment outcomes; however, an even larger lesson can be learned from the millions of Americans now in recovery from addiction to opioids and other drugs. The “evidence” of what recovery is and how it is achieved and sustained is available to everyone who knows or comes into contact with people in recovery. How did that near-miraculous transformation happen? Even more importantly, how is it sustained when relapse is so common in addiction? The millions of Americans in recovery are the inspiration for a new generation of improved addiction treatment.
Addiction reprioritizes the brain toward continued drug use first, rather than family, friends, health, job, or another important remnant of the addicted person’s past having any meaningful standing. It is often a question like that raised by the AA axiom that it is easy to change a cucumber (naive or new drug user) into a pickle (an addict), but turning a pickle into a cucumber is very difficult. Risk-benefit research has shown that drugs change the ability to accurately assess risks and benefits by prioritizing drug use over virtually everything else, including the interests of the drug users themselves.
Along with judgment deficits comes dishonesty – a hallmark of addiction. The person with addictions lies, minimizes, and denies drug use, thus keeping the addictive run going. That often is the heart of addiction. The point is that once the disease is in control of the addicted brain, those around that hijacked brain must intervene – and the goal of cutting down drug use or limiting it to exclude one or another drug is not useful. Rather, it perpetuates the addiction. Freedom from addiction, that modern chemical slavery, requires no use of alcohol and other drugs, including marijuana, and a return to healthy relationships, sleep, eating, exercise, etc.
Recovery is more than abstinence from all drug use; it includes character development and citizenship. The data supporting the essential goal of recovery are found in the people who are in recovery not in today’s scientific research, which generally is off-target on recovery. Just because recovering people are anonymous does not mean that they do not exist. They prove that recovery happens all the time. They show what recovery is, and how it is achieved and maintained. Current arguments over which MAT is the best in a 3-month study is too short-term for a lifetime disorder and it ignores the concept of recovery despite the millions of people who are living it. Their stories are the bedrock of our message.
Our core evidence, our inspiration, comes from asking the people in recovery from the deadly, chronic disease of addiction three questions: 1) What was your life like when using drugs? 2) What happened to get you to stop using drugs? and 3) What is your life like when not using any drugs?” Every American who knows someone in recovery can do this research for themselves. We have been doing that research for decades.
People in recovery all have sobriety dates. Few in MAT have sobriety dates. Recovery from addiction is not just not taking Vicodin but living the life of a drug-free, recovering person. How do they hold onto recovery, and prevent and deal with relapses and slips? MAT is a major achievement in addiction treatment, including agonist maintenance with buprenorphine and methadone, but it needs to build in the goal of sustained recovery and strong recovery support. That means building into MAT the 12-step fellowships and related recovery support, as is done every day by James H. Berry, DO, of the Chestnut Ridge Center at West Virginia University’s Comprehensive Opioid Addiction Treatment, or COAT, program.15
MAT is good. It needs to be targeted on recovery, which can include continued use of the medicines now widely used: methadone, buprenorphine, and naltrexone. But recovery cannot include continued nonmedical drug use, and it also must include character development – with honesty replacing the dishonesty that is at the heart of addiction.
Holding up that widely available picture of recovery and making it clear to our readers is our goal in this article. For too many people, including some of our most treasured colleagues in addiction treatment, this message is new and radical. The PHP model has put it together in a program that is now more than 4 decades old. It is real, possible, and understandable. The key to its success is the commitment to living drug free, the active and sustained testing for any use of alcohol or other drugs linked to prompt intervention to any relapse, the use of recovery support, and the long duration of active care management: 5 years. That package is seldom seen in the current approach to addiction treatment, which often is siloed out of mainstream medicine – with little or no monitoring or support after the typically short duration of treatment.
People with addictions in recovery remain vulnerable to relapse for life, but the disease now is being managed successfully by millions of people. As dishonesty and self-centeredness were the heart of behaviors during active addiction, so honesty and caring for others are at the heart of life in recovery. This is an easily seen spiritual transformation that gives hope and guidance to addiction treatment, and inspiration to us in our work in treatment – and to all people with addictions.
Dr. Gold is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville, professor of psychiatry (adjunct) at Washington University in St. Louis. Dr. DuPont is the first director of the National Institute on Drug Abuse and the second White House drug chief, founding president of the Institute for Behavior and Health in Rockville, Md., and author of “Chemical Slavery: Understanding Addiction and Stopping the Drug Epidemic” (Create Space Independent Publishing Platform), 2018.
References
1. Am J Public Health. 2018 Oct 108(10):1394-1400.
2. Florida Drug-Related Outcomes Surveillance & Tracking system (FROST)
3. Center on Addiction. Addiction Medicine: Closing the Gap Between Science and Practice. 2012 Jun.
4. Surgeon General’s Advisory on Naloxone and Opioid Overdose.
5. Mayo Clin Proc. 2018 Mar;93(3):269-72.
6. Ther Adv Drug Saf. 2015 Feb;6(1):20-31.
7. J Subst Abuse Treat. 2009 Mar;36(2):159-71.
8. J Subst Abuse Treat. 2015 Nov;58:1-5.
9. Prev Med. 2018 Aug;113:68-73.
10. Pediatrics. 2016 Jun;138(1). doi: 10.1542/peds.2016-1211.
11. Institute for Behavior and Health. (updated) 2018 Aug 29.
12. Pediatrics. 2018 Aug;142(2). doi: 10.1542/peds.2017-3498.
13. Office of the Surgeon General. 2016.
14. The ASAM Principles of Addiction Medicine. (6th ed.) (in press) Wolters Kluwer, 2018.
15. West Virginia Clinical and Translational Science Institute. 2017 Aug 21.
The drug epidemic of early initiation, frequent use, and a polydrug reality
The drug epidemic of early initiation, frequent use, and a polydrug reality
The national opioid epidemic is one of the most important public health challenges facing the United States today. This crisis has resulted in death, disability, and increased infectious and other comorbid diseases.
Public attention has been focused on the medical management of pain, patterns of opioid prescriptions, and use of heroin and fentanyl. But the opioid crisis is, in fact, part of a far larger drug epidemic. The foundation on which the opioid epidemic is built is recreational pharmacology – the widespread use of aggressively marketed chemicals that seductively superstimulate brain-reward producing alterations in consciousness and pleasure, often mislabeled “self-medication.”
Drugs of abuse are unique chemicals that stimulate their own taking by producing an intense reinforcement in the human brain, which tells users that they have done something monumentally good. Instead of preserving the species, this chemical stimulation of brain reward begins the process of retraining the brain and reward system to respond quickly to drugs of abuse and drug-promoting cues. Drugs of abuse do not come from one class or chemical structure, but, rather, from disparate chemical classes that have in common the stimulation of brain reward. This bad learning is accelerated to addiction when drugs of abuse are smoked, snorted, vaped, or injected, as these routes of administration produce rapidly rising and falling blood levels.
Thanks to the science of animal models, we understand drug self-administration and abstinence. However, in animals, we cannot approximate addiction beyond the mechanical because of the cultural complexity of human behavior. Most animal models are good at predicting what treatments will work for drug addiction in animals. They are less predictive when it comes to humans. Animal models are good for understanding withdrawal reversal and identifying self-administration reductions and even changes in place preference. Animal models have consistently shown that drugs of abuse raise the brain’s reward threshold and cause epigenetic changes, and that many of these changes are persistent, if not permanent. In animal models, clonidine or opioid detoxification followed by naltrexone is a cure for opioid use disorder. Again, in animal models, this protocol is tied to no relapses – just a cure. We know that this is not the case for humans suffering from opioid addiction, where relapses define the disorder.
A closer look at opioid overdoses
Opioid overdose deaths are skyrocketing in the United States. The number of deaths tied to opioid overdoses quadrupled between 1999 and 2015 (in this 15-year period, that is more than 500,000 deaths). Then, between 2015 and 2016, they further increased dramatically to more than 60,000 and in 2017 topped 72,000. This increase was driven partly by a sevenfold increase in overdose deaths involving synthetic opioids (excluding methadone): from 3,105 in 2013 to about 20,000 in 2016.
Illicitly manufactured fentanyl, a synthetic opioid 50-100 times more potent than morphine, is primarily responsible for this rapid increase. In addition, fentanyl analogs such as acetyl fentanyl, furanyl fentanyl, and carfentanil are being detected increasingly in overdose deaths and the illicit opioid drug supply. Drug overdose is the leading cause of accidental death in the United States, with opioids implicated in more than half of these deaths. Moreover, drug overdose is now the leading cause of death of all Americans under age 50. As if these data were not bad enough, recent analyses suggest that the number of opioid overdose deaths might be significantly undercounted. Without intervention, we would expect 235,000 opioid-related deaths (85,000 from prescription opioids and 150,000 from heroin) from 2016 to 2020; and 510,000 opioid-related deaths (170,000 from prescription opioids and 340,000 from heroin) from 2016 to 2025.1 In these opioid overdose deaths, rarely is the opioid the only drug present. Data from the Florida Drug-Related Outcomes Surveillance & Tracking System show that, in that state, more than 90% of opioid overdose deaths in 2016 showed other drugs of abuse present at death, an average of 2 to 4 – but as many as 11.2
It is well-accepted that medicine – in particular the overprescribing of opioids for pain and downplaying the risks of prescription opioid use – has played a fundamental role in the exponential rise in addiction and overdose death. The prescribing of other controlled substances, especially stimulants and benzodiazepines, also is a factor in overdose deaths.
To say that the country has an opioid problem would be a simplistic understatement. Drug sellers are innovative, consistently adding new chemicals to the menu of available drugs. The user market keeps adding potential customers who already have trained their brains and dopamine systems to respond vigorously to drug-promoting cues and drugs. We are a nation of polydrug users without drug or brand loyalty, engaging in “recreational pharmacology.” Framing the national drug problem around opioids misses the bigger target. The future of the national drug problem is more drugs used by more drug users – not simply prescription misuse or even opioids but instead globally produced illegal synthetic drugs as is now common in Hong Kong and Southeast Asia. A focus exclusively on opioid use disorders might yield great progress in new treatment developments that are specific to opioids. But few people addicted to opioids do not also use many other drugs in other drug classes. The opioid treatments (for example, buprenorphine, methadone, naltrexone) are irrelevant to these other addictive and problem-generating drugs.
Finally, as a very recent report found, the national opioid epidemic has had profound second- and third-hand effects on those with opioid use disorders, their families, and communities, costing about $80 billion yearly in lost productivity, treatment (including emergency, medical, psychiatric, and addiction-specific care), and criminal justice involvement.1 Worse yet, missing from current discussion is the simple fact that drug users in the United States spend $100 billion on drugs each year. The entire annual cost of all treatment – both public and private – for alcohol and other substance use disorders is $34 billion a year. Drug users could pay for all of the treatment in the country with one-third of the money they now spend on drugs.
How much do drug users themselves spend on addiction treatment? Close to zero. The costs of both treatment and prevention are almost all carried by nondrug users. While many drug policy discussions call for “more treatment,” as important as that objective is, overlooked is the fact that 95% of people with substance use disorders do not think they have a drug problem and do not want treatment. What actions are needed now?
Control drug supply
Illicit drug supply used to be centrally controlled and reasonably well understood by law enforcement. Today, the illegal supply of addicting chemicals is global, innovative, massive, and decentralized. More drugs, including opioids, are now manufactured and delivered to users in higher potency, at lower prices, and with greater convenience than ever before. At the same time, illegal drug suppliers are moving away from agriculturally produced drugs such as marijuana, cocaine, and heroin to purely synthetic drugs such as synthetic cannabis, methamphetamine, and fentanyl. These synthetics do not require growing fields that are difficult to conceal, nor do they require farmers, or complex, clandestine, and vulnerable modes of transportation.
Instead, these new drugs can be synthesized in small and mobile laboratories located in any part of the globe and delivered anonymously, often by mail, to the users’ addresses. In addition, there remains ample illegal access to the older addicting agricultural chemicals and access to the many addicting legal chemicals that are widely used in the practice of medicine (for example, prescription drugs, including opioids). These abundant and varied sources make addicting drugs widely available to millions of Americans. Strong supply reduction efforts are needed. We must use the Drug Enforcement Administration to increase the cost of doing business in the illegal drug supply chain, and decrease access to drugs by bolstering interdiction and reducing precursor access. We can work to screen packages for drugs sent by U.S. mail or other express services.
It is gratifying to see so many of the missing pieces identified in the classic report3 published in 2012 by Columbia University in New York. Health care providers and professionals-in-training are being taught addiction medicine principles and practices. The Surgeon General has helped mobilize the public response to this crisis, and rightly suggested4 that everyone learn how to use and carry naloxone. Researchers are refocused on more than supply reduction.5 In addition, the Substance Abuse and Mental Health Services Administration and the National Institute on Drug Abuse (NIDA) are working on delivery service improvements, developing nonopioid pain medications, and new treatments for addiction.
Increase access to naloxone
Increasing access to the opioid reversal medication is critical. Because of the surge in opioid overdose–related mortality, considerable resources have been devoted to emergency response and the widespread dissemination of the mu-opioid receptor antagonist naloxone.6
Naloxone should be readily available without prescription and at a price that makes access practical for emergency technicians and any concerned citizen. Administering naloxone should be analogous to CPR or cardioversion. They are similar, in that they are life-saving actions, but the target within the patient is the brain, rather than the heart. CPR education and cardioversion training efforts and access have been promoted well across the United States and can be done for naloxone.
Another comparison has been made between naloxone and giving an EpiPen to an allergic person in an anaphylaxis emergency or crisis. We need and want to rescue, resuscitate, and revive the overdosed patient and give the person another chance to make a change. We want to administer naloxone and get the patient evaluated and into long-term treatment. Now, rapid return to drug use is common after overdose reversal. We need to use overdose reversal as a path to treatment and see that it is sustained to long-term abstinence from drug use. The most recent report on the high cost of drug use correctly points out that none of the current treatment and policy proposals can reduce substantially the number of overdose deaths.1 Among 11 interventions analyzed by those researchers, making naloxone more available resulted in the greatest number of addiction deaths prevented.
Learn from physician health model of care
An assessment is needed of the 5-year recovery outcomes of all interventions for substance use disorder, including treatments that use and do not use medications, and harm-reduction interventions such as naloxone, needle exchange, and safe injection sites. A few years ago, researchers reported on a sample of 904 physicians consecutively admitted to 16 state Physician Health Programs (PHPs) that was monitored for 5 years or longer.7
This study characterized the outcomes of this episode of care and explored the elements of those programs that could improve the care routinely given to physicians but not to other addicted populations. PHPs were abstinence based and required physicians to abstain from any use of alcohol or other drugs of abuse as assessed by frequent random tests typically lasting for 5 years. Random tests rapidly identified any return to substance use, leading to swift and significant consequences.
Remarkably, 78% of participants had no positive test for either alcohol or drugs over the 5-year period of intensive monitoring. At posttreatment follow-up, 72% of the physicians were continuing to practice medicine. A key to the PHPs’ success is the 5 years of close monitoring with immediate consequences for any use and rapid, vigorous intervention upon any relapse to alcohol or drugs.
The unique PHP care management included close links to the 12-step fellowships of Alcoholics Anonymous (AA), Narcotics Anonymous, and other intensive recovery support for the entire 5 years of care management. The PHPs used relatively brief residential and outpatient treatment programs. Given the remarkable long-term outcomes of the PHPs, this model of care management should inspire new approaches to integrated and sustained care management of addiction in health care generally. The 5-year recovery standard should be applied to all addiction treatments to judge their value.8
Re-energize prevention efforts
The country must integrate addiction care into all of health care in the model of other chronic disease management: from prevention to intervention, treatment, monitoring, and intervention for any relapse. For prevention, we must retarget the health goal for youth under age 21 of no use of alcohol, nicotine, marijuana, or other drugs. Substance use disorders, including opioid use disorders, can be traced to adolescent use of alcohol and other drugs. The younger the age of a person initiating the use of any addicting substance – and the more chronic that use – the greater the likelihood of subsequent substance use problems persisting, or reigniting, later in life.
This later addiction risk resulting from adolescent drug use is no surprise, given the unique vulnerability of the adolescent brain, a brain that is especially vulnerable to addicting chemicals and that is not fully developed until about age 25. Effective addiction prevention – for example, helping youth grow up drug free – can improve dramatically public health by reducing the lifetime prevalence of substance use disorders, including opioid addiction.
Youth prevention efforts today vary tremendously in message and scope. Often, prevention messages for youth are limited to specific drugs (for example, nonmedical use of prescription drugs or tobacco) to specific situations (e.g., drunk driving), or to specific amounts of drug use (for example, binge drinking) when all substance use among youth is linked and all drug use poses health risks during adolescence and beyond. Among youth aged 12-17, the use of any one of the three most widely used and available drugs – alcohol, nicotine, and marijuana – increases the likelihood of using the other two drugs, as well as other illicit drugs.9 Similarly, no use of alcohol, nicotine, or marijuana decreases the likelihood of using the others, or of using other illicit drugs.
A recent clinical report and policy statement issued by the American Academy of Pediatrics affirms that it is in the best interests of young patients to not use any substances.10 The screening recommendations issued by the AAP further encourage pediatricians and adolescent medicine physicians to help guide their patients to this fundamental and easily-understood health goal.
A new and better vision for addiction prevention must focus on the single, clear goal of no use of alcohol, nicotine, marijuana, or other drugs for health by youth under age 21.11 Some good news for prevention is that, for the past 3 decades, there has been a slow but steadily increasing percentage of American high school seniors reporting abstinence from any use of alcohol, cigarettes, marijuana, and other illicit drugs.12 In 2014, 25.5% of high school seniors reported lifetime abstinence, and fully 50% reported past-month abstinence from all substances. Those figures are dramatic, compared with abstinence rates during the nation’s peak years of youth drug use. In 1978, among high school seniors, 4.4% reported lifetime abstinence from any use of alcohol, cigarettes, marijuana, and other illicit drugs and 21% reported past-month abstinence. Notably, similar increasing rates of abstinence have been recorded among eighth- and 10th-graders. This encouraging and largely overlooked reality demonstrates that the no-use prevention goal for youth is both realistic and attainable.
Expand drug and alcohol courts
We need to rehabilitate the role of the criminal justice system in a public health–oriented policy to achieve two essential goals: 1) to improve supply reduction as described above, and 2) to reshape the criminal justice system as an engine of recovery as it is now for alcohol addiction.
The landmark report, “Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs and Health,” called for a continuum of health care extending from prevention to early identification and treatment of substance use disorders and long-term health care management with the goal of sustained recovery.13 A growing number of pioneering programs within the criminal justice system (for example, Hawaii’s HOPE Probation, South Dakota’s 24/7 Sobriety Project, and drug courts) are using innovative monitoring strategies for individuals with substance use problems, including providing substance use disorder treatment, with results showing reduced substance use, reduced recidivism, and reduced incarceration.14
In HOPE, drug-involved offenders are subject to frequent random drug testing, rather than the typical drug testing done on standard probation, only at the time of scheduled meetings with probation officers. Failure to abstain from drugs or failure to show up for random drug testing always results in a brief jail sanction, usually 2-15 days, depending on the nature and severity of the offense. Upon placement in HOPE at a warning hearing, probationers are encouraged to succeed, and are fully informed of the length of the jail sanctions that will be imposed for each type of violation. They are assured of the certainty and speed with which the sanctions will be applied.
Sanctions are applied consistently and impartially to ensure fairness for all. Substance abuse treatment is available to all offenders who want it and to those who demonstrate a need for treatment through “behavioral triage.” Offenders who test positive for drugs two or more times in short order with jail sanctions are referred for a substance abuse assessment and instructed to follow any recommended treatment. For this reason, offenders in HOPE succeed in treatment – because they are the offenders in most need and are supported by the leverage provided by the court to help them complete treatment.
A randomized, controlled trial compared offenders assigned to HOPE Probation and a control group assigned to probation as usual. Compared with offenders on probation as usual, at 1-year follow-up, HOPE offenders were:
• 55% less likely to be arrested for a new crime.
• 72% less likely to test positive for illegal drugs.
• 61% less likely to skip appointments with their supervisory officer.
• 53% less likely to have their probation revoked.
There also is a growing potential to harness the latent but enormous strength of the families who have confronted and are continuing to confront addiction in a family member. Families and those with addictions can be engaged in alcohol or drug courts, which can act like the PHP for addicted individuals in the criminal justice system.
Implications for treatment
The diversion of medications that are prescribed and intended for patients in pain is just one part of the far larger drug use and overdose problem. An addicted person with a hijacked brain is not the same as a nonaddicted pain patient. Taking medication as prescribed for pain can produce physical dependence, but importantly, this is not addiction. The person who is using drugs – whether or not prescribed – to produce euphoria is a different person from the person in that same body who is abstinent and not using. Talking with a person in active addiction often is frustrating and futile. That addicted user’s brain wants to use drugs.
The PHP system of care management demonstrates that individuals with substance use disorders can refrain from any substance use for extended periods of time with a carrot and stick approach; permitting a physician to earn a livelihood as a physician is the carrot. In medication-assisted treatment (MAT), the carrot is provided by agonist drugs and the comfort-fit they provide in the brain. They protect the patient from anxiety, and reduce stress and craving responsivity. The stick is an environment that is intolerant of continued nonmedical or addicting drug use. This can be the family, an employer, the criminal justice system, or others in a position to insist on abstinence.
PHP care management shows the way to improve all treatment outcomes; however, an even larger lesson can be learned from the millions of Americans now in recovery from addiction to opioids and other drugs. The “evidence” of what recovery is and how it is achieved and sustained is available to everyone who knows or comes into contact with people in recovery. How did that near-miraculous transformation happen? Even more importantly, how is it sustained when relapse is so common in addiction? The millions of Americans in recovery are the inspiration for a new generation of improved addiction treatment.
Addiction reprioritizes the brain toward continued drug use first, rather than family, friends, health, job, or another important remnant of the addicted person’s past having any meaningful standing. It is often a question like that raised by the AA axiom that it is easy to change a cucumber (naive or new drug user) into a pickle (an addict), but turning a pickle into a cucumber is very difficult. Risk-benefit research has shown that drugs change the ability to accurately assess risks and benefits by prioritizing drug use over virtually everything else, including the interests of the drug users themselves.
Along with judgment deficits comes dishonesty – a hallmark of addiction. The person with addictions lies, minimizes, and denies drug use, thus keeping the addictive run going. That often is the heart of addiction. The point is that once the disease is in control of the addicted brain, those around that hijacked brain must intervene – and the goal of cutting down drug use or limiting it to exclude one or another drug is not useful. Rather, it perpetuates the addiction. Freedom from addiction, that modern chemical slavery, requires no use of alcohol and other drugs, including marijuana, and a return to healthy relationships, sleep, eating, exercise, etc.
Recovery is more than abstinence from all drug use; it includes character development and citizenship. The data supporting the essential goal of recovery are found in the people who are in recovery not in today’s scientific research, which generally is off-target on recovery. Just because recovering people are anonymous does not mean that they do not exist. They prove that recovery happens all the time. They show what recovery is, and how it is achieved and maintained. Current arguments over which MAT is the best in a 3-month study is too short-term for a lifetime disorder and it ignores the concept of recovery despite the millions of people who are living it. Their stories are the bedrock of our message.
Our core evidence, our inspiration, comes from asking the people in recovery from the deadly, chronic disease of addiction three questions: 1) What was your life like when using drugs? 2) What happened to get you to stop using drugs? and 3) What is your life like when not using any drugs?” Every American who knows someone in recovery can do this research for themselves. We have been doing that research for decades.
People in recovery all have sobriety dates. Few in MAT have sobriety dates. Recovery from addiction is not just not taking Vicodin but living the life of a drug-free, recovering person. How do they hold onto recovery, and prevent and deal with relapses and slips? MAT is a major achievement in addiction treatment, including agonist maintenance with buprenorphine and methadone, but it needs to build in the goal of sustained recovery and strong recovery support. That means building into MAT the 12-step fellowships and related recovery support, as is done every day by James H. Berry, DO, of the Chestnut Ridge Center at West Virginia University’s Comprehensive Opioid Addiction Treatment, or COAT, program.15
MAT is good. It needs to be targeted on recovery, which can include continued use of the medicines now widely used: methadone, buprenorphine, and naltrexone. But recovery cannot include continued nonmedical drug use, and it also must include character development – with honesty replacing the dishonesty that is at the heart of addiction.
Holding up that widely available picture of recovery and making it clear to our readers is our goal in this article. For too many people, including some of our most treasured colleagues in addiction treatment, this message is new and radical. The PHP model has put it together in a program that is now more than 4 decades old. It is real, possible, and understandable. The key to its success is the commitment to living drug free, the active and sustained testing for any use of alcohol or other drugs linked to prompt intervention to any relapse, the use of recovery support, and the long duration of active care management: 5 years. That package is seldom seen in the current approach to addiction treatment, which often is siloed out of mainstream medicine – with little or no monitoring or support after the typically short duration of treatment.
People with addictions in recovery remain vulnerable to relapse for life, but the disease now is being managed successfully by millions of people. As dishonesty and self-centeredness were the heart of behaviors during active addiction, so honesty and caring for others are at the heart of life in recovery. This is an easily seen spiritual transformation that gives hope and guidance to addiction treatment, and inspiration to us in our work in treatment – and to all people with addictions.
Dr. Gold is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville, professor of psychiatry (adjunct) at Washington University in St. Louis. Dr. DuPont is the first director of the National Institute on Drug Abuse and the second White House drug chief, founding president of the Institute for Behavior and Health in Rockville, Md., and author of “Chemical Slavery: Understanding Addiction and Stopping the Drug Epidemic” (Create Space Independent Publishing Platform), 2018.
References
1. Am J Public Health. 2018 Oct 108(10):1394-1400.
2. Florida Drug-Related Outcomes Surveillance & Tracking system (FROST)
3. Center on Addiction. Addiction Medicine: Closing the Gap Between Science and Practice. 2012 Jun.
4. Surgeon General’s Advisory on Naloxone and Opioid Overdose.
5. Mayo Clin Proc. 2018 Mar;93(3):269-72.
6. Ther Adv Drug Saf. 2015 Feb;6(1):20-31.
7. J Subst Abuse Treat. 2009 Mar;36(2):159-71.
8. J Subst Abuse Treat. 2015 Nov;58:1-5.
9. Prev Med. 2018 Aug;113:68-73.
10. Pediatrics. 2016 Jun;138(1). doi: 10.1542/peds.2016-1211.
11. Institute for Behavior and Health. (updated) 2018 Aug 29.
12. Pediatrics. 2018 Aug;142(2). doi: 10.1542/peds.2017-3498.
13. Office of the Surgeon General. 2016.
14. The ASAM Principles of Addiction Medicine. (6th ed.) (in press) Wolters Kluwer, 2018.
15. West Virginia Clinical and Translational Science Institute. 2017 Aug 21.
The national opioid epidemic is one of the most important public health challenges facing the United States today. This crisis has resulted in death, disability, and increased infectious and other comorbid diseases.
Public attention has been focused on the medical management of pain, patterns of opioid prescriptions, and use of heroin and fentanyl. But the opioid crisis is, in fact, part of a far larger drug epidemic. The foundation on which the opioid epidemic is built is recreational pharmacology – the widespread use of aggressively marketed chemicals that seductively superstimulate brain-reward producing alterations in consciousness and pleasure, often mislabeled “self-medication.”
Drugs of abuse are unique chemicals that stimulate their own taking by producing an intense reinforcement in the human brain, which tells users that they have done something monumentally good. Instead of preserving the species, this chemical stimulation of brain reward begins the process of retraining the brain and reward system to respond quickly to drugs of abuse and drug-promoting cues. Drugs of abuse do not come from one class or chemical structure, but, rather, from disparate chemical classes that have in common the stimulation of brain reward. This bad learning is accelerated to addiction when drugs of abuse are smoked, snorted, vaped, or injected, as these routes of administration produce rapidly rising and falling blood levels.
Thanks to the science of animal models, we understand drug self-administration and abstinence. However, in animals, we cannot approximate addiction beyond the mechanical because of the cultural complexity of human behavior. Most animal models are good at predicting what treatments will work for drug addiction in animals. They are less predictive when it comes to humans. Animal models are good for understanding withdrawal reversal and identifying self-administration reductions and even changes in place preference. Animal models have consistently shown that drugs of abuse raise the brain’s reward threshold and cause epigenetic changes, and that many of these changes are persistent, if not permanent. In animal models, clonidine or opioid detoxification followed by naltrexone is a cure for opioid use disorder. Again, in animal models, this protocol is tied to no relapses – just a cure. We know that this is not the case for humans suffering from opioid addiction, where relapses define the disorder.
A closer look at opioid overdoses
Opioid overdose deaths are skyrocketing in the United States. The number of deaths tied to opioid overdoses quadrupled between 1999 and 2015 (in this 15-year period, that is more than 500,000 deaths). Then, between 2015 and 2016, they further increased dramatically to more than 60,000 and in 2017 topped 72,000. This increase was driven partly by a sevenfold increase in overdose deaths involving synthetic opioids (excluding methadone): from 3,105 in 2013 to about 20,000 in 2016.
Illicitly manufactured fentanyl, a synthetic opioid 50-100 times more potent than morphine, is primarily responsible for this rapid increase. In addition, fentanyl analogs such as acetyl fentanyl, furanyl fentanyl, and carfentanil are being detected increasingly in overdose deaths and the illicit opioid drug supply. Drug overdose is the leading cause of accidental death in the United States, with opioids implicated in more than half of these deaths. Moreover, drug overdose is now the leading cause of death of all Americans under age 50. As if these data were not bad enough, recent analyses suggest that the number of opioid overdose deaths might be significantly undercounted. Without intervention, we would expect 235,000 opioid-related deaths (85,000 from prescription opioids and 150,000 from heroin) from 2016 to 2020; and 510,000 opioid-related deaths (170,000 from prescription opioids and 340,000 from heroin) from 2016 to 2025.1 In these opioid overdose deaths, rarely is the opioid the only drug present. Data from the Florida Drug-Related Outcomes Surveillance & Tracking System show that, in that state, more than 90% of opioid overdose deaths in 2016 showed other drugs of abuse present at death, an average of 2 to 4 – but as many as 11.2
It is well-accepted that medicine – in particular the overprescribing of opioids for pain and downplaying the risks of prescription opioid use – has played a fundamental role in the exponential rise in addiction and overdose death. The prescribing of other controlled substances, especially stimulants and benzodiazepines, also is a factor in overdose deaths.
To say that the country has an opioid problem would be a simplistic understatement. Drug sellers are innovative, consistently adding new chemicals to the menu of available drugs. The user market keeps adding potential customers who already have trained their brains and dopamine systems to respond vigorously to drug-promoting cues and drugs. We are a nation of polydrug users without drug or brand loyalty, engaging in “recreational pharmacology.” Framing the national drug problem around opioids misses the bigger target. The future of the national drug problem is more drugs used by more drug users – not simply prescription misuse or even opioids but instead globally produced illegal synthetic drugs as is now common in Hong Kong and Southeast Asia. A focus exclusively on opioid use disorders might yield great progress in new treatment developments that are specific to opioids. But few people addicted to opioids do not also use many other drugs in other drug classes. The opioid treatments (for example, buprenorphine, methadone, naltrexone) are irrelevant to these other addictive and problem-generating drugs.
Finally, as a very recent report found, the national opioid epidemic has had profound second- and third-hand effects on those with opioid use disorders, their families, and communities, costing about $80 billion yearly in lost productivity, treatment (including emergency, medical, psychiatric, and addiction-specific care), and criminal justice involvement.1 Worse yet, missing from current discussion is the simple fact that drug users in the United States spend $100 billion on drugs each year. The entire annual cost of all treatment – both public and private – for alcohol and other substance use disorders is $34 billion a year. Drug users could pay for all of the treatment in the country with one-third of the money they now spend on drugs.
How much do drug users themselves spend on addiction treatment? Close to zero. The costs of both treatment and prevention are almost all carried by nondrug users. While many drug policy discussions call for “more treatment,” as important as that objective is, overlooked is the fact that 95% of people with substance use disorders do not think they have a drug problem and do not want treatment. What actions are needed now?
Control drug supply
Illicit drug supply used to be centrally controlled and reasonably well understood by law enforcement. Today, the illegal supply of addicting chemicals is global, innovative, massive, and decentralized. More drugs, including opioids, are now manufactured and delivered to users in higher potency, at lower prices, and with greater convenience than ever before. At the same time, illegal drug suppliers are moving away from agriculturally produced drugs such as marijuana, cocaine, and heroin to purely synthetic drugs such as synthetic cannabis, methamphetamine, and fentanyl. These synthetics do not require growing fields that are difficult to conceal, nor do they require farmers, or complex, clandestine, and vulnerable modes of transportation.
Instead, these new drugs can be synthesized in small and mobile laboratories located in any part of the globe and delivered anonymously, often by mail, to the users’ addresses. In addition, there remains ample illegal access to the older addicting agricultural chemicals and access to the many addicting legal chemicals that are widely used in the practice of medicine (for example, prescription drugs, including opioids). These abundant and varied sources make addicting drugs widely available to millions of Americans. Strong supply reduction efforts are needed. We must use the Drug Enforcement Administration to increase the cost of doing business in the illegal drug supply chain, and decrease access to drugs by bolstering interdiction and reducing precursor access. We can work to screen packages for drugs sent by U.S. mail or other express services.
It is gratifying to see so many of the missing pieces identified in the classic report3 published in 2012 by Columbia University in New York. Health care providers and professionals-in-training are being taught addiction medicine principles and practices. The Surgeon General has helped mobilize the public response to this crisis, and rightly suggested4 that everyone learn how to use and carry naloxone. Researchers are refocused on more than supply reduction.5 In addition, the Substance Abuse and Mental Health Services Administration and the National Institute on Drug Abuse (NIDA) are working on delivery service improvements, developing nonopioid pain medications, and new treatments for addiction.
Increase access to naloxone
Increasing access to the opioid reversal medication is critical. Because of the surge in opioid overdose–related mortality, considerable resources have been devoted to emergency response and the widespread dissemination of the mu-opioid receptor antagonist naloxone.6
Naloxone should be readily available without prescription and at a price that makes access practical for emergency technicians and any concerned citizen. Administering naloxone should be analogous to CPR or cardioversion. They are similar, in that they are life-saving actions, but the target within the patient is the brain, rather than the heart. CPR education and cardioversion training efforts and access have been promoted well across the United States and can be done for naloxone.
Another comparison has been made between naloxone and giving an EpiPen to an allergic person in an anaphylaxis emergency or crisis. We need and want to rescue, resuscitate, and revive the overdosed patient and give the person another chance to make a change. We want to administer naloxone and get the patient evaluated and into long-term treatment. Now, rapid return to drug use is common after overdose reversal. We need to use overdose reversal as a path to treatment and see that it is sustained to long-term abstinence from drug use. The most recent report on the high cost of drug use correctly points out that none of the current treatment and policy proposals can reduce substantially the number of overdose deaths.1 Among 11 interventions analyzed by those researchers, making naloxone more available resulted in the greatest number of addiction deaths prevented.
Learn from physician health model of care
An assessment is needed of the 5-year recovery outcomes of all interventions for substance use disorder, including treatments that use and do not use medications, and harm-reduction interventions such as naloxone, needle exchange, and safe injection sites. A few years ago, researchers reported on a sample of 904 physicians consecutively admitted to 16 state Physician Health Programs (PHPs) that was monitored for 5 years or longer.7
This study characterized the outcomes of this episode of care and explored the elements of those programs that could improve the care routinely given to physicians but not to other addicted populations. PHPs were abstinence based and required physicians to abstain from any use of alcohol or other drugs of abuse as assessed by frequent random tests typically lasting for 5 years. Random tests rapidly identified any return to substance use, leading to swift and significant consequences.
Remarkably, 78% of participants had no positive test for either alcohol or drugs over the 5-year period of intensive monitoring. At posttreatment follow-up, 72% of the physicians were continuing to practice medicine. A key to the PHPs’ success is the 5 years of close monitoring with immediate consequences for any use and rapid, vigorous intervention upon any relapse to alcohol or drugs.
The unique PHP care management included close links to the 12-step fellowships of Alcoholics Anonymous (AA), Narcotics Anonymous, and other intensive recovery support for the entire 5 years of care management. The PHPs used relatively brief residential and outpatient treatment programs. Given the remarkable long-term outcomes of the PHPs, this model of care management should inspire new approaches to integrated and sustained care management of addiction in health care generally. The 5-year recovery standard should be applied to all addiction treatments to judge their value.8
Re-energize prevention efforts
The country must integrate addiction care into all of health care in the model of other chronic disease management: from prevention to intervention, treatment, monitoring, and intervention for any relapse. For prevention, we must retarget the health goal for youth under age 21 of no use of alcohol, nicotine, marijuana, or other drugs. Substance use disorders, including opioid use disorders, can be traced to adolescent use of alcohol and other drugs. The younger the age of a person initiating the use of any addicting substance – and the more chronic that use – the greater the likelihood of subsequent substance use problems persisting, or reigniting, later in life.
This later addiction risk resulting from adolescent drug use is no surprise, given the unique vulnerability of the adolescent brain, a brain that is especially vulnerable to addicting chemicals and that is not fully developed until about age 25. Effective addiction prevention – for example, helping youth grow up drug free – can improve dramatically public health by reducing the lifetime prevalence of substance use disorders, including opioid addiction.
Youth prevention efforts today vary tremendously in message and scope. Often, prevention messages for youth are limited to specific drugs (for example, nonmedical use of prescription drugs or tobacco) to specific situations (e.g., drunk driving), or to specific amounts of drug use (for example, binge drinking) when all substance use among youth is linked and all drug use poses health risks during adolescence and beyond. Among youth aged 12-17, the use of any one of the three most widely used and available drugs – alcohol, nicotine, and marijuana – increases the likelihood of using the other two drugs, as well as other illicit drugs.9 Similarly, no use of alcohol, nicotine, or marijuana decreases the likelihood of using the others, or of using other illicit drugs.
A recent clinical report and policy statement issued by the American Academy of Pediatrics affirms that it is in the best interests of young patients to not use any substances.10 The screening recommendations issued by the AAP further encourage pediatricians and adolescent medicine physicians to help guide their patients to this fundamental and easily-understood health goal.
A new and better vision for addiction prevention must focus on the single, clear goal of no use of alcohol, nicotine, marijuana, or other drugs for health by youth under age 21.11 Some good news for prevention is that, for the past 3 decades, there has been a slow but steadily increasing percentage of American high school seniors reporting abstinence from any use of alcohol, cigarettes, marijuana, and other illicit drugs.12 In 2014, 25.5% of high school seniors reported lifetime abstinence, and fully 50% reported past-month abstinence from all substances. Those figures are dramatic, compared with abstinence rates during the nation’s peak years of youth drug use. In 1978, among high school seniors, 4.4% reported lifetime abstinence from any use of alcohol, cigarettes, marijuana, and other illicit drugs and 21% reported past-month abstinence. Notably, similar increasing rates of abstinence have been recorded among eighth- and 10th-graders. This encouraging and largely overlooked reality demonstrates that the no-use prevention goal for youth is both realistic and attainable.
Expand drug and alcohol courts
We need to rehabilitate the role of the criminal justice system in a public health–oriented policy to achieve two essential goals: 1) to improve supply reduction as described above, and 2) to reshape the criminal justice system as an engine of recovery as it is now for alcohol addiction.
The landmark report, “Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs and Health,” called for a continuum of health care extending from prevention to early identification and treatment of substance use disorders and long-term health care management with the goal of sustained recovery.13 A growing number of pioneering programs within the criminal justice system (for example, Hawaii’s HOPE Probation, South Dakota’s 24/7 Sobriety Project, and drug courts) are using innovative monitoring strategies for individuals with substance use problems, including providing substance use disorder treatment, with results showing reduced substance use, reduced recidivism, and reduced incarceration.14
In HOPE, drug-involved offenders are subject to frequent random drug testing, rather than the typical drug testing done on standard probation, only at the time of scheduled meetings with probation officers. Failure to abstain from drugs or failure to show up for random drug testing always results in a brief jail sanction, usually 2-15 days, depending on the nature and severity of the offense. Upon placement in HOPE at a warning hearing, probationers are encouraged to succeed, and are fully informed of the length of the jail sanctions that will be imposed for each type of violation. They are assured of the certainty and speed with which the sanctions will be applied.
Sanctions are applied consistently and impartially to ensure fairness for all. Substance abuse treatment is available to all offenders who want it and to those who demonstrate a need for treatment through “behavioral triage.” Offenders who test positive for drugs two or more times in short order with jail sanctions are referred for a substance abuse assessment and instructed to follow any recommended treatment. For this reason, offenders in HOPE succeed in treatment – because they are the offenders in most need and are supported by the leverage provided by the court to help them complete treatment.
A randomized, controlled trial compared offenders assigned to HOPE Probation and a control group assigned to probation as usual. Compared with offenders on probation as usual, at 1-year follow-up, HOPE offenders were:
• 55% less likely to be arrested for a new crime.
• 72% less likely to test positive for illegal drugs.
• 61% less likely to skip appointments with their supervisory officer.
• 53% less likely to have their probation revoked.
There also is a growing potential to harness the latent but enormous strength of the families who have confronted and are continuing to confront addiction in a family member. Families and those with addictions can be engaged in alcohol or drug courts, which can act like the PHP for addicted individuals in the criminal justice system.
Implications for treatment
The diversion of medications that are prescribed and intended for patients in pain is just one part of the far larger drug use and overdose problem. An addicted person with a hijacked brain is not the same as a nonaddicted pain patient. Taking medication as prescribed for pain can produce physical dependence, but importantly, this is not addiction. The person who is using drugs – whether or not prescribed – to produce euphoria is a different person from the person in that same body who is abstinent and not using. Talking with a person in active addiction often is frustrating and futile. That addicted user’s brain wants to use drugs.
The PHP system of care management demonstrates that individuals with substance use disorders can refrain from any substance use for extended periods of time with a carrot and stick approach; permitting a physician to earn a livelihood as a physician is the carrot. In medication-assisted treatment (MAT), the carrot is provided by agonist drugs and the comfort-fit they provide in the brain. They protect the patient from anxiety, and reduce stress and craving responsivity. The stick is an environment that is intolerant of continued nonmedical or addicting drug use. This can be the family, an employer, the criminal justice system, or others in a position to insist on abstinence.
PHP care management shows the way to improve all treatment outcomes; however, an even larger lesson can be learned from the millions of Americans now in recovery from addiction to opioids and other drugs. The “evidence” of what recovery is and how it is achieved and sustained is available to everyone who knows or comes into contact with people in recovery. How did that near-miraculous transformation happen? Even more importantly, how is it sustained when relapse is so common in addiction? The millions of Americans in recovery are the inspiration for a new generation of improved addiction treatment.
Addiction reprioritizes the brain toward continued drug use first, rather than family, friends, health, job, or another important remnant of the addicted person’s past having any meaningful standing. It is often a question like that raised by the AA axiom that it is easy to change a cucumber (naive or new drug user) into a pickle (an addict), but turning a pickle into a cucumber is very difficult. Risk-benefit research has shown that drugs change the ability to accurately assess risks and benefits by prioritizing drug use over virtually everything else, including the interests of the drug users themselves.
Along with judgment deficits comes dishonesty – a hallmark of addiction. The person with addictions lies, minimizes, and denies drug use, thus keeping the addictive run going. That often is the heart of addiction. The point is that once the disease is in control of the addicted brain, those around that hijacked brain must intervene – and the goal of cutting down drug use or limiting it to exclude one or another drug is not useful. Rather, it perpetuates the addiction. Freedom from addiction, that modern chemical slavery, requires no use of alcohol and other drugs, including marijuana, and a return to healthy relationships, sleep, eating, exercise, etc.
Recovery is more than abstinence from all drug use; it includes character development and citizenship. The data supporting the essential goal of recovery are found in the people who are in recovery not in today’s scientific research, which generally is off-target on recovery. Just because recovering people are anonymous does not mean that they do not exist. They prove that recovery happens all the time. They show what recovery is, and how it is achieved and maintained. Current arguments over which MAT is the best in a 3-month study is too short-term for a lifetime disorder and it ignores the concept of recovery despite the millions of people who are living it. Their stories are the bedrock of our message.
Our core evidence, our inspiration, comes from asking the people in recovery from the deadly, chronic disease of addiction three questions: 1) What was your life like when using drugs? 2) What happened to get you to stop using drugs? and 3) What is your life like when not using any drugs?” Every American who knows someone in recovery can do this research for themselves. We have been doing that research for decades.
People in recovery all have sobriety dates. Few in MAT have sobriety dates. Recovery from addiction is not just not taking Vicodin but living the life of a drug-free, recovering person. How do they hold onto recovery, and prevent and deal with relapses and slips? MAT is a major achievement in addiction treatment, including agonist maintenance with buprenorphine and methadone, but it needs to build in the goal of sustained recovery and strong recovery support. That means building into MAT the 12-step fellowships and related recovery support, as is done every day by James H. Berry, DO, of the Chestnut Ridge Center at West Virginia University’s Comprehensive Opioid Addiction Treatment, or COAT, program.15
MAT is good. It needs to be targeted on recovery, which can include continued use of the medicines now widely used: methadone, buprenorphine, and naltrexone. But recovery cannot include continued nonmedical drug use, and it also must include character development – with honesty replacing the dishonesty that is at the heart of addiction.
Holding up that widely available picture of recovery and making it clear to our readers is our goal in this article. For too many people, including some of our most treasured colleagues in addiction treatment, this message is new and radical. The PHP model has put it together in a program that is now more than 4 decades old. It is real, possible, and understandable. The key to its success is the commitment to living drug free, the active and sustained testing for any use of alcohol or other drugs linked to prompt intervention to any relapse, the use of recovery support, and the long duration of active care management: 5 years. That package is seldom seen in the current approach to addiction treatment, which often is siloed out of mainstream medicine – with little or no monitoring or support after the typically short duration of treatment.
People with addictions in recovery remain vulnerable to relapse for life, but the disease now is being managed successfully by millions of people. As dishonesty and self-centeredness were the heart of behaviors during active addiction, so honesty and caring for others are at the heart of life in recovery. This is an easily seen spiritual transformation that gives hope and guidance to addiction treatment, and inspiration to us in our work in treatment – and to all people with addictions.
Dr. Gold is the 17th Distinguished Alumni Professor at the University of Florida, Gainesville, professor of psychiatry (adjunct) at Washington University in St. Louis. Dr. DuPont is the first director of the National Institute on Drug Abuse and the second White House drug chief, founding president of the Institute for Behavior and Health in Rockville, Md., and author of “Chemical Slavery: Understanding Addiction and Stopping the Drug Epidemic” (Create Space Independent Publishing Platform), 2018.
References
1. Am J Public Health. 2018 Oct 108(10):1394-1400.
2. Florida Drug-Related Outcomes Surveillance & Tracking system (FROST)
3. Center on Addiction. Addiction Medicine: Closing the Gap Between Science and Practice. 2012 Jun.
4. Surgeon General’s Advisory on Naloxone and Opioid Overdose.
5. Mayo Clin Proc. 2018 Mar;93(3):269-72.
6. Ther Adv Drug Saf. 2015 Feb;6(1):20-31.
7. J Subst Abuse Treat. 2009 Mar;36(2):159-71.
8. J Subst Abuse Treat. 2015 Nov;58:1-5.
9. Prev Med. 2018 Aug;113:68-73.
10. Pediatrics. 2016 Jun;138(1). doi: 10.1542/peds.2016-1211.
11. Institute for Behavior and Health. (updated) 2018 Aug 29.
12. Pediatrics. 2018 Aug;142(2). doi: 10.1542/peds.2017-3498.
13. Office of the Surgeon General. 2016.
14. The ASAM Principles of Addiction Medicine. (6th ed.) (in press) Wolters Kluwer, 2018.
15. West Virginia Clinical and Translational Science Institute. 2017 Aug 21.