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.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

“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.

[email protected]

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.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

“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.

[email protected]

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.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

“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.

[email protected]

Brain mapping patterns varied with clinical mental health diagnoses in a study of 218 patients with schizophrenia spectrum disorders.

copyright Thinkstock

“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).

Extreme positive deviations were significantly higher among healthy controls (1.08% of voxels), compared with bipolar patients and schizophrenia patients (0.79% and 0.78%, 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.

copyright Thinkstock

“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).

Extreme positive deviations were significantly higher among healthy controls (1.08% of voxels), compared with bipolar patients and schizophrenia patients (0.79% and 0.78%, 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.

copyright Thinkstock

“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).

Extreme positive deviations were significantly higher among healthy controls (1.08% of voxels), compared with bipolar patients and schizophrenia patients (0.79% and 0.78%, 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.

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.

sdominick/iStock/Getty Images

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. It has been too easy to zero in on opioids while ignoring the ubiquity of polysubstance use by almost all individuals suffering from opioid and other substance use disorders and related drug problems, including overdose. 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.

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.

sdominick/iStock/Getty Images

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. It has been too easy to zero in on opioids while ignoring the ubiquity of polysubstance use by almost all individuals suffering from opioid and other substance use disorders and related drug problems, including overdose. 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.

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.

sdominick/iStock/Getty Images

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. It has been too easy to zero in on opioids while ignoring the ubiquity of polysubstance use by almost all individuals suffering from opioid and other substance use disorders and related drug problems, including overdose. 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.

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.

Traditionally, a physician develops a differential diagnosis based primarily (>70%) on the history and the physical examination of a patient.¹ While modern medicine has developed with new technological devices and a growing number of diagnostic tests, one must not forget the value of a thorough physical examination.

Case

A 21-year-old woman, in previous good health, presented to the ED with the chief complaint of shortness of breath. She stated that she woke up with acute dyspnea and a stabbing pain on the left side of her thorax, related to her breathing. The patient looked distressed upon presentation.

Her vital signs at presentation were: blood pressure, 150/85 mm Hg; heart rate, 120 beats/min; respiratory rate, 22 breaths/min; and temperature, 100.6°F. Oxygen saturation was 100% on room air.

During physical examination, a loud ticking noise was heard originating from the thorax, even without a stethoscope (an example of the sound can be heard at https://www.youtube.com/watch?v=mXJHtJeL1mM). During auscultation, the ticking noise was prominent in early systole and audible over all parts of the thorax. The sound was only heard when the patient was in the supine position and disappeared when she sat up. It persisted when the patient was holding her breath. Breath sounds were equal and clear bilaterally. There was no subcutaneous emphysema palpable over the thorax or neck region.

Discussion

These loud intermittent noises originating from the thorax were described for the first time at the beginning of the 19th century.^2,3 However, it was Louis Virgil Hamman whose name would be linked to this physical examination finding. In 1937 he described typical clicking, crackling, and popping sounds over the precordium, synchronized with the heartbeat. This was usually in combination with subcutaneous emphysema in the neck region. Hamman presumed that the symptoms were due to mediastinal air caused by rupture alveoli or bronchioles, resulting in interstitial emphysema of the lung parenchyma. In addition, air could leak into the pleural space, causing a pneumothorax. He concluded that the clinical findings were pathognomonic for spontaneous mediastinal emphysema, and this physical examination finding became known as the “Hamman sign”.^4-11

Conclusion

The Hamman sign is a rare clinical examination finding in left-sided pneumothorax or pneumomediastinum, in which a ticking or crackling noise is heard over the thorax. This is mostly synchronous with the heartbeat and not related to respiration. It is caused by a small amount of accumulated air in the pleural space, which is being displaced by cardiac contractions during the cardiac cycle. Although typically small, pneumothoraces have a good prognosis. Recognition of the Hamman sign is important, and physicians must realize that even a normal chest X-ray does not rule out the diagnosis.

Traditionally, a physician develops a differential diagnosis based primarily (>70%) on the history and the physical examination of a patient.¹ While modern medicine has developed with new technological devices and a growing number of diagnostic tests, one must not forget the value of a thorough physical examination.

Case

A 21-year-old woman, in previous good health, presented to the ED with the chief complaint of shortness of breath. She stated that she woke up with acute dyspnea and a stabbing pain on the left side of her thorax, related to her breathing. The patient looked distressed upon presentation.

Her vital signs at presentation were: blood pressure, 150/85 mm Hg; heart rate, 120 beats/min; respiratory rate, 22 breaths/min; and temperature, 100.6°F. Oxygen saturation was 100% on room air.

During physical examination, a loud ticking noise was heard originating from the thorax, even without a stethoscope (an example of the sound can be heard at https://www.youtube.com/watch?v=mXJHtJeL1mM). During auscultation, the ticking noise was prominent in early systole and audible over all parts of the thorax. The sound was only heard when the patient was in the supine position and disappeared when she sat up. It persisted when the patient was holding her breath. Breath sounds were equal and clear bilaterally. There was no subcutaneous emphysema palpable over the thorax or neck region.

Discussion

These loud intermittent noises originating from the thorax were described for the first time at the beginning of the 19th century.^2,3 However, it was Louis Virgil Hamman whose name would be linked to this physical examination finding. In 1937 he described typical clicking, crackling, and popping sounds over the precordium, synchronized with the heartbeat. This was usually in combination with subcutaneous emphysema in the neck region. Hamman presumed that the symptoms were due to mediastinal air caused by rupture alveoli or bronchioles, resulting in interstitial emphysema of the lung parenchyma. In addition, air could leak into the pleural space, causing a pneumothorax. He concluded that the clinical findings were pathognomonic for spontaneous mediastinal emphysema, and this physical examination finding became known as the “Hamman sign”.^4-11

Conclusion

The Hamman sign is a rare clinical examination finding in left-sided pneumothorax or pneumomediastinum, in which a ticking or crackling noise is heard over the thorax. This is mostly synchronous with the heartbeat and not related to respiration. It is caused by a small amount of accumulated air in the pleural space, which is being displaced by cardiac contractions during the cardiac cycle. Although typically small, pneumothoraces have a good prognosis. Recognition of the Hamman sign is important, and physicians must realize that even a normal chest X-ray does not rule out the diagnosis.

Traditionally, a physician develops a differential diagnosis based primarily (>70%) on the history and the physical examination of a patient.¹ While modern medicine has developed with new technological devices and a growing number of diagnostic tests, one must not forget the value of a thorough physical examination.

Case

A 21-year-old woman, in previous good health, presented to the ED with the chief complaint of shortness of breath. She stated that she woke up with acute dyspnea and a stabbing pain on the left side of her thorax, related to her breathing. The patient looked distressed upon presentation.

Her vital signs at presentation were: blood pressure, 150/85 mm Hg; heart rate, 120 beats/min; respiratory rate, 22 breaths/min; and temperature, 100.6°F. Oxygen saturation was 100% on room air.

During physical examination, a loud ticking noise was heard originating from the thorax, even without a stethoscope (an example of the sound can be heard at https://www.youtube.com/watch?v=mXJHtJeL1mM). During auscultation, the ticking noise was prominent in early systole and audible over all parts of the thorax. The sound was only heard when the patient was in the supine position and disappeared when she sat up. It persisted when the patient was holding her breath. Breath sounds were equal and clear bilaterally. There was no subcutaneous emphysema palpable over the thorax or neck region.

Discussion

These loud intermittent noises originating from the thorax were described for the first time at the beginning of the 19th century.^2,3 However, it was Louis Virgil Hamman whose name would be linked to this physical examination finding. In 1937 he described typical clicking, crackling, and popping sounds over the precordium, synchronized with the heartbeat. This was usually in combination with subcutaneous emphysema in the neck region. Hamman presumed that the symptoms were due to mediastinal air caused by rupture alveoli or bronchioles, resulting in interstitial emphysema of the lung parenchyma. In addition, air could leak into the pleural space, causing a pneumothorax. He concluded that the clinical findings were pathognomonic for spontaneous mediastinal emphysema, and this physical examination finding became known as the “Hamman sign”.^4-11

Conclusion

The Hamman sign is a rare clinical examination finding in left-sided pneumothorax or pneumomediastinum, in which a ticking or crackling noise is heard over the thorax. This is mostly synchronous with the heartbeat and not related to respiration. It is caused by a small amount of accumulated air in the pleural space, which is being displaced by cardiac contractions during the cardiac cycle. Although typically small, pneumothoraces have a good prognosis. Recognition of the Hamman sign is important, and physicians must realize that even a normal chest X-ray does not rule out the diagnosis.

More patients had newly diagnosed HIV and hepatitis C virus (HCV) infection during an automated-laboratory-order HIV/HCV screening algorithm than with a nurse-order HIV/HCV screening algorithm, according to the results of a retrospective before/after comparison study of the two electronic health record (EHR)–based protocols.

©Getty Images

The results of nurse-order HIV/HCV screening in the 5-month period of March 1, 2016, through July 31, 2016, were compared to the subsequently adopted automated-laboratory-order system results from March 1, 2017, through July 31, 2017, according to Douglas A.E. White, MD, and his colleagues at Highland Hospital Emergency Department, Oakland, Calif.

Via the EHR, nurses were instructed to offer screening to all adults aged 18-75 years unless they were known to be HIV- or HCV-positive, unable to verbally consent (e.g., language barriers, intoxication), or medically unstable. Exclusion was at the discretion of the triage nurse. Using a drop-down menu, nurses could choose “accepts” or “declines” for HIV and HCV testing, according to patient response. Choosing “accepts” automatically ordered the test, according to the report (Ann Emerg Med. 2018 Oct;72[4]:438-48).

Automated-laboratory-order HIV/HCV screening was integrated into clinical care. With this protocol, the EHR-automated annual HIV/hepatitis C virus screening was performed on adult patients aged 18-75 years who had laboratory tests ordered. The EHR was configured to automatically order an HIV or HCV test for age-eligible patients who had any test ordered that required laboratory processing of whole blood (excluding point-of-care tests such as for lactate or glucose level) or a urine or urethral swab for chlamydia or gonorrhea testing, according to the researchers.

There were 20,975 and 19,887 unique, age-eligible patients during the nurse-order HIV/HCV virus screening algorithm and automated-laboratory-order HIV/HCV screening algorithm study periods, respectively. A total of 4,121 patients (19.6%) were screened for HIV and 2,968 (14.2%) patients were screened for HCV during the nurse-order period vs. 6,736 (33.9%) patients screened for HIV and 6,972 (35.1%) screened for HCV during the automated-laboratory-order period.

Overall, HIV screening increased from 19.6% to 33.9% and HCV screening, from 14.2% to 35.1% using the automated vs. the nurse-ordered EHR-based algorithm.

“An automated electronic health record algorithm that links nontargeted opt-out HIV and hepatitis C virus screening to physician laboratory ordering more effectively screens ED patients, provides results before discharge, minimizes repeated screening, and diagnoses more new infections than an algorithm that relies on nursing staff to offer screening. Because most EDs in the United States now use EHR systems, this model can be easily replicated and should be considered the standard for future programs,” the researchers concluded.

This work was supported, in part, by grant funding through the FOCUS program, Gilead Sciences, which also has provided funding to various of the authors of the study.

[email protected]

SOURCE: White DAE et al. Ann Emerg Med. 2018 Oct;72[4]:438-48.

More patients had newly diagnosed HIV and hepatitis C virus (HCV) infection during an automated-laboratory-order HIV/HCV screening algorithm than with a nurse-order HIV/HCV screening algorithm, according to the results of a retrospective before/after comparison study of the two electronic health record (EHR)–based protocols.

©Getty Images

The results of nurse-order HIV/HCV screening in the 5-month period of March 1, 2016, through July 31, 2016, were compared to the subsequently adopted automated-laboratory-order system results from March 1, 2017, through July 31, 2017, according to Douglas A.E. White, MD, and his colleagues at Highland Hospital Emergency Department, Oakland, Calif.

Via the EHR, nurses were instructed to offer screening to all adults aged 18-75 years unless they were known to be HIV- or HCV-positive, unable to verbally consent (e.g., language barriers, intoxication), or medically unstable. Exclusion was at the discretion of the triage nurse. Using a drop-down menu, nurses could choose “accepts” or “declines” for HIV and HCV testing, according to patient response. Choosing “accepts” automatically ordered the test, according to the report (Ann Emerg Med. 2018 Oct;72[4]:438-48).

Automated-laboratory-order HIV/HCV screening was integrated into clinical care. With this protocol, the EHR-automated annual HIV/hepatitis C virus screening was performed on adult patients aged 18-75 years who had laboratory tests ordered. The EHR was configured to automatically order an HIV or HCV test for age-eligible patients who had any test ordered that required laboratory processing of whole blood (excluding point-of-care tests such as for lactate or glucose level) or a urine or urethral swab for chlamydia or gonorrhea testing, according to the researchers.

There were 20,975 and 19,887 unique, age-eligible patients during the nurse-order HIV/HCV virus screening algorithm and automated-laboratory-order HIV/HCV screening algorithm study periods, respectively. A total of 4,121 patients (19.6%) were screened for HIV and 2,968 (14.2%) patients were screened for HCV during the nurse-order period vs. 6,736 (33.9%) patients screened for HIV and 6,972 (35.1%) screened for HCV during the automated-laboratory-order period.

Overall, HIV screening increased from 19.6% to 33.9% and HCV screening, from 14.2% to 35.1% using the automated vs. the nurse-ordered EHR-based algorithm.

“An automated electronic health record algorithm that links nontargeted opt-out HIV and hepatitis C virus screening to physician laboratory ordering more effectively screens ED patients, provides results before discharge, minimizes repeated screening, and diagnoses more new infections than an algorithm that relies on nursing staff to offer screening. Because most EDs in the United States now use EHR systems, this model can be easily replicated and should be considered the standard for future programs,” the researchers concluded.

This work was supported, in part, by grant funding through the FOCUS program, Gilead Sciences, which also has provided funding to various of the authors of the study.

[email protected]

SOURCE: White DAE et al. Ann Emerg Med. 2018 Oct;72[4]:438-48.

More patients had newly diagnosed HIV and hepatitis C virus (HCV) infection during an automated-laboratory-order HIV/HCV screening algorithm than with a nurse-order HIV/HCV screening algorithm, according to the results of a retrospective before/after comparison study of the two electronic health record (EHR)–based protocols.

©Getty Images

The results of nurse-order HIV/HCV screening in the 5-month period of March 1, 2016, through July 31, 2016, were compared to the subsequently adopted automated-laboratory-order system results from March 1, 2017, through July 31, 2017, according to Douglas A.E. White, MD, and his colleagues at Highland Hospital Emergency Department, Oakland, Calif.

Via the EHR, nurses were instructed to offer screening to all adults aged 18-75 years unless they were known to be HIV- or HCV-positive, unable to verbally consent (e.g., language barriers, intoxication), or medically unstable. Exclusion was at the discretion of the triage nurse. Using a drop-down menu, nurses could choose “accepts” or “declines” for HIV and HCV testing, according to patient response. Choosing “accepts” automatically ordered the test, according to the report (Ann Emerg Med. 2018 Oct;72[4]:438-48).

Automated-laboratory-order HIV/HCV screening was integrated into clinical care. With this protocol, the EHR-automated annual HIV/hepatitis C virus screening was performed on adult patients aged 18-75 years who had laboratory tests ordered. The EHR was configured to automatically order an HIV or HCV test for age-eligible patients who had any test ordered that required laboratory processing of whole blood (excluding point-of-care tests such as for lactate or glucose level) or a urine or urethral swab for chlamydia or gonorrhea testing, according to the researchers.

There were 20,975 and 19,887 unique, age-eligible patients during the nurse-order HIV/HCV virus screening algorithm and automated-laboratory-order HIV/HCV screening algorithm study periods, respectively. A total of 4,121 patients (19.6%) were screened for HIV and 2,968 (14.2%) patients were screened for HCV during the nurse-order period vs. 6,736 (33.9%) patients screened for HIV and 6,972 (35.1%) screened for HCV during the automated-laboratory-order period.

Overall, HIV screening increased from 19.6% to 33.9% and HCV screening, from 14.2% to 35.1% using the automated vs. the nurse-ordered EHR-based algorithm.

“An automated electronic health record algorithm that links nontargeted opt-out HIV and hepatitis C virus screening to physician laboratory ordering more effectively screens ED patients, provides results before discharge, minimizes repeated screening, and diagnoses more new infections than an algorithm that relies on nursing staff to offer screening. Because most EDs in the United States now use EHR systems, this model can be easily replicated and should be considered the standard for future programs,” the researchers concluded.

This work was supported, in part, by grant funding through the FOCUS program, Gilead Sciences, which also has provided funding to various of the authors of the study.

[email protected]

SOURCE: White DAE et al. Ann Emerg Med. 2018 Oct;72[4]:438-48.

CHICAGO – Diagnosing the cause of vaginal itching, which can have a significant negative impact on a woman’s quality of life, can be particularly difficult for multiple reasons, according to Rachel Kornik, MD, of the departments of dermatology and obstetrics and gynecology at the University of Wisconsin, Madison.

“The anatomy is really challenging in this area, and there’s a broad differential. Often there’s more than one thing happening,” Dr. Kornik said during a session on diagnosing and managing genital pruritus in women at the American Academy of Dermatology summer meeting. Like hair loss, vaginal pruritus is also very emotionally distressing.

“Patients are very anxious when they have all this itching,” she said. “It has an impact on personal relationships. Some patients find it difficult to talk about because it’s a taboo subject, so we have to make them comfortable.”

Dr. Kornik showed a chart of the many conditions that cause vaginal or vulvar pruritus, falling within a variety of categories: inflammatory, neoplastic, infections, infestations, environmental, neuropathic, and hormonal. But she focused her presentation primarily on the most common causes: contact dermatitis, lichen sclerosus, and lichen simplex chronicus.

Contact dermatitis

The most common factors that contribute to contact dermatitis are friction, hygiene practices, unique body exposures (such as body fluids and menstrual and personal care products), and occlusion/maceration, which facilitates penetration of external agents. Estrogen deficiency may also play a role.

Taking a thorough history from the patient is key to finding out possible causes. Dr. Kornik provided a list of common irritants to consider.

• Hygiene-related irritants, such as frequent washing and the use of soaps, wash cloths, loofahs, wipes, bath oil, bubbles, and water.
• Laundry products, such as fabric softeners or dryer sheets.
• Menstrual products, such as panty liners, pads, and scents or additives for retaining moisture.
• Over-the-counter itch products, such as those containing benzocaine.
• Medications, such as alcohol-based creams and gels, trichloroacetic acid, fluorouracil (Efudex), imiquimod, and topical antifungals.
• Heat-related irritants, such as use of hair dryers and heating pads.
• Body fluids, including urine, feces, menstrual blood, sweat, semen, and excessive discharge.

It’s also important to consider whether there is an allergic cause. “Contact dermatitis and allergic dermatitis can look very similar both clinically and histologically, and patients can even have them both at the same time,” Dr. Kornik said. “So really, patch testing is essential sometimes to identify a true allergic contact dermatitis.”

She cited a study that identified the top five most common allergens as fragrance mixes, balsam of Peru, benzocaine, terconazole, and quaternium-15 (a formaldehyde-releasing preservative) (Dermatitis. 2013 Mar-Apr;24(2):64-72).

“If somebody’s coming into your office and they have vulvar itching for any reason, the No. 1 thing is making sure that they eliminate and not use any products with fragrances,” Dr. Kornik said. “It’s also important to note that over time, industries’ use of preservatives does change, the concentrations change, and so we may see more emerging allergens or different ones over time.”

The causative allergens are rarely consumed orally, but they may be ectopic, such as shampoo or nail polish.

“What I’ve learned over the years in treating patients with vulvar itching is that they don’t always think to tell you about everything they are applying,” Dr. Kornik said. “You have to ask specific questions. Are you using any wipes or using any lubricants? What is the type and brand of menstrual pad you’re using?”

Patients might also think they can eliminate the cause of irritation by changing products, but “there are cross reactants in many preservatives and fragrances in many products, so they might not eliminate exposure, and intermittent exposures can lead to chronic dermatitis,” she pointed out.

One example is wipes: Some women may use them only periodically, such as after a yoga class, and not think of this as a possibility or realize that wipes could perpetuate chronic dermatitis.

Research has also found that it’s very common for patients with allergic contact dermatitis to have a concomitant vulvar diagnosis. In one study, more than half of patients had another condition, the most common of which was lichen sclerosus. Others included simplex chronicus, atopic dermatitis, condyloma acuminatum, psoriasis, and Paget disease.

Therefore, if patients are not responding as expected, it’s important to consider that the condition is multifactorial “and consider allergic contact dermatitis in addition to whatever other underlying dermatosis they have,” Dr. Kornik said.

Lichen sclerosus

Prevalence of the scarring disorder lichen sclerosus ranges from 1.7% to 3% in the research literature and pathogenesis is likely multifactorial.

“It’s a very frustrating condition for patients and for physicians because we don’t know exactly what causes it, but it definitely has a predilection for the vulva area, and it affects women of all ages,” she said. “I also think it’s more common than we think.”

Loss of normal anatomical structures are a key feature, so physicians need to know their anatomy well to look for what’s not there. Lichen sclerosus involves modified mucous membranes and the perianal area, and it may spread to the crural folds and upper thighs. Symptoms can include periclitoral edema, white patches, pale skin, textural changes (such as wrinkling, waxiness, or hyperkeratosis), fissures, melanosis, and sometimes ulcerations or erosions from scratching.

There is no standardized treatment for lichen sclerosus. Research suggests using a high potency topical steroid treatment daily until skin texture normalizes, which can take anywhere from 6 weeks to 5 months, depending on severity, Dr. Kornik said. Few data are available for management if topical steroids do not work, she added.*

If dealing with recalcitrant disease, she recommends first checking the patients’ compliance and then considering alternative diagnoses or secondary conditions. Do patch testing, rule out contact dermatitis, and rebiopsy if needed. Other options are to add tacrolimus ointment, offer intralesional triamcinolone, consider a systemic agent (acitretin, methotrexate, or possibly hydroxychloroquine), or try laser or photodynamic therapy. She emphasizes the importance of demonstrating to the patient where to apply ointment, since they may not be applying to the right areas.*

Lichen simplex chronicus

Lichen simplex chronicus is a clinical description of the result of chronic rubbing and scratching. It might be triggered by something that has now resolved or be linked to other itching conditions, but clinicians need to consider the possibility of neuropathic itch as well.

Features of lichen simplex chronicus can include bilateral or unilateral involvement of the labia majora, erythematous plaques with lichenification, hyper- or hypopigmentation, or angulated excoriations and hypertrophy of labia caused by thickened skin, though the signs may be subtle, she said.

Treatment requires management of the skin problem itself – the underlying cause of the itch – as well as the behavioral component. Topical steroids are first line, plus an antihistamine at night as needed to stop the scratching. If those are insufficient, the next treatments to consider are intralesional triamcinolone (Kenalog), tacrolimus ointment, topical or oral doxepin, mirtazapine, or even selective serotonin reuptake inhibitors.

Women using topical steroids should also be aware of the possible side effects, including atrophy, infections, and allergic contact dermatitis if the steroid itself or the cream it’s in is an allergen. If stinging or burning occurs, switch to a steroid without propylene glycol, she added.

If no changes occur in the skin, clinicians may have to consider the existence of neuropathic pruritus diagnosis, an injury or dysfunction along the afferent itch pathway. Burning is more common with this neuropathy, but itching can occur too.

Other issues include symptoms that worsen with sitting and pain that worsens throughout the day. Causes can include childbirth, surgery, pelvic trauma, infection, and chemoradiation, and diagnosis requires imaging to rule out other possible causes. Treatment involves pelvic floor physical therapy, pudendal nerve block, or gabapentin.

Dr. Kornik wrapped up with a reminder that vulvar itch is often multifactorial, so clinicians need to chip away at the potential causes – sometimes with cultures, scrapes, and biopsies as needed.

She reported no financial disclosures.

Correction, 10/26/18: Dr. Kornik's treatment recommendations for lichen sclerosus were misstated.

CHICAGO – Diagnosing the cause of vaginal itching, which can have a significant negative impact on a woman’s quality of life, can be particularly difficult for multiple reasons, according to Rachel Kornik, MD, of the departments of dermatology and obstetrics and gynecology at the University of Wisconsin, Madison.

“The anatomy is really challenging in this area, and there’s a broad differential. Often there’s more than one thing happening,” Dr. Kornik said during a session on diagnosing and managing genital pruritus in women at the American Academy of Dermatology summer meeting. Like hair loss, vaginal pruritus is also very emotionally distressing.

“Patients are very anxious when they have all this itching,” she said. “It has an impact on personal relationships. Some patients find it difficult to talk about because it’s a taboo subject, so we have to make them comfortable.”

Dr. Kornik showed a chart of the many conditions that cause vaginal or vulvar pruritus, falling within a variety of categories: inflammatory, neoplastic, infections, infestations, environmental, neuropathic, and hormonal. But she focused her presentation primarily on the most common causes: contact dermatitis, lichen sclerosus, and lichen simplex chronicus.

Contact dermatitis

The most common factors that contribute to contact dermatitis are friction, hygiene practices, unique body exposures (such as body fluids and menstrual and personal care products), and occlusion/maceration, which facilitates penetration of external agents. Estrogen deficiency may also play a role.

Taking a thorough history from the patient is key to finding out possible causes. Dr. Kornik provided a list of common irritants to consider.

• Hygiene-related irritants, such as frequent washing and the use of soaps, wash cloths, loofahs, wipes, bath oil, bubbles, and water.
• Laundry products, such as fabric softeners or dryer sheets.
• Menstrual products, such as panty liners, pads, and scents or additives for retaining moisture.
• Over-the-counter itch products, such as those containing benzocaine.
• Medications, such as alcohol-based creams and gels, trichloroacetic acid, fluorouracil (Efudex), imiquimod, and topical antifungals.
• Heat-related irritants, such as use of hair dryers and heating pads.
• Body fluids, including urine, feces, menstrual blood, sweat, semen, and excessive discharge.

It’s also important to consider whether there is an allergic cause. “Contact dermatitis and allergic dermatitis can look very similar both clinically and histologically, and patients can even have them both at the same time,” Dr. Kornik said. “So really, patch testing is essential sometimes to identify a true allergic contact dermatitis.”

She cited a study that identified the top five most common allergens as fragrance mixes, balsam of Peru, benzocaine, terconazole, and quaternium-15 (a formaldehyde-releasing preservative) (Dermatitis. 2013 Mar-Apr;24(2):64-72).

“If somebody’s coming into your office and they have vulvar itching for any reason, the No. 1 thing is making sure that they eliminate and not use any products with fragrances,” Dr. Kornik said. “It’s also important to note that over time, industries’ use of preservatives does change, the concentrations change, and so we may see more emerging allergens or different ones over time.”

The causative allergens are rarely consumed orally, but they may be ectopic, such as shampoo or nail polish.

“What I’ve learned over the years in treating patients with vulvar itching is that they don’t always think to tell you about everything they are applying,” Dr. Kornik said. “You have to ask specific questions. Are you using any wipes or using any lubricants? What is the type and brand of menstrual pad you’re using?”

Patients might also think they can eliminate the cause of irritation by changing products, but “there are cross reactants in many preservatives and fragrances in many products, so they might not eliminate exposure, and intermittent exposures can lead to chronic dermatitis,” she pointed out.

One example is wipes: Some women may use them only periodically, such as after a yoga class, and not think of this as a possibility or realize that wipes could perpetuate chronic dermatitis.

Research has also found that it’s very common for patients with allergic contact dermatitis to have a concomitant vulvar diagnosis. In one study, more than half of patients had another condition, the most common of which was lichen sclerosus. Others included simplex chronicus, atopic dermatitis, condyloma acuminatum, psoriasis, and Paget disease.

Therefore, if patients are not responding as expected, it’s important to consider that the condition is multifactorial “and consider allergic contact dermatitis in addition to whatever other underlying dermatosis they have,” Dr. Kornik said.

Lichen sclerosus

Prevalence of the scarring disorder lichen sclerosus ranges from 1.7% to 3% in the research literature and pathogenesis is likely multifactorial.

“It’s a very frustrating condition for patients and for physicians because we don’t know exactly what causes it, but it definitely has a predilection for the vulva area, and it affects women of all ages,” she said. “I also think it’s more common than we think.”

Loss of normal anatomical structures are a key feature, so physicians need to know their anatomy well to look for what’s not there. Lichen sclerosus involves modified mucous membranes and the perianal area, and it may spread to the crural folds and upper thighs. Symptoms can include periclitoral edema, white patches, pale skin, textural changes (such as wrinkling, waxiness, or hyperkeratosis), fissures, melanosis, and sometimes ulcerations or erosions from scratching.

There is no standardized treatment for lichen sclerosus. Research suggests using a high potency topical steroid treatment daily until skin texture normalizes, which can take anywhere from 6 weeks to 5 months, depending on severity, Dr. Kornik said. Few data are available for management if topical steroids do not work, she added.*

If dealing with recalcitrant disease, she recommends first checking the patients’ compliance and then considering alternative diagnoses or secondary conditions. Do patch testing, rule out contact dermatitis, and rebiopsy if needed. Other options are to add tacrolimus ointment, offer intralesional triamcinolone, consider a systemic agent (acitretin, methotrexate, or possibly hydroxychloroquine), or try laser or photodynamic therapy. She emphasizes the importance of demonstrating to the patient where to apply ointment, since they may not be applying to the right areas.*

Lichen simplex chronicus

Lichen simplex chronicus is a clinical description of the result of chronic rubbing and scratching. It might be triggered by something that has now resolved or be linked to other itching conditions, but clinicians need to consider the possibility of neuropathic itch as well.

Features of lichen simplex chronicus can include bilateral or unilateral involvement of the labia majora, erythematous plaques with lichenification, hyper- or hypopigmentation, or angulated excoriations and hypertrophy of labia caused by thickened skin, though the signs may be subtle, she said.

Treatment requires management of the skin problem itself – the underlying cause of the itch – as well as the behavioral component. Topical steroids are first line, plus an antihistamine at night as needed to stop the scratching. If those are insufficient, the next treatments to consider are intralesional triamcinolone (Kenalog), tacrolimus ointment, topical or oral doxepin, mirtazapine, or even selective serotonin reuptake inhibitors.

Women using topical steroids should also be aware of the possible side effects, including atrophy, infections, and allergic contact dermatitis if the steroid itself or the cream it’s in is an allergen. If stinging or burning occurs, switch to a steroid without propylene glycol, she added.

If no changes occur in the skin, clinicians may have to consider the existence of neuropathic pruritus diagnosis, an injury or dysfunction along the afferent itch pathway. Burning is more common with this neuropathy, but itching can occur too.

Other issues include symptoms that worsen with sitting and pain that worsens throughout the day. Causes can include childbirth, surgery, pelvic trauma, infection, and chemoradiation, and diagnosis requires imaging to rule out other possible causes. Treatment involves pelvic floor physical therapy, pudendal nerve block, or gabapentin.

Dr. Kornik wrapped up with a reminder that vulvar itch is often multifactorial, so clinicians need to chip away at the potential causes – sometimes with cultures, scrapes, and biopsies as needed.

She reported no financial disclosures.

Correction, 10/26/18: Dr. Kornik's treatment recommendations for lichen sclerosus were misstated.

CHICAGO – Diagnosing the cause of vaginal itching, which can have a significant negative impact on a woman’s quality of life, can be particularly difficult for multiple reasons, according to Rachel Kornik, MD, of the departments of dermatology and obstetrics and gynecology at the University of Wisconsin, Madison.

“The anatomy is really challenging in this area, and there’s a broad differential. Often there’s more than one thing happening,” Dr. Kornik said during a session on diagnosing and managing genital pruritus in women at the American Academy of Dermatology summer meeting. Like hair loss, vaginal pruritus is also very emotionally distressing.

“Patients are very anxious when they have all this itching,” she said. “It has an impact on personal relationships. Some patients find it difficult to talk about because it’s a taboo subject, so we have to make them comfortable.”

Dr. Kornik showed a chart of the many conditions that cause vaginal or vulvar pruritus, falling within a variety of categories: inflammatory, neoplastic, infections, infestations, environmental, neuropathic, and hormonal. But she focused her presentation primarily on the most common causes: contact dermatitis, lichen sclerosus, and lichen simplex chronicus.

Contact dermatitis

The most common factors that contribute to contact dermatitis are friction, hygiene practices, unique body exposures (such as body fluids and menstrual and personal care products), and occlusion/maceration, which facilitates penetration of external agents. Estrogen deficiency may also play a role.

Taking a thorough history from the patient is key to finding out possible causes. Dr. Kornik provided a list of common irritants to consider.

• Hygiene-related irritants, such as frequent washing and the use of soaps, wash cloths, loofahs, wipes, bath oil, bubbles, and water.
• Laundry products, such as fabric softeners or dryer sheets.
• Menstrual products, such as panty liners, pads, and scents or additives for retaining moisture.
• Over-the-counter itch products, such as those containing benzocaine.
• Medications, such as alcohol-based creams and gels, trichloroacetic acid, fluorouracil (Efudex), imiquimod, and topical antifungals.
• Heat-related irritants, such as use of hair dryers and heating pads.
• Body fluids, including urine, feces, menstrual blood, sweat, semen, and excessive discharge.

It’s also important to consider whether there is an allergic cause. “Contact dermatitis and allergic dermatitis can look very similar both clinically and histologically, and patients can even have them both at the same time,” Dr. Kornik said. “So really, patch testing is essential sometimes to identify a true allergic contact dermatitis.”

She cited a study that identified the top five most common allergens as fragrance mixes, balsam of Peru, benzocaine, terconazole, and quaternium-15 (a formaldehyde-releasing preservative) (Dermatitis. 2013 Mar-Apr;24(2):64-72).

“If somebody’s coming into your office and they have vulvar itching for any reason, the No. 1 thing is making sure that they eliminate and not use any products with fragrances,” Dr. Kornik said. “It’s also important to note that over time, industries’ use of preservatives does change, the concentrations change, and so we may see more emerging allergens or different ones over time.”

The causative allergens are rarely consumed orally, but they may be ectopic, such as shampoo or nail polish.

“What I’ve learned over the years in treating patients with vulvar itching is that they don’t always think to tell you about everything they are applying,” Dr. Kornik said. “You have to ask specific questions. Are you using any wipes or using any lubricants? What is the type and brand of menstrual pad you’re using?”

Patients might also think they can eliminate the cause of irritation by changing products, but “there are cross reactants in many preservatives and fragrances in many products, so they might not eliminate exposure, and intermittent exposures can lead to chronic dermatitis,” she pointed out.

One example is wipes: Some women may use them only periodically, such as after a yoga class, and not think of this as a possibility or realize that wipes could perpetuate chronic dermatitis.

Research has also found that it’s very common for patients with allergic contact dermatitis to have a concomitant vulvar diagnosis. In one study, more than half of patients had another condition, the most common of which was lichen sclerosus. Others included simplex chronicus, atopic dermatitis, condyloma acuminatum, psoriasis, and Paget disease.

Therefore, if patients are not responding as expected, it’s important to consider that the condition is multifactorial “and consider allergic contact dermatitis in addition to whatever other underlying dermatosis they have,” Dr. Kornik said.

Lichen sclerosus

Prevalence of the scarring disorder lichen sclerosus ranges from 1.7% to 3% in the research literature and pathogenesis is likely multifactorial.

“It’s a very frustrating condition for patients and for physicians because we don’t know exactly what causes it, but it definitely has a predilection for the vulva area, and it affects women of all ages,” she said. “I also think it’s more common than we think.”

Loss of normal anatomical structures are a key feature, so physicians need to know their anatomy well to look for what’s not there. Lichen sclerosus involves modified mucous membranes and the perianal area, and it may spread to the crural folds and upper thighs. Symptoms can include periclitoral edema, white patches, pale skin, textural changes (such as wrinkling, waxiness, or hyperkeratosis), fissures, melanosis, and sometimes ulcerations or erosions from scratching.

There is no standardized treatment for lichen sclerosus. Research suggests using a high potency topical steroid treatment daily until skin texture normalizes, which can take anywhere from 6 weeks to 5 months, depending on severity, Dr. Kornik said. Few data are available for management if topical steroids do not work, she added.*

If dealing with recalcitrant disease, she recommends first checking the patients’ compliance and then considering alternative diagnoses or secondary conditions. Do patch testing, rule out contact dermatitis, and rebiopsy if needed. Other options are to add tacrolimus ointment, offer intralesional triamcinolone, consider a systemic agent (acitretin, methotrexate, or possibly hydroxychloroquine), or try laser or photodynamic therapy. She emphasizes the importance of demonstrating to the patient where to apply ointment, since they may not be applying to the right areas.*

Lichen simplex chronicus

Lichen simplex chronicus is a clinical description of the result of chronic rubbing and scratching. It might be triggered by something that has now resolved or be linked to other itching conditions, but clinicians need to consider the possibility of neuropathic itch as well.

Features of lichen simplex chronicus can include bilateral or unilateral involvement of the labia majora, erythematous plaques with lichenification, hyper- or hypopigmentation, or angulated excoriations and hypertrophy of labia caused by thickened skin, though the signs may be subtle, she said.

Treatment requires management of the skin problem itself – the underlying cause of the itch – as well as the behavioral component. Topical steroids are first line, plus an antihistamine at night as needed to stop the scratching. If those are insufficient, the next treatments to consider are intralesional triamcinolone (Kenalog), tacrolimus ointment, topical or oral doxepin, mirtazapine, or even selective serotonin reuptake inhibitors.

Women using topical steroids should also be aware of the possible side effects, including atrophy, infections, and allergic contact dermatitis if the steroid itself or the cream it’s in is an allergen. If stinging or burning occurs, switch to a steroid without propylene glycol, she added.

If no changes occur in the skin, clinicians may have to consider the existence of neuropathic pruritus diagnosis, an injury or dysfunction along the afferent itch pathway. Burning is more common with this neuropathy, but itching can occur too.

Other issues include symptoms that worsen with sitting and pain that worsens throughout the day. Causes can include childbirth, surgery, pelvic trauma, infection, and chemoradiation, and diagnosis requires imaging to rule out other possible causes. Treatment involves pelvic floor physical therapy, pudendal nerve block, or gabapentin.

Dr. Kornik wrapped up with a reminder that vulvar itch is often multifactorial, so clinicians need to chip away at the potential causes – sometimes with cultures, scrapes, and biopsies as needed.

She reported no financial disclosures.

Correction, 10/26/18: Dr. Kornik's treatment recommendations for lichen sclerosus were misstated.

PHILADELPHIA – A low fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet was associated with improvement in fecal incontinence in 64.6% of patients who received dietary training, according to recent research presented at the American College of Gastroenterology annual meeting.

Jeff Craven/MDedge News

“In this case series, the low-FODMAP diet improved fecal incontinence in two-thirds of patients with fecal incontinence and loose stools,” Stacy Menees, MD, MS, assistant professor at the University of Michigan in Ann Arbor, said in her presentation.

Dr. Menees and her colleagues performed a retrospective chart review of 65 patients in the Michigan Bowel Control clinic with fecal incontinence (FI) “without alarming features” who were recommended a low FODMAP diet and received formal dietary teaching between August 2012 and December 2017. Patients received the teaching from a Michigan Medicine gastrointestinal dietitian. The dietitians performed a semi-quantitative analysis of patient response, including complete response, Dr. Menees said.

If we are going to help people with fecal incontinence, the key is to concentrate on the area of their stool consistency,” she explained. “We know that foods high in fermentable oligo-, di-, and monosaccharides and polyols, otherwise known as FODMAPS, can cause diarrhea and urgency.”

These FODMAP foods can include fruits with fructose exceeding glucose, fructan-containing vegetables, wheat-based products, sorbitol- and lactose-containing foods, and raffinose-containing foods, Dr. Menees said.

“We know from observations in data and research from the Monash University and our own group that patients with irritable bowel syndrome who are on a [low-]FODMAP diet [get relief from] their symptoms,” she added.

Most of the patients were female, and most were white. The mean age was 61.9 years, and mean body mass index was 26.7 kg/m². Among the patients, 27.7% had irritable bowel syndrome (IBS), 9.2% had inflammatory bowel disease (IBD), 16.9% had diabetes mellitus, and 20% had a prior cholecystectomy.

With regard to reports of loose stool and FI, 46.1% of patients said they had loose stool daily with a mean of 2.8 loose bowel movements daily. More than half of the patients (60.5%) reported FI daily; 37.8% said they experienced weekly FI, and 4.6% reported monthly FI. The number of patients reporting FI was higher than 100% because some patients reported in the chart that they had FI daily or weekly, Dr. Menees said.

FI improvement was reported by 64.6% of patients, with 88.1% of responders having a greater than 50% reduction in FI and 35.7% of patients experiencing complete resolution of FI. There were no serious adverse events in the study, Dr. Menees noted.

“The three patients with postinfection IBS and fecal incontinence had no response to a low-FODMAP diet,” she said. “Our dietitians noted that onion and garlic were the triggers that were most often identified.”

Limitations include the retrospective chart review design and small number of patients, which may overestimate or underestimate the study results, and the fact that the study was done at a tertiary care center, Dr. Menees said.

“We are nearing the completion of a confirmatory, prospective, pilot randomized clinical trial to confirm the efficacy of a low-FODMAP diet in patients who suffer from fecal incontinence and loose stools,” she concluded.

Dr. Menees reports being a consultant for Synergy.

Use AGA’s patient education materials to help your patients better understand the low-FODMAP diet, which can be found at http://ow.ly/Xfqj30maODu

SOURCE: Menees SB et al. ACG 2018. Presentation 9.

PHILADELPHIA – A low fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet was associated with improvement in fecal incontinence in 64.6% of patients who received dietary training, according to recent research presented at the American College of Gastroenterology annual meeting.

Jeff Craven/MDedge News

“In this case series, the low-FODMAP diet improved fecal incontinence in two-thirds of patients with fecal incontinence and loose stools,” Stacy Menees, MD, MS, assistant professor at the University of Michigan in Ann Arbor, said in her presentation.

Dr. Menees and her colleagues performed a retrospective chart review of 65 patients in the Michigan Bowel Control clinic with fecal incontinence (FI) “without alarming features” who were recommended a low FODMAP diet and received formal dietary teaching between August 2012 and December 2017. Patients received the teaching from a Michigan Medicine gastrointestinal dietitian. The dietitians performed a semi-quantitative analysis of patient response, including complete response, Dr. Menees said.

If we are going to help people with fecal incontinence, the key is to concentrate on the area of their stool consistency,” she explained. “We know that foods high in fermentable oligo-, di-, and monosaccharides and polyols, otherwise known as FODMAPS, can cause diarrhea and urgency.”

These FODMAP foods can include fruits with fructose exceeding glucose, fructan-containing vegetables, wheat-based products, sorbitol- and lactose-containing foods, and raffinose-containing foods, Dr. Menees said.

“We know from observations in data and research from the Monash University and our own group that patients with irritable bowel syndrome who are on a [low-]FODMAP diet [get relief from] their symptoms,” she added.

Most of the patients were female, and most were white. The mean age was 61.9 years, and mean body mass index was 26.7 kg/m². Among the patients, 27.7% had irritable bowel syndrome (IBS), 9.2% had inflammatory bowel disease (IBD), 16.9% had diabetes mellitus, and 20% had a prior cholecystectomy.

With regard to reports of loose stool and FI, 46.1% of patients said they had loose stool daily with a mean of 2.8 loose bowel movements daily. More than half of the patients (60.5%) reported FI daily; 37.8% said they experienced weekly FI, and 4.6% reported monthly FI. The number of patients reporting FI was higher than 100% because some patients reported in the chart that they had FI daily or weekly, Dr. Menees said.

FI improvement was reported by 64.6% of patients, with 88.1% of responders having a greater than 50% reduction in FI and 35.7% of patients experiencing complete resolution of FI. There were no serious adverse events in the study, Dr. Menees noted.

“The three patients with postinfection IBS and fecal incontinence had no response to a low-FODMAP diet,” she said. “Our dietitians noted that onion and garlic were the triggers that were most often identified.”

Limitations include the retrospective chart review design and small number of patients, which may overestimate or underestimate the study results, and the fact that the study was done at a tertiary care center, Dr. Menees said.

“We are nearing the completion of a confirmatory, prospective, pilot randomized clinical trial to confirm the efficacy of a low-FODMAP diet in patients who suffer from fecal incontinence and loose stools,” she concluded.

Dr. Menees reports being a consultant for Synergy.

Use AGA’s patient education materials to help your patients better understand the low-FODMAP diet, which can be found at http://ow.ly/Xfqj30maODu

SOURCE: Menees SB et al. ACG 2018. Presentation 9.

PHILADELPHIA – A low fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet was associated with improvement in fecal incontinence in 64.6% of patients who received dietary training, according to recent research presented at the American College of Gastroenterology annual meeting.

Jeff Craven/MDedge News

“In this case series, the low-FODMAP diet improved fecal incontinence in two-thirds of patients with fecal incontinence and loose stools,” Stacy Menees, MD, MS, assistant professor at the University of Michigan in Ann Arbor, said in her presentation.

Dr. Menees and her colleagues performed a retrospective chart review of 65 patients in the Michigan Bowel Control clinic with fecal incontinence (FI) “without alarming features” who were recommended a low FODMAP diet and received formal dietary teaching between August 2012 and December 2017. Patients received the teaching from a Michigan Medicine gastrointestinal dietitian. The dietitians performed a semi-quantitative analysis of patient response, including complete response, Dr. Menees said.

If we are going to help people with fecal incontinence, the key is to concentrate on the area of their stool consistency,” she explained. “We know that foods high in fermentable oligo-, di-, and monosaccharides and polyols, otherwise known as FODMAPS, can cause diarrhea and urgency.”

These FODMAP foods can include fruits with fructose exceeding glucose, fructan-containing vegetables, wheat-based products, sorbitol- and lactose-containing foods, and raffinose-containing foods, Dr. Menees said.

“We know from observations in data and research from the Monash University and our own group that patients with irritable bowel syndrome who are on a [low-]FODMAP diet [get relief from] their symptoms,” she added.

Most of the patients were female, and most were white. The mean age was 61.9 years, and mean body mass index was 26.7 kg/m². Among the patients, 27.7% had irritable bowel syndrome (IBS), 9.2% had inflammatory bowel disease (IBD), 16.9% had diabetes mellitus, and 20% had a prior cholecystectomy.

With regard to reports of loose stool and FI, 46.1% of patients said they had loose stool daily with a mean of 2.8 loose bowel movements daily. More than half of the patients (60.5%) reported FI daily; 37.8% said they experienced weekly FI, and 4.6% reported monthly FI. The number of patients reporting FI was higher than 100% because some patients reported in the chart that they had FI daily or weekly, Dr. Menees said.

FI improvement was reported by 64.6% of patients, with 88.1% of responders having a greater than 50% reduction in FI and 35.7% of patients experiencing complete resolution of FI. There were no serious adverse events in the study, Dr. Menees noted.

“The three patients with postinfection IBS and fecal incontinence had no response to a low-FODMAP diet,” she said. “Our dietitians noted that onion and garlic were the triggers that were most often identified.”

Limitations include the retrospective chart review design and small number of patients, which may overestimate or underestimate the study results, and the fact that the study was done at a tertiary care center, Dr. Menees said.

“We are nearing the completion of a confirmatory, prospective, pilot randomized clinical trial to confirm the efficacy of a low-FODMAP diet in patients who suffer from fecal incontinence and loose stools,” she concluded.

Dr. Menees reports being a consultant for Synergy.

Use AGA’s patient education materials to help your patients better understand the low-FODMAP diet, which can be found at http://ow.ly/Xfqj30maODu

SOURCE: Menees SB et al. ACG 2018. Presentation 9.

SAN FRANCISCO – An adjuvanted trivalent flu vaccine cuts the risk of hospitalizations in nursing home residents by about 6%, according to a new study presented at an annual scientific meeting on infectious diseases.

“It’s one thing to say you have a more immunogenic vaccine, it’s another thing to be able to say it offers clinical benefit, especially in the oldest old and the frailest frail,” says Stefan Gravenstein, MD, professor of medicine and health services, policy and practice at the Brown University School of Public Health, Providence, R.I. Dr. Gravenstein presented a poster outlying a randomized, clinical trial of the Fluad vaccine in nursing homes.

The study randomized the nursing homes so that some facilities would offer Fluad as part of their standard of care. The design helped address the problem of consent. Any clinical trial that requires individual consent would likely exclude many of the frailest patients, leading to an unrepresentative sample. “So if you want to have a generalizable result, you’d like to have it applied to the population the way you would in the real world, so randomizing the nursing homes rather than the people makes a lot of sense,” said Dr. Gravenstein.

Dr. Gravenstein chose to test the vaccine in nursing home residents, hoping to see a signal in a population in which flu complications are more common. “If you can get a difference in a nursing home population, that’s clinically important, that gives you hope that you can see it in all the other populations, too,” he said.

SOURCE: Gravenstein S et al. IDWeek 2018, Abstract 996.

SAN FRANCISCO – An adjuvanted trivalent flu vaccine cuts the risk of hospitalizations in nursing home residents by about 6%, according to a new study presented at an annual scientific meeting on infectious diseases.

“It’s one thing to say you have a more immunogenic vaccine, it’s another thing to be able to say it offers clinical benefit, especially in the oldest old and the frailest frail,” says Stefan Gravenstein, MD, professor of medicine and health services, policy and practice at the Brown University School of Public Health, Providence, R.I. Dr. Gravenstein presented a poster outlying a randomized, clinical trial of the Fluad vaccine in nursing homes.

The study randomized the nursing homes so that some facilities would offer Fluad as part of their standard of care. The design helped address the problem of consent. Any clinical trial that requires individual consent would likely exclude many of the frailest patients, leading to an unrepresentative sample. “So if you want to have a generalizable result, you’d like to have it applied to the population the way you would in the real world, so randomizing the nursing homes rather than the people makes a lot of sense,” said Dr. Gravenstein.

Dr. Gravenstein chose to test the vaccine in nursing home residents, hoping to see a signal in a population in which flu complications are more common. “If you can get a difference in a nursing home population, that’s clinically important, that gives you hope that you can see it in all the other populations, too,” he said.

SOURCE: Gravenstein S et al. IDWeek 2018, Abstract 996.

SAN FRANCISCO – An adjuvanted trivalent flu vaccine cuts the risk of hospitalizations in nursing home residents by about 6%, according to a new study presented at an annual scientific meeting on infectious diseases.

“It’s one thing to say you have a more immunogenic vaccine, it’s another thing to be able to say it offers clinical benefit, especially in the oldest old and the frailest frail,” says Stefan Gravenstein, MD, professor of medicine and health services, policy and practice at the Brown University School of Public Health, Providence, R.I. Dr. Gravenstein presented a poster outlying a randomized, clinical trial of the Fluad vaccine in nursing homes.

The study randomized the nursing homes so that some facilities would offer Fluad as part of their standard of care. The design helped address the problem of consent. Any clinical trial that requires individual consent would likely exclude many of the frailest patients, leading to an unrepresentative sample. “So if you want to have a generalizable result, you’d like to have it applied to the population the way you would in the real world, so randomizing the nursing homes rather than the people makes a lot of sense,” said Dr. Gravenstein.

Dr. Gravenstein chose to test the vaccine in nursing home residents, hoping to see a signal in a population in which flu complications are more common. “If you can get a difference in a nursing home population, that’s clinically important, that gives you hope that you can see it in all the other populations, too,” he said.

SOURCE: Gravenstein S et al. IDWeek 2018, Abstract 996.

Menopausal women with dyspareunia who received a bioidentical estradiol vaginal insert experienced no cardiovascular or breast effects that would suggest significant systemic absorption.

The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.

These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.

TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.

The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.

Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.

The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.

In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m². African American women made up 12% of the study; the remainder of the women were white.

In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.

Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.

Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.

Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.

Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.

“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.

The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.

[email protected]

SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.

Menopausal women with dyspareunia who received a bioidentical estradiol vaginal insert experienced no cardiovascular or breast effects that would suggest significant systemic absorption.

The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.

These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.

TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.

The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.

Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.

The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.

In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m². African American women made up 12% of the study; the remainder of the women were white.

In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.

Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.

Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.

Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.

Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.

“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.

The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.

[email protected]

SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.

Menopausal women with dyspareunia who received a bioidentical estradiol vaginal insert experienced no cardiovascular or breast effects that would suggest significant systemic absorption.

The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.

These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.

TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.

The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.

Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.

The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.

In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m². African American women made up 12% of the study; the remainder of the women were white.

In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.

Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.

Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.

Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.

Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.

“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.

The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.

[email protected]

SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.

In Episode 26, Lorenzo Norris, MD, welcomes Carl C. Bell, MD, for part 1 of 2 of a conversation about fetal alcohol spectrum disorder at the 2018 annual IPS Mental Health Services Conference. And later, Dr. Renee Kohanski discusses the Frye Test.

In Episode 26, Lorenzo Norris, MD, welcomes Carl C. Bell, MD, for part 1 of 2 of a conversation about fetal alcohol spectrum disorder at the 2018 annual IPS Mental Health Services Conference. And later, Dr. Renee Kohanski discusses the Frye Test.

In Episode 26, Lorenzo Norris, MD, welcomes Carl C. Bell, MD, for part 1 of 2 of a conversation about fetal alcohol spectrum disorder at the 2018 annual IPS Mental Health Services Conference. And later, Dr. Renee Kohanski discusses the Frye Test.