Opioid Resource Center

In a year when emergency department visits dropped by almost 18%, visits for benzodiazepine overdoses did the opposite, according to a report from the Centers for Disease Control and Prevention.

The actual increase in the number of overdose visits for benzodiazepine overdoses was quite small – from 15,547 in 2019 to 15,830 in 2020 (1.8%) – but the 11 million fewer ED visits magnified its effect, Stephen Liu, PhD, and associates said in the Morbidity and Mortality Weekly Report.

The rate of benzodiazepine overdose visits to all visits increased by 23.7% from 2019 (24.22 per 100,000 ED visits) to 2020 (29.97 per 100,000), with the larger share going to those involving opioids, which were up by 34.4%, compared with overdose visits not involving opioids (21.0%), the investigators said, based on data reported by 32 states and the District of Columbia to the CDC’s Drug Overdose Surveillance and Epidemiology system. All of the rate changes are statistically significant.

The number of overdose visits without opioid coinvolvement actually dropped, from 2019 (12,276) to 2020 (12,218), but not by enough to offset the decline in total visits, noted Dr. Liu, of the CDC’s National Center for Injury Prevention and Control and associates.

The number of deaths from benzodiazepine overdose, on the other hand, did not drop in 2020. Those data, coming from 23 states participating in the CDC’s State Unintentional Drug Overdose Reporting System, were available only for the first half of the year.

In those 6 months, benzodiazepines were involved in more than 2,700 overdose deaths, with second-quarter deaths increasing by 43% from 2019 (1,004) to 2020 (1,435). The first quarter of 2020 also showed an increase, but exact numbers were not provided in the report. Overdose deaths rose by 22% for prescription forms of benzodiazepine and 520% for illicit forms in Q2 of 2020, compared with 2019, the researchers said.

Almost all of the benzodiazepine deaths (93%) in the first half of 2020 also involved opioids, mostly in the form of illicitly manufactured fentanyls (67% of all deaths). Between Q2 of 2019 and Q2 of 2020, involvement of illicit fentanyls in benzodiazepine overdose deaths increased from almost 57% to 71%, Dr. Liu and associates reported.

“Despite progress in reducing coprescribing [of opioids and benzodiazepines] before 2019, this study suggests a reversal in the decline in benzodiazepine deaths from 2017 to 2019, driven in part by increasing involvement of [illicitly manufactured fentanyls] in benzodiazepine deaths and influxes of illicit benzodiazepines,” they wrote.

rfranki@mdedge.com

In a year when emergency department visits dropped by almost 18%, visits for benzodiazepine overdoses did the opposite, according to a report from the Centers for Disease Control and Prevention.

The actual increase in the number of overdose visits for benzodiazepine overdoses was quite small – from 15,547 in 2019 to 15,830 in 2020 (1.8%) – but the 11 million fewer ED visits magnified its effect, Stephen Liu, PhD, and associates said in the Morbidity and Mortality Weekly Report.

The rate of benzodiazepine overdose visits to all visits increased by 23.7% from 2019 (24.22 per 100,000 ED visits) to 2020 (29.97 per 100,000), with the larger share going to those involving opioids, which were up by 34.4%, compared with overdose visits not involving opioids (21.0%), the investigators said, based on data reported by 32 states and the District of Columbia to the CDC’s Drug Overdose Surveillance and Epidemiology system. All of the rate changes are statistically significant.

The number of overdose visits without opioid coinvolvement actually dropped, from 2019 (12,276) to 2020 (12,218), but not by enough to offset the decline in total visits, noted Dr. Liu, of the CDC’s National Center for Injury Prevention and Control and associates.

The number of deaths from benzodiazepine overdose, on the other hand, did not drop in 2020. Those data, coming from 23 states participating in the CDC’s State Unintentional Drug Overdose Reporting System, were available only for the first half of the year.

In those 6 months, benzodiazepines were involved in more than 2,700 overdose deaths, with second-quarter deaths increasing by 43% from 2019 (1,004) to 2020 (1,435). The first quarter of 2020 also showed an increase, but exact numbers were not provided in the report. Overdose deaths rose by 22% for prescription forms of benzodiazepine and 520% for illicit forms in Q2 of 2020, compared with 2019, the researchers said.

Almost all of the benzodiazepine deaths (93%) in the first half of 2020 also involved opioids, mostly in the form of illicitly manufactured fentanyls (67% of all deaths). Between Q2 of 2019 and Q2 of 2020, involvement of illicit fentanyls in benzodiazepine overdose deaths increased from almost 57% to 71%, Dr. Liu and associates reported.

“Despite progress in reducing coprescribing [of opioids and benzodiazepines] before 2019, this study suggests a reversal in the decline in benzodiazepine deaths from 2017 to 2019, driven in part by increasing involvement of [illicitly manufactured fentanyls] in benzodiazepine deaths and influxes of illicit benzodiazepines,” they wrote.

rfranki@mdedge.com

In a year when emergency department visits dropped by almost 18%, visits for benzodiazepine overdoses did the opposite, according to a report from the Centers for Disease Control and Prevention.

The actual increase in the number of overdose visits for benzodiazepine overdoses was quite small – from 15,547 in 2019 to 15,830 in 2020 (1.8%) – but the 11 million fewer ED visits magnified its effect, Stephen Liu, PhD, and associates said in the Morbidity and Mortality Weekly Report.

The rate of benzodiazepine overdose visits to all visits increased by 23.7% from 2019 (24.22 per 100,000 ED visits) to 2020 (29.97 per 100,000), with the larger share going to those involving opioids, which were up by 34.4%, compared with overdose visits not involving opioids (21.0%), the investigators said, based on data reported by 32 states and the District of Columbia to the CDC’s Drug Overdose Surveillance and Epidemiology system. All of the rate changes are statistically significant.

The number of overdose visits without opioid coinvolvement actually dropped, from 2019 (12,276) to 2020 (12,218), but not by enough to offset the decline in total visits, noted Dr. Liu, of the CDC’s National Center for Injury Prevention and Control and associates.

The number of deaths from benzodiazepine overdose, on the other hand, did not drop in 2020. Those data, coming from 23 states participating in the CDC’s State Unintentional Drug Overdose Reporting System, were available only for the first half of the year.

In those 6 months, benzodiazepines were involved in more than 2,700 overdose deaths, with second-quarter deaths increasing by 43% from 2019 (1,004) to 2020 (1,435). The first quarter of 2020 also showed an increase, but exact numbers were not provided in the report. Overdose deaths rose by 22% for prescription forms of benzodiazepine and 520% for illicit forms in Q2 of 2020, compared with 2019, the researchers said.

Almost all of the benzodiazepine deaths (93%) in the first half of 2020 also involved opioids, mostly in the form of illicitly manufactured fentanyls (67% of all deaths). Between Q2 of 2019 and Q2 of 2020, involvement of illicit fentanyls in benzodiazepine overdose deaths increased from almost 57% to 71%, Dr. Liu and associates reported.

“Despite progress in reducing coprescribing [of opioids and benzodiazepines] before 2019, this study suggests a reversal in the decline in benzodiazepine deaths from 2017 to 2019, driven in part by increasing involvement of [illicitly manufactured fentanyls] in benzodiazepine deaths and influxes of illicit benzodiazepines,” they wrote.

rfranki@mdedge.com

State laws capping initial opioid prescriptions to 7 days or less have led to a reduction in opioid prescribing, a new analysis of Medicare data shows.

While overall opioid prescribing has decreased, the reduction in states with legislation restricting opioid prescribing was “significantly greater than in states without such legislation,” study investigator Michael Brenner, MD, University of Michigan, Ann Arbor, said in an interview.

The study was published online August 9 in JAMA Internal Medicine.
 

Significant but limited effect

Because of rising concern around the opioid crisis, 23 states representing 43% of the U.S. population passed laws from 2016 through 2018 limiting initial opioid prescription to 7 days or less.

Using Medicare data from 2013 through 2018, Dr. Brenner and colleagues conducted a before-and-after study to assess the effect of these laws.

They found that on average, the number of days an opioid was prescribed for each Medicare beneficiary decreased by 11.6 days (from 44.2 days in 2013 to 32.7 days in 2018) in states that imposed duration limits, compared with 10.1 days in states without these laws (from 43.4 days in 2013 to 33.3 days in 2018).

Prior to the start of duration limits in 2016, days an opioid was prescribed were comparable among states.

After adjusting for state-level differences in race, urbanization, median income, tobacco and alcohol use, serious mental illness, and other factors, state laws limiting opioid prescriptions to 7 days or less were associated with a reduction in prescribing of 1.7 days per enrollee, “suggesting a significant but limited outcome” for these laws, the researchers note.

The largest decrease in opioid prescribing occurred in primary care, but this was not significantly different in states with limit laws versus those without. However, state laws limiting duration led to a significant reduction in days of opioid prescribed among surgeons, dentists, pain specialists, and other specialists.
 

Inadequate pain control?

The researchers note the study was limited to Medicare beneficiaries; however, excess opioid prescribing is prevalent across all patient populations.

In addition, it’s not possible to tell from the data whether acute pain was adequately controlled with fewer pills.

“The question of adequacy of pain control is a crucial one that has been investigated extensively in prior work but was not possible to evaluate in this particular study,” said Dr. Brenner.

However, “ample evidence supports a role for reducing opioid prescribing and that such reduction can be achieved while ensuring that pain is adequately controlled with fewer pills,” he noted.

“A persistent misconception is that opioids are uniquely powerful and effective for controlling pain. Patients may perceive that effective analgesia is being withheld when opioids are not included in a regimen,” Dr. Brenner added.

“Yet, the evidence from meta-analyses derived from large numbers of randomized clinical trials finds that [nonsteroidal anti-inflammatory drugs] NSAIDS combined with acetaminophen provide similar or improved acute pain when compared to commonly prescribed opioid regimens, based on number-needed-to-treat analyses,” he added.

In a related editorial, Deborah Grady, MD, MPH, with University of California, San Francisco, and Mitchell H. Katz, MD, president and CEO of NYC Health + Hospitals, say the decrease in opioid prescribing with duration limits was “small but probably meaningful.” 

Restricting initial prescriptions to seven or fewer days is “reasonable because patients with new onset of pain should be re-evaluated in a week if the pain continues,” they write. 

However, Dr. Grady and Dr. Katz “worry” that restricting initial prescriptions to shorter periods, such as 3 or 5 days, as has occurred in six states, “may result in patients with acute pain going untreated or having to go to extraordinary effort to obtain adequate pain relief.”

In their view, the data from this study suggest that limiting initial prescriptions to seven or fewer days is “helpful, but we would not restrict any further given that we do not know how it affected patients with acute pain.”

The study had no specific funding. Dr. Brenner, Dr. Grady, and Dr. Katz have disclosed no relevant financial relationships.

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

State laws capping initial opioid prescriptions to 7 days or less have led to a reduction in opioid prescribing, a new analysis of Medicare data shows.

While overall opioid prescribing has decreased, the reduction in states with legislation restricting opioid prescribing was “significantly greater than in states without such legislation,” study investigator Michael Brenner, MD, University of Michigan, Ann Arbor, said in an interview.

The study was published online August 9 in JAMA Internal Medicine.
 

Significant but limited effect

Because of rising concern around the opioid crisis, 23 states representing 43% of the U.S. population passed laws from 2016 through 2018 limiting initial opioid prescription to 7 days or less.

Using Medicare data from 2013 through 2018, Dr. Brenner and colleagues conducted a before-and-after study to assess the effect of these laws.

They found that on average, the number of days an opioid was prescribed for each Medicare beneficiary decreased by 11.6 days (from 44.2 days in 2013 to 32.7 days in 2018) in states that imposed duration limits, compared with 10.1 days in states without these laws (from 43.4 days in 2013 to 33.3 days in 2018).

Prior to the start of duration limits in 2016, days an opioid was prescribed were comparable among states.

After adjusting for state-level differences in race, urbanization, median income, tobacco and alcohol use, serious mental illness, and other factors, state laws limiting opioid prescriptions to 7 days or less were associated with a reduction in prescribing of 1.7 days per enrollee, “suggesting a significant but limited outcome” for these laws, the researchers note.

The largest decrease in opioid prescribing occurred in primary care, but this was not significantly different in states with limit laws versus those without. However, state laws limiting duration led to a significant reduction in days of opioid prescribed among surgeons, dentists, pain specialists, and other specialists.
 

Inadequate pain control?

The researchers note the study was limited to Medicare beneficiaries; however, excess opioid prescribing is prevalent across all patient populations.

In addition, it’s not possible to tell from the data whether acute pain was adequately controlled with fewer pills.

“The question of adequacy of pain control is a crucial one that has been investigated extensively in prior work but was not possible to evaluate in this particular study,” said Dr. Brenner.

However, “ample evidence supports a role for reducing opioid prescribing and that such reduction can be achieved while ensuring that pain is adequately controlled with fewer pills,” he noted.

“A persistent misconception is that opioids are uniquely powerful and effective for controlling pain. Patients may perceive that effective analgesia is being withheld when opioids are not included in a regimen,” Dr. Brenner added.

“Yet, the evidence from meta-analyses derived from large numbers of randomized clinical trials finds that [nonsteroidal anti-inflammatory drugs] NSAIDS combined with acetaminophen provide similar or improved acute pain when compared to commonly prescribed opioid regimens, based on number-needed-to-treat analyses,” he added.

In a related editorial, Deborah Grady, MD, MPH, with University of California, San Francisco, and Mitchell H. Katz, MD, president and CEO of NYC Health + Hospitals, say the decrease in opioid prescribing with duration limits was “small but probably meaningful.” 

Restricting initial prescriptions to seven or fewer days is “reasonable because patients with new onset of pain should be re-evaluated in a week if the pain continues,” they write. 

However, Dr. Grady and Dr. Katz “worry” that restricting initial prescriptions to shorter periods, such as 3 or 5 days, as has occurred in six states, “may result in patients with acute pain going untreated or having to go to extraordinary effort to obtain adequate pain relief.”

In their view, the data from this study suggest that limiting initial prescriptions to seven or fewer days is “helpful, but we would not restrict any further given that we do not know how it affected patients with acute pain.”

The study had no specific funding. Dr. Brenner, Dr. Grady, and Dr. Katz have disclosed no relevant financial relationships.

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

State laws capping initial opioid prescriptions to 7 days or less have led to a reduction in opioid prescribing, a new analysis of Medicare data shows.

While overall opioid prescribing has decreased, the reduction in states with legislation restricting opioid prescribing was “significantly greater than in states without such legislation,” study investigator Michael Brenner, MD, University of Michigan, Ann Arbor, said in an interview.

The study was published online August 9 in JAMA Internal Medicine.
 

Significant but limited effect

Because of rising concern around the opioid crisis, 23 states representing 43% of the U.S. population passed laws from 2016 through 2018 limiting initial opioid prescription to 7 days or less.

Using Medicare data from 2013 through 2018, Dr. Brenner and colleagues conducted a before-and-after study to assess the effect of these laws.

They found that on average, the number of days an opioid was prescribed for each Medicare beneficiary decreased by 11.6 days (from 44.2 days in 2013 to 32.7 days in 2018) in states that imposed duration limits, compared with 10.1 days in states without these laws (from 43.4 days in 2013 to 33.3 days in 2018).

Prior to the start of duration limits in 2016, days an opioid was prescribed were comparable among states.

After adjusting for state-level differences in race, urbanization, median income, tobacco and alcohol use, serious mental illness, and other factors, state laws limiting opioid prescriptions to 7 days or less were associated with a reduction in prescribing of 1.7 days per enrollee, “suggesting a significant but limited outcome” for these laws, the researchers note.

The largest decrease in opioid prescribing occurred in primary care, but this was not significantly different in states with limit laws versus those without. However, state laws limiting duration led to a significant reduction in days of opioid prescribed among surgeons, dentists, pain specialists, and other specialists.
 

Inadequate pain control?

The researchers note the study was limited to Medicare beneficiaries; however, excess opioid prescribing is prevalent across all patient populations.

In addition, it’s not possible to tell from the data whether acute pain was adequately controlled with fewer pills.

“The question of adequacy of pain control is a crucial one that has been investigated extensively in prior work but was not possible to evaluate in this particular study,” said Dr. Brenner.

However, “ample evidence supports a role for reducing opioid prescribing and that such reduction can be achieved while ensuring that pain is adequately controlled with fewer pills,” he noted.

“A persistent misconception is that opioids are uniquely powerful and effective for controlling pain. Patients may perceive that effective analgesia is being withheld when opioids are not included in a regimen,” Dr. Brenner added.

“Yet, the evidence from meta-analyses derived from large numbers of randomized clinical trials finds that [nonsteroidal anti-inflammatory drugs] NSAIDS combined with acetaminophen provide similar or improved acute pain when compared to commonly prescribed opioid regimens, based on number-needed-to-treat analyses,” he added.

In a related editorial, Deborah Grady, MD, MPH, with University of California, San Francisco, and Mitchell H. Katz, MD, president and CEO of NYC Health + Hospitals, say the decrease in opioid prescribing with duration limits was “small but probably meaningful.” 

Restricting initial prescriptions to seven or fewer days is “reasonable because patients with new onset of pain should be re-evaluated in a week if the pain continues,” they write. 

However, Dr. Grady and Dr. Katz “worry” that restricting initial prescriptions to shorter periods, such as 3 or 5 days, as has occurred in six states, “may result in patients with acute pain going untreated or having to go to extraordinary effort to obtain adequate pain relief.”

In their view, the data from this study suggest that limiting initial prescriptions to seven or fewer days is “helpful, but we would not restrict any further given that we do not know how it affected patients with acute pain.”

The study had no specific funding. Dr. Brenner, Dr. Grady, and Dr. Katz have disclosed no relevant financial relationships.

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

Terminally ill patients with advanced cancer may not be receiving adequate pain management, according to new findings.

There has been a sharp decrease in access to opioids during the past decade, and many patients are going to emergency departments for pain treatment.

Overall, during the study period (2007-2017), there was a 34% reduction in the number of opioid prescriptions filled per patient and a 38% reduction in the total dose of opioids filled near the end of life.

There was a dramatic drop in the use of long-acting opioids, which can provide patients with more consistent pain relief and are important for managing severe cancer pain. The investigators’ results show that during the study period, the number of long-acting opioid prescriptions filled per patient fell by 50%.

“We do believe that the decline in cancer patients’ access to opioids near the end of life is likely attributable to the efforts to curtail opioid misuse,” commented lead author Andrea Enzinger, MD, a medical oncologist at Dana-Farber Cancer Institute, Boston.

The study was published online July 22 in the Journal of Clinical Oncology.

“The study provides fascinating data that support our clinical observations,” said Marcin Chwistek, MD, FAAHPM, director of the supportive oncology and palliative care program at Fox Chase Cancer Center, Philadelphia, who was asked for comment. “Primarily, we have noticed a heightened reluctance on the parts of patients with cancer, including those with advanced cancer, to take opioids in general.”
 

Many factors involved

The crisis of opioid misuse and abuse led to the implementation of regulations to curb inappropriate prescribing. But these restrictions on opioid prescribing may have unintended consequences for patients with advanced, incurable malignancies who are experiencing pain.

“Many but not all opioid regulations specifically exclude cancer patients,” said Dr. Enzinger. “However, the cumulative effect of these regulations may have had a chilling effect on providers’ comfort or willingness to prescribe opioids, even for cancer pain.”

She said in an interview that the prescribing of opioids has become much more difficult. Prescribers are often required to sign an opioid agreement with patients prior to providing them with opioids. Health care professionals may need to use a two-factor authentication to prescribe, and prescribers in 49 of 50 U.S. states are required to check electronic prescription drug monitoring programs prior to providing the prescription.

“After the medications are prescribed, insurance companies require prior-authorization paperwork before filling the medications, particularly for long-acting opioids or high-dose opioids,” Dr. Enzinger said. “These barriers pile up and make the whole process onerous and time consuming.”

Patient factors may also have contributed to the decline in use.

“Cancer patients are often very hesitant to use opioids to treat their pain, as they worry about becoming addicted or being labeled a ‘pill seeker,’” she explained. “Also, the added regulations, such as requirements for prior authorization paperwork, signing opioid agreements, and so on, may add to the stigma of opioid therapy and send a message to patients that these medications are inherently dangerous.”

Dr. Enzinger added that there are legitimate reasons why patients may not want to use opioids and that these should be respected. “But addiction risk should really not weigh into the decisions about pain management for patients who are dying from cancer,” she said.
 

Decline in opioid dose and prescriptions

Dr. Enzinger and colleagues used administrative data from the Centers for Medicare & Medicaid Services to identify 270,632 Medicare fee-for-service patients who had cancers that were associated with poor prognoses and who died from 2007 to 2017. During this period, the opioid crisis was first recognized. There followed legislative reforms and subsequent declines in population-based opioid prescribing.

Among the patients in the study, the most common cancers were lung, colorectal, pancreatic, prostate, and breast cancers; 166,962 patients (61.7%) were enrolled in hospice before death. This percentage increased from 57.1% in 2007 to 66.2% in 2017 (P for trend < .001).

From 2007 to 2017, the proportion of patients filling greater than or equal to 1 opioid prescriptions declined from 42.0% to 35.5%. The proportion declined faster from 2012-2017 than from 2007-2011.

The proportion of patients who filled prescriptions for long-acting opioids dropped from 18.1% to 11.5%. Here again, the decline was faster from 2012-2017 than from 2007-2011. Prescriptions for strong short-acting opioids declined from 31.7% to 28.5%. Prescribing was initially stable from 2007-2011 and began to decline in 2012. Conversely, prescriptions for weak short-acting opioids dropped from 8.4% to 6.5% from 2007-2011 and then stabilized after 2012.

The mean daily dose fell 24.5%, from 85.6 morphine milligram equivalents per day (MMED) to 64.6 MMED. Overall, the total amount of opioids prescribed per decedent fell 38.0%, from 1,075 MMEs per person to 666 MMEs.

At the same time, the proportion of patients who visited EDs increased 50.8%, from 13.2% to 19.9%.
 

Experts weigh in

Approached for an independent comment, Amit Barochia, MD, a hematologist/oncologist with Health First Medical Group, Titusville, Fla., commented that the decline could be due, in part, to greater vigilance and awareness by physicians in light of more stringent requirements and of federal and state regulations. “Some physicians are avoiding prescribing opioids due to more regulations and requirements as well, which is routing patients to the ER for pain relief,” he said.

Dr. Barochia agreed that some of the decline could be due to patient factors. “I do think that some of the patients are hesitant about considering opioid use for better pain relief, in part due to fear of addiction as well as complications arising from their use,” he said. “This is likely resulting from more awareness in the community about their adverse effects.

“That awareness could come from aggressive media coverage as well as social media,” he continued. “It is also true that there is a difficulty in getting authorization for certain opioid products, which is delaying the onset of a proper pain regimen that would help to provide adequate pain relief early on.”

For patients with advanced cancer, earlier referral to palliative care would be beneficial, Dr. Barochia pointed out, because this would allow for a more in-depth discussion about pain in addition to addressing the physical and mental symptoms associated with cancer.

Fox Chase Cancer Center’s Dr. Chwistek noted that patients and their caregivers are often apprehensive about the potential adverse effects of opioids, because they often hear about community-based opioid overdoses and are fearful of taking the medications. “Additionally, it has become increasingly challenging to fill opioid prescriptions at local pharmacies, due to quantity limitations, ubiquitous need for prior authorizations, and stigma,” he said.

The fear of addiction is often brought up by the patients during clinic visits, and insurers and pharmacies have imposed many limits on opioid prescribing. “Most of these can be overcome with prior authorizations, but not always, and prior authorizations are time consuming, confusing, and very frustrating for patients,” he said in an interview.

These findings suggest that not enough patients are getting optimal palliative care. “One of the primary tenets of palliative care is optimal symptom control, including pain,” said Dr. Chwistek. “Palliative care teams have the experience and insight needed to help patients overcome the barriers to appropriate pain control. Education, support, and advocacy are critical to ensure that patients’ pain is appropriately addressed.”

The study was funded by a grant from the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services.

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

Terminally ill patients with advanced cancer may not be receiving adequate pain management, according to new findings.

There has been a sharp decrease in access to opioids during the past decade, and many patients are going to emergency departments for pain treatment.

Overall, during the study period (2007-2017), there was a 34% reduction in the number of opioid prescriptions filled per patient and a 38% reduction in the total dose of opioids filled near the end of life.

There was a dramatic drop in the use of long-acting opioids, which can provide patients with more consistent pain relief and are important for managing severe cancer pain. The investigators’ results show that during the study period, the number of long-acting opioid prescriptions filled per patient fell by 50%.

“We do believe that the decline in cancer patients’ access to opioids near the end of life is likely attributable to the efforts to curtail opioid misuse,” commented lead author Andrea Enzinger, MD, a medical oncologist at Dana-Farber Cancer Institute, Boston.

The study was published online July 22 in the Journal of Clinical Oncology.

“The study provides fascinating data that support our clinical observations,” said Marcin Chwistek, MD, FAAHPM, director of the supportive oncology and palliative care program at Fox Chase Cancer Center, Philadelphia, who was asked for comment. “Primarily, we have noticed a heightened reluctance on the parts of patients with cancer, including those with advanced cancer, to take opioids in general.”
 

Many factors involved

The crisis of opioid misuse and abuse led to the implementation of regulations to curb inappropriate prescribing. But these restrictions on opioid prescribing may have unintended consequences for patients with advanced, incurable malignancies who are experiencing pain.

“Many but not all opioid regulations specifically exclude cancer patients,” said Dr. Enzinger. “However, the cumulative effect of these regulations may have had a chilling effect on providers’ comfort or willingness to prescribe opioids, even for cancer pain.”

She said in an interview that the prescribing of opioids has become much more difficult. Prescribers are often required to sign an opioid agreement with patients prior to providing them with opioids. Health care professionals may need to use a two-factor authentication to prescribe, and prescribers in 49 of 50 U.S. states are required to check electronic prescription drug monitoring programs prior to providing the prescription.

“After the medications are prescribed, insurance companies require prior-authorization paperwork before filling the medications, particularly for long-acting opioids or high-dose opioids,” Dr. Enzinger said. “These barriers pile up and make the whole process onerous and time consuming.”

Patient factors may also have contributed to the decline in use.

“Cancer patients are often very hesitant to use opioids to treat their pain, as they worry about becoming addicted or being labeled a ‘pill seeker,’” she explained. “Also, the added regulations, such as requirements for prior authorization paperwork, signing opioid agreements, and so on, may add to the stigma of opioid therapy and send a message to patients that these medications are inherently dangerous.”

Dr. Enzinger added that there are legitimate reasons why patients may not want to use opioids and that these should be respected. “But addiction risk should really not weigh into the decisions about pain management for patients who are dying from cancer,” she said.
 

Decline in opioid dose and prescriptions

Dr. Enzinger and colleagues used administrative data from the Centers for Medicare & Medicaid Services to identify 270,632 Medicare fee-for-service patients who had cancers that were associated with poor prognoses and who died from 2007 to 2017. During this period, the opioid crisis was first recognized. There followed legislative reforms and subsequent declines in population-based opioid prescribing.

Among the patients in the study, the most common cancers were lung, colorectal, pancreatic, prostate, and breast cancers; 166,962 patients (61.7%) were enrolled in hospice before death. This percentage increased from 57.1% in 2007 to 66.2% in 2017 (P for trend < .001).

From 2007 to 2017, the proportion of patients filling greater than or equal to 1 opioid prescriptions declined from 42.0% to 35.5%. The proportion declined faster from 2012-2017 than from 2007-2011.

The proportion of patients who filled prescriptions for long-acting opioids dropped from 18.1% to 11.5%. Here again, the decline was faster from 2012-2017 than from 2007-2011. Prescriptions for strong short-acting opioids declined from 31.7% to 28.5%. Prescribing was initially stable from 2007-2011 and began to decline in 2012. Conversely, prescriptions for weak short-acting opioids dropped from 8.4% to 6.5% from 2007-2011 and then stabilized after 2012.

The mean daily dose fell 24.5%, from 85.6 morphine milligram equivalents per day (MMED) to 64.6 MMED. Overall, the total amount of opioids prescribed per decedent fell 38.0%, from 1,075 MMEs per person to 666 MMEs.

At the same time, the proportion of patients who visited EDs increased 50.8%, from 13.2% to 19.9%.
 

Experts weigh in

Approached for an independent comment, Amit Barochia, MD, a hematologist/oncologist with Health First Medical Group, Titusville, Fla., commented that the decline could be due, in part, to greater vigilance and awareness by physicians in light of more stringent requirements and of federal and state regulations. “Some physicians are avoiding prescribing opioids due to more regulations and requirements as well, which is routing patients to the ER for pain relief,” he said.

Dr. Barochia agreed that some of the decline could be due to patient factors. “I do think that some of the patients are hesitant about considering opioid use for better pain relief, in part due to fear of addiction as well as complications arising from their use,” he said. “This is likely resulting from more awareness in the community about their adverse effects.

“That awareness could come from aggressive media coverage as well as social media,” he continued. “It is also true that there is a difficulty in getting authorization for certain opioid products, which is delaying the onset of a proper pain regimen that would help to provide adequate pain relief early on.”

For patients with advanced cancer, earlier referral to palliative care would be beneficial, Dr. Barochia pointed out, because this would allow for a more in-depth discussion about pain in addition to addressing the physical and mental symptoms associated with cancer.

Fox Chase Cancer Center’s Dr. Chwistek noted that patients and their caregivers are often apprehensive about the potential adverse effects of opioids, because they often hear about community-based opioid overdoses and are fearful of taking the medications. “Additionally, it has become increasingly challenging to fill opioid prescriptions at local pharmacies, due to quantity limitations, ubiquitous need for prior authorizations, and stigma,” he said.

The fear of addiction is often brought up by the patients during clinic visits, and insurers and pharmacies have imposed many limits on opioid prescribing. “Most of these can be overcome with prior authorizations, but not always, and prior authorizations are time consuming, confusing, and very frustrating for patients,” he said in an interview.

These findings suggest that not enough patients are getting optimal palliative care. “One of the primary tenets of palliative care is optimal symptom control, including pain,” said Dr. Chwistek. “Palliative care teams have the experience and insight needed to help patients overcome the barriers to appropriate pain control. Education, support, and advocacy are critical to ensure that patients’ pain is appropriately addressed.”

The study was funded by a grant from the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services.

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

Terminally ill patients with advanced cancer may not be receiving adequate pain management, according to new findings.

There has been a sharp decrease in access to opioids during the past decade, and many patients are going to emergency departments for pain treatment.

Overall, during the study period (2007-2017), there was a 34% reduction in the number of opioid prescriptions filled per patient and a 38% reduction in the total dose of opioids filled near the end of life.

There was a dramatic drop in the use of long-acting opioids, which can provide patients with more consistent pain relief and are important for managing severe cancer pain. The investigators’ results show that during the study period, the number of long-acting opioid prescriptions filled per patient fell by 50%.

“We do believe that the decline in cancer patients’ access to opioids near the end of life is likely attributable to the efforts to curtail opioid misuse,” commented lead author Andrea Enzinger, MD, a medical oncologist at Dana-Farber Cancer Institute, Boston.

The study was published online July 22 in the Journal of Clinical Oncology.

“The study provides fascinating data that support our clinical observations,” said Marcin Chwistek, MD, FAAHPM, director of the supportive oncology and palliative care program at Fox Chase Cancer Center, Philadelphia, who was asked for comment. “Primarily, we have noticed a heightened reluctance on the parts of patients with cancer, including those with advanced cancer, to take opioids in general.”
 

Many factors involved

The crisis of opioid misuse and abuse led to the implementation of regulations to curb inappropriate prescribing. But these restrictions on opioid prescribing may have unintended consequences for patients with advanced, incurable malignancies who are experiencing pain.

“Many but not all opioid regulations specifically exclude cancer patients,” said Dr. Enzinger. “However, the cumulative effect of these regulations may have had a chilling effect on providers’ comfort or willingness to prescribe opioids, even for cancer pain.”

She said in an interview that the prescribing of opioids has become much more difficult. Prescribers are often required to sign an opioid agreement with patients prior to providing them with opioids. Health care professionals may need to use a two-factor authentication to prescribe, and prescribers in 49 of 50 U.S. states are required to check electronic prescription drug monitoring programs prior to providing the prescription.

“After the medications are prescribed, insurance companies require prior-authorization paperwork before filling the medications, particularly for long-acting opioids or high-dose opioids,” Dr. Enzinger said. “These barriers pile up and make the whole process onerous and time consuming.”

Patient factors may also have contributed to the decline in use.

“Cancer patients are often very hesitant to use opioids to treat their pain, as they worry about becoming addicted or being labeled a ‘pill seeker,’” she explained. “Also, the added regulations, such as requirements for prior authorization paperwork, signing opioid agreements, and so on, may add to the stigma of opioid therapy and send a message to patients that these medications are inherently dangerous.”

Dr. Enzinger added that there are legitimate reasons why patients may not want to use opioids and that these should be respected. “But addiction risk should really not weigh into the decisions about pain management for patients who are dying from cancer,” she said.
 

Decline in opioid dose and prescriptions

Dr. Enzinger and colleagues used administrative data from the Centers for Medicare & Medicaid Services to identify 270,632 Medicare fee-for-service patients who had cancers that were associated with poor prognoses and who died from 2007 to 2017. During this period, the opioid crisis was first recognized. There followed legislative reforms and subsequent declines in population-based opioid prescribing.

Among the patients in the study, the most common cancers were lung, colorectal, pancreatic, prostate, and breast cancers; 166,962 patients (61.7%) were enrolled in hospice before death. This percentage increased from 57.1% in 2007 to 66.2% in 2017 (P for trend < .001).

From 2007 to 2017, the proportion of patients filling greater than or equal to 1 opioid prescriptions declined from 42.0% to 35.5%. The proportion declined faster from 2012-2017 than from 2007-2011.

The proportion of patients who filled prescriptions for long-acting opioids dropped from 18.1% to 11.5%. Here again, the decline was faster from 2012-2017 than from 2007-2011. Prescriptions for strong short-acting opioids declined from 31.7% to 28.5%. Prescribing was initially stable from 2007-2011 and began to decline in 2012. Conversely, prescriptions for weak short-acting opioids dropped from 8.4% to 6.5% from 2007-2011 and then stabilized after 2012.

The mean daily dose fell 24.5%, from 85.6 morphine milligram equivalents per day (MMED) to 64.6 MMED. Overall, the total amount of opioids prescribed per decedent fell 38.0%, from 1,075 MMEs per person to 666 MMEs.

At the same time, the proportion of patients who visited EDs increased 50.8%, from 13.2% to 19.9%.
 

Experts weigh in

Approached for an independent comment, Amit Barochia, MD, a hematologist/oncologist with Health First Medical Group, Titusville, Fla., commented that the decline could be due, in part, to greater vigilance and awareness by physicians in light of more stringent requirements and of federal and state regulations. “Some physicians are avoiding prescribing opioids due to more regulations and requirements as well, which is routing patients to the ER for pain relief,” he said.

Dr. Barochia agreed that some of the decline could be due to patient factors. “I do think that some of the patients are hesitant about considering opioid use for better pain relief, in part due to fear of addiction as well as complications arising from their use,” he said. “This is likely resulting from more awareness in the community about their adverse effects.

“That awareness could come from aggressive media coverage as well as social media,” he continued. “It is also true that there is a difficulty in getting authorization for certain opioid products, which is delaying the onset of a proper pain regimen that would help to provide adequate pain relief early on.”

For patients with advanced cancer, earlier referral to palliative care would be beneficial, Dr. Barochia pointed out, because this would allow for a more in-depth discussion about pain in addition to addressing the physical and mental symptoms associated with cancer.

Fox Chase Cancer Center’s Dr. Chwistek noted that patients and their caregivers are often apprehensive about the potential adverse effects of opioids, because they often hear about community-based opioid overdoses and are fearful of taking the medications. “Additionally, it has become increasingly challenging to fill opioid prescriptions at local pharmacies, due to quantity limitations, ubiquitous need for prior authorizations, and stigma,” he said.

The fear of addiction is often brought up by the patients during clinic visits, and insurers and pharmacies have imposed many limits on opioid prescribing. “Most of these can be overcome with prior authorizations, but not always, and prior authorizations are time consuming, confusing, and very frustrating for patients,” he said in an interview.

These findings suggest that not enough patients are getting optimal palliative care. “One of the primary tenets of palliative care is optimal symptom control, including pain,” said Dr. Chwistek. “Palliative care teams have the experience and insight needed to help patients overcome the barriers to appropriate pain control. Education, support, and advocacy are critical to ensure that patients’ pain is appropriately addressed.”

The study was funded by a grant from the Agency for Healthcare Research and Quality of the U.S. Department of Health and Human Services.

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

More Americans died from drug overdoses in 2020 than in any other year, the CDC said July 14.

Fatal overdoses rose by nearly 30% last year to a total of more than 93,000 deaths, according to the provisional data the National Center for Health Statistics reported.

The spikes are largely attributed to the rise in use of fentanyl and other synthetic opioids.

The Washington Post reported that more than 69,000 overdose deaths involved opioids, up from 50,963 in 2019.

Amid the crush of overdoses, the White House announced that President Joe Biden has nominated Rahul Gupta, MD, to lead the White House Office of National Drug Control Policy.

Dr. Gupta is a former health commissioner of West Virginia, and is chief medical and health officer for the March of Dimes.

“Dr. Gupta led efforts in West Virginia to address the opioid crisis, gaining national prominence as a leader in tackling this issue,” March of Dimes President and CEO Stacey Stewart said in a statement. “At March of Dimes, he has advocated for policies and programs to prevent and treat substance use, with a focus on the safety and care of pregnant women and infants.”

Healthday contributed to this report. A version of this article first appeared on WebMD.com.

More Americans died from drug overdoses in 2020 than in any other year, the CDC said July 14.

Fatal overdoses rose by nearly 30% last year to a total of more than 93,000 deaths, according to the provisional data the National Center for Health Statistics reported.

The spikes are largely attributed to the rise in use of fentanyl and other synthetic opioids.

The Washington Post reported that more than 69,000 overdose deaths involved opioids, up from 50,963 in 2019.

Amid the crush of overdoses, the White House announced that President Joe Biden has nominated Rahul Gupta, MD, to lead the White House Office of National Drug Control Policy.

Dr. Gupta is a former health commissioner of West Virginia, and is chief medical and health officer for the March of Dimes.

“Dr. Gupta led efforts in West Virginia to address the opioid crisis, gaining national prominence as a leader in tackling this issue,” March of Dimes President and CEO Stacey Stewart said in a statement. “At March of Dimes, he has advocated for policies and programs to prevent and treat substance use, with a focus on the safety and care of pregnant women and infants.”

Healthday contributed to this report. A version of this article first appeared on WebMD.com.

More Americans died from drug overdoses in 2020 than in any other year, the CDC said July 14.

Fatal overdoses rose by nearly 30% last year to a total of more than 93,000 deaths, according to the provisional data the National Center for Health Statistics reported.

The spikes are largely attributed to the rise in use of fentanyl and other synthetic opioids.

The Washington Post reported that more than 69,000 overdose deaths involved opioids, up from 50,963 in 2019.

Amid the crush of overdoses, the White House announced that President Joe Biden has nominated Rahul Gupta, MD, to lead the White House Office of National Drug Control Policy.

Dr. Gupta is a former health commissioner of West Virginia, and is chief medical and health officer for the March of Dimes.

“Dr. Gupta led efforts in West Virginia to address the opioid crisis, gaining national prominence as a leader in tackling this issue,” March of Dimes President and CEO Stacey Stewart said in a statement. “At March of Dimes, he has advocated for policies and programs to prevent and treat substance use, with a focus on the safety and care of pregnant women and infants.”

Healthday contributed to this report. A version of this article first appeared on WebMD.com.

Medications typically used to treat opioid use disorder (OUD) may* also be effective for the growing public health problem of kratom addiction, new research shows.

Results of a comprehensive literature review and an expert survey suggest buprenorphine, naltrexone, and methadone may be effective for patients seeking help for kratom addiction, and if further research confirms these findings, the indication for OUD medications could potentially be expanded to include moderate-to-severe kratom addiction, study investigator Saeed Ahmed, MD, medical director of West Ridge Center at Rutland Regional Medical Center, Rutland, Vermont, said in an interview.

Dr. Ahmed, who practices general psychiatry and addiction psychiatry, presented the findings at the virtual American Psychiatric Association 2021 Annual Meeting.
 

Emerging public health problem

Kratom can be ingested in pill or capsule form or as an extract. Its leaves can be chewed or dried and powdered to make a tea. It can also be incorporated into topical creams, balms, or tinctures.

Products containing the substance are “readily available and legal for sale in many states and cities in the U.S.,” said Dr. Ahmed, adding that it can be purchased online or at local smoke shops and is increasingly used by individuals to self-treat a variety of conditions including pain, anxiety, and mood conditions and as an opioid substitute.

As reported by this news organization, a 2018 analysis conducted by the U.S. Food and Drug Administration showed kratom is, in fact, an opioid, a finding that garnered significant push-back from the American Kratom Association.

Kratom addiction is an “emerging public health problem,” said Dr. Ahmed, adding that in recent years the number of calls to poison control centers across the country has increased 52-fold – from one per month to two per day. He believes misinformation through social media has helped fuel its use.

Kratom use, the investigators note, can lead to muscle pain, weight loss, insomnia, hallucinations and, in some cases (particularly when combined with synthetic opioids or benzodiazepines), it can lead to respiratory depression, seizures, coma, and death.

In addition, the investigators note that to date, there are no guidelines on its management.

To investigate, the researchers conducted a systematic literature search for cases pertaining to maintenance treatment for kratom dependence. They also tapped into case reports and scientific posters from reliable online sources and conference proceedings. In addition, they conducted a survey of members from the American Society of Addiction Medicine (ASAM).

The researchers found 14 reports of long-term management of kratom addiction, half of which did not involve an OUD. It’s important to exclude OUDs to avoid possible confounding.

In most cases, buprenorphine was used, but in a few cases naltrexone or methadone were prescribed. All cases had a favorable outcome. Dr. Ahmed noted that buprenorphine maintenance doses appear to be lower than those required to effectively treat OUD.

With a response rate of 11.5% (82 respondents) the ASAM survey results showed 82.6% of respondents (n = 57) had experience managing KUD, including 27.5% (n = 19) who had kratom addiction only. Of these, 89.5% (n = 17-19), used buprenorphine to manage KUD and of these, 6 combined it with talk therapy.

Dr. Ahmed cautioned that the included cases varied significantly in terms of relevant data, including kratom dose and route of administration, toxicology screening used to monitor abstinence, and duration of maintenance follow-up.

Despite these limitations, the review and survey underscore the importance of including moderate to severe kratom dependence as an indication for current OUD medications, the researchers note.

Including kratom addiction as an indication for these medications is important, especially for patients who are heavily addicted, to meet DSM-5 diagnostic criteria for moderate or severe SUD, they add.

In addition, the researchers recommend that clinicians consider referring patients with moderate to severe kratom dependence for counseling or enrollment in 12-step addiction treatment programs.

A separate diagnosis?

Dr. Ahmed said he would like to see kratom dependence included in the DSM-5 as a separate entity because it is a botanical with properties similar to, but different from, traditional opioids.

“This will not only help to better inform clinicians about a diagnostic criteria encompassing problematic use and facilitate screening, but it will also pave the way for treatments to be explored for this diagnosable condition,” he said. Dr. Ahmed pointed to a review published in the Wisconsin Medical Journal earlier this year that explored potential treatments for kratom dependence.

Commenting on the study for an interview, Petros Levounis, MD, professor and chair, department of psychiatry, and associate dean for professional development, Rutgers New Jersey Medical School, Newark, said the authors “have done a great job reviewing the literature and asking experts” about kratom addiction treatment.

“The punchline of their study is that kratom behaves very much like an opioid and is treated like an opioid.”

Dr. Levounis noted that kratom dependence is so new that experts don’t know much about it. However, he added, emerging evidence suggests that kratom “should be considered an opioid more than anything else,” but specified that he does not believe it warrants its own diagnosis.

He noted that individual opioids don’t have their own diagnostic category and that opioid use disorder is an umbrella term that covers all of these drugs.

Dr. Ahmed and Dr. Levounis have disclosed no relevant financial relationships.

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

*Updated 5/18/2021

Medications typically used to treat opioid use disorder (OUD) may* also be effective for the growing public health problem of kratom addiction, new research shows.

Results of a comprehensive literature review and an expert survey suggest buprenorphine, naltrexone, and methadone may be effective for patients seeking help for kratom addiction, and if further research confirms these findings, the indication for OUD medications could potentially be expanded to include moderate-to-severe kratom addiction, study investigator Saeed Ahmed, MD, medical director of West Ridge Center at Rutland Regional Medical Center, Rutland, Vermont, said in an interview.

Dr. Ahmed, who practices general psychiatry and addiction psychiatry, presented the findings at the virtual American Psychiatric Association 2021 Annual Meeting.
 

Emerging public health problem

Kratom can be ingested in pill or capsule form or as an extract. Its leaves can be chewed or dried and powdered to make a tea. It can also be incorporated into topical creams, balms, or tinctures.

Products containing the substance are “readily available and legal for sale in many states and cities in the U.S.,” said Dr. Ahmed, adding that it can be purchased online or at local smoke shops and is increasingly used by individuals to self-treat a variety of conditions including pain, anxiety, and mood conditions and as an opioid substitute.

As reported by this news organization, a 2018 analysis conducted by the U.S. Food and Drug Administration showed kratom is, in fact, an opioid, a finding that garnered significant push-back from the American Kratom Association.

Kratom addiction is an “emerging public health problem,” said Dr. Ahmed, adding that in recent years the number of calls to poison control centers across the country has increased 52-fold – from one per month to two per day. He believes misinformation through social media has helped fuel its use.

Kratom use, the investigators note, can lead to muscle pain, weight loss, insomnia, hallucinations and, in some cases (particularly when combined with synthetic opioids or benzodiazepines), it can lead to respiratory depression, seizures, coma, and death.

In addition, the investigators note that to date, there are no guidelines on its management.

To investigate, the researchers conducted a systematic literature search for cases pertaining to maintenance treatment for kratom dependence. They also tapped into case reports and scientific posters from reliable online sources and conference proceedings. In addition, they conducted a survey of members from the American Society of Addiction Medicine (ASAM).

The researchers found 14 reports of long-term management of kratom addiction, half of which did not involve an OUD. It’s important to exclude OUDs to avoid possible confounding.

In most cases, buprenorphine was used, but in a few cases naltrexone or methadone were prescribed. All cases had a favorable outcome. Dr. Ahmed noted that buprenorphine maintenance doses appear to be lower than those required to effectively treat OUD.

With a response rate of 11.5% (82 respondents) the ASAM survey results showed 82.6% of respondents (n = 57) had experience managing KUD, including 27.5% (n = 19) who had kratom addiction only. Of these, 89.5% (n = 17-19), used buprenorphine to manage KUD and of these, 6 combined it with talk therapy.

Dr. Ahmed cautioned that the included cases varied significantly in terms of relevant data, including kratom dose and route of administration, toxicology screening used to monitor abstinence, and duration of maintenance follow-up.

Despite these limitations, the review and survey underscore the importance of including moderate to severe kratom dependence as an indication for current OUD medications, the researchers note.

Including kratom addiction as an indication for these medications is important, especially for patients who are heavily addicted, to meet DSM-5 diagnostic criteria for moderate or severe SUD, they add.

In addition, the researchers recommend that clinicians consider referring patients with moderate to severe kratom dependence for counseling or enrollment in 12-step addiction treatment programs.

A separate diagnosis?

Dr. Ahmed said he would like to see kratom dependence included in the DSM-5 as a separate entity because it is a botanical with properties similar to, but different from, traditional opioids.

“This will not only help to better inform clinicians about a diagnostic criteria encompassing problematic use and facilitate screening, but it will also pave the way for treatments to be explored for this diagnosable condition,” he said. Dr. Ahmed pointed to a review published in the Wisconsin Medical Journal earlier this year that explored potential treatments for kratom dependence.

Commenting on the study for an interview, Petros Levounis, MD, professor and chair, department of psychiatry, and associate dean for professional development, Rutgers New Jersey Medical School, Newark, said the authors “have done a great job reviewing the literature and asking experts” about kratom addiction treatment.

“The punchline of their study is that kratom behaves very much like an opioid and is treated like an opioid.”

Dr. Levounis noted that kratom dependence is so new that experts don’t know much about it. However, he added, emerging evidence suggests that kratom “should be considered an opioid more than anything else,” but specified that he does not believe it warrants its own diagnosis.

He noted that individual opioids don’t have their own diagnostic category and that opioid use disorder is an umbrella term that covers all of these drugs.

Dr. Ahmed and Dr. Levounis have disclosed no relevant financial relationships.

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

*Updated 5/18/2021

Medications typically used to treat opioid use disorder (OUD) may* also be effective for the growing public health problem of kratom addiction, new research shows.

Results of a comprehensive literature review and an expert survey suggest buprenorphine, naltrexone, and methadone may be effective for patients seeking help for kratom addiction, and if further research confirms these findings, the indication for OUD medications could potentially be expanded to include moderate-to-severe kratom addiction, study investigator Saeed Ahmed, MD, medical director of West Ridge Center at Rutland Regional Medical Center, Rutland, Vermont, said in an interview.

Dr. Ahmed, who practices general psychiatry and addiction psychiatry, presented the findings at the virtual American Psychiatric Association 2021 Annual Meeting.
 

Emerging public health problem

Kratom can be ingested in pill or capsule form or as an extract. Its leaves can be chewed or dried and powdered to make a tea. It can also be incorporated into topical creams, balms, or tinctures.

Products containing the substance are “readily available and legal for sale in many states and cities in the U.S.,” said Dr. Ahmed, adding that it can be purchased online or at local smoke shops and is increasingly used by individuals to self-treat a variety of conditions including pain, anxiety, and mood conditions and as an opioid substitute.

As reported by this news organization, a 2018 analysis conducted by the U.S. Food and Drug Administration showed kratom is, in fact, an opioid, a finding that garnered significant push-back from the American Kratom Association.

Kratom addiction is an “emerging public health problem,” said Dr. Ahmed, adding that in recent years the number of calls to poison control centers across the country has increased 52-fold – from one per month to two per day. He believes misinformation through social media has helped fuel its use.

Kratom use, the investigators note, can lead to muscle pain, weight loss, insomnia, hallucinations and, in some cases (particularly when combined with synthetic opioids or benzodiazepines), it can lead to respiratory depression, seizures, coma, and death.

In addition, the investigators note that to date, there are no guidelines on its management.

To investigate, the researchers conducted a systematic literature search for cases pertaining to maintenance treatment for kratom dependence. They also tapped into case reports and scientific posters from reliable online sources and conference proceedings. In addition, they conducted a survey of members from the American Society of Addiction Medicine (ASAM).

The researchers found 14 reports of long-term management of kratom addiction, half of which did not involve an OUD. It’s important to exclude OUDs to avoid possible confounding.

In most cases, buprenorphine was used, but in a few cases naltrexone or methadone were prescribed. All cases had a favorable outcome. Dr. Ahmed noted that buprenorphine maintenance doses appear to be lower than those required to effectively treat OUD.

With a response rate of 11.5% (82 respondents) the ASAM survey results showed 82.6% of respondents (n = 57) had experience managing KUD, including 27.5% (n = 19) who had kratom addiction only. Of these, 89.5% (n = 17-19), used buprenorphine to manage KUD and of these, 6 combined it with talk therapy.

Dr. Ahmed cautioned that the included cases varied significantly in terms of relevant data, including kratom dose and route of administration, toxicology screening used to monitor abstinence, and duration of maintenance follow-up.

Despite these limitations, the review and survey underscore the importance of including moderate to severe kratom dependence as an indication for current OUD medications, the researchers note.

Including kratom addiction as an indication for these medications is important, especially for patients who are heavily addicted, to meet DSM-5 diagnostic criteria for moderate or severe SUD, they add.

In addition, the researchers recommend that clinicians consider referring patients with moderate to severe kratom dependence for counseling or enrollment in 12-step addiction treatment programs.

A separate diagnosis?

Dr. Ahmed said he would like to see kratom dependence included in the DSM-5 as a separate entity because it is a botanical with properties similar to, but different from, traditional opioids.

“This will not only help to better inform clinicians about a diagnostic criteria encompassing problematic use and facilitate screening, but it will also pave the way for treatments to be explored for this diagnosable condition,” he said. Dr. Ahmed pointed to a review published in the Wisconsin Medical Journal earlier this year that explored potential treatments for kratom dependence.

Commenting on the study for an interview, Petros Levounis, MD, professor and chair, department of psychiatry, and associate dean for professional development, Rutgers New Jersey Medical School, Newark, said the authors “have done a great job reviewing the literature and asking experts” about kratom addiction treatment.

“The punchline of their study is that kratom behaves very much like an opioid and is treated like an opioid.”

Dr. Levounis noted that kratom dependence is so new that experts don’t know much about it. However, he added, emerging evidence suggests that kratom “should be considered an opioid more than anything else,” but specified that he does not believe it warrants its own diagnosis.

He noted that individual opioids don’t have their own diagnostic category and that opioid use disorder is an umbrella term that covers all of these drugs.

Dr. Ahmed and Dr. Levounis have disclosed no relevant financial relationships.

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

*Updated 5/18/2021

The composition of street drugs like heroin and cocaine are changing. According to a new analysis, almost all contain at least one toxic adulterant, and many contain a plethora. Most adulterants have pharmacologic activities and toxicities. Their presence has added impact in the context of the COVID-19 pandemic, since some may cause a drastic drop in white blood cells that could leave drug users more vulnerable to infection.

“It’s remarkable that we just forgot to notice, in the horrendous transition from prescription opioid epidemic to the illicit opioid and psychostimulant epidemics, that we would have to pay special attention to what the medications are in the drugs that the person was exposed to – and for how long,” said Mark S. Gold, MD, a coauthor of the review.

The analysis showed that adulterants include new psychoactive substances, industrial compounds, fungicides, veterinary medications, and various impurities. In addition, other various medications are being found in street drugs, such as antipsychotics, antidepressants, anxiolytics, antihistamines, anthelmintics, anesthetics, anti-inflammatory agents, antipyretics, analgesics, antispasmodics, antiarrhythmics, antimalarials, bronchodilators, decongestants, expectorants, muscle relaxers, natural/synthetic hallucinogens, and sedatives.

Illicit drugs are by nature manufactured without Food and Drug Administration oversight, and it is becoming increasingly common that substances like leftover medicines and other active drugs are added to illicit drug batches to add weight, said Dr. Gold, a professor at Washington University,St. Louis. The study appeared in Current Psychopharmacology.
 

Effects of adulterants ‘terrifying’

The findings of adulterants and their consequences are concerning, according to Jean Lud Cadet, MD, who was asked to comment on the findings. “The blood dysplasia, the pulmonary problems that some of those adulterants can cause – it’s actually terrifying, to put it bluntly,” said Dr. Cadet, who is a senior investigator and chief of the Molecular Neuropsychiatry Research Branch at the National Institute on Drug Abuse.

Before 2000, street drugs were generally diluted with comparatively benign substances such as caffeine, sugars, or lidocaine. Drugs like phenacetin, levamisole, acetaminophen, and diltiazem began to appear in heroin and cocaine in the late 1990s, and by 2010, more powerful adulterants like fentanyl, ketamine, and quetiapine became common. Adulterants can lead to a range of clinical effects, including renal and liver problems, blood disorders, infections, respiratory depression, and cardiac arrest.

In 2015, the U.S. Department of State partnered with the Colombo Plan, an international organization based in Sri Lanka, to use field spectroscopy to detect toxins directly in cocaine and heroin samples found in Argentina, Brazil, Ecuador, Peru, Sri Lanka, Thailand, Honduras, Guatemala, Mexico, Colombia, and South Africa. They found a range of adulterants such as aminopyrine, diltiazem, metamizole, levamisole, and phenacetin.

A similar project with 431 heroin and cocaine samples from Vermont and Kentucky found that 69% of samples had five or more controlled drugs, toxic adulterants, or impurities. About 15% had nine or more, and 95% of samples had at least one toxic adulterant.

In the midst of the COVID-19 pandemic, these adulterants take on even greater significance. Individuals with substance use disorders often have other health conditions that can make them more vulnerable to viral infections, and this could be exacerbated by the effects of adulterants on white blood cells or other systems. The pandemic has also had an indirect effect by causing a shortage of street drugs. During production shortages, traffickers might boost potency by adding more cutting agents and adulterants. As a result, COVID-19 and opioid addiction tend to reinforce each other.

“The clinical message would be that our [substance use] patients will contract infectious disease and need to be prioritized for [COVID-19] vaccination,” said Dr. Gold.

The findings came as a surprise to Dr. Cadet, and that illustrates a need to publicize the presence of adulterants in street drugs.

“If I wasn’t aware of many of these, then the general public is also not going to be aware of them,” Dr. Cadet said. “Scientists, including myself, and government agencies need to do a better job [of communicating this issue].”

The study references individuals with substance use disorder, but Dr. Cadet cautioned that anyone who uses street drugs, even once or twice, could be a victim of adulterants. “You don’t need to have met criteria for diagnosis in order to suffer the consequences.”

The study had no funding. Dr. Gold and Dr. Cadet have no relevant financial disclosures.

The composition of street drugs like heroin and cocaine are changing. According to a new analysis, almost all contain at least one toxic adulterant, and many contain a plethora. Most adulterants have pharmacologic activities and toxicities. Their presence has added impact in the context of the COVID-19 pandemic, since some may cause a drastic drop in white blood cells that could leave drug users more vulnerable to infection.

“It’s remarkable that we just forgot to notice, in the horrendous transition from prescription opioid epidemic to the illicit opioid and psychostimulant epidemics, that we would have to pay special attention to what the medications are in the drugs that the person was exposed to – and for how long,” said Mark S. Gold, MD, a coauthor of the review.

The analysis showed that adulterants include new psychoactive substances, industrial compounds, fungicides, veterinary medications, and various impurities. In addition, other various medications are being found in street drugs, such as antipsychotics, antidepressants, anxiolytics, antihistamines, anthelmintics, anesthetics, anti-inflammatory agents, antipyretics, analgesics, antispasmodics, antiarrhythmics, antimalarials, bronchodilators, decongestants, expectorants, muscle relaxers, natural/synthetic hallucinogens, and sedatives.

Illicit drugs are by nature manufactured without Food and Drug Administration oversight, and it is becoming increasingly common that substances like leftover medicines and other active drugs are added to illicit drug batches to add weight, said Dr. Gold, a professor at Washington University,St. Louis. The study appeared in Current Psychopharmacology.
 

Effects of adulterants ‘terrifying’

The findings of adulterants and their consequences are concerning, according to Jean Lud Cadet, MD, who was asked to comment on the findings. “The blood dysplasia, the pulmonary problems that some of those adulterants can cause – it’s actually terrifying, to put it bluntly,” said Dr. Cadet, who is a senior investigator and chief of the Molecular Neuropsychiatry Research Branch at the National Institute on Drug Abuse.

Before 2000, street drugs were generally diluted with comparatively benign substances such as caffeine, sugars, or lidocaine. Drugs like phenacetin, levamisole, acetaminophen, and diltiazem began to appear in heroin and cocaine in the late 1990s, and by 2010, more powerful adulterants like fentanyl, ketamine, and quetiapine became common. Adulterants can lead to a range of clinical effects, including renal and liver problems, blood disorders, infections, respiratory depression, and cardiac arrest.

In 2015, the U.S. Department of State partnered with the Colombo Plan, an international organization based in Sri Lanka, to use field spectroscopy to detect toxins directly in cocaine and heroin samples found in Argentina, Brazil, Ecuador, Peru, Sri Lanka, Thailand, Honduras, Guatemala, Mexico, Colombia, and South Africa. They found a range of adulterants such as aminopyrine, diltiazem, metamizole, levamisole, and phenacetin.

A similar project with 431 heroin and cocaine samples from Vermont and Kentucky found that 69% of samples had five or more controlled drugs, toxic adulterants, or impurities. About 15% had nine or more, and 95% of samples had at least one toxic adulterant.

In the midst of the COVID-19 pandemic, these adulterants take on even greater significance. Individuals with substance use disorders often have other health conditions that can make them more vulnerable to viral infections, and this could be exacerbated by the effects of adulterants on white blood cells or other systems. The pandemic has also had an indirect effect by causing a shortage of street drugs. During production shortages, traffickers might boost potency by adding more cutting agents and adulterants. As a result, COVID-19 and opioid addiction tend to reinforce each other.

“The clinical message would be that our [substance use] patients will contract infectious disease and need to be prioritized for [COVID-19] vaccination,” said Dr. Gold.

The findings came as a surprise to Dr. Cadet, and that illustrates a need to publicize the presence of adulterants in street drugs.

“If I wasn’t aware of many of these, then the general public is also not going to be aware of them,” Dr. Cadet said. “Scientists, including myself, and government agencies need to do a better job [of communicating this issue].”

The study references individuals with substance use disorder, but Dr. Cadet cautioned that anyone who uses street drugs, even once or twice, could be a victim of adulterants. “You don’t need to have met criteria for diagnosis in order to suffer the consequences.”

The study had no funding. Dr. Gold and Dr. Cadet have no relevant financial disclosures.

The composition of street drugs like heroin and cocaine are changing. According to a new analysis, almost all contain at least one toxic adulterant, and many contain a plethora. Most adulterants have pharmacologic activities and toxicities. Their presence has added impact in the context of the COVID-19 pandemic, since some may cause a drastic drop in white blood cells that could leave drug users more vulnerable to infection.

“It’s remarkable that we just forgot to notice, in the horrendous transition from prescription opioid epidemic to the illicit opioid and psychostimulant epidemics, that we would have to pay special attention to what the medications are in the drugs that the person was exposed to – and for how long,” said Mark S. Gold, MD, a coauthor of the review.

The analysis showed that adulterants include new psychoactive substances, industrial compounds, fungicides, veterinary medications, and various impurities. In addition, other various medications are being found in street drugs, such as antipsychotics, antidepressants, anxiolytics, antihistamines, anthelmintics, anesthetics, anti-inflammatory agents, antipyretics, analgesics, antispasmodics, antiarrhythmics, antimalarials, bronchodilators, decongestants, expectorants, muscle relaxers, natural/synthetic hallucinogens, and sedatives.

Illicit drugs are by nature manufactured without Food and Drug Administration oversight, and it is becoming increasingly common that substances like leftover medicines and other active drugs are added to illicit drug batches to add weight, said Dr. Gold, a professor at Washington University,St. Louis. The study appeared in Current Psychopharmacology.
 

Effects of adulterants ‘terrifying’

The findings of adulterants and their consequences are concerning, according to Jean Lud Cadet, MD, who was asked to comment on the findings. “The blood dysplasia, the pulmonary problems that some of those adulterants can cause – it’s actually terrifying, to put it bluntly,” said Dr. Cadet, who is a senior investigator and chief of the Molecular Neuropsychiatry Research Branch at the National Institute on Drug Abuse.

Before 2000, street drugs were generally diluted with comparatively benign substances such as caffeine, sugars, or lidocaine. Drugs like phenacetin, levamisole, acetaminophen, and diltiazem began to appear in heroin and cocaine in the late 1990s, and by 2010, more powerful adulterants like fentanyl, ketamine, and quetiapine became common. Adulterants can lead to a range of clinical effects, including renal and liver problems, blood disorders, infections, respiratory depression, and cardiac arrest.

In 2015, the U.S. Department of State partnered with the Colombo Plan, an international organization based in Sri Lanka, to use field spectroscopy to detect toxins directly in cocaine and heroin samples found in Argentina, Brazil, Ecuador, Peru, Sri Lanka, Thailand, Honduras, Guatemala, Mexico, Colombia, and South Africa. They found a range of adulterants such as aminopyrine, diltiazem, metamizole, levamisole, and phenacetin.

A similar project with 431 heroin and cocaine samples from Vermont and Kentucky found that 69% of samples had five or more controlled drugs, toxic adulterants, or impurities. About 15% had nine or more, and 95% of samples had at least one toxic adulterant.

In the midst of the COVID-19 pandemic, these adulterants take on even greater significance. Individuals with substance use disorders often have other health conditions that can make them more vulnerable to viral infections, and this could be exacerbated by the effects of adulterants on white blood cells or other systems. The pandemic has also had an indirect effect by causing a shortage of street drugs. During production shortages, traffickers might boost potency by adding more cutting agents and adulterants. As a result, COVID-19 and opioid addiction tend to reinforce each other.

“The clinical message would be that our [substance use] patients will contract infectious disease and need to be prioritized for [COVID-19] vaccination,” said Dr. Gold.

The findings came as a surprise to Dr. Cadet, and that illustrates a need to publicize the presence of adulterants in street drugs.

“If I wasn’t aware of many of these, then the general public is also not going to be aware of them,” Dr. Cadet said. “Scientists, including myself, and government agencies need to do a better job [of communicating this issue].”

The study references individuals with substance use disorder, but Dr. Cadet cautioned that anyone who uses street drugs, even once or twice, could be a victim of adulterants. “You don’t need to have met criteria for diagnosis in order to suffer the consequences.”

The study had no funding. Dr. Gold and Dr. Cadet have no relevant financial disclosures.

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

The Food and Drug Administration has approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression.

Olivier Le Moal/Getty Images

Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.

When administered quickly, naloxone can counter opioid overdose effects, usually within minutes. A higher dose of naloxone provides an additional option for the treatment of opioid overdoses, the FDA said in a news release.

“This approval meets another critical need in combating opioid overdose,” Patrizia Cavazzoni, MD, director, FDA Center for Drug Evaluation and Research, said in the release.

“Addressing the opioid crisis is a top priority for the FDA, and we will continue our efforts to increase access to naloxone and place this important medicine in the hands of those who need it most,” said Dr. Cavazzoni.

In a company news release announcing the approval, manufacturer Hikma Pharmaceuticals noted that a recent survey of community organizations in which the 4-mg naloxone nasal spray had been distributed showed that for 34% of attempted reversals, two or more doses of naloxone were used.

A separate study found that the percentage of overdose-related emergency medical service calls in the United States that led to the administration of multiple doses of naloxone increased to 21% during the period of 2013-2016, which represents a 43% increase over 4 years.

“The approval of Kloxxado is an important step in providing patients, friends, and family members – as well as the public health community – with an important new option for treating opioid overdose,” Brian Hoffmann, president of Hikma Generics, said in the release.

The company expects Kloxxado to available in the second half of 2021.

The FDA approved Kloxxado through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

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

The Food and Drug Administration has approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression.

Olivier Le Moal/Getty Images

Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.

When administered quickly, naloxone can counter opioid overdose effects, usually within minutes. A higher dose of naloxone provides an additional option for the treatment of opioid overdoses, the FDA said in a news release.

“This approval meets another critical need in combating opioid overdose,” Patrizia Cavazzoni, MD, director, FDA Center for Drug Evaluation and Research, said in the release.

“Addressing the opioid crisis is a top priority for the FDA, and we will continue our efforts to increase access to naloxone and place this important medicine in the hands of those who need it most,” said Dr. Cavazzoni.

In a company news release announcing the approval, manufacturer Hikma Pharmaceuticals noted that a recent survey of community organizations in which the 4-mg naloxone nasal spray had been distributed showed that for 34% of attempted reversals, two or more doses of naloxone were used.

A separate study found that the percentage of overdose-related emergency medical service calls in the United States that led to the administration of multiple doses of naloxone increased to 21% during the period of 2013-2016, which represents a 43% increase over 4 years.

“The approval of Kloxxado is an important step in providing patients, friends, and family members – as well as the public health community – with an important new option for treating opioid overdose,” Brian Hoffmann, president of Hikma Generics, said in the release.

The company expects Kloxxado to available in the second half of 2021.

The FDA approved Kloxxado through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

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

The Food and Drug Administration has approved a higher-dose naloxone hydrochloride nasal spray (Kloxxado) for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression.

Olivier Le Moal/Getty Images

Kloxxado delivers 8 mg of naloxone into the nasal cavity, which is twice as much as the 4 mg of naloxone contained in Narcan nasal spray.

When administered quickly, naloxone can counter opioid overdose effects, usually within minutes. A higher dose of naloxone provides an additional option for the treatment of opioid overdoses, the FDA said in a news release.

“This approval meets another critical need in combating opioid overdose,” Patrizia Cavazzoni, MD, director, FDA Center for Drug Evaluation and Research, said in the release.

“Addressing the opioid crisis is a top priority for the FDA, and we will continue our efforts to increase access to naloxone and place this important medicine in the hands of those who need it most,” said Dr. Cavazzoni.

In a company news release announcing the approval, manufacturer Hikma Pharmaceuticals noted that a recent survey of community organizations in which the 4-mg naloxone nasal spray had been distributed showed that for 34% of attempted reversals, two or more doses of naloxone were used.

A separate study found that the percentage of overdose-related emergency medical service calls in the United States that led to the administration of multiple doses of naloxone increased to 21% during the period of 2013-2016, which represents a 43% increase over 4 years.

“The approval of Kloxxado is an important step in providing patients, friends, and family members – as well as the public health community – with an important new option for treating opioid overdose,” Brian Hoffmann, president of Hikma Generics, said in the release.

The company expects Kloxxado to available in the second half of 2021.

The FDA approved Kloxxado through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

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

More adolescent girls than boys experienced nonfatal opioid overdose and reported baseline levels of anxiety, depression, and self-harm, according to data from a retrospective cohort study of more than 20,000 youth in the United States.

Previous studies have identified sex-based differences in opioid overdose such as a higher prevalence of co-occurring psychiatric disorders in women compared with men, wrote Sarah M. Bagley, MD, of Boston University, and colleagues. “However, few studies have examined whether such sex-based differences in opioid overdose risk extend to the population of adolescents and young adults,” they said.

In a retrospective cohort study published in JAMA Network Open, the researchers identified 20,312 commercially insured youth aged 11-24 years who experienced a nonfatal opioid overdose between Jan. 1, 2006, and Dec. 31, 2017, and reviewed data using the IBM MarketScan Commercial Database. The average age of the study population was 20 years and approximately 42% were female.

Females aged 11-16 years had a significantly higher incidence of nonfatal opioid overdose (60%) compared with males, but this trend reversed at age 17 years, after which the incidence of nonfatal opioid overdose became significantly higher in males. “Our finding that females younger than 17 years had a higher incidence of NFOD is consistent with epidemiologic data that have indicated changes in alcohol and drug prevalence among female youths,” the researchers wrote.

Overall, 57.8% of the cohort had mood and anxiety disorders, 12.8% had trauma- or stress-related disorders, and 11.7% had attention-deficit/hyperactivity disorder.

When analyzed by sex, females had a significantly higher prevalence than that of males of mood or anxiety disorders (65.5% vs. 51.9%) trauma or stress-related disorders (16.4% vs. 10.1%) and attempts at suicide or self-harm (14.6% vs. 9.9%). Males had significantly higher prevalence than that of females of opioid use disorder (44.7% vs. 29.2%), cannabis use disorder (18.3% vs. 11.3%), and alcohol use disorder (20.3% vs. 14.4%).

“Although in our study, female youths had a lower prevalence of all substance use disorders, including OUD [opioid use disorder], and a higher prevalence of mood and trauma-associated disorders, both male and female youths had a higher prevalence of psychiatric illness and substance use disorder than youths in the general population,” the researchers noted.

The study findings were limited by several factors including the inclusion only of youth with commercial insurance, with no uninsured or publicly insured youth, and only those youth who sought health care after a nonfatal opioid overdose, the researchers noted. The prevalence of substance use and mental health disorders may be over- or underdiagnosed, and race was not included as a variable because of unreliable data, they added. The database also did not allow for gender identity beyond sex as listed by the insurance carrier, they said.

However, the results indicate significant differences in the incidence of nonfatal opioid overdose and accompanying mental health and substance use disorders based on age and sex, they said.

“These differences may have important implications for developing effective interventions to prevent first-time NFOD and to engage youths in care after an NFOD,” they concluded.

The study was supported by grants to several researchers from the National Institute on Drug Abuse, National Institutes of Health, and the Charles A. King Trust. The researchers had no financial conflicts to disclose. 

More adolescent girls than boys experienced nonfatal opioid overdose and reported baseline levels of anxiety, depression, and self-harm, according to data from a retrospective cohort study of more than 20,000 youth in the United States.

Previous studies have identified sex-based differences in opioid overdose such as a higher prevalence of co-occurring psychiatric disorders in women compared with men, wrote Sarah M. Bagley, MD, of Boston University, and colleagues. “However, few studies have examined whether such sex-based differences in opioid overdose risk extend to the population of adolescents and young adults,” they said.

In a retrospective cohort study published in JAMA Network Open, the researchers identified 20,312 commercially insured youth aged 11-24 years who experienced a nonfatal opioid overdose between Jan. 1, 2006, and Dec. 31, 2017, and reviewed data using the IBM MarketScan Commercial Database. The average age of the study population was 20 years and approximately 42% were female.

Females aged 11-16 years had a significantly higher incidence of nonfatal opioid overdose (60%) compared with males, but this trend reversed at age 17 years, after which the incidence of nonfatal opioid overdose became significantly higher in males. “Our finding that females younger than 17 years had a higher incidence of NFOD is consistent with epidemiologic data that have indicated changes in alcohol and drug prevalence among female youths,” the researchers wrote.

Overall, 57.8% of the cohort had mood and anxiety disorders, 12.8% had trauma- or stress-related disorders, and 11.7% had attention-deficit/hyperactivity disorder.

When analyzed by sex, females had a significantly higher prevalence than that of males of mood or anxiety disorders (65.5% vs. 51.9%) trauma or stress-related disorders (16.4% vs. 10.1%) and attempts at suicide or self-harm (14.6% vs. 9.9%). Males had significantly higher prevalence than that of females of opioid use disorder (44.7% vs. 29.2%), cannabis use disorder (18.3% vs. 11.3%), and alcohol use disorder (20.3% vs. 14.4%).

“Although in our study, female youths had a lower prevalence of all substance use disorders, including OUD [opioid use disorder], and a higher prevalence of mood and trauma-associated disorders, both male and female youths had a higher prevalence of psychiatric illness and substance use disorder than youths in the general population,” the researchers noted.

The study findings were limited by several factors including the inclusion only of youth with commercial insurance, with no uninsured or publicly insured youth, and only those youth who sought health care after a nonfatal opioid overdose, the researchers noted. The prevalence of substance use and mental health disorders may be over- or underdiagnosed, and race was not included as a variable because of unreliable data, they added. The database also did not allow for gender identity beyond sex as listed by the insurance carrier, they said.

However, the results indicate significant differences in the incidence of nonfatal opioid overdose and accompanying mental health and substance use disorders based on age and sex, they said.

“These differences may have important implications for developing effective interventions to prevent first-time NFOD and to engage youths in care after an NFOD,” they concluded.

The study was supported by grants to several researchers from the National Institute on Drug Abuse, National Institutes of Health, and the Charles A. King Trust. The researchers had no financial conflicts to disclose. 

More adolescent girls than boys experienced nonfatal opioid overdose and reported baseline levels of anxiety, depression, and self-harm, according to data from a retrospective cohort study of more than 20,000 youth in the United States.

Previous studies have identified sex-based differences in opioid overdose such as a higher prevalence of co-occurring psychiatric disorders in women compared with men, wrote Sarah M. Bagley, MD, of Boston University, and colleagues. “However, few studies have examined whether such sex-based differences in opioid overdose risk extend to the population of adolescents and young adults,” they said.

In a retrospective cohort study published in JAMA Network Open, the researchers identified 20,312 commercially insured youth aged 11-24 years who experienced a nonfatal opioid overdose between Jan. 1, 2006, and Dec. 31, 2017, and reviewed data using the IBM MarketScan Commercial Database. The average age of the study population was 20 years and approximately 42% were female.

Females aged 11-16 years had a significantly higher incidence of nonfatal opioid overdose (60%) compared with males, but this trend reversed at age 17 years, after which the incidence of nonfatal opioid overdose became significantly higher in males. “Our finding that females younger than 17 years had a higher incidence of NFOD is consistent with epidemiologic data that have indicated changes in alcohol and drug prevalence among female youths,” the researchers wrote.

Overall, 57.8% of the cohort had mood and anxiety disorders, 12.8% had trauma- or stress-related disorders, and 11.7% had attention-deficit/hyperactivity disorder.

When analyzed by sex, females had a significantly higher prevalence than that of males of mood or anxiety disorders (65.5% vs. 51.9%) trauma or stress-related disorders (16.4% vs. 10.1%) and attempts at suicide or self-harm (14.6% vs. 9.9%). Males had significantly higher prevalence than that of females of opioid use disorder (44.7% vs. 29.2%), cannabis use disorder (18.3% vs. 11.3%), and alcohol use disorder (20.3% vs. 14.4%).

“Although in our study, female youths had a lower prevalence of all substance use disorders, including OUD [opioid use disorder], and a higher prevalence of mood and trauma-associated disorders, both male and female youths had a higher prevalence of psychiatric illness and substance use disorder than youths in the general population,” the researchers noted.

The study findings were limited by several factors including the inclusion only of youth with commercial insurance, with no uninsured or publicly insured youth, and only those youth who sought health care after a nonfatal opioid overdose, the researchers noted. The prevalence of substance use and mental health disorders may be over- or underdiagnosed, and race was not included as a variable because of unreliable data, they added. The database also did not allow for gender identity beyond sex as listed by the insurance carrier, they said.

However, the results indicate significant differences in the incidence of nonfatal opioid overdose and accompanying mental health and substance use disorders based on age and sex, they said.

“These differences may have important implications for developing effective interventions to prevent first-time NFOD and to engage youths in care after an NFOD,” they concluded.

The study was supported by grants to several researchers from the National Institute on Drug Abuse, National Institutes of Health, and the Charles A. King Trust. The researchers had no financial conflicts to disclose. 

Buprenorphine for the treatment of opioid-use disorder (OUD) may also mitigate the risk associated with concomitant benzodiazepine and Z-drug use, which is frequent in this patient population, new research suggests.

A case-crossover study of more than 20,000 participants with OUD showed that drug treatment days in which benzodiazepines and Z-drugs were taken were associated with an 88% increase in nonfatal overdose; buprenorphine appeared to reduce this risk by almost 40%.

“One of our two primary findings is that patients with opioid use disorder can still benefit substantially from buprenorphine treatment, even if they have benzodiazepines on board,” lead author Kevin Xu, MD, a resident at the Washington University, St. Louis, told this news organization.

The other key finding was that “not all benzodiazepines are equal” and that some are associated with higher risk than others, Dr. Xu added.

“If anything, patients who are on buprenorphine and benzodiazepines do not necessarily need to be abruptly tapered off their benzodiazepines. Our data actually demonstrate that there are safe avenues for them,” he added.

The findings were published online March 3 in the American Journal of Psychiatry.
 

Cloudy relationship

Buprenorphine is commonly used to treat patients with OUD because of its ability to decrease all-cause mortality. However, up to 30% of these patients also take benzodiazepines for comorbid mood and anxiety disorders, Dr. Xu noted.

In addition, recent research shows that benzodiazepine/Z-drug use is associated with a variety of potential adverse effects, including respiratory depression, overdose, and addiction risk.

The relationship between benzodiazepine use and buprenorphine treatment outcomes is poorly characterized in individuals with OUD. Although some studies suggest benzodiazepines may enhance retention in buprenorphine maintenance treatment, others suggest a link to increased adverse events, including all-cause mortality, drug-related poisonings, and accidental injury–related emergency department visits.

In addition, there has been little research on the potential adverse effects associated with use of selective benzodiazepine receptor modulators in patients with OUD. These so-called Z-drugs include zolpidem, zaleplon, and eszopiclone.

Nevertheless, previous research in the general population shows that these medications have a range of adverse effects similar to those of benzodiazepines, with comparable dose-response effects on all-cause mortality.

“The challenge for any clinician is that many patients who are addicted to opioids are also polysubstance users,” said Dr. Xu. “There are so many hopeful articles regarding the benefits of buprenorphine treatment in opioid use disorder patients, but it seems like the individuals with polysubstance use are largely ignored in the setting of the opioid epidemic.”

“And this is really the back story that got me inspired to study this particular topic,” he added.
 

Improve, nullify, or reverse?

Given these questions, the researchers set out to quantify the odds of nonfatal drug-related poisoning, including overdoses, associated with benzodiazepine or Z-drug use by patients with OUD who were also taking buprenorphine.

“While the drug-related poisoning variable encompasses opioid overdoses, we used a broad definition per CDC guidelines to also include other types of drug overdoses – including poisoning events involving stimulants, overdoses involving sedatives, and overdoses involving psychotropic prescription drugs” that are commonly used by patients with OUD, said Dr. Xu.

They also wanted to determine whether the use of benzodiazepines or Z-drugs would improve, nullify, or reverse the protective effect of buprenorphine. The researchers also evaluated whether different sedative and hypnotic subtypes of these drugs were associated with different poisoning risks.

The researchers analyzed pharmaceutical claims data from 304,676 individuals (aged 12-64 years) in the IBM MarketScan Commercial and Multi-State Medicaid Databases. All had received buprenorphine treatment for OUD between Jan. 1, 2006, and Dec. 31, 2016.

Buprenorphine use was converted to a daily milligram dose and was classified as either greater than 12 mg or less than or equal to 12 mg, because previous research suggests there may be differences in treatment retention associated with this dose. Given the case-control nature of the investigation, patients who did not experience a drug-related poisoning were excluded from the analysis.

The study’s primary unit of observation was person-days, which were those days during which patients were enrolled in a health insurance plan. Participants were evaluated for 1 year before their first drug-related poisoning and 1 year after their first such poisoning. The primary outcome was nonfatal drug-related poisonings, including overdoses. The primary exposure was determined on the basis of benzodiazepine or Z-drug prescriptions.

The daily dose of benzodiazepines or Z-drugs was standardized as a function of diazepam-equivalent milligrams. Doses were classified as either high dose (diazepam-equivalent mg dose >30 mg) or low dose (≤30 mg). The drugs were also distinguished on the basis of their pharmacologic properties, such as whether they were short-acting or long-acting.
 

37% risk reduction

Of the original cohort of 304,676 patients with OUD, the study’s final analytic sample included 23,036 patients (mean age, 30 years; 51% men), representing 14,213,075 person-days of insurance coverage. Of these, 2,210,927 person-days (15.6%) entailed claims for buprenorphine (mean daily dose, 15.4 mg; SD, 7.31 mg).

A total of 474,181 person-days included claims for benzodiazepines or Z-drugs with concurrent buprenorphine treatment. The mean daily dose of any benzodiazepine or Z-drug was 23.4 diazepam-milligram equivalents. The mean daily dose of short-acting benzodiazepines, long-acting benzodiazepines, and Z-drugs was 25.3, 31.3, and 4.9 diazepam-milligram equivalents, respectively.

Buprenorphine treatment days were associated with a 37% lower chance of drug-related poisoning (95% confidence interval, 0.60-0.66) in comparison with nontreatment days. On the other hand, the odds of poisoning increased by 81% on days on which patients were treated with Z-drugs or benzodiazepines (95% CI, 1.73-1.91).

Interestingly, individual analyses showed that benzodiazepine and Z-drug treatment days were associated with increased odds of poisoning events (odds ratio, 1.29; 95% CI, 1.19-1.39). Odds of poisoning events on benzodiazepine-only treatment days, on the other hand, were markedly lower (OR, 1.88; 95% CI, 1.78-1.98).

Subgroup analyses revealed that both short-acting and long-acting benzodiazepine treatment days were associated with comparably elevated odds of drug-related poisoning (OR, 1.86 and 1.68, respectively). High-dose benzodiazepine treatment days were associated with higher increased odds of a poisoning event (122%) in comparison with low-dose treatment days (78%).

High-dose, but not low-dose, benzodiazepine or Z-drug treatment was linked to increased poisonings when the drug was taken concurrently with buprenorphine (OR, 1.64; 95% CI, 1.39-1.93). However, the risk was still lower than the risk associated with taking the agents without concurrent treatment with buprenorphine (low-dose OR, 1.69; high-dose OR, 2.23).
 

‘Not all benzodiazepines are bad’

Dr. Xu noted that the findings have potentially important implications for clinical practice, beginning with the dose-dependent relationship between benzodiazepine/Z-drug use and drug-related poisonings among individuals with OUD. This indicates that lowering doses or shortening treatment duration may reduce risk, he said.

Similarly, the lower risk associated with long-acting benzodiazepines relative to short-acting beonzodiazepines – as well as the substantially lower risk associated with Z-drugs, compared with either short- or long-acting benzodiazepines – suggests that switching from benzodiazepines to long-acting agents or Z-drugs may lower the risk for overdose, he added.

“Clinicians are often challenged by patients with opioid use disorder who are also on benzodiazepines or Z-drugs. There’s an inclination to say no to them, because they’re too high risk to start buprenorphine maintenance, or abruptly taper the benzodiazepines, which can be very destabilizing,” he noted.

“Our data show that people on benzodiazepines can absolutely receive buprenorphine and still get some benefit,” Dr. Xu said. “In addition, not all benzodiazepines are bad for these individuals. There are safer formulations and safer doses, too.”

However, he added, he would not initiate benzodiazepine treatment if he didn’t have to, especially long-term treatment.

“One of the messages from our data is that this clearly contributes to higher overdose risk. But we often inherit patients who already have benzodiazepines on board, so we need to figure out what to do. That is the question that nobody had really clearly addressed prior to this study,” Dr. Xu concluded.
 

Vigilance needed

Commenting on the findings for this news organization, Jerrold F. Rosenbaum, MD, Stanley Cobb Professor of Psychiatry, Harvard Medical School, Boston, urged caution when combining benzodiazepines with opioids.

“There are situations where you need to be circumspect about the use of benzodiazepines, and that’s clearly when people are being prescribed them in combination with other drugs that could be either sedating or respiratory depressant,” said Dr. Rosenbaum, who was not involved with the research.

“This paper reminds us that physicians need to be particularly vigilant about situations where patients might be combining the two agents,” he added.

Dr. Rosenbaum noted that patients who are using more medication than prescribed are at risk “for not appreciating the synergy” between the two treatments in terms of adverse events such as respiratory depression.

In addition, “if they’re intending to do themselves harm, the lethality of an overdose will be certainly far more than the benzodiazepines or opiates alone,” he said.

Another potential challenge for clinicians are situations in which patients are taking benzodiazepines for preexisting conditions that also require opiates. “Then you have to use special vigilance and try to use lowest doses to reduce the total burden of medication to minimize the potential risk,” said Dr. Rosenbaum.

The study was funded by the National Institutes of Health. Dr. Xu has reported no relevant financial relationships.

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

Buprenorphine for the treatment of opioid-use disorder (OUD) may also mitigate the risk associated with concomitant benzodiazepine and Z-drug use, which is frequent in this patient population, new research suggests.

A case-crossover study of more than 20,000 participants with OUD showed that drug treatment days in which benzodiazepines and Z-drugs were taken were associated with an 88% increase in nonfatal overdose; buprenorphine appeared to reduce this risk by almost 40%.

“One of our two primary findings is that patients with opioid use disorder can still benefit substantially from buprenorphine treatment, even if they have benzodiazepines on board,” lead author Kevin Xu, MD, a resident at the Washington University, St. Louis, told this news organization.

The other key finding was that “not all benzodiazepines are equal” and that some are associated with higher risk than others, Dr. Xu added.

“If anything, patients who are on buprenorphine and benzodiazepines do not necessarily need to be abruptly tapered off their benzodiazepines. Our data actually demonstrate that there are safe avenues for them,” he added.

The findings were published online March 3 in the American Journal of Psychiatry.
 

Cloudy relationship

Buprenorphine is commonly used to treat patients with OUD because of its ability to decrease all-cause mortality. However, up to 30% of these patients also take benzodiazepines for comorbid mood and anxiety disorders, Dr. Xu noted.

In addition, recent research shows that benzodiazepine/Z-drug use is associated with a variety of potential adverse effects, including respiratory depression, overdose, and addiction risk.

The relationship between benzodiazepine use and buprenorphine treatment outcomes is poorly characterized in individuals with OUD. Although some studies suggest benzodiazepines may enhance retention in buprenorphine maintenance treatment, others suggest a link to increased adverse events, including all-cause mortality, drug-related poisonings, and accidental injury–related emergency department visits.

In addition, there has been little research on the potential adverse effects associated with use of selective benzodiazepine receptor modulators in patients with OUD. These so-called Z-drugs include zolpidem, zaleplon, and eszopiclone.

Nevertheless, previous research in the general population shows that these medications have a range of adverse effects similar to those of benzodiazepines, with comparable dose-response effects on all-cause mortality.

“The challenge for any clinician is that many patients who are addicted to opioids are also polysubstance users,” said Dr. Xu. “There are so many hopeful articles regarding the benefits of buprenorphine treatment in opioid use disorder patients, but it seems like the individuals with polysubstance use are largely ignored in the setting of the opioid epidemic.”

“And this is really the back story that got me inspired to study this particular topic,” he added.
 

Improve, nullify, or reverse?

Given these questions, the researchers set out to quantify the odds of nonfatal drug-related poisoning, including overdoses, associated with benzodiazepine or Z-drug use by patients with OUD who were also taking buprenorphine.

“While the drug-related poisoning variable encompasses opioid overdoses, we used a broad definition per CDC guidelines to also include other types of drug overdoses – including poisoning events involving stimulants, overdoses involving sedatives, and overdoses involving psychotropic prescription drugs” that are commonly used by patients with OUD, said Dr. Xu.

They also wanted to determine whether the use of benzodiazepines or Z-drugs would improve, nullify, or reverse the protective effect of buprenorphine. The researchers also evaluated whether different sedative and hypnotic subtypes of these drugs were associated with different poisoning risks.

The researchers analyzed pharmaceutical claims data from 304,676 individuals (aged 12-64 years) in the IBM MarketScan Commercial and Multi-State Medicaid Databases. All had received buprenorphine treatment for OUD between Jan. 1, 2006, and Dec. 31, 2016.

Buprenorphine use was converted to a daily milligram dose and was classified as either greater than 12 mg or less than or equal to 12 mg, because previous research suggests there may be differences in treatment retention associated with this dose. Given the case-control nature of the investigation, patients who did not experience a drug-related poisoning were excluded from the analysis.

The study’s primary unit of observation was person-days, which were those days during which patients were enrolled in a health insurance plan. Participants were evaluated for 1 year before their first drug-related poisoning and 1 year after their first such poisoning. The primary outcome was nonfatal drug-related poisonings, including overdoses. The primary exposure was determined on the basis of benzodiazepine or Z-drug prescriptions.

The daily dose of benzodiazepines or Z-drugs was standardized as a function of diazepam-equivalent milligrams. Doses were classified as either high dose (diazepam-equivalent mg dose >30 mg) or low dose (≤30 mg). The drugs were also distinguished on the basis of their pharmacologic properties, such as whether they were short-acting or long-acting.
 

37% risk reduction

Of the original cohort of 304,676 patients with OUD, the study’s final analytic sample included 23,036 patients (mean age, 30 years; 51% men), representing 14,213,075 person-days of insurance coverage. Of these, 2,210,927 person-days (15.6%) entailed claims for buprenorphine (mean daily dose, 15.4 mg; SD, 7.31 mg).

A total of 474,181 person-days included claims for benzodiazepines or Z-drugs with concurrent buprenorphine treatment. The mean daily dose of any benzodiazepine or Z-drug was 23.4 diazepam-milligram equivalents. The mean daily dose of short-acting benzodiazepines, long-acting benzodiazepines, and Z-drugs was 25.3, 31.3, and 4.9 diazepam-milligram equivalents, respectively.

Buprenorphine treatment days were associated with a 37% lower chance of drug-related poisoning (95% confidence interval, 0.60-0.66) in comparison with nontreatment days. On the other hand, the odds of poisoning increased by 81% on days on which patients were treated with Z-drugs or benzodiazepines (95% CI, 1.73-1.91).

Interestingly, individual analyses showed that benzodiazepine and Z-drug treatment days were associated with increased odds of poisoning events (odds ratio, 1.29; 95% CI, 1.19-1.39). Odds of poisoning events on benzodiazepine-only treatment days, on the other hand, were markedly lower (OR, 1.88; 95% CI, 1.78-1.98).

Subgroup analyses revealed that both short-acting and long-acting benzodiazepine treatment days were associated with comparably elevated odds of drug-related poisoning (OR, 1.86 and 1.68, respectively). High-dose benzodiazepine treatment days were associated with higher increased odds of a poisoning event (122%) in comparison with low-dose treatment days (78%).

High-dose, but not low-dose, benzodiazepine or Z-drug treatment was linked to increased poisonings when the drug was taken concurrently with buprenorphine (OR, 1.64; 95% CI, 1.39-1.93). However, the risk was still lower than the risk associated with taking the agents without concurrent treatment with buprenorphine (low-dose OR, 1.69; high-dose OR, 2.23).
 

‘Not all benzodiazepines are bad’

Dr. Xu noted that the findings have potentially important implications for clinical practice, beginning with the dose-dependent relationship between benzodiazepine/Z-drug use and drug-related poisonings among individuals with OUD. This indicates that lowering doses or shortening treatment duration may reduce risk, he said.

Similarly, the lower risk associated with long-acting benzodiazepines relative to short-acting beonzodiazepines – as well as the substantially lower risk associated with Z-drugs, compared with either short- or long-acting benzodiazepines – suggests that switching from benzodiazepines to long-acting agents or Z-drugs may lower the risk for overdose, he added.

“Clinicians are often challenged by patients with opioid use disorder who are also on benzodiazepines or Z-drugs. There’s an inclination to say no to them, because they’re too high risk to start buprenorphine maintenance, or abruptly taper the benzodiazepines, which can be very destabilizing,” he noted.

“Our data show that people on benzodiazepines can absolutely receive buprenorphine and still get some benefit,” Dr. Xu said. “In addition, not all benzodiazepines are bad for these individuals. There are safer formulations and safer doses, too.”

However, he added, he would not initiate benzodiazepine treatment if he didn’t have to, especially long-term treatment.

“One of the messages from our data is that this clearly contributes to higher overdose risk. But we often inherit patients who already have benzodiazepines on board, so we need to figure out what to do. That is the question that nobody had really clearly addressed prior to this study,” Dr. Xu concluded.
 

Vigilance needed

Commenting on the findings for this news organization, Jerrold F. Rosenbaum, MD, Stanley Cobb Professor of Psychiatry, Harvard Medical School, Boston, urged caution when combining benzodiazepines with opioids.

“There are situations where you need to be circumspect about the use of benzodiazepines, and that’s clearly when people are being prescribed them in combination with other drugs that could be either sedating or respiratory depressant,” said Dr. Rosenbaum, who was not involved with the research.

“This paper reminds us that physicians need to be particularly vigilant about situations where patients might be combining the two agents,” he added.

Dr. Rosenbaum noted that patients who are using more medication than prescribed are at risk “for not appreciating the synergy” between the two treatments in terms of adverse events such as respiratory depression.

In addition, “if they’re intending to do themselves harm, the lethality of an overdose will be certainly far more than the benzodiazepines or opiates alone,” he said.

Another potential challenge for clinicians are situations in which patients are taking benzodiazepines for preexisting conditions that also require opiates. “Then you have to use special vigilance and try to use lowest doses to reduce the total burden of medication to minimize the potential risk,” said Dr. Rosenbaum.

The study was funded by the National Institutes of Health. Dr. Xu has reported no relevant financial relationships.

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

Buprenorphine for the treatment of opioid-use disorder (OUD) may also mitigate the risk associated with concomitant benzodiazepine and Z-drug use, which is frequent in this patient population, new research suggests.

A case-crossover study of more than 20,000 participants with OUD showed that drug treatment days in which benzodiazepines and Z-drugs were taken were associated with an 88% increase in nonfatal overdose; buprenorphine appeared to reduce this risk by almost 40%.

“One of our two primary findings is that patients with opioid use disorder can still benefit substantially from buprenorphine treatment, even if they have benzodiazepines on board,” lead author Kevin Xu, MD, a resident at the Washington University, St. Louis, told this news organization.

The other key finding was that “not all benzodiazepines are equal” and that some are associated with higher risk than others, Dr. Xu added.

“If anything, patients who are on buprenorphine and benzodiazepines do not necessarily need to be abruptly tapered off their benzodiazepines. Our data actually demonstrate that there are safe avenues for them,” he added.

The findings were published online March 3 in the American Journal of Psychiatry.
 

Cloudy relationship

Buprenorphine is commonly used to treat patients with OUD because of its ability to decrease all-cause mortality. However, up to 30% of these patients also take benzodiazepines for comorbid mood and anxiety disorders, Dr. Xu noted.

In addition, recent research shows that benzodiazepine/Z-drug use is associated with a variety of potential adverse effects, including respiratory depression, overdose, and addiction risk.

The relationship between benzodiazepine use and buprenorphine treatment outcomes is poorly characterized in individuals with OUD. Although some studies suggest benzodiazepines may enhance retention in buprenorphine maintenance treatment, others suggest a link to increased adverse events, including all-cause mortality, drug-related poisonings, and accidental injury–related emergency department visits.

In addition, there has been little research on the potential adverse effects associated with use of selective benzodiazepine receptor modulators in patients with OUD. These so-called Z-drugs include zolpidem, zaleplon, and eszopiclone.

Nevertheless, previous research in the general population shows that these medications have a range of adverse effects similar to those of benzodiazepines, with comparable dose-response effects on all-cause mortality.

“The challenge for any clinician is that many patients who are addicted to opioids are also polysubstance users,” said Dr. Xu. “There are so many hopeful articles regarding the benefits of buprenorphine treatment in opioid use disorder patients, but it seems like the individuals with polysubstance use are largely ignored in the setting of the opioid epidemic.”

“And this is really the back story that got me inspired to study this particular topic,” he added.
 

Improve, nullify, or reverse?

Given these questions, the researchers set out to quantify the odds of nonfatal drug-related poisoning, including overdoses, associated with benzodiazepine or Z-drug use by patients with OUD who were also taking buprenorphine.

“While the drug-related poisoning variable encompasses opioid overdoses, we used a broad definition per CDC guidelines to also include other types of drug overdoses – including poisoning events involving stimulants, overdoses involving sedatives, and overdoses involving psychotropic prescription drugs” that are commonly used by patients with OUD, said Dr. Xu.

They also wanted to determine whether the use of benzodiazepines or Z-drugs would improve, nullify, or reverse the protective effect of buprenorphine. The researchers also evaluated whether different sedative and hypnotic subtypes of these drugs were associated with different poisoning risks.

The researchers analyzed pharmaceutical claims data from 304,676 individuals (aged 12-64 years) in the IBM MarketScan Commercial and Multi-State Medicaid Databases. All had received buprenorphine treatment for OUD between Jan. 1, 2006, and Dec. 31, 2016.

Buprenorphine use was converted to a daily milligram dose and was classified as either greater than 12 mg or less than or equal to 12 mg, because previous research suggests there may be differences in treatment retention associated with this dose. Given the case-control nature of the investigation, patients who did not experience a drug-related poisoning were excluded from the analysis.

The study’s primary unit of observation was person-days, which were those days during which patients were enrolled in a health insurance plan. Participants were evaluated for 1 year before their first drug-related poisoning and 1 year after their first such poisoning. The primary outcome was nonfatal drug-related poisonings, including overdoses. The primary exposure was determined on the basis of benzodiazepine or Z-drug prescriptions.

The daily dose of benzodiazepines or Z-drugs was standardized as a function of diazepam-equivalent milligrams. Doses were classified as either high dose (diazepam-equivalent mg dose >30 mg) or low dose (≤30 mg). The drugs were also distinguished on the basis of their pharmacologic properties, such as whether they were short-acting or long-acting.
 

37% risk reduction

Of the original cohort of 304,676 patients with OUD, the study’s final analytic sample included 23,036 patients (mean age, 30 years; 51% men), representing 14,213,075 person-days of insurance coverage. Of these, 2,210,927 person-days (15.6%) entailed claims for buprenorphine (mean daily dose, 15.4 mg; SD, 7.31 mg).

A total of 474,181 person-days included claims for benzodiazepines or Z-drugs with concurrent buprenorphine treatment. The mean daily dose of any benzodiazepine or Z-drug was 23.4 diazepam-milligram equivalents. The mean daily dose of short-acting benzodiazepines, long-acting benzodiazepines, and Z-drugs was 25.3, 31.3, and 4.9 diazepam-milligram equivalents, respectively.

Buprenorphine treatment days were associated with a 37% lower chance of drug-related poisoning (95% confidence interval, 0.60-0.66) in comparison with nontreatment days. On the other hand, the odds of poisoning increased by 81% on days on which patients were treated with Z-drugs or benzodiazepines (95% CI, 1.73-1.91).

Interestingly, individual analyses showed that benzodiazepine and Z-drug treatment days were associated with increased odds of poisoning events (odds ratio, 1.29; 95% CI, 1.19-1.39). Odds of poisoning events on benzodiazepine-only treatment days, on the other hand, were markedly lower (OR, 1.88; 95% CI, 1.78-1.98).

Subgroup analyses revealed that both short-acting and long-acting benzodiazepine treatment days were associated with comparably elevated odds of drug-related poisoning (OR, 1.86 and 1.68, respectively). High-dose benzodiazepine treatment days were associated with higher increased odds of a poisoning event (122%) in comparison with low-dose treatment days (78%).

High-dose, but not low-dose, benzodiazepine or Z-drug treatment was linked to increased poisonings when the drug was taken concurrently with buprenorphine (OR, 1.64; 95% CI, 1.39-1.93). However, the risk was still lower than the risk associated with taking the agents without concurrent treatment with buprenorphine (low-dose OR, 1.69; high-dose OR, 2.23).
 

‘Not all benzodiazepines are bad’

Dr. Xu noted that the findings have potentially important implications for clinical practice, beginning with the dose-dependent relationship between benzodiazepine/Z-drug use and drug-related poisonings among individuals with OUD. This indicates that lowering doses or shortening treatment duration may reduce risk, he said.

Similarly, the lower risk associated with long-acting benzodiazepines relative to short-acting beonzodiazepines – as well as the substantially lower risk associated with Z-drugs, compared with either short- or long-acting benzodiazepines – suggests that switching from benzodiazepines to long-acting agents or Z-drugs may lower the risk for overdose, he added.

“Clinicians are often challenged by patients with opioid use disorder who are also on benzodiazepines or Z-drugs. There’s an inclination to say no to them, because they’re too high risk to start buprenorphine maintenance, or abruptly taper the benzodiazepines, which can be very destabilizing,” he noted.

“Our data show that people on benzodiazepines can absolutely receive buprenorphine and still get some benefit,” Dr. Xu said. “In addition, not all benzodiazepines are bad for these individuals. There are safer formulations and safer doses, too.”

However, he added, he would not initiate benzodiazepine treatment if he didn’t have to, especially long-term treatment.

“One of the messages from our data is that this clearly contributes to higher overdose risk. But we often inherit patients who already have benzodiazepines on board, so we need to figure out what to do. That is the question that nobody had really clearly addressed prior to this study,” Dr. Xu concluded.
 

Vigilance needed

Commenting on the findings for this news organization, Jerrold F. Rosenbaum, MD, Stanley Cobb Professor of Psychiatry, Harvard Medical School, Boston, urged caution when combining benzodiazepines with opioids.

“There are situations where you need to be circumspect about the use of benzodiazepines, and that’s clearly when people are being prescribed them in combination with other drugs that could be either sedating or respiratory depressant,” said Dr. Rosenbaum, who was not involved with the research.

“This paper reminds us that physicians need to be particularly vigilant about situations where patients might be combining the two agents,” he added.

Dr. Rosenbaum noted that patients who are using more medication than prescribed are at risk “for not appreciating the synergy” between the two treatments in terms of adverse events such as respiratory depression.

In addition, “if they’re intending to do themselves harm, the lethality of an overdose will be certainly far more than the benzodiazepines or opiates alone,” he said.

Another potential challenge for clinicians are situations in which patients are taking benzodiazepines for preexisting conditions that also require opiates. “Then you have to use special vigilance and try to use lowest doses to reduce the total burden of medication to minimize the potential risk,” said Dr. Rosenbaum.

The study was funded by the National Institutes of Health. Dr. Xu has reported no relevant financial relationships.

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