Clinical trials showing similar treatment retention with sublingual buprenorphine and extended-release naltrexone may not be representative of standard clinical practice or the broader patient population as seen in everyday settings. This study examined Medicaid data to compare the real-world effects of sublingual buprenorphine and injectable extended-release naltrexone on opioid use disorder medication treatment discontinuation, overdose, and death.
l
Buprenorphine (an opioid receptor agonist) and extended-release naltrexone (an opioid receptor antagonist) are two FDA-approved medications for the treatment of opioid use disorder that can be provided in any medical setting, including primary care. Buprenorphine and naltrexone come in many forms (e.g., injectable, sublingual, oral) but buprenorphine is most commonly prescribed as sublingual and naltrexone is only approved as an injectable form for the treatment of opioid use disorder.
In randomized trials, most patients assigned to sublingual buprenorphine successfully initiate the medication (73% to 94%), but there is wide variability in the percentage of patients who are assigned to extended-release naltrexone and actually start it (47% to 89%), likely due to the need to completely withdrawal from opioids prior to receiving extended-release naltrexone which can be difficult. However, among those who do initiate the medications, treatment retention appears to be similar for groups receiving buprenorphine and naltrexone. Still, additional research is needed to investigate other clinically-relevant outcomes (e.g., overdoses) and to examine real-world populations who aren’t assigned and/or blinded to their medication treatments. Real-world data is important because patients in clinical trials may not be representative of the general population of patients with opioid use disorder, and treatment delivery and procedures can differ between research and real-world clinical settings – e.g., challenges with personal and financial resources are common in real-world settings – which have the potential to influence treatment effectiveness in real-world scenarios.
Given the wider availability of these medications relative to more controlled medication treatments like methadone, and the need for studies examining real-world treatment outcomes outside of randomized controlled trial settings, additional naturalistic research is needed to better understand medication treatment outcomes to inform real-world clinical practice. To address this gap, this study compared the effects of sublingual buprenorphine and injectable extended-release naltrexone on opioid use disorder medication treatment discontinuation, overdose, and death, using real-world data from Medicaid patients.
This study was an observational active-comparator cohort study that compared the real-world effectiveness of sublingual buprenorphine versus extended-release injectable naltrexone (also known by the brand name Vivitrol) on medication retention and opioid-involved overdose among Medicaid patients at weeks 9, 13, 18, 22, and 26 after initiating the medication. Data was obtained from Medicaid claim records for patients in New Jersey and California between 2016 and 2019, which include inpatient and other services claims as well as pharmacy dispensing claims for Medicaid enrolled patients.
The researchers investigated the effects of these medication treatments on the following primary outcomes: (1) occurrence of medication treatment discontinuation or death; (2) occurrence of overdose or death. Overdose was defined as an ICD-10 diagnosis code for service claims for opioid overdose or unspecified narcotic poisoning. Death was defined as a death occurring due to any cause during the study period, as defined by state Medicaid data. Medication treatment discontinuation was defined as 31 days without a new medication claim, after a prior prescription claim was finished (no medication remaining). Continued use of medication treatment was defined as ongoing access to dispensed or administered patient medication per Medicaid claims.
Two outcomes were assessed for discontinuation, including (1) overall discontinuation from all medication treatment (i.e. didn’t remain on medication or switch to a different medication), and (2) discontinuation of baseline medication treatment (stopping the medication they originally initiated at the start of the study period). The pattern of outcomes were the same regardless of which discontinuation measure the researchers examined. Thus, only overall discontinuation outcomes are presented here. Outcomes were assessed (1) from baseline (treatment day 15) to the first occurrence of an outcome measure (i.e. discontinuation or death; overdose or death), over 26 weeks of treatment. The researchers assessed claims data within the first 9, 13, 18, 22, and 26 weeks of treatment (end of observation period).
To be included in the analysis, Medicaid enrollees had to be adults continuously enrolled and with opioid use disorder or a history of opioid overdose during the 6 months before treatment initiation. They could not already be receiving medication treatment in the 3 months prior to the study period, and did not have cancer and were not pregnant or receiving palliative care. Medication initiation was defined as the first day of treatment or prescription receipt, and treatment groups were defined by the type of medication (sublingual buprenorphine or extended-release naltrexone) participants were taking at baseline (i.e. 15 days into treatment to assess patients after acute stabilization). Patients were allowed to switch to different treatments (i.e. to buprenorphine, extended-release naltrexone, methadone) during the study period but their treatment group remained the same as it was at baseline. Individuals who received less than 7 days of sublingual buprenorphine were excluded from analysis to exclude patients who received these medications as part of medically-managed withdrawal. Individuals lost to follow-up were also excluded from analysis, as were those who had the first occurrence of an outcome measure of interest within the first 14 days of treatment to avoid time-related bias. To emulate randomization, the researchers controlled for baseline confounders.
For the primary outcomes noted above, the researchers estimated the average treatment effect of each medication by estimating the marginal cumulative risk (risk of an event happening in a given time frame) of each outcome throughout the 6-month follow-up period, under 2 fictional scenarios: (1) if everyone in the study initiated extended-release naltrexone and (2) if everyone in the study initiated sublingual buprenorphine.
All participants in this study (n=11,641) were ages 18 to 64, and had recently initiated extended-release injectable naltrexone (n=1,755) or sublingual buprenorphine (n=9,886) treatment for opioid use disorder. At baseline, individuals who initiated extended-release naltrexone had more severe clinical histories including greater likelihood of physical health conditions and co-occurring alcohol use disorder, to use prescribed psychotropic medications (e.g., antidepressants), and to use healthcare services than patients initiating buprenorphine. Individuals who initiated buprenorphine had higher rates of disability and chronic pain. Analyses adjusted for these baseline differences to increase their ability to attribute any outcome differences to the medications themselves and not to other factors.
Over half of patients discontinued medication treatment or died after 6 months of treatment
Fifty-eight percent of all individuals either discontinued all medication treatment (>6,738 occurrences of discontinuation) or died (<11 deaths) at some point during the 6-month follow up. When investigating the outcome of overdose or death, 3% of patients experienced an overdose (>341 overdoses) or death (<11 deaths) within 6 months of treatment.
Risk of discontinuing medication treatment or dying was greater with extended-release naltrexone
After treatment-week 9 (when analyses began counting outcomes for both groups) total discontinuation of medication treatment or death was greater among those who received extended-release naltrexone (see Figure below). By week 26 of treatment, the risk of medication discontinuation or death for patients who received extended-release naltrexone and sublingual buprenorphine was 76% and 62%, respectively. This was a risk difference of 14%, favoring sublingual buprenorphine – If all patients had been treated with extended-release naltrexone, an additional 14 patients out of every 100 patients would be expected to discontinue medication treatment or die by week 26, compared to if all patients had received sublingual buprenorphine.
Risk of overdose or death was similar for extended-release naltrexone and sublingual buprenorphine
Individuals who received extended-release naltrexone and buprenorphine had relatively similar rates of overdose or death throughout the 6-month follow up (see Figure below). By week 26 of treatment, the risk of overdose or death for patients who received extended-release naltrexone and sublingual buprenorphine was 3.9% and 3.3%, respectively. This was a risk difference of 0.5%, marginally favoring sublingual buprenorphine – If all patients had been treated with extended-release naltrexone, an additional 0.5 patients out of every 100 patients would be expected to overdose or die by week 26, compared to if all patients had received sublingual buprenorphine. When the researchers did not control for clinical severity (sensitivity analyses), individuals who received extended-release naltrexone (who had more severe and complex clinical and addiction histories) had slightly increased risk of overdose by month 6, relative to those who received buprenorphine.
In this real-world cohort study of Medicaid data, patients with opioid use disorder or a history of opioid-involved overdose receiving sublingual buprenorphine compared to extended-release naltrexone had similar risk of overdose, but lower risk of medication discontinuation, after 6 months of treatment. There were substantial differences between the groups at baseline. However, the extended-release naltrexone group was overall more clinically severe, with a greater likelihood of co-occurring substance use and other psychiatric disorders, more prior inpatient treatment and overdose experiences, and greater prior use of medications. Though the study took many steps to control statistically for this more chronic and severe case mix in the naltrexone group, it is possible that this severity marked other challenges in the extended-release naltrexone group not measured in these Medicaid claims data – such as housing instability – that explained their lower retention. That said, there may be a true advantage for the partial agonist buprenorphine on patients to continuing to take it more so than the long-acting antagonist naltrexone, because any discontinuation of agonist medications results in withdrawal symptoms that are very unpleasant. Of note, the full agonist, methadone, on average, is even better at keeping individuals on it than the partial agonist buprenorphine, possibly because of the same, but amplified, reasons of physiologic dependence.
Other clinical trials have observed similar effects on retention for these two medications. This may be due to differences in study samples (e.g., focus on populations in other countries or patients with HIV), follow-up periods (e.g., 12 vs. 26 weeks), and study design (naturalistic real-world studies vs. randomized controlled trials). For example, clinical trials often provide more intensive follow up of patients and provide outreach when appointments are missed, which is not standard in real-world clinical settings as was the case in this study. Indeed, other real-world research using commercial insurance claims in similar populations has revealed comparable outcomes to those observed in the current study, with individuals having double the risk of treatment discontinuation with extended-release naltrexone than sublingual buprenorphine. These findings too, though, may be explained – at least in part – by individuals who are more severe also being more likely to receive extended-release naltrexone compared to buprenorphine.
Extended-release naltrexone and sublingual buprenorphine both protect against opioid overdose by acting at opioid receptors in the brain. However, once a person discontinues these medications, the risk of overdose returns and may be somewhat higher for extended-release naltrexone. This is because people who discontinue buprenorphine may still have a tolerance to opioids that protects them from overdose if they return to illicit opioid use – at least for a while – whereas those who discontinue naltrexone do not have such protective opioid tolerance and, in theory, might have an increased risk of overdose if they return to illicit opioid use. It is not entirely clear why there was a similar risk of overdose for patients who received buprenorphine and naltrexone, despite the greater risk of discontinuation observed for extended-release naltrexone. Individuals receiving extended-release naltrexone were somewhat more likely to overdose when these baseline characteristics were not accounted for, suggesting that their greater clinical severity accounted in part for overdose risk in the context of medication treatment discontinuation.
Finally, despite the convenience of once-monthly dosing for injectable medication treatments, research to date is mixed as to whether injectable medications are better at retaining patients than daily dosing and additional research is needed to compare the effectiveness of extended-release buprenorphine to extended-release naltrexone and sublingual-buprenorphine during the early stages of opioid use disorder treatment.
Over half of Medicaid patients who initiated medication treatment with extended-release naltrexone or sublingual buprenorphine discontinued medication treatment after 6 months. Only 3% of patients experienced overdose or death by month 6. Stopping medication use by month 6 was greater for extended-release naltrexone than sublingual buprenorphine. Had all patients initiated extended-release naltrexone, an additional 14 out of every 100 patients would be expected to discontinue their medication within 6 months. Despite this increased risk of discontinuation for extended-release naltrexone, overdose rates from this Medicaid data were relatively low (~3% overdosed or died) and did not differ between naltrexone and buprenorphine treatment groups. The extended-release naltrexone group had higher raw overdose rates, but this disadvantage disappeared once this group’s greater clinical severity was controlled for statistically, suggesting clinical severity rather than medication type may be more responsible for this higher rate of overdose. Findings emphasize potential differences between clinical trials and real-world data that demand additional research to clarify what medications work best for whom in real-world clinical settings.
Ross, R. K., Nunes, E. V., Olfson, M., Shulman, M., Krawczyk, N., Stuart, E. A., & Rudolph, K. E. (2024). Comparative effectiveness of extended release naltrexone and sublingual buprenorphine for treatment of opioid use disorder among Medicaid patients. Addiction, 119(11). doi: 10.1111/add.16630.
l
Buprenorphine (an opioid receptor agonist) and extended-release naltrexone (an opioid receptor antagonist) are two FDA-approved medications for the treatment of opioid use disorder that can be provided in any medical setting, including primary care. Buprenorphine and naltrexone come in many forms (e.g., injectable, sublingual, oral) but buprenorphine is most commonly prescribed as sublingual and naltrexone is only approved as an injectable form for the treatment of opioid use disorder.
In randomized trials, most patients assigned to sublingual buprenorphine successfully initiate the medication (73% to 94%), but there is wide variability in the percentage of patients who are assigned to extended-release naltrexone and actually start it (47% to 89%), likely due to the need to completely withdrawal from opioids prior to receiving extended-release naltrexone which can be difficult. However, among those who do initiate the medications, treatment retention appears to be similar for groups receiving buprenorphine and naltrexone. Still, additional research is needed to investigate other clinically-relevant outcomes (e.g., overdoses) and to examine real-world populations who aren’t assigned and/or blinded to their medication treatments. Real-world data is important because patients in clinical trials may not be representative of the general population of patients with opioid use disorder, and treatment delivery and procedures can differ between research and real-world clinical settings – e.g., challenges with personal and financial resources are common in real-world settings – which have the potential to influence treatment effectiveness in real-world scenarios.
Given the wider availability of these medications relative to more controlled medication treatments like methadone, and the need for studies examining real-world treatment outcomes outside of randomized controlled trial settings, additional naturalistic research is needed to better understand medication treatment outcomes to inform real-world clinical practice. To address this gap, this study compared the effects of sublingual buprenorphine and injectable extended-release naltrexone on opioid use disorder medication treatment discontinuation, overdose, and death, using real-world data from Medicaid patients.
This study was an observational active-comparator cohort study that compared the real-world effectiveness of sublingual buprenorphine versus extended-release injectable naltrexone (also known by the brand name Vivitrol) on medication retention and opioid-involved overdose among Medicaid patients at weeks 9, 13, 18, 22, and 26 after initiating the medication. Data was obtained from Medicaid claim records for patients in New Jersey and California between 2016 and 2019, which include inpatient and other services claims as well as pharmacy dispensing claims for Medicaid enrolled patients.
The researchers investigated the effects of these medication treatments on the following primary outcomes: (1) occurrence of medication treatment discontinuation or death; (2) occurrence of overdose or death. Overdose was defined as an ICD-10 diagnosis code for service claims for opioid overdose or unspecified narcotic poisoning. Death was defined as a death occurring due to any cause during the study period, as defined by state Medicaid data. Medication treatment discontinuation was defined as 31 days without a new medication claim, after a prior prescription claim was finished (no medication remaining). Continued use of medication treatment was defined as ongoing access to dispensed or administered patient medication per Medicaid claims.
Two outcomes were assessed for discontinuation, including (1) overall discontinuation from all medication treatment (i.e. didn’t remain on medication or switch to a different medication), and (2) discontinuation of baseline medication treatment (stopping the medication they originally initiated at the start of the study period). The pattern of outcomes were the same regardless of which discontinuation measure the researchers examined. Thus, only overall discontinuation outcomes are presented here. Outcomes were assessed (1) from baseline (treatment day 15) to the first occurrence of an outcome measure (i.e. discontinuation or death; overdose or death), over 26 weeks of treatment. The researchers assessed claims data within the first 9, 13, 18, 22, and 26 weeks of treatment (end of observation period).
To be included in the analysis, Medicaid enrollees had to be adults continuously enrolled and with opioid use disorder or a history of opioid overdose during the 6 months before treatment initiation. They could not already be receiving medication treatment in the 3 months prior to the study period, and did not have cancer and were not pregnant or receiving palliative care. Medication initiation was defined as the first day of treatment or prescription receipt, and treatment groups were defined by the type of medication (sublingual buprenorphine or extended-release naltrexone) participants were taking at baseline (i.e. 15 days into treatment to assess patients after acute stabilization). Patients were allowed to switch to different treatments (i.e. to buprenorphine, extended-release naltrexone, methadone) during the study period but their treatment group remained the same as it was at baseline. Individuals who received less than 7 days of sublingual buprenorphine were excluded from analysis to exclude patients who received these medications as part of medically-managed withdrawal. Individuals lost to follow-up were also excluded from analysis, as were those who had the first occurrence of an outcome measure of interest within the first 14 days of treatment to avoid time-related bias. To emulate randomization, the researchers controlled for baseline confounders.
For the primary outcomes noted above, the researchers estimated the average treatment effect of each medication by estimating the marginal cumulative risk (risk of an event happening in a given time frame) of each outcome throughout the 6-month follow-up period, under 2 fictional scenarios: (1) if everyone in the study initiated extended-release naltrexone and (2) if everyone in the study initiated sublingual buprenorphine.
All participants in this study (n=11,641) were ages 18 to 64, and had recently initiated extended-release injectable naltrexone (n=1,755) or sublingual buprenorphine (n=9,886) treatment for opioid use disorder. At baseline, individuals who initiated extended-release naltrexone had more severe clinical histories including greater likelihood of physical health conditions and co-occurring alcohol use disorder, to use prescribed psychotropic medications (e.g., antidepressants), and to use healthcare services than patients initiating buprenorphine. Individuals who initiated buprenorphine had higher rates of disability and chronic pain. Analyses adjusted for these baseline differences to increase their ability to attribute any outcome differences to the medications themselves and not to other factors.
Over half of patients discontinued medication treatment or died after 6 months of treatment
Fifty-eight percent of all individuals either discontinued all medication treatment (>6,738 occurrences of discontinuation) or died (<11 deaths) at some point during the 6-month follow up. When investigating the outcome of overdose or death, 3% of patients experienced an overdose (>341 overdoses) or death (<11 deaths) within 6 months of treatment.
Risk of discontinuing medication treatment or dying was greater with extended-release naltrexone
After treatment-week 9 (when analyses began counting outcomes for both groups) total discontinuation of medication treatment or death was greater among those who received extended-release naltrexone (see Figure below). By week 26 of treatment, the risk of medication discontinuation or death for patients who received extended-release naltrexone and sublingual buprenorphine was 76% and 62%, respectively. This was a risk difference of 14%, favoring sublingual buprenorphine – If all patients had been treated with extended-release naltrexone, an additional 14 patients out of every 100 patients would be expected to discontinue medication treatment or die by week 26, compared to if all patients had received sublingual buprenorphine.
Risk of overdose or death was similar for extended-release naltrexone and sublingual buprenorphine
Individuals who received extended-release naltrexone and buprenorphine had relatively similar rates of overdose or death throughout the 6-month follow up (see Figure below). By week 26 of treatment, the risk of overdose or death for patients who received extended-release naltrexone and sublingual buprenorphine was 3.9% and 3.3%, respectively. This was a risk difference of 0.5%, marginally favoring sublingual buprenorphine – If all patients had been treated with extended-release naltrexone, an additional 0.5 patients out of every 100 patients would be expected to overdose or die by week 26, compared to if all patients had received sublingual buprenorphine. When the researchers did not control for clinical severity (sensitivity analyses), individuals who received extended-release naltrexone (who had more severe and complex clinical and addiction histories) had slightly increased risk of overdose by month 6, relative to those who received buprenorphine.
In this real-world cohort study of Medicaid data, patients with opioid use disorder or a history of opioid-involved overdose receiving sublingual buprenorphine compared to extended-release naltrexone had similar risk of overdose, but lower risk of medication discontinuation, after 6 months of treatment. There were substantial differences between the groups at baseline. However, the extended-release naltrexone group was overall more clinically severe, with a greater likelihood of co-occurring substance use and other psychiatric disorders, more prior inpatient treatment and overdose experiences, and greater prior use of medications. Though the study took many steps to control statistically for this more chronic and severe case mix in the naltrexone group, it is possible that this severity marked other challenges in the extended-release naltrexone group not measured in these Medicaid claims data – such as housing instability – that explained their lower retention. That said, there may be a true advantage for the partial agonist buprenorphine on patients to continuing to take it more so than the long-acting antagonist naltrexone, because any discontinuation of agonist medications results in withdrawal symptoms that are very unpleasant. Of note, the full agonist, methadone, on average, is even better at keeping individuals on it than the partial agonist buprenorphine, possibly because of the same, but amplified, reasons of physiologic dependence.
Other clinical trials have observed similar effects on retention for these two medications. This may be due to differences in study samples (e.g., focus on populations in other countries or patients with HIV), follow-up periods (e.g., 12 vs. 26 weeks), and study design (naturalistic real-world studies vs. randomized controlled trials). For example, clinical trials often provide more intensive follow up of patients and provide outreach when appointments are missed, which is not standard in real-world clinical settings as was the case in this study. Indeed, other real-world research using commercial insurance claims in similar populations has revealed comparable outcomes to those observed in the current study, with individuals having double the risk of treatment discontinuation with extended-release naltrexone than sublingual buprenorphine. These findings too, though, may be explained – at least in part – by individuals who are more severe also being more likely to receive extended-release naltrexone compared to buprenorphine.
Extended-release naltrexone and sublingual buprenorphine both protect against opioid overdose by acting at opioid receptors in the brain. However, once a person discontinues these medications, the risk of overdose returns and may be somewhat higher for extended-release naltrexone. This is because people who discontinue buprenorphine may still have a tolerance to opioids that protects them from overdose if they return to illicit opioid use – at least for a while – whereas those who discontinue naltrexone do not have such protective opioid tolerance and, in theory, might have an increased risk of overdose if they return to illicit opioid use. It is not entirely clear why there was a similar risk of overdose for patients who received buprenorphine and naltrexone, despite the greater risk of discontinuation observed for extended-release naltrexone. Individuals receiving extended-release naltrexone were somewhat more likely to overdose when these baseline characteristics were not accounted for, suggesting that their greater clinical severity accounted in part for overdose risk in the context of medication treatment discontinuation.
Finally, despite the convenience of once-monthly dosing for injectable medication treatments, research to date is mixed as to whether injectable medications are better at retaining patients than daily dosing and additional research is needed to compare the effectiveness of extended-release buprenorphine to extended-release naltrexone and sublingual-buprenorphine during the early stages of opioid use disorder treatment.
Over half of Medicaid patients who initiated medication treatment with extended-release naltrexone or sublingual buprenorphine discontinued medication treatment after 6 months. Only 3% of patients experienced overdose or death by month 6. Stopping medication use by month 6 was greater for extended-release naltrexone than sublingual buprenorphine. Had all patients initiated extended-release naltrexone, an additional 14 out of every 100 patients would be expected to discontinue their medication within 6 months. Despite this increased risk of discontinuation for extended-release naltrexone, overdose rates from this Medicaid data were relatively low (~3% overdosed or died) and did not differ between naltrexone and buprenorphine treatment groups. The extended-release naltrexone group had higher raw overdose rates, but this disadvantage disappeared once this group’s greater clinical severity was controlled for statistically, suggesting clinical severity rather than medication type may be more responsible for this higher rate of overdose. Findings emphasize potential differences between clinical trials and real-world data that demand additional research to clarify what medications work best for whom in real-world clinical settings.
Ross, R. K., Nunes, E. V., Olfson, M., Shulman, M., Krawczyk, N., Stuart, E. A., & Rudolph, K. E. (2024). Comparative effectiveness of extended release naltrexone and sublingual buprenorphine for treatment of opioid use disorder among Medicaid patients. Addiction, 119(11). doi: 10.1111/add.16630.
l
Buprenorphine (an opioid receptor agonist) and extended-release naltrexone (an opioid receptor antagonist) are two FDA-approved medications for the treatment of opioid use disorder that can be provided in any medical setting, including primary care. Buprenorphine and naltrexone come in many forms (e.g., injectable, sublingual, oral) but buprenorphine is most commonly prescribed as sublingual and naltrexone is only approved as an injectable form for the treatment of opioid use disorder.
In randomized trials, most patients assigned to sublingual buprenorphine successfully initiate the medication (73% to 94%), but there is wide variability in the percentage of patients who are assigned to extended-release naltrexone and actually start it (47% to 89%), likely due to the need to completely withdrawal from opioids prior to receiving extended-release naltrexone which can be difficult. However, among those who do initiate the medications, treatment retention appears to be similar for groups receiving buprenorphine and naltrexone. Still, additional research is needed to investigate other clinically-relevant outcomes (e.g., overdoses) and to examine real-world populations who aren’t assigned and/or blinded to their medication treatments. Real-world data is important because patients in clinical trials may not be representative of the general population of patients with opioid use disorder, and treatment delivery and procedures can differ between research and real-world clinical settings – e.g., challenges with personal and financial resources are common in real-world settings – which have the potential to influence treatment effectiveness in real-world scenarios.
Given the wider availability of these medications relative to more controlled medication treatments like methadone, and the need for studies examining real-world treatment outcomes outside of randomized controlled trial settings, additional naturalistic research is needed to better understand medication treatment outcomes to inform real-world clinical practice. To address this gap, this study compared the effects of sublingual buprenorphine and injectable extended-release naltrexone on opioid use disorder medication treatment discontinuation, overdose, and death, using real-world data from Medicaid patients.
This study was an observational active-comparator cohort study that compared the real-world effectiveness of sublingual buprenorphine versus extended-release injectable naltrexone (also known by the brand name Vivitrol) on medication retention and opioid-involved overdose among Medicaid patients at weeks 9, 13, 18, 22, and 26 after initiating the medication. Data was obtained from Medicaid claim records for patients in New Jersey and California between 2016 and 2019, which include inpatient and other services claims as well as pharmacy dispensing claims for Medicaid enrolled patients.
The researchers investigated the effects of these medication treatments on the following primary outcomes: (1) occurrence of medication treatment discontinuation or death; (2) occurrence of overdose or death. Overdose was defined as an ICD-10 diagnosis code for service claims for opioid overdose or unspecified narcotic poisoning. Death was defined as a death occurring due to any cause during the study period, as defined by state Medicaid data. Medication treatment discontinuation was defined as 31 days without a new medication claim, after a prior prescription claim was finished (no medication remaining). Continued use of medication treatment was defined as ongoing access to dispensed or administered patient medication per Medicaid claims.
Two outcomes were assessed for discontinuation, including (1) overall discontinuation from all medication treatment (i.e. didn’t remain on medication or switch to a different medication), and (2) discontinuation of baseline medication treatment (stopping the medication they originally initiated at the start of the study period). The pattern of outcomes were the same regardless of which discontinuation measure the researchers examined. Thus, only overall discontinuation outcomes are presented here. Outcomes were assessed (1) from baseline (treatment day 15) to the first occurrence of an outcome measure (i.e. discontinuation or death; overdose or death), over 26 weeks of treatment. The researchers assessed claims data within the first 9, 13, 18, 22, and 26 weeks of treatment (end of observation period).
To be included in the analysis, Medicaid enrollees had to be adults continuously enrolled and with opioid use disorder or a history of opioid overdose during the 6 months before treatment initiation. They could not already be receiving medication treatment in the 3 months prior to the study period, and did not have cancer and were not pregnant or receiving palliative care. Medication initiation was defined as the first day of treatment or prescription receipt, and treatment groups were defined by the type of medication (sublingual buprenorphine or extended-release naltrexone) participants were taking at baseline (i.e. 15 days into treatment to assess patients after acute stabilization). Patients were allowed to switch to different treatments (i.e. to buprenorphine, extended-release naltrexone, methadone) during the study period but their treatment group remained the same as it was at baseline. Individuals who received less than 7 days of sublingual buprenorphine were excluded from analysis to exclude patients who received these medications as part of medically-managed withdrawal. Individuals lost to follow-up were also excluded from analysis, as were those who had the first occurrence of an outcome measure of interest within the first 14 days of treatment to avoid time-related bias. To emulate randomization, the researchers controlled for baseline confounders.
For the primary outcomes noted above, the researchers estimated the average treatment effect of each medication by estimating the marginal cumulative risk (risk of an event happening in a given time frame) of each outcome throughout the 6-month follow-up period, under 2 fictional scenarios: (1) if everyone in the study initiated extended-release naltrexone and (2) if everyone in the study initiated sublingual buprenorphine.
All participants in this study (n=11,641) were ages 18 to 64, and had recently initiated extended-release injectable naltrexone (n=1,755) or sublingual buprenorphine (n=9,886) treatment for opioid use disorder. At baseline, individuals who initiated extended-release naltrexone had more severe clinical histories including greater likelihood of physical health conditions and co-occurring alcohol use disorder, to use prescribed psychotropic medications (e.g., antidepressants), and to use healthcare services than patients initiating buprenorphine. Individuals who initiated buprenorphine had higher rates of disability and chronic pain. Analyses adjusted for these baseline differences to increase their ability to attribute any outcome differences to the medications themselves and not to other factors.
Over half of patients discontinued medication treatment or died after 6 months of treatment
Fifty-eight percent of all individuals either discontinued all medication treatment (>6,738 occurrences of discontinuation) or died (<11 deaths) at some point during the 6-month follow up. When investigating the outcome of overdose or death, 3% of patients experienced an overdose (>341 overdoses) or death (<11 deaths) within 6 months of treatment.
Risk of discontinuing medication treatment or dying was greater with extended-release naltrexone
After treatment-week 9 (when analyses began counting outcomes for both groups) total discontinuation of medication treatment or death was greater among those who received extended-release naltrexone (see Figure below). By week 26 of treatment, the risk of medication discontinuation or death for patients who received extended-release naltrexone and sublingual buprenorphine was 76% and 62%, respectively. This was a risk difference of 14%, favoring sublingual buprenorphine – If all patients had been treated with extended-release naltrexone, an additional 14 patients out of every 100 patients would be expected to discontinue medication treatment or die by week 26, compared to if all patients had received sublingual buprenorphine.
Risk of overdose or death was similar for extended-release naltrexone and sublingual buprenorphine
Individuals who received extended-release naltrexone and buprenorphine had relatively similar rates of overdose or death throughout the 6-month follow up (see Figure below). By week 26 of treatment, the risk of overdose or death for patients who received extended-release naltrexone and sublingual buprenorphine was 3.9% and 3.3%, respectively. This was a risk difference of 0.5%, marginally favoring sublingual buprenorphine – If all patients had been treated with extended-release naltrexone, an additional 0.5 patients out of every 100 patients would be expected to overdose or die by week 26, compared to if all patients had received sublingual buprenorphine. When the researchers did not control for clinical severity (sensitivity analyses), individuals who received extended-release naltrexone (who had more severe and complex clinical and addiction histories) had slightly increased risk of overdose by month 6, relative to those who received buprenorphine.
In this real-world cohort study of Medicaid data, patients with opioid use disorder or a history of opioid-involved overdose receiving sublingual buprenorphine compared to extended-release naltrexone had similar risk of overdose, but lower risk of medication discontinuation, after 6 months of treatment. There were substantial differences between the groups at baseline. However, the extended-release naltrexone group was overall more clinically severe, with a greater likelihood of co-occurring substance use and other psychiatric disorders, more prior inpatient treatment and overdose experiences, and greater prior use of medications. Though the study took many steps to control statistically for this more chronic and severe case mix in the naltrexone group, it is possible that this severity marked other challenges in the extended-release naltrexone group not measured in these Medicaid claims data – such as housing instability – that explained their lower retention. That said, there may be a true advantage for the partial agonist buprenorphine on patients to continuing to take it more so than the long-acting antagonist naltrexone, because any discontinuation of agonist medications results in withdrawal symptoms that are very unpleasant. Of note, the full agonist, methadone, on average, is even better at keeping individuals on it than the partial agonist buprenorphine, possibly because of the same, but amplified, reasons of physiologic dependence.
Other clinical trials have observed similar effects on retention for these two medications. This may be due to differences in study samples (e.g., focus on populations in other countries or patients with HIV), follow-up periods (e.g., 12 vs. 26 weeks), and study design (naturalistic real-world studies vs. randomized controlled trials). For example, clinical trials often provide more intensive follow up of patients and provide outreach when appointments are missed, which is not standard in real-world clinical settings as was the case in this study. Indeed, other real-world research using commercial insurance claims in similar populations has revealed comparable outcomes to those observed in the current study, with individuals having double the risk of treatment discontinuation with extended-release naltrexone than sublingual buprenorphine. These findings too, though, may be explained – at least in part – by individuals who are more severe also being more likely to receive extended-release naltrexone compared to buprenorphine.
Extended-release naltrexone and sublingual buprenorphine both protect against opioid overdose by acting at opioid receptors in the brain. However, once a person discontinues these medications, the risk of overdose returns and may be somewhat higher for extended-release naltrexone. This is because people who discontinue buprenorphine may still have a tolerance to opioids that protects them from overdose if they return to illicit opioid use – at least for a while – whereas those who discontinue naltrexone do not have such protective opioid tolerance and, in theory, might have an increased risk of overdose if they return to illicit opioid use. It is not entirely clear why there was a similar risk of overdose for patients who received buprenorphine and naltrexone, despite the greater risk of discontinuation observed for extended-release naltrexone. Individuals receiving extended-release naltrexone were somewhat more likely to overdose when these baseline characteristics were not accounted for, suggesting that their greater clinical severity accounted in part for overdose risk in the context of medication treatment discontinuation.
Finally, despite the convenience of once-monthly dosing for injectable medication treatments, research to date is mixed as to whether injectable medications are better at retaining patients than daily dosing and additional research is needed to compare the effectiveness of extended-release buprenorphine to extended-release naltrexone and sublingual-buprenorphine during the early stages of opioid use disorder treatment.
Over half of Medicaid patients who initiated medication treatment with extended-release naltrexone or sublingual buprenorphine discontinued medication treatment after 6 months. Only 3% of patients experienced overdose or death by month 6. Stopping medication use by month 6 was greater for extended-release naltrexone than sublingual buprenorphine. Had all patients initiated extended-release naltrexone, an additional 14 out of every 100 patients would be expected to discontinue their medication within 6 months. Despite this increased risk of discontinuation for extended-release naltrexone, overdose rates from this Medicaid data were relatively low (~3% overdosed or died) and did not differ between naltrexone and buprenorphine treatment groups. The extended-release naltrexone group had higher raw overdose rates, but this disadvantage disappeared once this group’s greater clinical severity was controlled for statistically, suggesting clinical severity rather than medication type may be more responsible for this higher rate of overdose. Findings emphasize potential differences between clinical trials and real-world data that demand additional research to clarify what medications work best for whom in real-world clinical settings.
Ross, R. K., Nunes, E. V., Olfson, M., Shulman, M., Krawczyk, N., Stuart, E. A., & Rudolph, K. E. (2024). Comparative effectiveness of extended release naltrexone and sublingual buprenorphine for treatment of opioid use disorder among Medicaid patients. Addiction, 119(11). doi: 10.1111/add.16630.
SIGN UP FOR THE BULLETIN
