Buprenorphine for the remedy of opioid-use dysfunction (OUD) may mitigate the danger related to concomitant benzodiazepine and Z-drug use, which is frequent on this affected person inhabitants, new analysis suggests.
A case-crossover research of greater than 20,000 members with OUD confirmed that drug remedy days by which benzodiazepines and Z-drugs had been taken had been related to an 88% improve in nonfatal overdose; buprenorphine appeared to scale back this threat by nearly 40%.
“One in every of our two major findings is that sufferers with opioid use dysfunction can nonetheless profit considerably from buprenorphine remedy, even when they’ve benzodiazepines on board,” lead creator Kevin Xu, MD, a resident on the Washington College College of Medication, St. Louis, Missouri, advised Medscape Medical Information.
The opposite key discovering was that “not all benzodiazepines are equal” and that some are related to larger threat than others, Xu added.
“If something, sufferers who’re on buprenorphine and benzodiazepines don’t essentially have to be abruptly tapered off their benzodiazepines. Our information truly reveal that there are protected avenues for them,” he added.
The findings had been published online March 3 within the American Journal of Psychiatry.
Buprenorphine is often used to deal with sufferers with OUD due to its capacity to lower all-cause mortality. Nonetheless, as much as 30% of those sufferers additionally take benzodiazepines for comorbid temper and anxiety disorders, Xu famous.
The connection between benzodiazepine use and buprenorphine remedy outcomes is poorly characterised in people with OUD. Though some research recommend benzodiazepines might improve retention in buprenorphine upkeep remedy, others recommend a hyperlink to elevated hostile occasions, together with all-cause mortality, drug-related poisonings, and unintentional damage–associated emergency division visits.
As well as, there was little analysis on the potential hostile results related to use of selective benzodiazepine receptor modulators in sufferers with OUD. These so-called Z-drugs embody zolpidem, zaleplon, and eszopiclone.
Nonetheless, earlier analysis within the common inhabitants exhibits that these drugs have a variety of hostile results just like these of benzodiazepines, with comparable dose-response results on all-cause mortality.
“The problem for any clinician is that many sufferers who’re hooked on opioids are additionally polysubstance customers,” mentioned Xu. “There are such a lot of hopeful articles relating to the advantages of buprenorphine remedy in opioid use dysfunction sufferers, nevertheless it looks like the people with polysubstance use are largely ignored within the setting of the opioid epidemic.
“And that is actually the again story that acquired me impressed to review this specific subject,” he added.
Enhance, Nullify, or Reverse?
Given these questions, the researchers got down to quantify the chances of nonfatal drug-related poisoning, together with overdoses, related to benzodiazepine or Z-drug use by sufferers with OUD who had been additionally taking buprenorphine.
“Whereas the drug-related poisoning variable encompasses opioid overdoses, we used a broad definition per CDC pointers to additionally embody different sorts of drug overdoses ― together with poisoning occasions involving stimulants, overdoses involving sedatives, and overdoses involving psychotropic prescribed drugs” which might be generally utilized by sufferers with OUD, mentioned Xu.
Additionally they wished to find out whether or not the usage of benzodiazepines or Z-drugs would enhance, nullify, or reverse the protecting impact of buprenorphine. The researchers additionally evaluated whether or not completely different sedative and hypnotic subtypes of those medication had been related to completely different poisoning dangers.
The researchers analyzed pharmaceutical claims information from 304,676 people (aged 12 to 64 years) within the IBM MarketScan Industrial and Multi-State Medicaid Databases. All had acquired buprenorphine remedy for OUD between January 1, 2006, and December 31, 2016.
Buprenorphine use was transformed to a every day milligram dose and was labeled as both >12 mg or ≤12 mg, as a result of previous research suggests there could also be variations in remedy retention related to this dose. Given the case-control nature of the investigation, sufferers who didn’t expertise a drug-related poisoning had been excluded from the evaluation.
The research’s major unit of remark was person-days, which had been these days throughout which sufferers had been enrolled in a medical insurance plan. Contributors had been evaluated for 1 yr earlier than their first drug-related poisoning and 1 yr after their first such poisoning. The first end result was nonfatal drug-related poisonings, together with overdoses. The first publicity was decided on the premise of benzodiazepine or Z-drug prescriptions.
The every day dose of benzodiazepines or Z-drugs was standardized as a perform of diazepam-equivalent milligrams. Doses had been labeled as both excessive dose (diazepam-equivalent mg dose >30 mg) or low dose (≤30 mg). The medication had been additionally distinguished on the premise of their pharmacologic properties, corresponding to whether or not they had been quick performing or lengthy performing.
37% Danger Discount
Of the unique cohort of 304,676 sufferers with OUD, the research’s closing analytic pattern included 23,036 sufferers (imply age, 30 years; 51% males), representing 14,213,075 person-days of insurance coverage protection. Of those, 2,210,927 person-days (15.6%) entailed claims for buprenorphine (imply every day dose, 15.4 mg; SD, 7.31 mg).
A complete of 474,181 person-days included claims for benzodiazepines or Z-drugs with concurrent buprenorphine remedy. The imply every day dose of any benzodiazepine or Z-drug was 23.4 diazepam-milligram equivalents. The imply every day dose of short-acting benzodiazepines, long-acting benzodiazepines, and Z-drugs was 25.3, 31.3, and 4.9 diazepam-milligram equivalents, respectively.
Buprenorphine remedy days had been related to a 37% decrease likelihood of drug-related poisoning (95% CI, 0.60 – 0.66) compared with nontreatment days. However, the chances of poisoning elevated by 81% on days on which sufferers had been handled with Z-drugs or benzodiazepines (95% CI, 1.73 – 1.91).
Curiously, particular person analyses confirmed that benzodiazepine and Z-drug remedy days had been related to elevated odds of poisoning occasions (odds ratio [OR], 1.29; 95% CI, 1.19 – 1.39). Odds of poisoning occasions on benzodiazepine-only remedy days, alternatively, had been markedly decrease (OR, 1.88; 95% CI, 1.78 – 1.98).
Subgroup analyses revealed that each short-acting and long-acting benzodiazepine remedy days had been related to comparably elevated odds of drug-related poisoning (OR, 1.86 and 1.68, respectively). Excessive-dose benzodiazepine remedy days had been related to larger elevated odds of a poisoning occasion (122%) compared with low-dose remedy days (78%).
Excessive-dose, however not low-dose, benzodiazepine or Z-drug remedy was linked to elevated poisonings when the drug was taken concurrently with buprenorphine (OR, 1.64; 95% CI, 1.39 – 1.93). Nonetheless, the danger was nonetheless decrease than the danger related to taking the brokers with out concurrent remedy with buprenorphine (low-dose OR, 1.69; high-dose OR, 2.23).
“Not All Benzodiazepines Are Unhealthy”
Xu famous that the findings have doubtlessly vital implications for medical follow, starting with the dose-dependent relationship between benzodiazepine/Z-drug use and drug-related poisonings amongst people with OUD. This means that reducing doses or shortening remedy period might cut back threat, he mentioned.
Equally, the decrease threat related to long-acting benzodiazepines relative to short-acting beonzodiazepines – in addition to the considerably decrease threat related to Z-drugs in contrast with both short- or long-acting benzodiazepines – means that switching from benzodiazepines to long-acting brokers or Z-drugs might decrease the danger for overdose, he added.
“Clinicians are sometimes challenged by sufferers with opioid use dysfunction who’re additionally on benzodiazepines or Z-drugs. There’s an inclination to say no to them, as a result of they’re too excessive threat to begin buprenorphine upkeep, or abruptly taper the benzodiazepines, which might be very destabilizing,” he famous.
“Our information present that folks on benzodiazepines can completely obtain buprenorphine and nonetheless get some profit,” Xu mentioned. “As well as, not all benzodiazepines are dangerous for these people. There are safer formulations and safer doses, too.”
Nonetheless, he added, he wouldn’t provoke benzodiazepine remedy if he did not need to, particularly long-term remedy.
“One of many messages from our information is that this clearly contributes to larger overdose threat. However we regularly inherit sufferers who have already got benzodiazepines on board, so we have to determine what to do. That’s the query that no person had actually clearly addressed previous to this research,” Xu concluded.
Commenting on the findings for Medscape Medical Information, Jerrold F. Rosenbaum, MD, Stanley Cobb Professor of Psychiatry, Harvard Medical College, Boston, Massachusetts, urged warning when combining benzodiazepines with opioids.
“There are conditions the place it’s essential to be circumspect about the usage of benzodiazepines, and that is clearly when individuals are being prescribed them together with different medication that may very well be both sedating or respiratory depressant,” mentioned Rosenbaum, who was not concerned with the analysis.
“This paper reminds us that physicians have to be significantly vigilant about conditions the place sufferers is likely to be combining the 2 brokers,” he added.
Rosenbaum famous that sufferers who’re utilizing extra remedy than prescribed are in danger “for not appreciating the synergy” between the 2 therapies by way of hostile occasions corresponding to respiratory despair.
As well as, “in the event that they’re aspiring to do themselves hurt, the lethality of an overdose shall be actually way over the benzodiazepines or opiates alone,” he mentioned.
One other potential problem for clinicians are conditions by which sufferers are taking benzodiazepines for preexisting circumstances that additionally require opiates. “Then you need to use particular vigilance and attempt to use lowest doses to scale back the entire burden of remedy to attenuate the potential threat,” mentioned Rosenbaum.
The research was funded by the Nationwide Institutes of Well being. Xu has reported no related monetary relationships.
Am J Psychiatry. Revealed on-line March 3, 2021. Abstract