the overdose the prescription was part of
picture a man in his fifties with a bad back and a bad year. one doctor prescribes the painkiller. another prescribes something for the anxiety and the sleep. both prescriptions are legal, filled at the pharmacy, taken as directed. this page is about what the death records say happens next, how often, and what changed in 2016. it is also about the two findings that cut the other way, because a page that only had the scary half would be selling you something.
the study that counted the prescriptions
half of the deaths happened inside a quarter of the patients
the veterans health system prescribes to millions of people and records every death. researchers took everyone receiving an opioid painkiller over six years and every one of them who died of an overdose, and asked one question: what else was on the prescription record.[1] about a quarter of the people on opioids were also prescribed a benzodiazepine. about half of the overdose deaths happened while a person held both prescriptions at once. a current benzodiazepine prescription meant nearly four times the risk of dying compared with none; a former one, more than twice. the risk rose with the dose. these were not street drugs. these were two bottles from the pharmacy, each one legal, each one taken as directed.
what changed in 2016
on 31 august 2016 the food and drug administration put its strongest warning, the boxed warning, on every prescription opioid and every benzodiazepine, and told prescribers to combine them only when nothing else works.[2] its own review explained why: between 2002 and 2014, the share of people on opioids who also held a benzodiazepine prescription had grown by about two fifths, which meant more than two and a half million additional people taking both. the people most likely to be on the combination were women, people over sixty-five, and long-term opioid users.
the deaths had grown with the prescriptions. across seventeen years the rate of overdose deaths involving a benzodiazepine rose more than fivefold, while the share of adults filling a prescription grew by about a third.[3] the death rate stopped rising after 2010; it did not fall in any group the researchers looked at.
what the combination looks like now
in the most recent multi-state count, more than nine in ten benzodiazepine overdose deaths also involved an opioid, and the opioid was usually illicit fentanyl.[4] the pill alone is rarely what kills; the combination is. in a single year, deaths involving prescription benzodiazepines rose by about a fifth, while deaths involving counterfeit benzodiazepines, pills pressed to look like the prescription, rose more than sixfold. the prescribed and the illicit are now the same problem seen from two sides.
beyond the two famous classes
the one large cohort that followed people on psychiatric medications long term and counted unintended overdose deaths was 154,558 women veterans over fifty.[5] compared with women not on each class: opioids carried more than three and a half times the risk, benzodiazepines nearly three, sleep medications nearly twice, antipsychotics nearly twice, antidepressants about one and a half times. taking three or more psychoactive medications at once, any three, carried about two and a half times the risk, after accounting for psychiatric and substance use diagnoses. the authors call polypharmacy an indicator of risk, not a cause; it is also the most common thing a psychiatrist’s chart shows.
the other direction
most of the deaths in one state were not the monitored patient
in 2006, in the middle of the years the veterans study covers, west virginia linked every unintentional pharmaceutical overdose death to its prescription monitoring records.[6] nearly two thirds of the deaths involved a drug the person had never been prescribed. of those who died with an opioid painkiller in their system, fewer than half had ever been prescribed one. about one in five had collected prescriptions from five or more clinicians in the year before. the picture of the monitored patient quietly dying of a legal combination is real, and it is one picture. the other is a market.
the heart-rhythm warning that never became deaths
in 2011 regulators warned that citalopram above forty milligrams prolongs a heart-rhythm interval. it was the best-known “interaction” warning in psychiatry for a decade. when researchers followed 54,220 people on high-dose antidepressants in tennessee and counted sudden deaths, high-dose citalopram and escitalopram were no different from comparable doses of three other SSRIs.[7] a laboratory finding and a body count are different things. this page exists to keep them apart, in both directions.
what to take from this
- if you take a benzodiazepine and an opioid, from one prescriber or two, that is the combination with the strongest death record in psychiatry, and the fda’s strongest warning since 2016. the question is whether each prescriber knows about the other.
- three or more psychoactive medications at once is a risk marker on its own in the best cohort. it is a reason to ask for a medication review, not a reason to stop anything.
- the scariest-sounding warning on this page, the heart-rhythm one, did not turn into deaths when someone counted. warnings and outcomes are different rows in the table.
- never stop on your own. on that, every source here agrees.
the numbers behind the comparisons
every comparison above, with the raw values it came from.
| what was measured | one side | the other | the comparison |
|---|---|---|---|
| overdose deaths among veterans on opioids, 2004–2009[1] | 1,185 of 2,400 while prescribed both | 27% of opioid recipients were co-prescribed | about half the deaths happened inside a quarter of the patients |
| risk of overdose death vs no benzodiazepine prescription[1] | current prescription: 3.86× | former prescription: 2.33× | nearly four times; rises with dose |
| opioid recipients also holding a benzodiazepine prescription[2] | 2002 baseline | 2014: up 41% | more than 2.5 million more people |
| benzodiazepine-involved overdose deaths per 100,000 adults[3] | 1996: 0.58 | 2013: 3.07 | more than fivefold |
| benzodiazepine deaths that also involved an opioid, early 2020[4] | 92.7% | mostly illicit fentanyl | the combination is the killer, not the pill alone |
| prescription vs illicit benzodiazepine deaths, one year[4] | prescription: up 21.8% | illicit: up 519.6% | the fastest growth is in pills nobody prescribed |
| unintended overdose death, women veterans 50+, long-term use[5] | benzodiazepines 2.77×; opioids 3.62× | antidepressants 1.47×; antipsychotics 1.81× | three or more psychoactive drugs at once: 2.6× |
| West Virginia overdose deaths, 2006[6] | 63.1% involved a drug never prescribed to the person | 44.4% of opioid decedents had ever been prescribed one | most deaths were not the monitored patient |
| high-dose citalopram sudden death vs other SSRIs[7] | no significant difference | n = 54,220 | the 2011 heart-rhythm warning did not show up as deaths |
questions people ask
Can you die from a drug interaction between psychiatric medications?
Yes, and the best-documented case is the combination of a benzodiazepine (for anxiety or sleep) with an opioid painkiller: both slow breathing. In the largest study, about half of the overdose deaths among people prescribed opioids happened while they also held a benzodiazepine prescription, and a current benzodiazepine prescription nearly quadrupled the risk. The FDA put its strongest warning on both drug classes in August 2016.
How often are overdose deaths from drugs that were actually prescribed?
It depends on where you look. In the veterans study, the deaths were inside the prescribing system: legal prescriptions, taken concurrently. In West Virginia in 2006, most overdose deaths involved a drug nobody had prescribed to the person, and fewer than half of the people who died with an opioid in their system had ever been prescribed one. Both are true; they describe different populations.
Do antidepressants or antipsychotics raise overdose risk?
Modestly, in the one large cohort that measured it: among women veterans over fifty, long-term antidepressants carried about one and a half times the risk of unintended overdose death and antipsychotics a little under twice, compared with roughly three times for benzodiazepines and opioids. Taking three or more psychoactive medications at once carried about two and a half times the risk. This was after adjusting for psychiatric and substance use diagnoses.
Didn’t the FDA warn that citalopram can stop your heart?
In 2011 regulators warned that citalopram above 40 mg prolongs the QT interval, a heart-rhythm measure. The one large study that looked for the deaths, 54,220 people on high-dose SSRIs in Tennessee, found no difference in sudden death between high-dose citalopram or escitalopram and comparable doses of other SSRIs. A lab finding and a body count are different things, and this is a case where the second did not follow the first.
Should I stop one of my medications?
Not from a web page. Stopping a benzodiazepine abruptly can cause seizures; stopping an opioid abruptly has its own risks. If you take a benzodiazepine and an opioid together, the question for your prescriber is the one this page exists to give you: do you know I take both, and is there a plan?
sources
- Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert ASB. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ. 2015;350:h2698. PMID 26063215. 2,400 overdose deaths among veterans receiving opioids, 2004–2009; 27% of opioid recipients also received benzodiazepines; about half of the deaths (1,185) occurred during concurrent prescriptions; adjusted hazard ratio 3.86 for a current benzodiazepine prescription and 2.33 for a former one, versus none; risk rose with dose. https://pubmed.ncbi.nlm.nih.gov/26063215/
- US Food and Drug Administration. Drug Safety Communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. 31 August 2016 (updated 20 September 2017). Data summary: patients dispensed a benzodiazepine rose 31% from 2002 to 2014 (23 million to 30 million); the share of opioid recipients with an overlapping benzodiazepine prescription rose 41%, more than 2.5 million additional people in 2014 versus 2002. Archived copy cited because the live URL has moved. https://web.archive.org/web/20201231174453/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-serious-risks-and-death-when-combining-opioid-pain-or
- Bachhuber MA, Hennessy S, Cunningham CO, Starrels JL. Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996–2013. Am J Public Health. 2016;106(4):686-688. PMID 26890165. Adults filling a benzodiazepine prescription rose from 4.1% to 5.6%; the benzodiazepine-involved overdose death rate rose from 0.58 to 3.07 per 100,000 adults, with a plateau after 2010. https://pubmed.ncbi.nlm.nih.gov/26890165/
- Liu S, O’Donnell J, Gladden RM, McGlone L, Chowdhury F. Trends in nonfatal and fatal overdoses involving benzodiazepines, 38 states and DC, 2019–2020. MMWR. 2021;70(34):1136-1141. PMID 34437522. April–June 2019 to April–June 2020: benzodiazepine-involved deaths up 42.9%; prescription benzodiazepine deaths up 21.8%; illicit benzodiazepine deaths up 519.6%; 92.7% of benzodiazepine deaths in January–June 2020 also involved opioids, mainly illicitly manufactured fentanyls. https://pubmed.ncbi.nlm.nih.gov/34437522/
- Gibson CJ, Li Y, Jasuja GK, et al. Long-term psychoactive medications, polypharmacy, and risk of suicide and unintended overdose death among midlife and older women veterans. J Gen Intern Med. 2022;37(Suppl 3):770-777. PMID 36042093. 154,558 women aged 50 and over, followed about 5.6 years; unintended overdose death hazard ratios: opioids 3.62, benzodiazepines 2.77, sedative-hypnotics 1.87, antidepressants 1.47, antipsychotics 1.81, antiepileptics 2.17; three or more psychoactive medications at once, 2.60; adjusted for psychiatric and substance use disorders. https://pubmed.ncbi.nlm.nih.gov/36042093/
- Hall AJ, Logan JE, Toblin RL, et al. Patterns of abuse among unintentional pharmaceutical overdose fatalities. JAMA. 2008;300(22):2613-2620. PMID 19066381. All 295 unintentional pharmaceutical overdose deaths in West Virginia in 2006, linked to prescription monitoring records: diversion (a drug with no documented prescription) in 63.1%; doctor shopping in 21.4%; of the 275 who took opioid analgesics, only 44.4% had ever been prescribed them; multiple substances in 79.3%. https://pubmed.ncbi.nlm.nih.gov/19066381/
- Ray WA, Chung CP, Murray KT, et al. High-dose citalopram and escitalopram and the risk of out-of-hospital death. J Clin Psychiatry. 2017;78(2):190-195. PMID 27736049. Tennessee Medicaid cohort of 54,220 people on high-dose SSRIs, 1998–2011: no significant difference in sudden unexpected death, sudden cardiac death, or total mortality for high-dose citalopram or escitalopram versus comparable doses of fluoxetine, paroxetine and sertraline. https://pubmed.ncbi.nlm.nih.gov/27736049/
- Hedegaard H, Bastian BA, Trinidad JP, Spencer M, Warner M. Drugs most frequently involved in drug overdose deaths: United States, 2011–2016. National Vital Statistics Reports. 2018;67(9):1-14. PMID 30707673. Alprazolam and diazepam are among the ten drugs most frequently mentioned on US overdose death certificates; deaths involving more than one drug are counted under each. https://pubmed.ncbi.nlm.nih.gov/30707673/
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