isolating “pure” cases remains methodologically challenging for the FDA and CDC -so they use “dirty data” to support their conclusions

Posted on April 22, 2025 by Pharmaciststeve

I asked www.perplexity.ai several questions concerning a pt’s concurrent prescribed use of an opioid, benzodiazepine, and muscle relaxant. It kept giving me answers that might, could cause respiratory suppression.  It was obvious all the answers were based on – IMO – sloppy documentation of a death from a person taking the three meds together, and maybe – maybe not – took prescribed meds as directed in mgs dose and frequency, and what other substances – legal or illegal – the person had taken.

Statistics can be your friend or your enemy. When someone has an agenda and they are in the position to choose which particular pieces of data they can use to support the conclusion that will serve their agenda. One can just figure out which pieces of data are ignored or discarded, and which ones are used to match the conclusion that they want.

Below is my final question, trying to get Perplexity to find some definitive data. The last sentence in Perplexity’s answer pretty much says and clarifies it all.

So what you are saying is that no one bothered to document any evidence that confirmed ODs that the person was taking their prescribed meds, in the doses and frequency prescribed and had taken no other legal or illegal substances concurrently. Published statistics have stated that the typical OD involved 4 to 7 different substances, with alcohol and marijuana typically being in the polysubstance OD. While all three classes of meds will suppress respiration, but is suppression at therapeutic doses typically fatal – can you provide clinical studies that shows a high probability of it being fatal

The FDA and CDC warnings are grounded in this evidence, though isolating “pure” cases remains methodologically challenging  1 4 10.

The user raises valid concerns about confounding factors in overdose statistics, but clinical and pharmacological evidence confirms that fatal respiratory depression can occur even when opioids, benzodiazepines, and muscle relaxants are taken as prescribed, without other substances. Here’s the breakdown:

1. Evidence from Prescribed-Use Cohorts

  • FDA’s 2016 Analysis (prescribed regimens):

    • Patients co-dispensed opioids + benzodiazepines had a 10x higher overdose death rate (7.0 vs. 0.7 per 10,000 person-years) compared to opioids alone1.

    • 31% of opioid overdose deaths involved benzodiazepines, with no requirement for supratherapeutic dosing18.

  • Veterans Health Study:

    • Patients prescribed opioids + benzodiazepines had a 3.86x higher fatal overdose risk vs. opioids alone, even after adjusting for dose and comorbidities18.

2. Pharmacodynamic Synergy at Therapeutic Doses

  • Respiratory Depression Mechanism:

    • Opioids (µ-opioid receptors) and benzodiazepines (GABA-A receptors) synergistically suppress brainstem respiratory drive710.

    • Muscle relaxants like carisoprodol further amplify GABA-A receptor activity, eliminating the “ceiling effect” of partial opioids (e.g., buprenorphine)109.

    • Animal/human studies show synergistic hypoxia even at sedative (not overdose) doses810.

3. Limitations in Isolating “Pure” Cases

  • Polysubstance Overdose Prevalence:

    • Most fatal overdoses involve 4–7 substances (e.g., alcohol, illicit drugs), complicating isolation of prescribed triple-therapy fatalities79.

  • Indirect Evidence from Hospitalizations:

    • Triple-threat users had 8.52x higher hospitalization odds (proxy for severe respiratory events) vs. non-users4.

    • Baclofen + opioids had 2.52x higher overdose risk than cyclobenzaprine + opioids in prescribed cohorts3.

4. Key Studies on Therapeutic-Dose Risks

  1. Human Experimental Trial:

    • Fentanyl (opioid) + midazolam (benzodiazepine) at sedative doses caused severe hypoxia in 100% of subjects vs. 50% with fentanyl alone8.

  2. Buprenorphine/Methadone Patients:

    • 82% of buprenorphine-related deaths involved benzodiazepines, often at prescribed doses9.

  3. Postoperative Mortality:

    • Combined preoperative opioids + benzodiazepines (as prescribed) increased short- and long-term mortality vs. either drug alone7.

Conclusion

While polysubstance use dominates overdose statistics, mechanistic and cohort studies confirm that respiratory depression from triple therapy can be fatal at therapeutic doses, particularly in high-risk groups (e.g., sleep apnea patients, elderly). The FDA and CDC warnings are grounded in this evidence, though isolating “pure” cases remains methodologically challenging   1 4 10.

Citations:

  1. https://www.fda.gov/media/99761/download
  2. https://pharmacy.ufl.edu/2020/07/06/uf-study-finds-some-combinations-of-opioids-and-muscle-relaxants-are-safe-others-raise-overdose-risk/
  3. https://pubmed.ncbi.nlm.nih.gov/35835561/
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC7502868/
  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC7726637/
  6. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2773826
  7. https://apm.amegroups.org/article/view/35734/html
  8. https://cdn.amegroups.cn/journals/amepc/files/journals/8/articles/35734/public/35734-PB10-9925-R3.pdf?filename=apm-09-02-542.pdf&t=1722012648
  9. https://health.baltimorecity.gov/sites/default/files/Final%20Draft%20FDA%20petition-Full%20Co-Signers-2.19.16%20(2)%20(1).pdf
  10. https://onlinelibrary.wiley.com/doi/10.1111/bcpt.12655
  11. https://www.neurology.org/doi/10.1212/WNL.0000000000200904
  12. https://nida.nih.gov/research-topics/opioids/benzodiazepines-opioids
  13. https://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm
  14. https://www.sciencedirect.com/science/article/pii/S0955395922003498
  15. https://jamanetwork.com/journals/jama-health-forum/fullarticle/2796898
  16. https://pubmed.ncbi.nlm.nih.gov/32022906/
  17. https://ufhealth.org/news/2020/uf-study-finds-some-combinations-opioids-and-muscle-relaxants-are-safe-others-raise
  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC3454351/
  19. https://www.cdc.gov/overdose-prevention/about/prescription-opioids.html
  20. https://www.sciencedirect.com/science/article/abs/pii/S0376871619304703
  21. https://www.tandfonline.com/doi/full/10.1080/24740527.2020.1714431
  22. https://pmc.ncbi.nlm.nih.gov/articles/PMC5939871/
  23. https://academic.oup.com/painmedicine/article/19/1/79/3611356
  24. https://academic.oup.com/painmedicine/article/16/8/1566/2460700
  25. https://www.sciencedirect.com/science/article/abs/pii/S0379073821001390
  26. https://labeling.pfizer.com/ShowLabeling.aspx?id=4503
  27. https://dsps.wi.gov/Documents/BoardCouncils/MED/MEBGuideline.pdf
  28. https://www.hysinglaer.com
  29. https://academic.oup.com/painmedicine/article-pdf/19/1/79/24350605/pnx038.pdf
  30. https://www.cdc.gov/mmwr/volumes/71/rr/rr7103a1.htm
  31. https://www.nmhealth.org/publication/view/guide/6327/
  32. https://www.aafp.org/pubs/afp/issues/2016/0615/p982.html
  33. https://www.oxycontin.com
  34. https://www.dol.gov/sites/dolgov/files/owcp/dfec/opioidactionplan/FullPaper-PatternsofChronicHigher-DoseandLower-DoseOpioidUseinFederalWorkersCompensationClaimants.pdf
  35. https://academic.oup.com/painmedicine/article/15/11/1911/1835923
  36. https://oxycontin.com/report-adverse-reactions/
  37. https://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNMattersArticles/downloads/SE19011.pdf
  38. https://apm.amegroups.org/article/view/35734/html
  39. https://health.baltimorecity.gov/sites/default/files/Final%20Draft%20FDA%20petition-Full%20Co-Signers-2.19.16%20(2)%20(1).pdf
  40. https://onlinelibrary.wiley.com/doi/10.1111/bcpt.12655
  41. https://www.oxycontin.com/important-safety-information/

Answer from Perplexity: pplx.ai/share

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