The Perfect Storm: Opioid Risks and 'The Holy Trinity'


'The Holy Trinity' is a drug regimen that includes at least an opioid, a benzodiazepine, and carisoprodol.

As pharmacists and health care professionals, one of our major concerns is preventing harm to our patients. A familiar mantra among health care providers is “at first, to do no harm.” Oftentimes, patients require our expertise to help avoid such harm or to improve their health.

One of the many things that can go wrong in patient care is drug interactions, as they can result in patient suffering, costly and avoidable medical care, or even death. ”The Holy Trinity” is a drug regimen that includes at least 1 opioid, a benzodiazepine, and carisoprodol. This combination has been rising in popularity and is commonly prescribed by “pill mills.”1

In 2002, some of the most commonly abused drugs included oxycodone, hydrocodone, hydromorphone, morphine, codeine, clonazepam, alprazolam, lorazepam, diazepam, and carisoprodol.2 That year, hydrocodone was only manufactured with acetaminophen, which was still the case until the recent release of single entity Zohydro ER in March 2014.

Immediate-release formulations may add to the unsafe nature of mixing these agents, because the peak concentrations (Cmax) are generally elevated compared to their extended-release counterparts. Consequently, they have a relatively short duration of action, yet a rapid onset when compared to the extended-release agents. However, this is what abusers seek for the rapid onset of euphoria.

Opioids, benzodiazepines, and carisoprodol all have some overlapping side effects in terms of drowsiness, respiratory depression (opioid), confusion, tremor, and seizures risk.3-5 When combined, these drugs are synergistic in causing respiratory depression and could collectively result in death. More concerning is the lack of emphasis placed on these interactions in tertiary databases such as Clinical Pharmacology that are used by many pharmacists, both in the community setting and hospital and/or ambulatory care.

When running a drug interaction report for oxycodone, alprazolam, and carisoprodol, for example, only “moderate” severity drug interaction information is populated. Only after adding ethanol to the list of substances does alprazolam/ethanol and oxycodone/ethanol become “major” drug interactions, citing increased central nervous system (CNS) depression.6 Although these tertiary resources are somewhat useful, we must remember that no database is ever complete, as all 3 agents cause CNS depression alone and in combination.

Many legitimate patients have genuine needs for these medications separately and sometimes combined, but there is little rationale for combining all 3 agents. Clearly, the benefits don't outweigh the risks when considering the combined pharmacology and the alternatives.

Carisoprodol is metabolized extensively by the liver and is a substrate for the CYP450 enzyme, 2C19. It has several metabolites, one of which is meprobamate and has a half-life of about 10 hours. Carisoprodol itself has a half-life of approximately 2.4 hours.5

Meprobamate is considered an active metabolite and also has anti-anxiety effects, much like a benzodiazepine. But, from a toxicity standpoint, it more closely resembles the sedative properties of barbiturates.7

Phenobarbital is a barbiturate that has a mean half-life of 96 hours, and most of the drug is metabolized into inactive metabolites by many liver CYP450 enzymes (2C family, 3A4, 2E1, etc.). Phenobarbital, however, is most frequently employed as an anticonvulsant, as its anxiolytic usage has largely been replaced by the safer alternative benzodiazepines.8

Alprazolam undergoes metabolism via 3A4 and produces several metabolites of little significance. For example, unlike carisoprodol’s metabolite, meprobamate, the alpha-hydroxy-alprazolam metabolite is approximately half the potency as the parent compound, but the benzophenone derivative is found to be inactive.3

Oxycodone is metabolized by 3A4 and 2D6, via 3A4 to noroxycodone, via 3A4 and 2D6 to noroxymorphone, and via 2D6 alone to oxymorphone (Opana). Noroxycodone has very little analgesic properties, but oxycodone and oxymorphone have algesic properties that come with respiratory depressive properties.4

Carisoprodol alone or with other agents (opioids and benzodiazepines, in particular) reportedly caused more than 30,000 emergency department (ED) visits in 2009.9 The US Centers for Disease Control and Prevention published that, in 13% of all deaths due to poisoning by opioids in 1999, the patients had also ingested benzodiazepines. By 2011, that percentage had risen to 31% of opioid poisonings also involving the consumption of benzodiazepines.10 Also, in 2009, benzodiazepines--which have little, if any, evidence to support their chronic use--resulted in 373,000 ED visits.9 All of these drugs also carry the risk for dependence.

Safety should always be a concern. Some patients take their benzodiazepine intermittently, while others receive them on a more scheduled basis despite their directions being “as needed.” Intermittent PRN opioids will depend on the acute or chronic nature of the pain and, despite much safer alternatives, a patient may be prescribed carisoprodol for muscle spasms, especially if he or she is receiving opioids and/or benzodiazepines.

Our job as pharmacists is to intervene when we have a patient who is complaining of muscle spasms, pain, and anxiety all around the same time. Carisoprodol combined with a benzodiazepine and oxycodone is surely a recipe for disaster and is often the subject of legal cases that I encounter. In fact, many calls received inquiring about retaining a pharmacist expert involves this very combination prescribed from “pill mills” and dispensed by collaborating scandalous pharmacists.

Your first clue is when a patient comes in with prescriptions for very high doses of an extended-release opioid such as OxyContin 80mg PO Q8H; oxycodone immediate-release 30mg tablets PO Q4H; high dose benzodiazepines such as alprazolam 2mg PO QID; and carisopridol 350mg PO QID, all for a month supply at maximum quantities, and paying cash to boot! Intuitively, it seems that, at one time, there were as many “legitimate” prescriptions for this combination as there were deaths from the same drug combination purchased illegally.

When patients use different pharmacies, this may leave you feeling overwhelmed. Most states have a prescription drug monitoring program (PDMP) that can be accessed from all pharmacy settings. These can provide useful information that pharmacists may not otherwise have access to, but most state PDMP software does not allow access to contiguous states, nor does it include the Departments of Defense or Veterans Affairs, or other federal facilities. For instance, I live on the border of New York (their PDMP being ISTOP) and Vermont, in addition to Massachusetts having their own PDMP, and the Candian boarder being located less than 4 hours away. Patients can be quite creative in obtaining their filled prescriptions, so it would be very easy for a patient that lives in northern New York State to have prescriptions filled in all 3 contiguous states at different pharmacy chains.

In order to better protect the patients we serve, we should be proactive in considering the appropriateness of the medication for the patient and their condition, including more effective and safer treatment alternatives. Ask yourself: does this patient require an opioid to manage their pain? Can they be controlled on NSAIDs or other non-opioid agents effectively? Do they have any contraindications to NSAIDs or opioids? Do they have a history of past substance abuse? Do they require carisoprodol for muscle spasms, or can they use a medication with an alternative pharmacology, such as methocarbamol, cyclobenzaprine, or metaxalone? None of these alternatives carry the same inherent risks of carisoprodol with or without a benzodiazepine when combined with opioids.

Also ask: are they taking their benzodiazepine regularly? What are they taking it for? If it's for sleep issues, can they benefit from a safer agent, such as diphenhydramine, trazodone, or mirtazapine?

Once you have pondered these alternatives, you are bound to protect the patient’s best interest and safety. That may include a professional discussion with the patient and/or a call to the prescriber. In the case of suspected criminal intent, we have an obligation to contact the appropriate regulatory agencies. Moreover, we must never forget that the pharmacist has a corresponding responsibility.

“The responsibility for the proper prescribing and dispensing of controlled substances is upon the prescribing practitioner, but a corresponding responsibility rests with the pharmacist who fills the prescription.”11 You are the last stop before the drug(s) are handed to the patient, and the last gatekeeper to safety.

This article was collaboratively written with Autumn Amber Wolf, BA, a PharmD Candidate 2015 at Western New England University College of Pharmacy. She received her BA in mathematics from Massachusetts College of Liberal Arts in 2011.


1. Michelle Castillo. With drug overdose deaths on rise, experts push to recognize signs of addiction [Internet]. 2013. [accessed 2014 Sept 21]. Available from:

2. Manchikanti L, Brown KR, Singh V. National All Schedules Prescription Electronic Reporting Act (NASPER): balancing substance abuse and medical necessity. Pain Physician. 2002 Jul;5(3):294-319. Erratum in: Pain Physician. 2002 Oct;5(4):445. PubMed PMID: 16902657.

3. Alprazolam. In: Clinical pharmacology [database on internet]. Tampa (FL): Gold Standard. 2014. [updated 2011 Sept 13; cited 2014 Sept 21].

4. Oxycodone. In: Clinical pharmacology [database on internet]. Tampa (FL): Gold Standard. 2014. [updated 2014 May 5; cited 2014 Sept 21].

5. Carisoprodol. In: Clinical pharmacology [database on internet]. Tampa (FL): Gold Standard. 2014. [updated 2013 Feb 7; cited 2014 Sept 21].

6. Drug interaction Report. In: Clinical pharmacology [database on internet]. Tampa (FL): Gold Standard. 2014. [updated 2014 Sept 21; cited 2014 Sept 21].

7. Tse SA, Atayee RS, Ma JD, Best BM. Factors affecting carisoprodol metabolism in pain patients using urinary excretion data. J Anal Toxicol. 2014 Apr;38(3):122-8. doi: 10.1093/jat/bku002. Epub 2014 Jan 31. PubMed PMID: 24488112.

8. Phenobarbital. In: Clinical pharmacology [database on internet]. Tampa (FL): Gold Standard. 2014. [updated 2013 Sept 17; cited 2014 Sept 23].

9. Deadly Drug Combinations Escaping Notice: A Health systems Report [Internet]. 2013. [accessed 2014 Sept 21]. Available from:

10. LH Chen, H Hedegaard, M Warner. Drug-poisoning Deaths Involving Opioid Analgesics: United States, 1999- 2011 [Internet]. 2014. [accessed 2014 Sept 21]. Available from:

11. DHHS FDA CFR —Code of Federal Regulations Title 21 [Internet]. 2014. [Accessed 2014 Sept 23]. Available from:

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