FDA Conclusions on Benzhydrocodone/Acetaminophen Abuse-Deterrence Studies
The correct answer is D: all of the above - the FDA concluded that benzhydrocodone/acetaminophen (Apadaz) showed no overall advantage in deterring drug extraction by physical manipulation, no significant difference in overall hydrocodone exposure, and no significant difference in peak drug liking effects compared to standard hydrocodone/acetaminophen.
Evidence from Abuse-Deterrence Studies
Physical Manipulation and Extraction
- Benzhydrocodone is a prodrug of hydrocodone that requires intestinal metabolism to convert into active hydrocodone, theoretically providing abuse-deterrent properties 1, 2.
- However, the FDA guidance on abuse-deterrent opioids explicitly states that these technologies do not prevent opioid misuse or overdose through oral intake (the most common route of opioid misuse) and can still be misused by nonoral routes 3.
- The "abuse-deterrent" label does not indicate there is no risk for misuse or opioid use disorder 3.
Hydrocodone Exposure Findings
- When administered intranasally, benzhydrocodone showed 36% lower peak hydrocodone plasma concentration (Cmax) and approximately 20% lower total hydrocodone exposures compared to hydrocodone bitartrate 2.
- For intranasal benzhydrocodone/acetaminophen versus hydrocodone bitartrate/acetaminophen, hydrocodone Cmax was only 11% lower, with early cumulative exposures reduced by approximately 50% at 0.5 hours, 29% at 1 hour, and 15% at 2 hours 1.
- These reductions in early exposure do not translate to clinically meaningful differences in overall hydrocodone bioavailability when taken orally as intended 1.
Drug Liking and Abuse Potential
- Peak Drug Liking scores (Emax) were not significantly different between intranasal benzhydrocodone/acetaminophen and intranasal hydrocodone bitartrate/acetaminophen (P = 0.2814) 1.
- While Drug Liking scores at early time points (up to 2 hours) were lower for benzhydrocodone, the peak effects - which drive abuse potential - remained equivalent 1.
- When benzhydrocodone API was compared to hydrocodone bitartrate API intranasally, Drug Liking Emax was lower (P = 0.004), but only 45% of subjects showed a ≥30% reduction, indicating substantial variability and limited clinical impact 2.
Critical FDA Perspective on Abuse-Deterrent Formulations
Lack of Evidence for Clinical Benefit
- No studies were found in clinical evidence reviews assessing the effectiveness of "abuse-deterrent" technologies as a risk mitigation strategy for deterring or preventing opioid misuse, opioid use disorder, or overdose 3.
- The CDC guidelines explicitly note that abuse-deterrent technologies do not prevent unintentional overdose through oral intake 3.
Limitations of Prodrug Technology
- While benzhydrocodone requires intestinal metabolism, this mechanism primarily affects intranasal and intravenous routes but provides minimal deterrence to oral abuse 1, 2.
- The prodrug design resulted in adverse nasal effects that may provide some level of deterrence to intranasal abuse, but this does not address the most common route of opioid misuse (oral) 1.
Clinical Implications
The FDA's conclusions reflect that benzhydrocodone/acetaminophen does not offer meaningful advantages over standard hydrocodone/acetaminophen in terms of abuse deterrence, overall drug exposure, or subjective drug effects 3. This aligns with the broader FDA position that abuse-deterrent labeling should not be interpreted as indicating reduced risk for misuse or addiction 3.
Important Caveats
- Clinicians should not assume that prescribing benzhydrocodone/acetaminophen reduces the risk of opioid use disorder, overdose, or diversion compared to standard hydrocodone formulations 3.
- All standard opioid prescribing precautions, monitoring requirements, and risk mitigation strategies apply equally to benzhydrocodone/acetaminophen 3.
- The abuse-deterrent properties may provide marginal benefit against intranasal abuse but do not address oral misuse, which remains the predominant route 3, 1.