What is the most common prescription opioid involved in overdose?

Most Common Prescription Opioid Involved in Overdose

Methadone is the most common prescription opioid involved in overdose deaths relative to its prescribing frequency, accounting for as much as one-third of opioid-related overdose deaths despite representing less than 2% of opioid prescriptions outside of opioid treatment programs. 1, 2

Prescription Opioid Overdose Risk Hierarchy

The risk of overdose varies significantly among prescription opioids:

1. Methadone: Disproportionately high overdose risk due to:

   • Complex pharmacokinetics with a long, variable half-life
   • Peak respiratory depression occurring later and lasting longer than peak analgesic effect
   • Association with cardiac arrhythmias and QT prolongation 1

2. Oxycodone: High overdose risk due to:

   • High "liking" and "wanting" scores among users
   • Significantly higher overdose hazard ratio (2.18) when prescribed as monotherapy compared to hydrocodone with acetaminophen 3
   • Widespread prescribing and high abuse potential 4, 5

3. Long-acting/extended-release opioids: Higher overdose risk than immediate-release formulations, particularly at initiation of therapy 1

4. High-dose opioid therapy: Doses above 50-100 MME/day associated with substantially increased overdose risk 1, 2

Risk Factors That Amplify Overdose Risk

Several factors significantly increase the risk of prescription opioid overdose:

• Concurrent benzodiazepine use: Present in 31-61% of opioid overdose deaths 2
• History of prior overdose: Strong predictor of future overdose risk 1
• Substance use disorders: Particularly alcohol, benzodiazepines, or opioids 1
• Respiratory compromise: Any condition affecting respiratory function 1
• Renal or hepatic dysfunction: Impairs clearance of many opioid drugs 1
• Central sleep apnea: Increases risk for respiratory depression 1
• Major depression or suicidal ideation: May contribute to intentional overdose 1

Evolving Nature of the Opioid Overdose Crisis

The opioid crisis has evolved through distinct phases:

1. Prescription opioid phase (1999-2010)
2. Heroin phase (2011-2013)
3. Synthetic opioid phase (2014-present) 6

Current data shows that while prescription opioids remain a concern, many overdoses now involve illicit opioids. A Massachusetts study found that only 1.3% of overdose decedents had an active prescription for each opioid detected in toxicology reports 7.

Overdose Prevention Strategies

1. Prescribing practices:

   • Initiate with immediate-release rather than extended-release/long-acting opioids 1
   • Avoid methadone for pain management when alternatives exist
   • Consider hydrocodone with acetaminophen over oxycodone when appropriate, as it carries lower overdose risk 3
   • Maintain vigilance with doses exceeding 50 MME/day

2. Risk assessment:

   • Conduct thorough risk assessment before prescribing
   • Use urine drug screens to detect concurrent substance use
   • Check prescription drug monitoring programs (PDMPs) 2

3. Patient education:

   • Educate patients and families about overdose risks
   • Consider naloxone prescriptions for high-risk patients 1

4. Monitoring:

   • Implement more frequent clinical follow-up for high-risk patients
   • Use opioid treatment contracts when appropriate 1

Clinical Implications

When prescribing opioids, clinicians should recognize that methadone carries the highest risk of overdose death relative to prescribing frequency, followed by oxycodone. The risk is further amplified by high doses, extended-release formulations, and concurrent use of benzodiazepines or other sedatives. For patients requiring opioid therapy, hydrocodone with acetaminophen may offer a safer alternative to oxycodone in terms of overdose risk, though it may have slightly higher rates of chronic use 3.