How can the risk of all-cause mortality be minimized when using controlled substances, such as opioids (e.g. morphine, oxycodone), stimulants (e.g. methylphenidate, amphetamine), and benzodiazepines (e.g. alprazolam, clonazepam)?

Minimizing All-Cause Mortality Risk When Using Controlled Substances

To minimize all-cause mortality risk when using controlled substances, avoid concurrent use of multiple central nervous system depressants, particularly the combination of opioids with benzodiazepines, which increases overdose death risk nearly four-fold compared to opioid use alone. 1

Key Risk Reduction Strategies

1. Avoid Dangerous Drug Combinations

• Opioids + Benzodiazepines: This combination causes profound respiratory depression, sedation, coma, and death 2, 1
• Opioids + Alcohol: Significantly increases risk of fatal respiratory depression 3
• Opioids + Other CNS depressants: Muscle relaxants and hypnotics potentiate respiratory depression 1
• Stimulants + Benzodiazepines: Co-abuse amplifies organ toxicity, particularly to liver and kidneys 4

2. Safe Storage and Disposal

• Store controlled substances in secure, locked locations
• Keep medications away from individuals at risk of misuse/overdose
• Properly dispose of unused medications 1

3. Naloxone Availability

• Have naloxone readily available for opioid users
• Educate patients and family members on recognizing overdose signs and naloxone administration 1

4. Medication Management

• Use the lowest effective dose of controlled substances
• Consider non-opioid and non-pharmacological alternatives for pain when possible 1
• If discontinuing controlled substances:
  • Taper gradually to prevent withdrawal
  • For patients on both benzodiazepines and opioids, taper opioids first 1
  • Typical benzodiazepine taper: reduce dose by 25% every 1-2 weeks 1

5. Patient Education

• Inform patients about:
  • Risks of respiratory depression and overdose
  • Dangers of combining controlled substances with other medications or alcohol
  • Signs of overdose and appropriate emergency response
  • Safe storage and disposal practices 1

Special Considerations by Drug Class

Opioids (morphine, oxycodone)

• Highest mortality risk comes from respiratory depression
• Risk increases with:
  • Higher doses
  • Concurrent use of other CNS depressants
  • History of sleep apnea 3
• Case reports document fatal interactions between oxycodone and benzodiazepines like clonazepam 5

Benzodiazepines (alprazolam, clonazepam)

• FDA boxed warning: Concomitant use with opioids may result in profound sedation, respiratory depression, coma, and death 2
• Reserve concurrent prescribing with opioids only when alternative treatment options are inadequate 2
• Abrupt discontinuation can cause rebound anxiety, hallucinations, seizures, and rarely death 1

Stimulants (methylphenidate, amphetamine)

• Cardiovascular risks (hypertension, tachycardia) are primary mortality concerns
• Co-administration with benzodiazepines increases hepato-renal toxicity 4
• Benzodiazepines are sometimes used to manage stimulant-induced anxiety but this combination requires careful monitoring 6

Monitoring and Risk Assessment

Universal Precautions Approach

• Screen for substance use disorders before prescribing
• Use prescription drug monitoring programs (PDMPs) to identify concerning patterns
• Consider urine drug testing to monitor adherence 1

High-Risk Populations

• Patients with:
  • Sleep apnea
  • Liver or kidney disease
  • History of substance use disorder
  • Concurrent psychiatric disorders 1

When to Seek Treatment for Substance Use Disorder

• Evidence-based treatment should be offered for patients with opioid use disorder
• Medication-assisted treatment with buprenorphine or methadone combined with behavioral therapies is most effective 1

Common Pitfalls to Avoid

1. Abruptly discontinuing controlled substances
2. Dismissing patients based solely on urine drug test results or PDMP findings
3. Failing to recognize signs of substance use disorder
4. Not providing naloxone to patients at risk of opioid overdose
5. Ignoring pharmacological interactions with over-the-counter medications 1

By implementing these evidence-based strategies, the risk of all-cause mortality associated with controlled substance use can be significantly reduced.