Can one develop tolerance to the interaction between opioids (narcotic pain relievers) and benzodiazepines (central nervous system depressants)?

From the Guidelines

Individuals can develop tolerance to the combined effects of opioids and benzodiazepines, but this tolerance does not mitigate the significant risks associated with their concurrent use, particularly the risk of fatal respiratory depression. The development of tolerance occurs through neuroadaptation, where the brain adjusts to the presence of these substances by changing receptor sensitivity and neurotransmitter systems 1. For opioids, tolerance develops to analgesic effects, while for benzodiazepines, tolerance to the anxiolytic and sedative effects occurs. However, tolerance to respiratory depression effects develops more slowly, which creates a dangerous situation where individuals may increase doses to overcome tolerance to desired effects while inadvertently increasing their risk of respiratory depression and overdose.

Some key points to consider when evaluating the risks and benefits of concurrent opioid and benzodiazepine use include:

• The potential for increased risk of fatal respiratory depression, even in individuals who have developed tolerance to the therapeutic effects of these medications
• The importance of avoiding concurrent prescribing of opioids and benzodiazepines whenever possible, as recommended by the CDC guideline for prescribing opioids for chronic pain 1
• The need for careful consideration of the benefits and risks of concurrent use of these medications, particularly in patients with a history of substance use disorder or other risk factors for overdose
• The potential for cross-tolerance between opioids and benzodiazepines, which can complicate the management of dependence and withdrawal.

Given the significant risks associated with concurrent opioid and benzodiazepine use, clinicians should prioritize alternative treatment strategies that minimize the use of these medications, and carefully monitor patients for signs of tolerance, dependence, and overdose. This may involve tapering opioids first when reducing concurrent use, and gradually tapering benzodiazepines to avoid rebound anxiety, hallucinations, seizures, delirium tremens, and other withdrawal symptoms 1.

From the Research

Opioid and Benzodiazepine Interaction

• The combined use of opioids and benzodiazepines increases the risk for potentially lethal respiratory depression, as shown in a review of 29 manuscripts 2.
• Concurrent use of opioids and benzodiazepines is associated with increased risk of opioid overdose and death, with 6% of opioid users concurrently using these substances for at least 30 days 3.
• Patients using opioids and benzodiazepines are more likely to have mood disorders, depression, and higher daily opioid doses, making them a high-risk population 3.

Tolerance to Opioid and Benzodiazepine Interaction

• There is no direct evidence to suggest that one can become tolerant to the opioid and benzodiazepine interaction, as the focus of existing research is on the risks and adverse effects of combined use rather than tolerance development.
• However, it is known that long-term use of opioids and benzodiazepines can lead to physical dependence and increased risk of adverse events, such as respiratory depression and overdose 4, 5.
• The effectiveness of naloxone in reversing opioid-induced respiratory depression can vary depending on the pharmacokinetics and pharmacodynamics of the opioid, and may not always be effective in preventing cardiac arrest 5.

Adverse Respiratory Events

• The use of opioid and benzodiazepine medications, alone or in combination, is associated with increased adverse respiratory events in older adults with chronic obstructive pulmonary disease (COPD) 6.
• Concurrent use of opioids and benzodiazepines increases the risk of hospitalization for respiratory conditions, with an adjusted odds ratio of 2.32 compared to no use of either medication 6.