What is the risk of respiratory depression associated with different opioids (narcotic analgesics)?

From the Guidelines

The risk of respiratory depression associated with opioids is highest with fentanyl, remifentanil, and methadone, and can be mitigated by starting with the lowest effective dose, avoiding combination with other sedatives, and considering naloxone prescriptions for high-risk patients. Opioids vary in their risk of causing respiratory depression, with some posing higher dangers than others due to their potency and pharmacokinetic properties 1. Patient factors significantly influence risk, including age (elderly patients are more vulnerable), opioid tolerance status, concurrent use of other central nervous system depressants (especially benzodiazepines), sleep apnea, and underlying pulmonary conditions. Respiratory depression occurs because opioids bind to mu-opioid receptors in the brainstem's respiratory centers, decreasing sensitivity to carbon dioxide and suppressing the drive to breathe.

Some key points to consider when prescribing opioids include:

• Starting with the lowest effective dose to minimize the risk of respiratory depression
• Avoiding combination with other sedatives, such as benzodiazepines, to reduce the risk of overdose
• Monitoring patients closely, especially during initiation and dose increases, to quickly identify any signs of respiratory depression
• Considering naloxone prescriptions for high-risk patients, as it can be used to reverse opioid-induced respiratory depression in emergency situations 1
• Being aware of the potential risks and benefits of naloxone administration, including the possibility of precipitating acute opioid withdrawal syndrome in opioid-tolerant patients

It's also important to note that certain clinical characteristics are predictive of opioid overdose risk, including a history of prior overdose, substance addiction, health problems associated with respiratory compromise, and renal or hepatic dysfunction 1. By carefully assessing these risk factors and taking steps to mitigate them, healthcare providers can help minimize the risk of respiratory depression and overdose in patients taking opioids.

From the FDA Drug Label

Respiratory depression is the chief hazard of opioid agonists, including fentanyl the active ingredient in fentanyl transdermal system Respiratory depression is more likely to occur in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of morphine sulfate tablets, the risk is greatest during the initiation of therapy or following a dosage increase.

The risk of respiratory depression associated with different opioids (narcotic analgesics) is:

• High in elderly or debilitated patients
• High when opioids are given in conjunction with other drugs that depress respiration
• Greatest during the initiation of therapy or following a dosage increase
• Present at any time during the use of opioids, even when used as recommended Key factors that increase the risk of respiratory depression include:
• Large initial doses in non-tolerant patients
• Concomitant use of CNS depressants
• Prolonged use of opioids during pregnancy, which can result in neonatal opioid withdrawal syndrome 2 and 3

From the Research

Risk of Respiratory Depression Associated with Opioids

The risk of respiratory depression associated with opioids is a significant concern, with approximately 80,000 opioid-induced respiratory depression (OIRD) deaths per year in the US 4. Several studies have investigated the risk factors for severe OIRD, including:

• Renal failure, with an odds ratio (OR) of 2.176 (95% CI, 1.021-4.640, P = 0.044) 5
• The first 24 hours of opioid administration, with an OR of 1.899 (95% CI, 1.090-3.309, P = 0.024) 5
• Concomitant central nervous system (CNS) depressants, with an OR of 1.785 (95% CI, 1.023-3.113, P = 0.041) 5
• Increasing age, with an OR of 1.019 (95% CI, 1.002-1.035, P = 0.028) 5

Opioid-Specific Risks

Different opioids have varying risks of causing respiratory depression, with:

• Fentanyl having the greatest risk of causing both respiratory depression and reduced cerebral circulation 6
• Buprenorphine, morphine, and hydromorphone being preferred over fentanyl due to their lower risks 6
• Oxycodone having a significant risk of abuse relative to buprenorphine and morphine 6

Patient-Specific Risks

Patient-specific factors can also increase the risk of respiratory depression, including:

• Opioid-naïve patients, although one study found no higher risk of respiratory depression in opioid-naïve palliative care patients during symptomatic therapy of dyspnea with strong opioids 7
• Patients with a history of substance abuse or those taking concomitant CNS depressants 8

Treatment and Prevention

Naloxone is the main treatment used to reverse OIRD, and its availability in higher-dose formulations is important for emergency treatment, especially in cases involving synthetic opioids such as fentanyl 4. Education about the benefits of naloxone and how to obtain it is crucial, as well as calling emergency services after administering naloxone due to the short half-life of naloxone and the long-lasting potency of fentanyl and its analogs 4.