Which medicine is more likely to increase the risk of infections: hydromorphone, methadone, or morphine/buprenorphine?

Morphine is Most Likely to Increase Infection Risk

Among the opioids listed, morphine poses the highest risk for increasing infections, followed by hydromorphone, then methadone, with buprenorphine being the safest option with minimal to no immunosuppressive effects. 1

Evidence-Based Ranking of Infection Risk

Highest Risk: Morphine

• Morphine has been consistently identified as the most immunosuppressive opioid in international expert consensus guidelines 1
• Morphine displays potent immunosuppressive effects that interfere with both innate and acquired immune responses 1
• The immunosuppression is not dose-related to the antinociceptive effect, meaning even lower analgesic doses can suppress immunity 2
• Observational studies indicate morphine increases both the incidence and severity of infections in patients 1

High Risk: Hydromorphone

• While hydromorphone is a semi-synthetic derivative of morphine, the evidence shows conflicting data on its immunosuppressive potential 2
• One preclinical study found hydromorphone devoid of immunosuppressive effects despite potent antinociceptive activity, attributed to its C6 carbonyl substitution with C7-8 single bond 2
• However, as a morphine derivative, clinical caution is warranted given the structural similarities and lack of robust human clinical data specifically examining infection rates

Moderate Risk: Methadone

• Methadone shows variable immunosuppressive effects with some concerning specific viral interactions 3, 4
• Methadone significantly enhances human influenza A virus replication in lung cells and increases viral load in animal models 4
• Long-term evidence suggests methadone likely does not significantly impair overall immune function and may even allow some immune improvement compared to active heroin use 3
• The clinical relevance remains uncertain, with methadone maintenance therapy generally considered safe for HIV-infected individuals 1, 3

Lowest Risk: Buprenorphine

• Based on available data, buprenorphine is the safest opioid for immunocompromised or elderly patients susceptible to infection 1
• Buprenorphine does not enhance viral replication (unlike methadone with influenza) 4
• Its higher binding affinity may preserve analgesic function without the same degree of immune suppression seen with morphine or methadone 1

Clinical Mechanisms

How Opioids Suppress Immunity

• Opioids interfere with innate and acquired immune responses 1
• They act on the hypothalamic-pituitary-adrenal axis and autonomic nervous system 1
• Higher doses and longer duration of therapy correlate with greater immunosuppression 1
• Opioids suppress natural killer cell activity, decrease cytotoxic T cells, and reduce neutrophil phagocytic activity 1

Important Caveats

• The clinical relevance of opioid-induced immunosuppression in humans remains somewhat unclear despite strong laboratory evidence 5, 6
• Individual opioids differ substantially in their immunosuppressive effects 1
• Most evidence comes from in-vitro studies and animal models; adequately designed human trials are lacking 6
• Comorbidities, age, and chronic pain itself independently increase infection risk, making it difficult to isolate opioid effects 1

Practical Recommendations

When infection risk is a concern, prioritize buprenorphine over other opioids 1. If buprenorphine is not appropriate, avoid morphine and fentanyl as first-line agents given their established immunosuppressive profiles 1. Consider that the choice of opioid may be particularly important in elderly patients, those with existing immunocompromise, or during infectious disease outbreaks 1.