Drug Interaction Report

Oxycodone and Hydromorphone Rectal: Interaction Details

A pharmacist-reviewed analysis of the Oxycodone and Hydromorphone Rectal interaction: the documented clinical effects, severity rating, onset, mechanism, and management considerations, with cited references throughout.

AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature

Oxycodone

Oxaydo Oxycontin Roxicodone Roxybond Xtampza
+

Hydromorphone Rectal

available generically
Dr. Brian Staiger, PharmD, BCPS
Medically reviewed by
Dr. Brian Staiger, PharmD, BCPS
Updated Aug 8, 2026
Editorial policy · Data sources
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Interaction severity
Major
Potentially serious — often needs a change or close monitoring.
How we grade severity & evidence

Severity levels

  • Contraindicated: These should generally not be used together.
  • Major: Potentially serious — often needs a change or close monitoring.
  • Moderate: Can be significant — usually manageable with monitoring.
  • Minor: Usually limited clinical impact.

Evidence grades

  • Established: Well documented — supported by controlled studies or strong clinical data.
  • Probable: Good supporting evidence, though not definitively proven.
  • Suspected: Some evidence suggests this interaction, but it is not well established.
  • Possible: Limited or conflicting evidence; the interaction may occur.
  • Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.

Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.

Of 62 documented Oxycodone interactions, 59 are rated major — including this one.
Worried about symptoms right now? Contact your pharmacist or prescriber, or call Poison Control at 1-800-222-1222 (US). Call 911 for an emergency.
Onset
unspecified
Evidence
theoretical
Severity
Major

What happens

Increased risk of respiratory and CNS depression and an increased risk of serotonin syndrome

Interaction Deep Dive

Coadministration of oxyCODONE and a serotonergic CNS depressant may result in serotonin syndrome, additive CNS depression and an increased risk of respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. If concomitant use is necessary, use the lowest effective dosage and minimum duration of use. Monitor patients for serotonin syndrome, sedation and respiratory depression particularly during treatment initiation and dose adjustment. Discontinue oxyCODONE if serotonin syndrome is suspected. Consider prescribing naloxone for the emergency treatment of opioid overdose1. Initiate oxyCODONE extended-release tablets and oxyCODONE/naloxone combination at one-third to one-half of the usual initial dosage 23 and initiate oxyCODONE/acetaminophen extended-release tablets at a reduced dose of 1 tablet every 12 hours 4.

Why it happens (mechanism)

Additive CNS depression; additive serotonergic effects

Literature reports

1 report — tap to read

a) Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics 3.

Common questions

Can I take Oxycodone and Hydromorphone Rectal together?

Increased risk of respiratory and CNS depression and an increased risk of serotonin syndrome Always confirm with your pharmacist or prescriber before making any change.

How serious is the Oxycodone and Hydromorphone Rectal interaction?

It is rated major. Potentially serious — often needs a change or close monitoring.

How quickly could this interaction happen?

The documented onset is "unspecified". The timing of this interaction is not well characterized.

How strong is the evidence for this interaction?

The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.

From our Q&A

Real reader questions about these medications, each personally answered by our pharmacist:

Questions for your pharmacist

  • Does my dose of Oxycodone or Hydromorphone Rectal need adjusting while I take them together?
  • What symptoms should prompt me to call you or my prescriber right away?
  • Does the timing of my doses matter for this combination?
  • Is there a safer alternative to one of these medications for me?

References (4)

  1. Product Information: Oxycodone HCl acetaminophen oral tablets, oxycodone HCl acetaminophen oral tablets. Mayne Pharma (per DailyMed), Greenville, NC, 2021.
  2. Product Information: TARGINIQ(TM) ER oral extended release tablets, oxycodone HCl naloxone HCl oral extended release tablets. Purdue Pharma LP (per FDA), Stamford, CT, 2016.
  3. Product Information: OXYCONTIN(R) oral extended-release tablets, oxycodone HCl oral extended-release tablets. Purdue Pharma LP (per FDA), Stamford, CT, 2023. DailyMed
  4. Product Information: XARTEMIS(TM) XR oral extended-release tablets, oxycodone HCl acetaminophen oral extended-release tablets. Mallinckrodt Brand Pharmaceuticals, Inc. (per FDA), Hazelwood, MO, 2016.
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Oxycodone

Keep reading about Oxycodone

All Oxycodone interactions (62)
Also serious with: Ketoconazole Topical Lacosamide Injection Midazolam Nasal Spray Buprenorphine
Hydromorphone Rectal

Keep reading about Hydromorphone Rectal

All Hydromorphone Rectal interactions (344) Hydromorphone Rectal drug information
Also serious with: Isocarboxazid Naltrexone Phenelzine Tranylcypromine
Beyond drug–drug

These medications also interact with supplements

Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:

Oxycodone + 1,4-butanediol Activated Charcoal Beer Gamma-hydroxybutyrate (ghb) Kava L-tryptophan St. John's Wort Wine + 137 more

major · moderate · minor — check everything you take with our drug–supplement interaction checker.

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This information is for education, not a substitute for professional medical advice. Do not start, stop, or change any medication without talking to your pharmacist or prescriber.