Oxycodone
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Oxycodone: From Opioid Analgesia to Restless Legs Syndrome
One-Sentence Summary
Oxycodone is a mu-opioid receptor agonist marketed in Singapore as an analgesic, in single-ingredient and oxycodone/naloxone products. The TxGNN model's top-ranked prediction with real clinical support is Restless Legs Syndrome (RLS), backed by 1 completed Phase 3 randomised trial and 20 publications, including a Cochrane review and an American Academy of Sleep Medicine guideline. The model's highest-scoring prediction overall, methemoglobinemia, has no supporting evidence and is not recommended.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not listed in the Singapore licence records compiled for this report (used as an opioid analgesic) |
| Predicted New Indication | Restless legs syndrome (the highest-ranked prediction, methemoglobinemia, has no supporting evidence, so the best-supported prediction is evaluated here) |
| TxGNN Prediction Score | 90.35% (methemoglobinemia, rank 1: 92.74%) |
| Evidence Level | L1 (the L1 grading comes from the compiled evidence assessment; note that only one completed Phase 3 trial is listed, whereas the stated rule requires two) |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 9 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data for oxycodone is not available in the data compiled for this report. Based on known pharmacology, oxycodone is a mu-opioid receptor agonist. Opioid receptor activation modulates pain and sensory pathways and interacts with dopaminergic signalling, both of which are implicated in RLS.
RLS is a sensorimotor disorder with an urge to move the legs, worse at rest and in the evening. First-line treatment is usually an alpha-2-delta ligand (gabapentin, pregabalin) or a dopamine agonist. Long-term dopaminergic therapy can lead to augmentation (symptoms worsening with treatment). Opioids are an established option for severe or refractory cases. Prolonged-release oxycodone/naloxone is approved in Europe for second-line treatment of severe to very severe idiopathic RLS after dopaminergic therapy has failed. The Movement Disorder Society evidence review (2017 revision) considers oxycodone/naloxone efficacious.
Other predictions are much weaker:
- Methemoglobinemia (including the alpha type), nephrogenic syndrome of inappropriate antidiuresis, myositis fibrosa and idiopathic granulomatous myositis have no clinical or literature support and no plausible mechanism. These look like knowledge-graph artefacts. For nephrogenic syndrome of inappropriate antidiuresis, opioids may even worsen antidiuresis.
- Myofascial pain syndrome, headache disorder, tendinitis and common cold: oxycodone offers at most symptomatic analgesia. Long-term opioid use is generally discouraged for these conditions. The evidence is indirect or consists of postoperative pain studies. All are rated Hold.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01112644 | Phase 3 | Completed | 205 | Randomised, double-blind, placebo-controlled, multicentre study of prolonged-release oxycodone/naloxone vs placebo in moderate to severe idiopathic RLS with daytime symptoms; primary aim was superior improvement in RLS symptom severity over a 12-week titration/maintenance period |
For headache disorder, the only listed trial (NCT01431326) is a paediatric pharmacokinetic study of understudied drugs and does not assess headache efficacy, so it is not counted as supporting evidence.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 39324694 | 2025 | Guideline | J Clin Sleep Med | AASM clinical practice guideline on treatment of RLS and periodic limb movement disorder in adults and children |
| 27355187 | 2016 | Systematic review | Cochrane Database Syst Rev | Review of opioids for RLS |
| 29756335 | 2018 | Evidence-based review | Mov Disord | Revised 2017 MDS review; oxycodone/naloxone now considered efficacious in RLS |
| 23746768 | 2014 | Meta-analysis | Sleep Med Rev | Meta-analyses and indirect comparisons of dopaminergic and non-dopaminergic RLS treatments |
| 26135898 | 2015 | Review | CNS Drugs | Oxycodone/naloxone PR in severe refractory RLS; approved in Europe as second-line therapy after dopaminergic failure |
| 26966363 | 2016 | Review | Neuropsychiatr Dis Treat | Role of prolonged-release oxycodone/naloxone in intractable RLS |
| 27310338 | 2016 | Review | Expert Opin Drug Metab Toxicol | Pharmacological and clinical aspects of opioids in RLS |
| 27964861 | 2017 | Review | Sleep Med | Opioids relieve sensory and motor RLS symptoms and improve sleep; mechanism still speculative |
| 33985652 | 2021 | Review | Sleep Med Clin | Alpha-2 ligands now first-line; opioids such as oxycodone/naloxone as second-line |
| 26215616 | 2015 | Review | Nat Rev Neurol | Current RLS therapies and management of augmentation; opioids where approved |
Further reviews also cover RLS, but only the most relevant are listed above. For the other predicted indications, the literature is sparse or indirect (for example, postoperative pain after rotator cuff repair for tendinitis).
Singapore Market Information
The approved indication text is not recorded for any of the licences.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN14885P | OXYCONTIN NEO Controlled-Release Tablets 20 mg | Film-coated extended-release tablet | Not recorded |
| SIN14884P | OXYCONTIN NEO Controlled-Release Tablet 10 mg | Film-coated extended-release tablet | Not recorded |
| SIN13079P | OXYNORM 10 mg Capsule | Capsule | Not recorded |
| SIN13083P | OXYNORM 5 mg Capsule | Capsule | Not recorded |
| SIN16635P | Oxycodone Kalceks Solution for Injection or Infusion 10 mg/ml | Solution for injection | Not recorded |
Four more licences are valid: Oxycodone Wockhardt injection (SIN15996P), OxyNorm sterile injection (SIN13733P), and Targin prolonged-release tablets 5 mg/2.5 mg (SIN14031P) and 10 mg/5 mg (SIN14032P). Targin is the oxycodone/naloxone product, which is the formulation studied in RLS. All nine registrations are valid.
Safety Considerations
- Contraindications flagged in the knowledge graph (derived from TxGNN drug–disease edges, not from label text): liver failure, liver disease, kidney disease, respiratory failure, epilepsy, hypothyroidism/myxedema, inflammatory bowel disease, benign prostatic hyperplasia, hypotensive disorder, hypertensive disorder, substance abuse/dependence, myocardial infarction, sudden cardiac arrest, heart conduction disease, blood coagulation disorders, thrombocytopenia, anaemia and gallbladder disease, among others. These should be checked against the official package insert.
- Drug Interactions: 100 interactions were found. Major interactions include alvimopan, bupropion, aprepitant, morphine, dexamethasone, cimetidine, clarithromycin and clotrimazole. Moderate interactions include anticholinergics (hyoscyamine, atropine, glycopyrronium, dicyclomine, clidinium), loperamide, eluxadoline, dolasetron and dronabinol. Concomitant use with other opioids, CNS depressants and CYP3A4/CYP2D6 modulators needs particular care.
- Use-specific risks (from the evidence review): misuse, dependence, respiratory depression and sleep-disordered breathing. The last is especially relevant in RLS, where patients have disrupted sleep.
Please refer to the package insert for full warnings and contraindications.
Conclusion and Next Steps
Decision: Proceed with Guardrails (restless legs syndrome only; Hold for all other predicted indications)
Rationale: A completed Phase 3 placebo-controlled trial of prolonged-release oxycodone/naloxone, together with a Cochrane review, MDS and AASM guidance and European approval for second-line use, supports RLS as a credible new indication. The risks of dependence, misuse and respiratory depression call for strict limits on use. The other nine predictions lack evidence or a plausible mechanism and should not be pursued.
To proceed, the following is needed:
- Singapore package insert warnings, contraindications and approved indications. These are currently missing and are a blocking gap for safety screening.
- Detailed mechanism-of-action data (for example from DrugBank).
- Confirmation of the Phase 3 results and of whether a second adequate trial exists. Only one is listed, so L1 under the strict two-trial rule is not met.
- Clinical guardrails: restrict use to severe, intractable or augmented RLS after failure of alpha-2-delta ligands and dopamine agonists, with monitoring for misuse, dependence, respiratory depression and sleep-disordered breathing.
- Confirmation that the oxycodone/naloxone formulation (Targin, already registered in Singapore) is the appropriate product, and a regulatory assessment of an RLS indication.
- Route compatibility and similarity-to-original-indication analyses, which are still pending.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.