Naloxone
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Naloxone: From Opioid Dependence to Continuous Spikes and Waves During Sleep
One-Sentence Summary
Naloxone is an opioid antagonist, originally used for opioid dependence and substance abuse, and it is the standard agent for reversing opioid effects. The TxGNN model's top-ranked prediction is continuous spikes and waves during sleep, but no clinical trials and no publications support this prediction. The best-supported alternative in the data compiled for this report is hypoglycemia (3 clinical trials, all terminated, and a 2025 clinical study of intranasal naloxone).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Opiate dependence, substance abuse/dependence, morphine dependence (the HSA licence entries contain no indication text) |
| Predicted New Indication | Continuous spikes and waves during sleep |
| TxGNN Prediction Score | 88.17% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 4 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available. Based on known information, naloxone is a competitive opioid-receptor antagonist (mainly at the mu receptor). It is used to reverse opioid effects and to treat opioid dependence and overdose.
For the top-ranked prediction, continuous spikes and waves during sleep (an epileptic encephalopathy with electrical status epilepticus in sleep), no plausible link to opioid-receptor antagonism was identified in the data. The prediction rests on the model score alone. Notably, the knowledge graph also lists epilepsy as a contraindication for naloxone, which argues against this use.
Other predictions are more plausible mechanistically:
- Hypoglycemia (rank 7): Opioid signalling is thought to blunt counterregulatory and autonomic responses in hypoglycemia-associated autonomic failure (HAAF). Blocking opioid receptors may restore these responses. This is the best-supported direction, backed by trials and a 2025 clinical study.
- Drug-induced dyskinesia (rank 9): The opioid system modulates basal ganglia dopamine signalling. Naloxone reduced levodopa-induced dyskinesia in primate models, but human data are small and old.
- Schizophreniform and psychotic disorders (ranks 4 and 6): This direction comes from the 1980s endogenous-opioid hypothesis of psychosis, and results were inconsistent or negative.
The remaining predictions (lissencephaly with cerebellar hypoplasia, DECR deficiency encephalopathy, acute laryngopharyngitis) have no evidence and no apparent mechanistic link.
Clinical Trial Evidence
There are no clinical trials for the top-ranked prediction (continuous spikes and waves during sleep). Currently no related clinical trials are registered.
For reference, the trials found for the better-supported alternative, hypoglycemia:
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02700048 | Phase 1/2 | Terminated | 11 | Intranasal naloxone vs saline during experimental hypoglycemia, for impaired awareness of hypoglycemia (most direct match) |
| NCT00678145 | Phase 2 | Terminated | 39 | Mechanisms of hypoglycemia-associated autonomic failure in type 1 diabetes |
| NCT03608163 | Phase 4 | Terminated | 4 | Naloxone and diazoxide to prevent HAAF; healthy subjects only |
For psychotic disorder, the only trial is NCT01591629 (Early Phase 1, completed, n=6). It studied cannabinoid-opioid interactions in cannabis use disorder, not psychosis treatment.
Literature Evidence
There is no literature for the top-ranked prediction. Currently no related literature is available.
For reference, key publications for the alternative indications:
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 39026458 | 2025 | Clinical study | J Clin Endocrinol Metab | Intranasal naloxone in HAAF-susceptible individuals; opioid blockade with IV naloxone ameliorates HAAF experimentally but is not feasible therapeutically |
| 39331519 | 2025 | Commentary | J Clin Endocrinol Metab | Discussion of whether intranasal naloxone can prevent HAAF |
| 20811039 | 2011 | Preclinical | Diabetes | Naloxone, but not valsartan, preserved responses to hypoglycemia after antecedent hypoglycemia |
| 12804390 | 2003 | Cochrane review | Cochrane Database Syst Rev | Miscellaneous treatments for neuroleptic-induced tardive dyskinesia |
| 12373562 | 2002 | Preclinical (primate) | J Neural Transm | Naloxone reduced levodopa-induced dyskinesias in marmoset models of parkinsonism |
| 3070611 | 1988 | Clinical study | Psychiatry Res | High-dose IV naloxone (20 mg, 40 mg) vs placebo in 20 tardive dyskinesia patients |
| 6121545 | 1982 | Double-blind clinical study | Arch Gen Psychiatry | WHO collaborative study; naloxone reduced symptoms in schizophrenic patients on neuroleptics, but not in medication-free patients |
| 7435717 | 1980 | Placebo-controlled study | Am J Psychiatry | Naloxone failed to improve manic symptoms |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN05964P | Naloxone Hydrochloride Injection USP 0.4 mg/ml | Injection | Not stated in the data |
| SIN10290P | Mapin Injection 0.4 mg/ml | Injection | Not stated in the data |
| SIN14032P | Targin® Prolonged Release Tablets 10mg/5mg | Tablet, film coated, extended release | Not stated in the data |
| SIN14031P | Targin® Prolonged Release Tablets 5mg/2.5mg | Tablet, film coated, extended release | Not stated in the data |
All four licences are valid single-ingredient registrations. Both injectable and oral routes are available.
Safety Considerations
Please refer to the package insert for safety information. The package insert warnings were not available for this report.
- Contraindications flagged in the knowledge graph (these come from drug-disease relationships, not label text): epilepsy, long QT syndrome, torsades de pointes, heart conduction disease, sudden cardiac arrest, orthostatic hypotension, chronic obstructive pulmonary disease, respiratory failure, kidney disease, liver disease, adrenal insufficiency/Addison disease, hypothyroidism, inflammatory bowel disease, hepatitis B/C infection and benign prostatic hyperplasia. The epilepsy flag is particularly relevant to the top-ranked prediction.
- Drug interactions: 88 interactions were recorded. Among those listed, droperidol is rated Major. Most others are Moderate, including opioids (fentanyl, morphine, codeine, tramadol, methadone, oxycodone, hydrocodone), peripherally acting opioid antagonists (methylnaltrexone, naldemedine, naloxegol) and binimetinib. Hydrocortisone is Minor.
- Other: A 1996 rat study reported naloxone-induced seizures in the setting of viral encephalitis.
Conclusion and Next Steps
Decision: Hold
Rationale: The top-ranked prediction (continuous spikes and waves during sleep) has only a model score behind it (L5), with no trials, no literature and no plausible mechanism. Epilepsy is also listed as a contraindication in the knowledge graph. Among the other predictions, hypoglycemia (HAAF) is the most promising and could be pursued as a separate research question. However, its trials were terminated with very small enrollment, so efficacy is unconfirmed.
To proceed, the following is needed:
- Re-evaluate the candidate list and consider prioritising hypoglycemia/HAAF (and possibly drug-induced dyskinesia) over the top-ranked prediction
- Full results and conclusions of the 2025 intranasal naloxone HAAF studies
- Mechanism of action data
- Package insert warnings and contraindications from the HSA, to enable safety screening
- Assessment of the epilepsy contraindication and the major droperidol interaction
- Route and formulation compatibility (for example, intranasal use for HAAF versus the currently registered injection and oral combination products)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.