Diazepam
| Evidence Level: L3 | Predicted Indications: 10 |
Table of Contents
Diazepam: From Benzodiazepine Sedative-Anxiolytic to Insomnia
One-Sentence Summary
Diazepam is a benzodiazepine sedative-anxiolytic that is registered as a tablet in South Africa. The TxGNN model predicts it may be effective for insomnia, but no trial has tested diazepam for insomnia. The evidence is one small 1981 comparative trial, reviews, and mostly benzodiazepine-withdrawal studies, and the trials that mention benzodiazepines mostly concern stopping them.
Quick Overview
| Item | Content |
|---|---|
| Predicted New Indication | Insomnia |
| TxGNN Prediction Score | 99.9997% (model rank 5) |
| Evidence Level | L3 |
| South Africa Market Status | Marketed |
| Number of SAHPRA Registrations | 1 |
| Recommended Decision | Hold |
The registered indication text is not recorded in the SAHPRA data supplied, so the original indication could not be confirmed from the registration record.
Why is This Prediction Reasonable?
Diazepam is a positive allosteric modulator of the GABA-A receptor. It enhances inhibitory signalling in the brain, which produces sedative and hypnotic effects. Benzodiazepines as a class are widely used for anxiety and insomnia (PMID 39581171), so a link between diazepam and insomnia is biologically plausible.
The supporting clinical data are thin:
- The only direct comparison is a 1981 double-blind study of 100 outpatients. In it, lormetazepam 1 mg outperformed diazepam 5 mg on time to fall asleep and sleep continuity (PMID 6113175).
- Most other material concerns the harms of long-term benzodiazepine hypnotic use: tolerance, dependence, altered sleep architecture, and cognitive impairment. This includes a mouse study linking chronic diazepam to impaired spine plasticity (PMID 35228700).
- Detailed mechanism-of-action data were not available in the Evidence Pack.
The model also produced a separate prediction for “sleep disorder, initiating and maintaining sleep”. It is essentially the same clinical concept as insomnia and should be merged with this entry in review.
Clinical Trial Evidence
No trial in the pack tests diazepam as a treatment for insomnia. The trials below are the most relevant, and they concern hypnotic or benzodiazepine discontinuation. No SANCTR or PACTR registrations were identified.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT04050176 | Phase 3 | Active, not recruiting | 260 | Blinded hypnotic tapering plus CBT for insomnia versus open-label tapering. Relevant to exit strategy, not to diazepam efficacy. |
| NCT02831894 | Phase 2 | Completed | 74 | Role of tapering pace on hypnotic discontinuation in insomnia. |
| NCT03461042 | Phase 4 | Completed | 17 | Ramelteon versus placebo to help reduce or stop benzodiazepine and Z-drug hypnotics in chronic insomnia. Very small. |
| NCT04751851 | N/A | Completed | 128 | Acceptance and Commitment Therapy via telepsychology during benzodiazepine withdrawal in hypnotic-dependent insomnia. |
| NCT03687086 | N/A | Completed | 188 | Non-drug programme to help older adults stop sleeping pills. |
| NCT02281175 | N/A | Completed | 114 | Psychosocial programme to help older benzodiazepine users wean off. |
| NCT01244711 | Phase 4 | Terminated | 1 | Quetiapine substituted for benzodiazepines. Uninformative (n=1). |
| NCT01893632 | Phase 2 | Terminated | 2 | Gabapentin for benzodiazepine dependence. Uninformative (n=2). |
| NCT05935553 | Phase 2/3 | Recruiting | 93 | Baclofen to improve benzodiazepine titration in dependence. |
| NCT04364321 | N/A | Unknown | 74 | Single-dose clonazepam versus intermittent oral diazepam to prevent recurrent febrile seizures in children. Diazepam is the comparator, and the condition is unrelated to insomnia. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 6113175 | 1981 | Comparative RCT | J Int Med Res | 100 outpatients over 7 days: lormetazepam 1 mg was significantly better than diazepam 5 mg at shortening sleep onset and prolonging uninterrupted sleep. |
| 39374004 | 2024 | RCT | JAMA Intern Med | Masked taper plus behavioural intervention for discontinuing benzodiazepine receptor agonist hypnotics. Concerns stopping, not efficacy. |
| 39581171 | 2024 | Review | Bioorg Chem | GABA-A modulators, including diazepam, used in epilepsy, anxiety, insomnia and depression, with sedation-type side effects. |
| 7595266 | 1995 | Systematic review | J Fam Pract | Benefit and risk of benzodiazepines for insomnia in community-dwelling elderly. No studies of long-term effectiveness. |
| 7525193 | 1994 | Review | Drugs | Guidelines for rational benzodiazepine use. As hypnotics they are mainly indicated for transient or short-term insomnia. |
| 36692463 | 2023 | Meta-analysis | Acta Pharm | Tranquilizer use in elderly patients with chronic non-communicable diseases. Assesses dose, outcomes and adverse effects. |
| 40570297 | 2025 | Cohort | Sleep | Chronic benzodiazepine and receptor agonist use in older adults with chronic insomnia. Assesses effects on sleep architecture and brain oscillations. |
| 35228700 | 2022 | Preclinical | Nat Neurosci | Long-term diazepam in mice increased microglial spine engulfment and impaired cognition via TSPO. |
| 40583063 | 2025 | Clinical and molecular study | Cell Mol Biol Lett | Long-term benzodiazepine and Z-drug use is linked to a higher risk and worse course of breast cancer. |
| 6114852 | 1981 | Review | Drugs | Triazolam in insomnia. Not diazepam, but a shorter-acting benzodiazepine hypnotic. |
South Africa Market Information
| Registration Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| L/2.6/90 | Benzopin 2 | Tablet (oral) | Not recorded in the registration data supplied |
Safety Considerations
Please refer to the SAHPRA-approved Professional Information (PI) for safety information. Report adverse drug reactions to SAHPRA. No warnings, contraindications, or drug interaction records were available in the Evidence Pack.
Signals from the supplied literature, not from the PI:
- Tolerance and dependence with long-term use
- Cognitive impairment, including in older adults
- Altered sleep architecture
- Abuse and misuse liability
- A reported association with breast cancer risk (observational)
Conclusion and Next Steps
Decision: Hold
Rationale: The GABA-A mechanism makes an insomnia effect plausible. However, no trial tests diazepam for insomnia, the only direct comparison is a 1981 study in which another benzodiazepine performed better, and the literature is dominated by dependence and withdrawal concerns. The SAHPRA package insert safety data are still missing, which blocks safety screening.
The other nine predicted indications are also on Hold, at evidence level L4–L5:
- Cauda equina syndrome, ADHD (both types), specific developmental disorder and neurogenic bladder have no supportive evidence. Neurogenic bladder is also an obsolete ontology term.
- Antidepressant, hallucinogen and barbiturate abuse show only indirect evidence about benzodiazepine dependence and withdrawal.
To proceed, the following is needed:
- Download and review the SAHPRA package insert (warnings, contraindications, registered indication) for Benzopin 2 (L/2.6/90)
- DrugBank mechanism-of-action data to complete the mechanistic analysis
- Confirmation of whether insomnia is already on the registered label
- Head-to-head or placebo-controlled trial data for diazepam in insomnia, including comparison with current first-line options
- A risk plan for dependence, cognitive effects, and use in older adults
These results are for research reference only and do not constitute medical advice. Repurposing candidates require clinical validation before clinical use.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.