Nimetazepam

Summary

Nimetazepam, known by its brand names Erimin and Lavol, is an intermediate-acting hypnotic drug belonging to the benzodiazepine derivative class. It was initially synthesized in 1964 by a team at Hoffmann-La Roche. This compound is renowned for its potent hypnotic, anxiolytic (anxiety-reducing), soothing, and skeletal muscle relaxant properties. Additionally, Nimetazepam exhibits remarkable anticonvulsant effects.
Erimin, available in 5 mg tablets, is the brand name under which it is manufactured and marketed by the prominent Japanese corporation Sumitomo. Japan holds the exclusive rights to the production of Nimetazepam worldwide. While Erimin was widely distributed across East and Southeast Asia for the short-term treatment of severe insomnia, Sumitomo ceased its manufacturing in November 2015. Nevertheless, it can still be found in the form of a generic drug or as Lavol.
During the 1980s and 1990s, Nimetazepam was extensively prescribed, particularly in countries like Japan, Malaysia, Brunei, the Philippines, Thailand, Indonesia, Hong Kong, and Singapore. However, due to widespread misuse and addiction issues, prescriptions for the drug have significantly dwindled since 2005. Presently, it is primarily administered as an anticonvulsant for children or in severe cases of inpatient insomnia treatment. Hypnotic benzodiazepines such as estazolam and nitrazepam are favoured for this purpose, along with antidepressants like trazodone and mirtazapine or Z-drugs such as zopiclone and zolpidem.
Despite the decline in prescriptions, Nimetazepam abuse remains prevalent in Brunei, Singapore, Malaysia, and the Philippines. It is frequently used in combination with substances like methamphetamine, MDMA (Ecstasy), and opiates, particularly heroin or morphine. Strict legal restrictions in Malaysia have led to a scarcity of the drug, resulting in many counterfeit pills being sold on the black market. Diazepam and nitrazepam, more commonly prescribed benzodiazepines in the region, are often diverted and sold as Nimetazepam.
Illicit production of Nimetazepam (marketed as Erimin-5) is widespread in the area, and its abuse has continued to rise over the years. Seizures of illicitly manufactured Erimin-5 tablets have followed the increasing trend of methamphetamine seizures in Malaysia. A small seizure of 46 illicit Erimin-5 tablets underwent testing to determine their physical and chemical composition. The results revealed that Nimetazepam was the primary active ingredient in the majority of the tablets. Lactose was identified as the significant diluent in most samples, followed by mannitol and calcium phosphate dibasic dihydrate. Various dyes, including sunset yellow, were used to give the tablets different colours. Notably, diazepam, mainly an anxiolytic, was the active ingredient in just one out of the 46 tablets. At the same time, nitrazepam, a potent sedative-hypnotic and the parent drug of Nimetazepam appeared as a minor compound in combination with caffeine as the primary compound in three of the tablets.
In 2003, Singapore authorities seized 94,200 Erimin-5 tablets, subsequently confirming their content as Nimetazepam through laboratory testing by the Central Narcotics Bureau (CNB).

Identifiers

IUPAC name
CAS Number	2011-67-8
PubChem CID	4496
ChemSpider	4340
UNII	4532264KW6
KEGG	D01593
ChEBI	CHEBI:31912
ChEMBL	ChEMBL13341
CompTox Dashboard (EPA)	DTXSID6023369
ECHA InfoCard	100.016.302
Chemical and physical data
Formula	C16H13N3O3
Molar mass	295.298 g·mol−1

Pharmacokinetics

When taken orally, Nimetazepam exhibits exceptional bioavailability, with nearly 100% absorption in the gastrointestinal tract. Among oral benzodiazepines, it ranks as one of the most rapidly absorbed, leading to a swift onset of hypnotic effects within 15–30 minutes after ingestion. The decline in blood levels of the parent drug follows a biphasic pattern, with a short half-life ranging from 0.5 to 0.7 hours and a terminal half-life ranging from 8 to 26.5 hours (with an average of 17.25 hours)[citation needed]. Nimetazepam is the N-methylated analogue of nitrazepam (Mogadon, Alodorm), to which it is partially metabolized. Nitrazepam, known for its long elimination half-life, results in cumulative effects with repeated dosages.

Recreational Use

The pharmacological profile of Nimetazepam, including high affinity binding, potent efficacy, short to intermediate duration of action, and rapid onset, increases its potential for misuse and dependence. Additionally, the physical dependence and withdrawal syndrome associated with Nimetazepam contribute to its addictive nature.

Nimetazepam has gained notoriety for its recreational use in Southeast Asia, often priced at around USD 7 per tablet. It is trendy among individuals addicted to amphetamines or opioids. Furthermore, Nimetazepam has displayed antidepressant and muscle relaxant effects. It also aids in suppressing withdrawal symptoms and exhibits lower drug-seeking behaviour compared to nitrazepam in rhesus monkeys (Macaca Mulatta), which can assist stimulant addicts in overcoming withdrawal.

Drug Misuse

Nimetazepam is known for its susceptibility to abuse and is sometimes referred to as ‘Happy 5’. While it remains a significant drug of abuse in some Asian countries like Japan and Malaysia, it is subject to legal restrictions in Malaysia. As a result, many tablets sold on the black market are counterfeit, containing alternative benzodiazepines such as diazepam or nitrazepam instead.

Legal Status

In the United States, Nimetazepam is classified as a Schedule IV drug by the FDA and DEA.

Internationally, Nimetazepam is categorized as a Schedule IV drug under the Convention on Psychotropic Substances of 1971.

In Singapore, Nimetazepam is a physician-prescribed drug and is regulated under the Misuse of Drugs Act. Illegal possession or consumption of Nimetazepam is punishable by up to 10 years in prison, a fine of 20,000 Singapore dollars, or both. Importing or exporting Nimetazepam can lead to up to 20 years of imprisonment and caning.

In Hong Kong, Nimetazepam is regulated under Schedule 1 of Hong Kong’s Chapter 134 Dangerous Drugs Ordinance. Its legal use is restricted to health professionals and university research. Pharmacists can provide the substance only with a prescription. Supplying the substance without a prescription can result in a $10,000 (HKD) fine. The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment. Possession of the substance for consumption without a license from the Department of Health is illegal and may incur a $1,000,000 (HKD) fine and/or 7 years in jail[14].

Likewise, in Taiwan and Indonesia, Nimetazepam is regulated as a controlled prescribed substance.

In Victoria, Australia, Nimetazepam is regulated under Schedule 11 of the “Drugs, Poisons, and Controlled Substances Act 1981”. It falls under the category of “7-NITRO-1,4-BENZODIAZEPINES not included elsewhere in this Part”.

Toxicity

In a rat study, Nimetazepam showed more significant damage to the fetus, as did nitrazepam, when compared to other benzodiazepines, all at a dosage of 100 mg/kg. However, diazepam displayed relatively weaker fetal toxicities. The same fetotoxicity of nitrazepam could not be observed in mice and is likely due to the particular metabolism of the drug in rats.

In another rat study, Nimetazepam resulted in slight enlargement of the liver and adrenals, and atrophy of the testes and ovaries was found in high-dose groups for both drugs at the 4th and 12th week. However, in histopathological examination, there were no changes observed in the liver, adrenals, and ovaries. Degenerative changes in the seminiferous epithelium in the testes were noted, but these atrophic changes returned to normal after the drugs were withdrawn for 12 weeks.

FAQ

• What is Nimetazepam?
• Nimetazepam is an intermediate-acting hypnotic drug belonging to the benzodiazepine family. It possesses properties such as hypnotic, anxiolytic, sedative, and skeletal muscle relaxant effects. It is also an anticonvulsant.
• How is Nimetazepam typically administered?
• Nimetazepam is typically taken orally in tablet form. It has excellent bioavailability, with almost 100% absorption from the gastrointestinal tract.
• How quickly does Nimetazepam take effect?
• Nimetazepam is known for its rapid onset of action, and its hypnotic effects are typically felt within 15 to 30 minutes after oral ingestion.
• What are the half-life characteristics of Nimetazepam?
• The blood level decline of Nimetazepam follows a biphasic pattern. It has a short half-life ranging from 0.5 to 0.7 hours and a terminal half-life ranging from 8 to 26.5 hours, with an average of 17.25 hours.
• Is Nimetazepam used for recreational purposes?
• Yes, Nimetazepam is known for recreational use, especially in South East Asia. It is popular among individuals addicted to amphetamines or opioids. It has an antidepressant and muscle relaxant effect, which can contribute to its recreational use.
• What is the legal status of Nimetazepam in various countries?
• The legal status of Nimetazepam varies by country. It is a Schedule IV drug in the United States, while internationally, it is categorized as a Schedule IV drug under the Convention on Psychotropic Substances of 1971. In Singapore, it is regulated under the Misuse of Drugs Act, and its illegal possession or consumption carries severe penalties. Similar regulations apply in countries like Malaysia, Hong Kong, Taiwan, and Indonesia.
• Are there any known toxic effects associated with Nimetazepam?
• Nimetazepam has been associated with fetal damage in rat studies when compared to other benzodiazepines. However, it’s important to note that the extent of toxicity may vary between species.
• Is Nimetazepam still prescribed for medical purposes?
• While Nimetazepam was once prescribed for severe insomnia, especially in East and Southeast Asia, its prescription rates have decreased significantly due to misuse and addiction. Other medications, such as hypnotic benzodiazepines, antidepressants, or Z-drugs, are now preferred for treating insomnia.
• Why is Nimetazepam associated with the nickname ‘Happy 5’?
• ‘Happy 5’ is a street name often used to refer to Nimetazepam, reflecting its reputation for recreational use and euphoric effects.
• Is Nimetazepam similar to other benzodiazepines?
• Nimetazepam is a benzodiazepine derivative and shares some properties with other benzodiazepines, including sedative and anxiolytic effects. However, its distinct pharmacological profile sets it apart from other drugs in the same class.

References

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2. US patent 3109843, Reeder E, Sternbach LH, “Method for Producing 5-Phenyl-1,2-Dihydro-3H-1,4-Benzodiazepines”, granted on 1963-11-05, assigned to Hoffmann-La Roche.
3. Fukinaga M, Ishizawa K, Kamei C (November 1998). “Anticonvulsant Properties of 1,4-Benzodiazepine Derivatives in Amygdaloid-Kindled Seizures and their Relationship to Chemical Structure”. Published in Pharmacology. Volume 57 (5): 233–41. doi:10.1159/000028247. PMID 9742288. S2CID 25773207.
4. Kunalan, V (2012). “Forensic Drug Profiling of Erimin-5 Using TLC and GC-MS”. Published in the Malaysian Journal of Forensic Sciences. Volume 3: 1–14 – available via ResearchGate.
5. Chong YK, Kaprawi MM, Chan KB (2004). “Quantification of Nimetazepam in Erimin-5 Tablets and Powders using Reverse-Phase HPLC”. Published in the Microgram Journal. Volume 2 (1–4): 27–33. Archived from the original on 2011-08-10. Retrieved on 2011-12-07.
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7. Sakai S, Kitagawa S, Yamamoto H (March 1972). “Pharmacological Studies on 1-Methyl-7-Nitro-5-Phenyl-1,3-Dihydro-2H-1,4-Benzodiazepin-2-one (S-1530)”. Published in Arzneimittel-Forschung. Volume 22 (3): 534–9. PMID 5067925.
8. Yanagita T, Takahashi S, Oinuma N. “Drug Dependence Liability of Nimetazepam Evaluated in the Rhesus Monkey”.
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10. Binti Abdul Rahim, Rusdiyah. “Profiling of Illicit Erimin 5 Tablets Seized in Malaysia”. A Research Project Report Submitted to the Department of Chemistry, Faculty of Science, University of Malaya.
11. “Erimin 5 Tablets In Singapore”. Published by The Centre for Forensic Science, HSA, Singapore in 2006.
12. “List of Psychotropic Substances under International Control” (PDF). Green List Annex to the Annual Statistical Report on Psychotropic Substances (Form P) (23rd ed.). International Narcotics Control Board. August 2003. Archived from the original (PDF) on 2012-08-31. Retrieved on 2011-12-06.
13. “Misuse of Drugs Act, Chapter 185”. Archived from the original on 2012-02-15. Retrieved on 2011-09-08.
14. “Bilingual Laws Information System”. Published by The Government of the Hong Kong Special Administrative Region of the People’s Republic of China.
15. “Victorian Legislation and Parliamentary Documents”. Published by The State Government Victoria.
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17. Takeno S, Hirano Y, Kitamura A, Sakai T (August 1993). “Comparative Developmental Toxicity and Metabolism of Nitrazepam in Rats and Mice”. Published in Toxicology and Applied Pharmacology. Volume 121 (2): 233–8. doi:10.1006/taap.1993.1150. PMID 8346540.
18. Yamamoto T, Kato T, Wada H, Kerata Y (1972). “Chronic Toxicity of 1-Methyl-7-Nitro-5-Phenyl-1,3-Dihydro-2H-1,4-Benzodiazepin-2-one (Nimetazepam) in Rats”. Chronic Toxicity Study.