Fatal overdose may occur when benzodiazepines are combined with other depressants such as opiates, barbiturates, gabapentinoids, thienodiazepines, alcohol or other GABAergic substances.
It is strongly discouraged to combine these substances, particularly in common to heavy doses.
|Summary sheet: Nifoxipam|
|Routes of Administration|
Nifoxipam is a an analytical reference material and a novel depressant substance of the nitrobenzodiazepine class.
Nifoxipam has potential use for the short-term treatment of anxiety, insomnia, acute seizures, and the sedation of hospitalized patients. However, it is currently exclusively sold by online research chemical vendors for use as a recreational psychoactive substance.
Subjective effects include anxiety suppression, disinhibition, anticonvulsant, hypnotic, muscle relaxing, and amnesia. The effects of nifoxipam are notably long-lived, although reported to be relatively subtle.
It is worth noting that the sudden discontinuation of benzodiazepines can be potentially dangerous or life-threatening for individuals using regularly for extended periods of time, sometimes resulting in seizures or death. It is highly recommended to taper one's dose by gradually lowering the amount taken each day for a prolonged period of time instead of stopping abruptly.
As with other benzodiazepines, nifoxipam has abuse potential and produces dependence with prolonged use. Additionally, very little data exists about its metabolism, pharmacology, and toxicity. It is highly advised to use harm reduction practices if using this substance.
Nifoxipam is a drug of the benzodiazepine class. Benzodiazepine drugs contain a benzene ring fused to a diazepine ring, which is a seven membered ring with the two nitrogen constituents located at R1 and R4. Nifoxipam, or 3-hydroxydesmethylflunitrazepam, is an active metabolite of flunitrazepam. The benzyl ring of nifoxipam is substituted at R7 with a nitro group, NO2-. AR2flourine substituted phenyl ring is bound to this structure at R5. Additionally, nifoxipam contains a hydroxy (OH-) group substituted at R3. Nifoxipam also contains an oxygen group double bonded to R2 of its diazepine ring to form a ketone. This oxygen substitution at R2 is shared with benzodiazepine drugs with the suffix -azepam.
As with flunitrazepam, nifoxipam is likely insoluble in water, although the addition of a hydroxyl group may increase water solubility.
Nifoxipam has a molecular weight of 315.26 g/mol.
Nifoxipam produces strong tranquillising and sleep-prolonging effects and has much lower toxicity compared to lormetazepam and flunitrazepam in mice.
As with other benzodiazepines, nifoxipam binds to specific sites on the GABAA receptor, and is in the same class of hypnotic nitrobenzodiazepines as nitrazepam, nimetazepam, flunitrazepam, and flurazepam. As with all GABAergic drugs, overdose can be lethal when mixed with other depressants such as opioids and alcohol. This is particularly concerning because Nifoxipam is a research chemical and has not been approved for medicinal use.
Usage of Nifoxipam on a regular basis can cause typical benzodiazepine addiction, habituation, and tolerance.
Benzodiazepines produce a variety of effects by binding to the benzodiazepine receptor site and magnifying the efficiency and effects of the neurotransmitter gamma aminobutyric acid (GABA) by acting on its receptors. As this site is the most prolific inhibitory receptor set within the brain, its modulation results in the sedating (or calming effects) of nifoxipam on the nervous system. The anticonvulsant properties of benzodiazepines may be, in part or entirely, due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors.
Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), an open research literature based on anecdotal user reports and the personal analyses of PsychonautWiki contributors. As a result, they should be viewed with a healthy degree of skepticism.
It is also worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become increasingly likely with higher doses and may include addiction, severe injury, or death ☠.
- Sedation - In terms of energy level alterations, nifoxipam is moderately sedating and can potentially result in a lethargic state. At higher levels, this causes users to suddenly feel as if they are extremely sleep deprived and have not slept for days, forcing them to sit down and generally feel as if they are constantly on the verge of passing out instead of engaging in physical activities. This sense of sleep deprivation increases proportional to dosage and eventually becomes powerful enough to force a person into complete unconsciousness.
- Motor control loss - Lack of coordination may result in falls and injuries, and the elderly are especially susceptible. Another result of motor control loss is the impairment of driving skills and the increased likelihood of road traffic accidents.
- Muscle relaxation
- Respiratory depression - This effect is reported to occur only at high doses.
Paradoxical reactions to benzodiazepines such as increased seizures (in epileptics), aggression, increased anxiety, violent behavior, loss of impulse control, irritability and suicidal behavior sometimes occur (although they are rare in the general population, with an incidence rate below 1%).
These paradoxical effects occur with greater frequency in recreational abusers, individuals with mental disorders, children, and patients on high-dosage regimes.
The cognitive effects of nifoxipam can be broken down into several components which progressively intensify proportional to dosage. The general head space of nifoxipam is described by many as one of mild sedation and decreased inhibition. It produces a large number of cognitive effects associated with depressants and benzodiazepines.
The most prominent of these cognitive effects generally include:
- Anxiety suppression
- Cognitive euphoria
- Thought deceleration
- Analysis suppression
- Motivation suppression
- Emotion suppression - Although this compound primarily suppresses anxiety, it also dulls other emotions in a manner which is distinct but less intensive than that of antipsychotics.
- Memory suppression
- Delusions of sobriety - This is the false belief that one is perfectly sober despite obvious evidence to the contrary such as severe cognitive impairment and an inability to fully communicate with others. It most commonly occurs at heavy dosages.
- Compulsive redosing
- Rebound anxiety - Rebound anxiety is a commonly observed effect with anxiety relieving substances like benzodiazepines and etizolam. It typically corresponds to the total duration spent under the substance's influence along with the total amount consumed in a given period, an effect which can easily lend itself to cycles of dependence and addiction.
- Dream potentiation or Dream suppression
- Residual sleepiness - While etizolam can be used as an effective sleep-inducing aid, its effects may persist into the morning afterwards, which may lead users to feeling "groggy" or "dull" for up to a few hours.
- Thought deceleration
- Thought disorganization
- Motivation suppression
There are currently no anecdotal reports which describe the effects of this compound within our experience index.
Toxicity and harm potential
This toxicity and harm potential section is a stub.
As a result, it may contain incomplete or even dangerously wrong information! You can help by expanding upon or correcting it.
Nifoxipam likely has a low toxicity relative to dose. However, it is potentially lethal when mixed with depressants like alcohol or opioids.
It is strongly recommended that one use harm reduction practices, such as volumetric dosing, when using this substance to ensure the accurate administration of the intended dose.
Dependence and abuse potential
Nifoxipam is extremely physically and psychologically addictive.
Tolerance will develop to the sedative-hypnotic effects within a couple of days of continuous use. After cessation, the tolerance returns to baseline in 7 - 14 days. However, in certain cases this may take significantly longer in a manner which is proportional to the duration and intensity of one's long-term usage.
Withdrawal symptoms or rebound symptoms may occur after ceasing usage abruptly following a few weeks or longer of steady dosing, and may necessitate a gradual dose reduction. For more information on tapering from benzodiazepines in a controlled manner, please see this guide.
Benzodiazepine discontinuation is notoriously difficult; it is potentially life-threatening for individuals using regularly to discontinue use without tapering their dose over a period of weeks. There is an increased risk of hypertension, seizures, and death. Drugs which lower the seizure threshold such as tramadol should be avoided during withdrawal.
Nifoxipam presents cross-tolerance with all benzodiazepines, meaning that after its consumption all benzodiazepines will have a reduced effect.
Benzodiazepine overdose may occur when a benzodiazepine is taken in extremely heavy quantities or concurrently with other depressants. This is particularly dangerous with other GABAergic depressants such as barbiturates and alcohol since they work in a similar fashion, but bind to distinct allosteric sites on the GABAA receptor, thus their effects potentiate one another. Benzodiazepines increase the frequency in which the chlorine ion pore opens on the GABAA receptor while barbiturates increase the duration in which they are open, meaning when both are consumed, the ion pore will open more frequently and stay open longer. Benzodiazepine overdose is a medical emergency that may lead to a coma, permanent brain injury or death if not treated promptly and properly.
Symptoms of a benzodiazepine overdose may include severe thought deceleration, slurred speech, confusion, delusions, respiratory depression, coma or death. Benzodiazepine overdoses may be treated effectively in a hospital environment, with generally favorable outcomes. Benzodiazepine overdoses are sometimes treated with flumazenil, a GABAA antagonist, however care is primarily supportive in nature.
Although many drugs are safe on their own, they can become dangerous and even life-threatening when combined with other substances. The list below contains some common potentially dangerous combinations, but may not include all of them. Certain combinations may be safe in low doses of each but still increase the potential risk of death. Independent research should always be done to ensure that a combination of two or more substances is safe before consumption.
- Depressants (1,4-Butanediol, 2-methyl-2-butanol, alcohol, barbiturates, GHB/GBL, methaqualone, opioids) - This combination can result in dangerous or even fatal levels of respiratory depression. These substances potentiate the muscle relaxation, sedation and amnesia caused by one another and can lead to unexpected loss of consciousness at high doses. There is also an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
- Dissociatives - This combination can result in an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
- Stimulants - It is dangerous to combine benzodiazepines with stimulants due to the risk of excessive intoxication. Stimulants decrease the sedative effect of benzodiazepines, which is the main factor most people consider when determining their level of intoxication. Once the stimulant wears off, the effects of benzodiazepines will be significantly increased, leading to intensified disinhibition as well as other effects. If combined, one should strictly limit themselves to only dosing a certain amount of benzodiazepines per hour. This combination can also potentially result in severe dehydration if hydration is not monitored.
This legality section is a stub.
As such, it may contain incomplete or wrong information. You can help by expanding it.
Nifoxipam is currently a gray area compound within most parts of the world. This means that it is not known to be specifically illegal within any country, but people may still be charged for its possession under certain circumstances such as under analogue laws and with intent to sell or consume.
- Canada: All benzodiazepines are listed in Schedule IV.
- Germany: Nifoxipam is controlled under the NpSG (New Psychoactive Substances Act) as of July 18, 2019. Production and import with the aim to place it on the market, administration to another person and trading is punishable. Possession is illegal but not penalized.
- Russia: Nifoxipam is a Schedule III controlled substance since 2017.
- Switzerland: Nifoxipam is a controlled substance specifically named under Verzeichnis E.
- Turkey: Nifoxipam is a classed as drug and is illegal to possess, produce, supply, or import.
- United Kingdom: Nifoxipam is illegal to produce, supply, or import under the Psychoactive Substance Act, which came into effect on May 26th, 2016.
- ↑ Risks of Combining Depressants - TripSit
- ↑ Newer Unregulated Drugs (KFx) | http://www.kfx.org.uk/drug_facts/drug_facts_images_and_pdfs/researchchemicals_4.2015.pdf
- ↑ Meyer, M. R., Bergstrand, M. P., Helander, A., Beck, O. (1 May 2016). "Identification of main human urinary metabolites of the designer nitrobenzodiazepines clonazolam, meclonazepam, and nifoxipam by nano-liquid chromatography-high-resolution mass spectrometry for drug testing purposes". Analytical and Bioanalytical Chemistry. 408 (13): 3571–3591. doi:10.1007/s00216-016-9439-6. ISSN 1618-2650.
- ↑ 4.0 4.1 Lann, M. A., Molina, D. K. (June 2009). "A fatal case of benzodiazepine withdrawal". The American Journal of Forensic Medicine and Pathology. 30 (2): 177–179. doi:10.1097/PAF.0b013e3181875aa0. ISSN 1533-404X.
- ↑ CKahan, M., Wilson, L., Mailis-Gagnon, A., Srivastava, A. (November 2011). "Canadian guideline for safe and effective use of opioids for chronic noncancer pain. Appendix B-6: Benzodiazepine Tapering". Canadian Family Physician. 57 (11): 1269–1276. ISSN 0008-350X.
- ↑ Kilicarslan, T., Haining, R. L., Rettie, A. E., Busto, U., Tyndale, R. F., Sellers, E. M. (1 April 2001). "Flunitrazepam Metabolism by Cytochrome P450s 2C19 and 3A4". Drug Metabolism and Disposition. 29 (4): 460–465. ISSN 0090-9556.
- ↑ Malanciuc, C., Aramă, C., Şaramet, I., Monciu, C.-M., Nedelcu, A., Davila, C. (2009). "Analytical characterization of flunitrazepam" (PDF). Farmacia. 57: 167–83.
- ↑ Posselt, K. D., Wagener, H. H. P. D. M., Gruber, K. D., Pharmaceutical composition containing 5-(2-fluorophenyl)-1,3-dihydro-3-hydroxy-7-nitro- or 5-(2-fluorophenyl)-1,3-dihydro-3-hydroxy-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one and process for their preparation
- ↑ Haefely, W. (29 June 1984). "Benzodiazepine interactions with GABA receptors". Neuroscience Letters. 47 (3): 201–206. doi:10.1016/0304-3940(84)90514-7. ISSN 0304-3940.
- ↑ McLean, M. J., Macdonald, R. L. (February 1988). "Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture". The Journal of Pharmacology and Experimental Therapeutics. 244 (2): 789–795. ISSN 0022-3565.
- ↑ Saïas, T., Gallarda, T. (September 2008). "[Paradoxical aggressive reactions to benzodiazepine use: a review]". L’Encephale. 34 (4): 330–336. doi:10.1016/j.encep.2007.05.005. ISSN 0013-7006.
- ↑ Paton, C. (December 2002). "Benzodiazepines and disinhibition: a review". Psychiatric Bulletin. 26 (12): 460–462. doi:10.1192/pb.26.12.460. ISSN 0955-6036.
- ↑ Bond, A. J. (1 January 1998). "Drug- Induced Behavioural Disinhibition". CNS Drugs. 9 (1): 41–57. doi:10.2165/00023210-199809010-00005. ISSN 1179-1934.
- ↑ Drummer, O. H. (February 2002). "Benzodiazepines - Effects on Human Performance and Behavior". Forensic Science Review. 14 (1–2): 1–14. ISSN 1042-7201.
- ↑ Mandrioli, R., Mercolini, L., Raggi, M. A. (October 2008). "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism. 9 (8): 827–844. doi:10.2174/138920008786049258. ISSN 1389-2002.
- ↑ Twyman, R. E., Rogers, C. J., Macdonald, R. L. (March 1989). "Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital". Annals of Neurology. 25 (3): 213–220. doi:10.1002/ana.410250302. ISSN 0364-5134.
- ↑ Hoffman, E. J., Warren, E. W. (September 1993). "Flumazenil: a benzodiazepine antagonist". Clinical Pharmacy. 12 (9): 641–656; quiz 699–701. ISSN 0278-2677.
- ↑ Branch, L. S. (2022), Consolidated federal laws of Canada, Controlled Drugs and Substances Act
- ↑ "Anlage NpSG" (in German). Bundesministerium der Justiz und für Verbraucherschutz. Retrieved December 10, 2019.
- ↑ "Verordnung zur Änderung der Anlage des Neue-psychoaktive-Stoffe-Gesetzes und von Anlagen des Betäubungsmittelgesetzes" (PDF). Bundesgesetzblatt Jahrgang 2019 Teil I Nr. 27 (in German). Bundesanzeiger Verlag. July 17, 2019. Retrieved December 28, 2019.
- ↑ "§ 4 NpSG" (in German). Bundesministerium der Justiz und für Verbraucherschutz. Retrieved December 10, 2019.
- ↑ Постановление Правительства РФ от 12.07.2017 N 827 “О внесении изменений в некоторые акты Правительства Российской Федерации в связи с совершенствованием контроля за оборотом наркотических средств и психотропных веществ” - КонсультантПлюс
- ↑ "Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien" (in German). Bundeskanzlei [Federal Chancellery of Switzerland]. Retrieved January 1, 2020.
- ↑ "Karar Sayısı: 2016/9019" (PDF). Resmî Gazete, Sayı: 29790 (in Turkish). June 22, 2016.
- ↑ Psychoactive Substances Act 2016