Fatal overdose may occur when benzodiazepines are combined with other depressants such as opiates, barbiturates, gabapentinoids, thienodiazepines, alcohol or other GABAergic substances.[1] It is strongly discouraged to combine these substances, particularly in common to heavy doses.

Nifoxipam is a novel depressant substance of the benzodiazepine class.

Nifoxipam has potential use for the short-term treatment of anxiety, insomnia, acute seizures, and the sedation of hospitalized patients.[citation needed] However, it is currently exclusively sold by online research chemical vendors for use as a recreational psychoactive substance.[2][3][4]

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.[5] 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.[6]

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.

Chemistry

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 R 1 and R 4 . Nifoxipam, or 3-hydroxydesmethylflunitrazepam, is an active metabolite of flunitrazepam.[7] The benzyl ring of nifoxipam is substituted at R 7 with a nitro group, NO 2 -. AR 2 flourine substituted phenyl ring is bound to this structure at R 5 . Additionally, nifoxipam contains a hydroxy (OH-) group substituted at R 3 . Nifoxipam also contains an oxygen group double bonded to R 2 of its diazepine ring to form a ketone. This oxygen substitution at R 2 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.[8]

Pharmacology

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.[9] 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.[10]

Subjective effects

Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), a literature which relies on collected anecdotal reports and the personal experiences of PsychonautWiki contributors. As a result, they should be taken with a healthy amount of skepticism. It is worth noting that these effects will not necessarily occur in a consistent or reliable manner, although higher doses (common+) are more likely to induce the full spectrum of reported effects. Likewise, adverse effects become much more likely with higher doses and may include serious injury or death.

Experience reports

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 such, it may contain incomplete or even dangerously wrong information. You can help by expanding or correcting it.

We also recommend that you conduct independent research and use harm reduction practices when using this substance.

Nifoxipam likely has a low toxicity relative to dose.[15] 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.[16] 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.

Overdose

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 GABA A receptor, thus their effects potentiate one another. Benzodiazepines increase the frequency in which the chlorine ion pore opens on the GABA A 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[17]. 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 GABA A antagonist[18], however care is primarily supportive in nature.

Dangerous interactions

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.

( ) - 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.

- 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.

Legal status

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. [19]

: All benzodiazepines are listed in Schedule IV. Germany : Nifoxipam is controlled under the NpSG ( New Psychoactive Substances Act ) [20] as of July 18, 2019. [21] 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. [22]

: Nifoxipam is controlled under the NpSG ( ) 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. [23]

: Nifoxipam is a Schedule III controlled substance since 2017. Switzerland : Nifoxipam is a controlled substance specifically named under Verzeichnis E. [24]

: Nifoxipam is a controlled substance specifically named under Verzeichnis E. United Kingdom: Nifoxipam is illegal to produce, supply, or import under the Psychoactive Substance Act, which came into effect on May 26th, 2016.[25]

See also