Benzodiazepine

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Death may occur when benzodiazepines are combined with other depressants such as opiates, barbiturates, thienodiazepines, alcohol or other GABAergic substances.[1]

It is strongly discouraged to consume moderate to heavy dosages of these substances together.

The core structure of benzodiazepines
Xanax (alprazolam) 2 mg tri-score tablets

Benzodiazepines (commonly referred to as benzos) are a class of psychoactive substances that act as central nervous system depressants. These substances work by magnifying the efficiency and effects of the principal inhibitory neurotransmitter gamma-aminobutyric acid (GABA) by binding to and acting on its receptors.[2]

The characteristic effects of benzodiazepines include anxiety suppression, sedation, muscle relaxation, disinhibition, sleepiness and amnesia. In a medical context, short-acting benzodiazepines are typically recommended for treating insomnia or acute anxiety or panic attack disorders while long-acting ones are recommended for the treatment of generalized anxiety disorders.

The sudden discontinuation of benzodiazepines can lead to life-threatening seizures or death for individuals who have been using them regularly, in heavy doses, or for extended periods of time.[3] For this reason, it is recommended to discontinue use by tapering one's dose by gradually lowering the amount taken each day for a prolonged period of time instead of stopping one's usage abruptly.[4]

History

Chemical structure diagram of a benzene ring fused to a diazepine ring. Cl is attached to the benzene; N, H, CH3, and O are attached to the diazepine.
The molecular structure of chlordiazepoxide, the first benzodiazepine. It was marketed by Hoffmann–La Roche from 1960 branded as Librium.

The first benzodiazepine, chlordiazepoxide (Librium), was synthesized in 1955 by Leo Sternbach while working at Hoffmann–La Roche on the development of tranquilizers. The pharmacological properties of the compounds prepared initially were disappointing, and Sternbach abandoned the project.

Two years later, in April 1957, co-worker Earl Reeder noticed a "nicely crystalline" compound left over from the discontinued project while spring-cleaning in the lab. This compound, later named chlordiazepoxide, had not been tested in 1955 because of Sternbach's focus on other issues. Expecting pharmacology results to be negative, and hoping to publish the chemistry-related findings, researchers submitted it for a standard battery of animal tests.

However, the compound showed very strong sedative, anticonvulsant, and muscle relaxant effects. These impressive clinical findings led to its speedy introduction throughout the world in 1960 under the brand name Librium.[5][6] Following chlordiazepoxide, diazepam marketed by Hoffmann–La Roche under the brand name Valium in 1963, and for a while the two were the most commercially successful drugs. The introduction of benzodiazepines led to a decrease in the prescription of barbiturates, and by the 1970s they had largely replaced the older drugs for sedative and hypnotic uses.[7]

Society and culture

The new group of drugs was initially greeted with optimism by the medical profession, but gradually concerns arose; in particular, the risk of dependence became evident in the 1980s. Benzodiazepines have a unique history in that they were responsible for the largest-ever class-action lawsuit against drug manufacturers in the United Kingdom, involving 14,000 patients and 1,800 law firms that alleged the manufacturers knew of the dependence potential but intentionally withheld this information from doctors.

At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages for the harmful effects of dependence and withdrawal. This led some doctors to require a signed consent form from their patients and to recommend that all patients be adequately warned of the risks of dependence and withdrawal before starting treatment with benzodiazepines.[8] The court case against the drug manufacturers never reached a verdict; legal aid had been withdrawn and there were allegations that the consultant psychiatrists, the expert witnesses, had a conflict of interest. This litigation led to changes in the British law, making class action lawsuits more difficult.[9]

Although antidepressants with anxiolytic properties have been introduced, and there is increasing awareness of the adverse effects of benzodiazepines, prescriptions for short-term anxiety relief have not significantly dropped.[10] For treatment of insomnia, benzodiazepines are now less popular than nonbenzodiazepines, which include zolpidem, zaleplon and eszopiclone.[11] Nonbenzodiazepines are molecularly distinct, but nonetheless, they work on the same benzodiazepine receptors and produce similar sedative effects.[12]

Chemistry

Benzodiazepine is a heterocyclic compound comprised of a benzene ring fused to a seven-member nitrogenous diazepine ring. Benzodiazepine drugs contain an additional substituted phenyl ring bonded at R5, resulting in 5-phenyl-1,4-benzodiazepines with different side groups attached to the structure to create a number of drugs with different strength, duration, and efficacy.

Benzodiazepine drugs commonly contain an aromatic electrophilic substitution such as aromatic halogenation or nitration on R7 of their rings. Benzodiazepines can be subdivided into triazolobenzodiazepines and ketone substituted benzodiazepines. Triazolobenzodiazepines contain a triazole ring bonded to the benzodiazepine structure and are distinguished by the suffix "-zolam." Ketone substituted rings contain a ketone oxygen bond at R2 of their benzodiazepine structure and are distinguished by their suffix "-azepam."

Chemical classes

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.[13] As this site is the most prolific inhibitory receptor set within the brain, its modulation results in the sedating (or calming effects) of benzodiazepines 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.[14]

Subjective effects

The effects listed below are based upon the subjective effects index and personal experiences of PsychonautWiki contributors. The listed effects should be taken with a grain of salt and will rarely (if ever) occur all at once, but heavier doses will increase the chances and are more likely to induce a full range of effects. Likewise, adverse effects become much more likely on higher doses and may include injury or death. These effects are listed and defined in detail within their own dedicated articles below:

Physical effects
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Paradoxical effects
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Cognitive effects
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After effects
Aftereffects (3).svg


Equivalent dosages

The dosages below represent approximate equivalent dosages between various benzodiazepines in comparison to 10mg of diazepam.

The authors of this table specifically state that their equivalents differ from those used by other authors and "are firmly based on clinical experience during switch-over to diazepam at the start of withdrawal programs but may vary between individuals."[22]

Prescription benzodiazepines Half-life (Hours)
[active metabolite]
Approx. equivalent
oral dosage (mg)
Predominant effect
(a= anxiolytic,
c= anticonvulsant,
h= hypnotic)
Alprazolam 6-12 0.5 a
Bromazepam 10-20 5-6 a
Chlordiazapoxide 5-30 [36-200] 25 a
Clobazam 12-60 20 a, c
Clonazepam 18-50 0.5 a, c
Clorazepate 20-179 [36-200] 15 a
Diazepam 20-100 [36-200] 10 a, h, c
Estazolam 10-24 1-2 h
Etizolam 4-12 1 a
Flunitrazepam 18-36 [36-200] 1 h
Flurazepam 40-250 15-30 h
Halazepam 14 [30-200] 20 a
Ketazolam 30-100 [36-200] 15-30 a
Loprazolam 6-12 1-2 h
Lorazepam 10-20 1 a
Lormetazepam 10-12 1-2 h
Medazepam 36-200 10 a
Nitrazepam 15-38 10 h
Nordazepam 36-200 10 a
Oxazepam 4-15 20 a
Prazepam 29-224 [36-200] 10-20 a
Quazepam 25-100 20 h
Temazepam 8-22 20 h
Triazolam 2 0.5 h
Research chemicals Half-life (Hours)
[active metabolite]
Approx. equivalent
oral dosage (mg)
Predominant effect
(a= anxiolytic,
c= anticonvulsant,
h= hypnotic)
Clonazolam  ? 0.5 h
Deschloroetizolam ~9-20 6 a
Diclazepam ~120 1 a, h
Flubromazepam 106 4 h
Flubromazolam  ? 0.25 h
Nifoxipam 4-6 2 a
Meclonazepam  ? 5 a, c
Metizolam ~9-20 2 a
Phenazepam 60 1 a
Pyrazolam 17 1 a
Z-drugs Half-life (Hours)
[active metabolite]
Approx. equivalent
oral dosage (mg)
Predominant effect
(a= anxiolytic,
c= anticonvulsant,
h= hypnotic)
Zaleplon 2 20 h
Zolpidem 2 20 h
Zopiclone 5-6 15 h
Eszopiclone 6 3 h

Preparation methods

  • Volumetric liquid dosing - If one's benzodiazepines are in powder form, they are unlikely to weigh out accurately without the most expensive of scales due to their extreme potency. To avoid this, one can dissolve the benzodiazepine volumetrically into a solution and dose it accurately based upon the methodological instructions linked within this tutorial here.

Medical uses

When combined with benzodiazepines, the visual hallucinations induced by hallucinogenic substances (particularly psychedelics) may significantly decrease along with any underlying anxiety that may be present.[citation needed]

Along with antipsychotics such as quetiapine (Seroquel), benzodiazepines are commonly administered in hospital settings to treat patients presenting symptoms of hallucinogen overdose or psychosis.[citation needed]

Toxicity and harm potential

Radar plot showing relative physical harm, social harm, and dependence of benzodiazepines in comparison to other drugs.[23]

Benzodiazepines have a low toxicity relative to dose, and are considered to be effectively non-lethal on their own.[24] However, their potential potentially lethality increases significantly when mixed with depressants like alcohol or opioids.

It is strongly recommended that one use harm reduction practices when using this class of substances.

Tolerance and addiction potential

Benzodiazepines are known to be extremely physically and psychologically addictive.[citation needed]

Tolerance will develop to the sedative-hypnotic effects within a couple of days of continuous use.[25] After cessation, the tolerance returns to baseline in 7-14 days. Withdrawal symptoms or rebound symptoms may occur after ceasing one's usage abruptly following a few weeks or longer of steady dosing, and may necessitate a gradual dose reduction.[26][27]

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 GABAA receptor, cross-potentiating each other.[citation needed]

For example, 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.[28] This can result in dangerously disinhibited, total blackout states along with potential lethal respiratory depression.[citation needed]

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;[29] however, care is primarily supportive in nature.

Discontinuation and withdrawal

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 high blood pressure, seizures, and death.[30] Substances which lower the seizure threshold such as tramadol should be avoided during withdrawal.[citation needed] Abrupt discontinuation also causes rebound stimulation which presents as anxiety, insomnia and restlessness.[citation needed]

If one wishes to discontinue after a period of regular use, it is safest to reduce the dose each day by a very small amount for a couple of weeks until close to abstinence. If using a short half-life benzodiazepine such as alprazolam or etizolam, a longer acting variety such as diazepam or clonazepam can be substituted. Symptoms may still be present, but their severity will be reduced significantly.

For more information on tapering from benzodiazepines in a controlled manner, please see this guide. Small quantities of alcohol can also help to reduce the symptoms, but otherwise cannot be used as an effective tapering agent.

The duration and severity of withdrawal symptoms depend on a number of factors including the half-life of the substance used, tolerance and the duration of abuse. Major symptoms will usually start within just a few days after discontinuation and persist for around a week for shorter lasting benzodiazepines. Benzodiazepines with longer half-lives will exhibit withdrawal symptoms with a slow onset and extended duration.[citation needed]

Dangerous interactions

Although many psychoactive substances 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.

  • Stimulants - It can be dangerous to combine depressants with stimulants due to the risk of accidental excessive intoxication. Stimulants mask the sedative effect of depressants, which is the main factor most people use to gauge their level of intoxication. Once the stimulant effects wear off, the effects of the depressant will significantly increase, leading to intensified disinhibition, motor control loss, and dangerous black-out states. This combination can also potentially result in severe dehydration if one's fluid intake is not closely monitored. If choosing to combine these substances, one should strictly limit themselves to a pre-set schedule of dosing only a certain amount per hour until a maximum threshold has been reached.

See also

External links

References

  1. Risks of Combining Depressants (Tripsit) | https://tripsit.me/combining-depressants/
  2. Benzodiazepine interactions with GABA receptors (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/6147796
  3. A fatal case of benzodiazepine withdrawal. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/19465812
  4. Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain - Appendix B-6: Benzodiazepine Tapering | http://nationalpaincentre.mcmaster.ca/opioid/cgop_b_app_b06.html
  5. Sternbach LH (1979). "The benzodiazepine story". Journal of Medicinal Chemistry. 22 (1): 1–7. doi:10.1021/jm00187a001. PMID 34039. During this cleanup operation, my co-worker, Earl Reeder, drew my attention to a few hundred milligrams of two products, a nicely crystalline base and its hydrochloride. Both the base, which had been prepared by treating the quinazoline N-oxide 11 with methylamine, and its hydrochloride had been made sometime in 1955. The products were not submitted for pharmacological testing at that time because of our involvement with other problems 
  6. Miller NS, Gold MS (1990). "Benzodiazepines: reconsidered". Adv Alcohol Subst Abuse. 8 (3–4): 67–84. doi:10.1300/J251v08n03_06. PMID 1971487. 
  7. Shorter E (2005). "Benzodiazepines". A Historical Dictionary of Psychiatry. Oxford University Press. pp. 41–2. ISBN 0-19-517668-5. 
  8. King MB (1992). "Is there still a role for benzodiazepines in general practice?". Br J Gen Pract. 42 (358): 202–5. PMC 1372025Freely accessible. PMID 1389432. 
  9. Peart R (1999-06-01). "Memorandum by Dr Reg Peart". Minutes of Evidence. Select Committee on Health, House of Commons, UK Parliament. Retrieved 2009-05-27. 
  10. Lader M (2008). "Effectiveness of benzodiazepines: do they work or not?". Expert Rev Neurother (PDF). 8 (8): 1189–91. doi:10.1586/14737175.8.8.1189. PMID 18671662. 
  11. Jufe GS (Jul–Aug 2007). "[New hypnotics: perspectives from sleep physiology]". Vertex. 18 (74): 294–9. PMID 18265473. 
  12. Lemmer B (2007). "The sleep–wake cycle and sleeping pills". Physiol Behav. 90 (2–3): 285–93. doi:10.1016/j.physbeh.2006.09.006. PMID 17049955. 
  13. Benzodiazepine interactions with GABA receptors (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/6147796
  14. Benzodiazepines, but not beta-carbolines, limit high-frequency repetitive firing of action potentials of spinal cord neurons in cell culture. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/2450203
  15. Henriksen, O. (1998) ‘An overview of Benzodiazepines in seizure management’, Epilepsia, 39(SUPPL. 1), pp. 2–6. doi: 10.1111/j.1528-1157.1998.tb02601.x.
  16. http://www.ncbi.nlm.nih.gov/pubmed/18922233 | Saïas T, Gallarda T | Paradoxical aggressive reactions to benzodiazepine use: a review
  17. Paton C | Benzodiazepines and disinhibition: a review | Psychiatr Bull R Coll Psychiatr | http://pb.rcpsych.org/cgi/reprint/26/12/460.pdf
  18. Bond AJ | Drug-induced behavioural disinhibition: incidence, mechanisms and therapeutic implications | CNS Drugs
  19. Drummer OH | Benzodiazepines—effects on human performance and behavior | Forensic Sci Rev
  20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684331/ | Benzodiazepine Pharmacology and Central Nervous System–Mediated Effects
  21. Goyal, Sarita. "Drugs and Dreams." Indian Journal of Clinical Practice (n.d.): n. pag. Web. | http://medind.nic.in/iaa/t13/i3/iaat13i3p624.pdf
  22. BENZODIAZEPINE EQUIVALENCE TABLE | http://www.benzo.org.uk/bzequiv.htm
  23. Development of a rational scale to assess the harm of drugs of potential misuse (ScienceDirect) | http://www.sciencedirect.com/science/article/pii/S0140673607604644
  24. Benzodiazepine metabolism: an analytical perspective (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/18855614
  25. Principles and Practice of Psychopharmacotherapy | http://books.google.com/books?id=_ePK9wwcQUMC&pg=PA535
  26. Clinical Pharmacology, Clinical Efficacy, and Behavioral Toxicity of Alprazolam: A Review of the Literature | http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2004.tb00003.x/pdf
  27. The American Psychiatric Publishing Textbook of Substance Abuse Treatment | http://books.google.com/books?id=6wdJgejlQzYC&pg=PA222&hl=en#v=onepage&q&f=false
  28. Twyman, R. E., Rogers, C. J., & Macdonald, R. L. (1989). Differential regulation of γ‐aminobutyric acid receptor channels by diazepam and phenobarbital. Annals of Neurology, 25(3), 213-220. https://doi.org/10.1002/ana.410250302
  29. Amrein, R., Leishman, B., Bentzinger, C., & Roncari, G. (1987). Flumazenil in benzodiazepine antagonism. Medical Toxicology and Adverse Drug Experience, 2(6), 411-429. PMID: 8306565
  30. A fatal case of benzodiazepine withdrawal. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/19465812