Benzodiazepines: Uses, Dangers, and Clinical Considerations
and Alan D. Kaye 3Round 1
Reviewer 1 Report
This manuscript has a lot of potential yet a lot of shortcomings.
1 brain penetration cannot be equated with the effects of a drug (ie. Cocaine)
- addiction cannot be equated with withdrawal potential. Although the harder the withdrawal the harder to quit
- 1,4 BDz should be clarified as 1, 5 have different effects
- line 69 is there market analysis ?
- line 183 Have the authors compared Kd with clinical use ? (Richelson et al. 1991)?
- Abrahamsson et al line 230?
- line 270 please explain “rapid absorption, and low lipophilicity”
- The use of different drugs for withdrawal is not well documented. How about replacing for long half-life BDZ?
- The manuscript would befit from a modest discussion of subunit composition and possible replacement in chronic use.
Author Response
1 brain penetration cannot be equated with the effects of a drug (ie. Cocaine)
Answer: The drug does penetrate the brain and work on Gaba receptors there. It can be argued that the effects of the drug can be equated with brain penetration. Effects cannot happen if the receptors cannot be reached.
- addiction cannot be equated with withdrawal potential. Although the harder the withdrawal the harder to quit
Answer: Addiction can lead to tolerance which can lead to withdrawal if the medication is stopped suddenly. There are only two substances that have this which are alcohol and sedatives. This was clarified in the text.
- 1,4 BDz should be clarified as 1, 5 have different effects
Answer: This is a good point. There are also different isoforms of the alpha subunits responsible for different effects. This was added to the manuscript.
- line 69 is there market analysis ?
Answer: The manuscript has been updated with common uses.
- line 183 Have the authors compared Kd with clinical use ? (Richelson et al. 1991)?
Answer: This was not the comparison made in the text.
- Abrahamsson et al line 230?
Answer: This line is an introductory line for the study that is discussed within this paragraph and cited as reference 47. - line 270 please explain “rapid absorption, and low lipophilicity”
Answer: This part of the text was edited for clarity.
- The use of different drugs for withdrawal is not well documented. How about replacing for long half-life BDZ?
Answer: This will be tied to the answer for number 9. Withdrawal drugs and drugs for chronic use is just a taper with long acting BZDs.
- The manuscript would befit from a modest discussion of subunit composition and possible replacement in chronic use
Answer: This is tied into the answer for number 3. Chronic use replacement is really just with long acting BZDs. This will be clarified in this manuscript.
Reviewer 2 Report
Edinoff et al:
This is a very important review, and the authors cover the urgent need for more research in benzodiazepine withdrawl protocols. However, there are some issues that need attention as indicated below:
Generally, the molecular basics are often poorly described, this aspect needs careful revising as indicated in the individual points listed below.
The authors describe how BZDs are grouped into short and long acting cpds, but ATC codes are not even mentioned. There is strong evidence for relevant differences in side effect and desired effect proviles between compounds primarlily considered anxiolytics (N05B) and those primarily considered hypnotic-sedative (N05C). In addition, few compounds are classified as anticonvulsants. I suggest to also cover the differences in ATC codes, and how compounds might have compound- specific issues that might correlate with their primary ATC code.
Specific text passages that require revision:
lines 16/17: It is wrong to state that benzodiazepines bind to GABA, they bind to the benzodiazepine binding site localized on specific GABA-A receptor subtypes (ionotropic GABA receptor subtypes). The same mistake is in lines 34/35 of the introduction.
line 20: What is "over-dependence", and how would it differ from dependence?
line 86: No benzodiazepine binds to any alpha subunit, they all bind to high affinity sites at interfaces between an alpha and a gamma subunit. The so-called diazepam sensitive alpha isoforms are alpha1, 2, 3 and 5.
line 91: Here again "BZDs bind to ...GABA", even though a few lines above it is stated that the bind to alpha subunits.... The authors are encouraged to describe the molecular basis of BZDs action consistently and correctly throughout the entire manuscript.
lines 262, 263 "Symptoms associated with withdrawal occur due to the chronic exposure of GABA neurotransmitters in the CNS to BZDs." This sentence makes no sense at all, it is once more the GABA-A receptors, not GABA itself, that mediate both short and long term effects including withdrawal.
line 265: "and possibly sensitization of N-methyl-D-aspartate (NMDA),"" - presumably NMDA receptors are meant?
line 329: Please cite the clinical studies that have been made, or refer to the table if you refer to thos studies in the table.
lines 361-363: "One medication that is not a BZD that has been used to treat BZD withdrawals is
flumazenil. This medication is currently FDA approved for BZD overdose. Flumazenil
works by directly facilitating the coupling of GABAA receptors to BZD receptors (65)." This passage is partly misleading, partly incorrect: Chemically speaking, flumazenil is a benzodiazepine. Pharmacologically speaking, it is an "antagonist" of other benzodiazepines, displacing them from the high affinity binding sites, but without enhancing GABA elicited currents. The "coupling" theory is rather old, and mechanistically unclear. I suggest to rephrase e.g. "Flumazenil is approved to treat BZD overdose, which is accomplished by competition for their binding site on GABA-A receptors. In addition, it is thought to revert changes in receptor subunit expression that result from chronic BDZ use, thus assisting in withdrawl" or something similar that is mechanistically closer to the molecular changes that are likely involved.
lines 486, 487: Again, BDZ bind to ionotropic GABA receptors, and not to GABA. (GABA is a pretty small molecule...)
lines 495- 498: "As the drug concentration in blood and tissue decline, the sympathetic nervous system, possible seizures, and generally symptoms opposite that of its intended, therapeutic effect." is not a complete sentence. Please rewrite.
The references need editing, e.f. Lader is cited twice (15, 77)
Grammar checking and improving the English would be helpful.
Author Response
This is a very important review, and the authors cover the urgent need for more research in benzodiazepine withdrawl protocols. However, there are some issues that need attention as indicated below:
Generally, the molecular basics are often poorly described, this aspect needs careful revising as indicated in the individual points listed below.
The authors describe how BZDs are grouped into short and long acting cpds, but ATC codes are not even mentioned. There is strong evidence for relevant differences in side effect and desired effect proviles between compounds primarlily considered anxiolytics (N05B) and those primarily considered hypnotic-sedative (N05C). In addition, few compounds are classified as anticonvulsants. I suggest to also cover the differences in ATC codes, and how compounds might have compound- specific issues that might correlate with their primary ATC code.
Answer: ATC codes are not used in the US in pharmacies or in the literature. This is why they are described as long acting and short acting BZDs. The idea of the different isoforms of the alpha subunit, there different actions and locations have been added to the manuscript to show how they can act different.
Specific text passages that require revision:
lines 16/17: It is wrong to state that benzodiazepines bind to GABA, they bind to the benzodiazepine binding site localized on specific GABA-A receptor subtypes (ionotropic GABA receptor subtypes). The same mistake is in lines 34/35 of the introduction.
Answer: This was clarified.
line 20: What is "over-dependence", and how would it differ from dependence?
Answer: Over-dependence and dependence is the same thing. This was clarified in the text.
line 86: No benzodiazepine binds to any alpha subunit, they all bind to high affinity sites at interfaces between an alpha and a gamma subunit. The so-called diazepam sensitive alpha isoforms are alpha1, 2, 3 and 5.
Answer: This has been clarified.
line 91: Here again "BZDs bind to ...GABA", even though a few lines above it is stated that the bind to alpha subunits.... The authors are encouraged to describe the molecular basis of BZDs action consistently and correctly throughout the entire manuscript.
Answer: This has been corrected.
lines 262, 263 "Symptoms associated with withdrawal occur due to the chronic exposure of GABA neurotransmitters in the CNS to BZDs." This sentence makes no sense at all, it is once more the GABA-A receptors, not GABA itself, that mediate both short and long term effects including withdrawal.
Answer: This has been clarified
line 265: "and possibly sensitization of N-methyl-D-aspartate (NMDA),"" - presumably NMDA receptors are meant?
Answer: This has been clarified.
line 329: Please cite the clinical studies that have been made, or refer to the table if you refer to thos studies in the table.
Answer: They are in the table. A reference to this as being summarized to the table was added to the text.
lines 361-363: "One medication that is not a BZD that has been used to treat BZD withdrawals is
flumazenil. This medication is currently FDA approved for BZD overdose. Flumazenil
works by directly facilitating the coupling of GABAA receptors to BZD receptors (65)." This passage is partly misleading, partly incorrect: Chemically speaking, flumazenil is a benzodiazepine. Pharmacologically speaking, it is an "antagonist" of other benzodiazepines, displacing them from the high affinity binding sites, but without enhancing GABA elicited currents. The "coupling" theory is rather old, and mechanistically unclear. I suggest to rephrase e.g. "Flumazenil is approved to treat BZD overdose, which is accomplished by competition for their binding site on GABA-A receptors. In addition, it is thought to revert changes in receptor subunit expression that result from chronic BDZ use, thus assisting in withdrawl" or something similar that is mechanistically closer to the molecular changes that are likely involved.
Answer: This has been clarified
lines 486, 487: Again, BDZ bind to ionotropic GABA receptors, and not to GABA. (GABA is a pretty small molecule...)
Answer: This has been corrected
lines 495- 498: "As the drug concentration in blood and tissue decline, the sympathetic nervous system, possible seizures, and generally symptoms opposite that of its intended, therapeutic effect." is not a complete sentence. Please rewrite.
The references need editing, e.f. Lader is cited twice (15, 77)
Answer: This has been corrected.
Round 2
Reviewer 1 Report
The manuscript has improved . Howevere the authors must be careful in their nomenclatur of GABAa vs alfa subunit line 35-42 are VERY confusing unless reader is well versed in GABAa dynamics
Author Response
The manuscript has improved . Howevere the authors must be careful in their nomenclatur of GABAa vs alfa subunit line 35-42 are VERY confusing unless reader is well versed in GABAa dynamics.
Answer: That line has been clarified
