Pharmacologic and Clinical Considerations of Nalmefene, a Long Duration Opioid Antagonist, in Opioid Overdose
and Alan D. Kaye 6Round 1
Reviewer 1 Report
In this article, Edinoff and colleagues reviewed Nalmefene, a long-duration of FDA-approved opioid receptor antagonist, as a potential alternative antidote for the treatment of opioid overdose-induced respiratory depression. Overall, the article is well written and read well. I have only a few minor comments.
1) The authors did not explain how nalmefene produces such a long-duration effect (T1/2 8-11 hours). Is it a prodrug or metabolically stable?
2) The authors may consider to add a table to compare the pharmacological and PK/PD profiles of both naloxone and Nalmefene. In addition to AOD, it looks like that their receptor binding and metabolic profiles and some pharmacological action are also different.
3) Given that the findings with Nalmefene in the limited clinical studies are negative and didn't show much advantages compared to naloxone, some over-positive statements about its safety and efficacy should be toned down to reveal the uncertainty about this drug as a potential naloxone alternative.
Author Response
- The authors did not explain how nalmefene produces such a long-duration effect (T1/2 8-11 hours). Is it a prodrug or metabolically stable?
Answer: This is a good point that was missed. This was added to this to the paper under the general nalmefene sections
- The authors may consider to add a table to compare the pharmacological and PK/PD profiles of both naloxone and Nalmefene. In addition to AOD, it looks like that their receptor binding and metabolic profiles and some pharmacological action are also different.
Answer: This table is a great idea. It was added.
- Given that the findings with Nalmefene in the limited clinical studies are negative and didn't show much advantages compared to naloxone, some over-positive statements about its safety and efficacy should be toned down to reveal the uncertainty about this drug as a potential naloxone alternative.
Answer: This is a good point. This was toned down.
Reviewer 2 Report
This is a useful contribution to the literature on an important subject. The manuscript is well constructed but suffers from occasional misuse of English.
For example, the phrase below:
"Its methylene group is suspected to be due to its increased DOA, higher affinity at the μ 183
opioid receptor (MOR), and greater oral bioavailability relative to naloxone (37–40)."
Would be better written as
Its methylene group is suspected to result in increased DOA, higher affinity at the μ
opioid receptor (MOR), a G protein coupled receptor (X). It has greater oral bioavailability relative to naloxone (37–40).
Cite:
X. Thompson MD, Siminovitch KA, Cole DE. G protein-coupled receptor pharmacogenetics. Methods Mol Biol. 2008;448:139-85. doi: 10.1007/978-1-59745-205-2_8.
The table is useful. It might help to add a figure, if possibly, to summarize aspect of the mechanism.
Author Response
This is a useful contribution to the literature on an important subject. The manuscript is well constructed but suffers from occasional misuse of English.
For example, the phrase below:
"Its methylene group is suspected to be due to its increased DOA, higher affinity at the μ 183
opioid receptor (MOR), and greater oral bioavailability relative to naloxone (37–40)."
Would be better written as
Its methylene group is suspected to result in increased DOA, higher affinity at the μ
opioid receptor (MOR), a G protein coupled receptor (X). It has greater oral bioavailability relative to naloxone (37–40).
Cite:
X. Thompson MD, Siminovitch KA, Cole DE. G protein-coupled receptor pharmacogenetics. Methods Mol Biol. 2008;448:139-85. doi: 10.1007/978-1-59745-205-2_8.
Answer: This has been fixed.
The table is useful. It might help to add a figure, if possibly, to summarize aspect of the mechanism.
Answer: another table was added to highlight the different MOA of Nalmefene and Naloxone.
Reviewer 3 Report
I advise to include the other historic opiate antagonist which is widely used in the treatment of narcotic use disorder and alcoholism: naltrexone. Otherwise, it is not clear why authors chose nalmefene only.
The second issue is that narcotic overdose has different features according to the type of overdosed narcotic : so, it would be interesting to know whether there is a better option for specific narcotic overdoses . Authors are mainly accounting for the classic heroin overdose, or short and fast acting narcotic overdose.
Author Response
I advise to include the other historic opiate antagonist which is widely used in the treatment of narcotic use disorder and alcoholism: naltrexone. Otherwise, it is not clear why authors chose nalmefene only.
Answer: this is a good point. Naltrexone was included in the edit.
The second issue is that narcotic overdose has different features according to the type of overdosed narcotic : so, it would be interesting to know whether there is a better option for specific narcotic overdoses . Authors are mainly accounting for the classic heroin overdose, or short and fast acting narcotic overdose.
Answer: Right now the better one is Naloxone due to the studies. Nalmefene is promising but more research needs to be done.
Round 2
Reviewer 3 Report
I am afraid no actual amending of the flaws I had noted have been made.
With respect to naltrexone, I see a few lines mentioning its existence, but it is not displayed in the comparison table about mechanisms of action, and it is not explained what level of effectiveness it owns against opioid overdose.
Moreover, I had noticed that opioid overdose may result from different compounds, with different kinetics: therefore, it may be an emergency or develop slowly. According to which situation one has to face, antidotes with a peak time of one or two hours may to be pointless (fast acting opiates) or viable (slow acting opiates). This should be specified and discussed. Are there studies assessing different kinds of opioids as a cause od overdose, and the effectiveness of treatments ? When authors report of cases of emergecy room overdoses which can be reversed after 1-2 hours (plus the time from the call for aid), it means we are talking about non fatal overdoses from fasting opiates, which have a spontaneous remission; or, otherwise, we may be dealing with slow acting opioid overdose, but I doubt one would use a slow acting antidote instead of an intravenous one if unaware of which opiate drug is responsible for the overdose.
Thereby, the discussion must include naltrexone, as well as the background and the comparison with the studied treatment (nalmefene), as it has been done for naloxone.
The discussion about the role of different mode of administration in different situations is required. Differently, it seems as intranasal nalmefene is a rescue remedy for heroin overdose "on the spot", for instance, or that naloxone is effective against all kinds of opiates overdose, while it justs fits the fast acting and short-life ones.
Author Response
Comments: With respect to naltrexone, I see a few lines mentioning its existence, but it is not displayed in the comparison table about mechanisms of action, and it is not explained what level of effectiveness it owns against opioid overdose.
Answer: It was added to the table with Naloxone and Nalmefene. An explanation of how it is not effective in opioid overdose was also added.
Comments: Moreover, I had noticed that opioid overdose may result from different compounds, with different kinetics: therefore, it may be an emergency or develop slowly. According to which situation one has to face, antidotes with a peak time of one or two hours may to be pointless (fast acting opiates) or viable (slow acting opiates). This should be specified and discussed. Are there studies assessing different kinds of opioids as a cause od overdose, and the effectiveness of treatments ? When authors report of cases of emergecy room overdoses which can be reversed after 1-2 hours (plus the time from the call for aid), it means we are talking about non fatal overdoses from fasting opiates, which have a spontaneous remission; or, otherwise, we may be dealing with slow acting opioid overdose, but I doubt one would use a slow acting antidote instead of an intravenous one if unaware of which opiate drug is responsible for the overdose.
Thereby, the discussion must include naltrexone, as well as the background and the comparison with the studied treatment (nalmefene), as it has been done for naloxone.
Answer: a discussion about naltrexone was added, However, the evolving literature was a major reason we created this important review paper and we really appreciate the comments and insight of the Reviewer. On pubmed, if you type the words “nalmefene” and “opioid overdose” there are only 11 articles. These articles include reviews and only a few studies that look at different routes of nalmefene administration in the setting of opioid overdose. It is true and we certainly agree with the Reviewer that there are different opioids that can result in opioid overdosage and therefore, they have different pharmacokinetics. In this regard, as we have mentioned in the manuscript, naloxone is limited by its duration of action whereby many opioids have a longer duration of action and therefore, there is potential for opioid mediated respiratory/central nervous system depression beyond the duration of the administered naloxone. We have included the comment that antidotes may be pointless or viable depending on the specific opioid agent and that best practice guidelines need to be developed to help guide clinicians managing these patients. It is important as well to consider different doses of the opioid making it challenging to define best practice guidelines. To date, there really is limited data in the literature examining specific drugs and doses. We have also expanded our discussion of the role of nalmefene in the setting opioid overdose vis-à-vis the comments the Reviewer has provided.
Comments: The discussion about the role of different mode of administration in different situations is required. Differently, it seems as intranasal nalmefene is a rescue remedy for heroin overdose "on the spot", for instance, or that naloxone is effective against all kinds of opiates overdose, while it justs fits the fast acting and short-life ones.
Answer: A short discussion and a table was added
