Lacosamide: Abuse Potential

[Hammilton]

Lacosamide (above) is a new pharmaceutical being put out by the belgian pharmaceutical company UCB under the name "Vimpat." It works by enhancing slow inactivation of Na channels. To read more, go to Wikipedia.

I don't think I've mentioned it here before, but when the DEA published the notice of proposal to place Lacosamide in Schedule V, I filed a comment asking for it to not be scheduled. I'm pretty sure I was one of the only people to even file a comment. I don't know if you realize this, but everyday citizens are able to file comments, and even more: they get read. What's more is that everyday citizens are able to ask for public hearings to be held; this is what I did. I filed the formal paperwork to this end on Apr 30 or May 1. Unfortunately, this means that UCB has been prevented from putting their drug on the market, which as I'm told, would have happened the first week of May. Apparently, it may be held up for as long as a year. This means that if I fail, and the drug is scheduled anyway, I will have epileptics from obtaining a needed drug for no reason. If I win, I'll have made access easier, and I think be the first person to have done so. I might even be the first person to have challenged the scheduling of a new drug using this process.

The process may be a useful tool to prevent the scheduling (or lower the scheduling) for any number of potentially scheduled drugs.

Drug abuse:
In order to assess the potential abuse liability of lacosamide three dedicated animal studies were
performed.

1) Drug discrimination study a group of drug-naïve rats were trained to discriminate between ip injections of vehicle (physiological saline) and 10 mg/kg of lacosamide while responding under a fixed-ratio 10 schedule of food reinforcement. Consistent with the weak nature of the stimulus effects of lacosamide, the time taken to achieve discrimination with it (59.0 ± 4.2
training sessions) was longer than has been reported for establishing two-choice discrimination with the comparison substances used in the present study (Carter et al, 2004, Bartoletti et al, 2000, Mori et al, 2002). In the subsequent generalization testing, lacosamide itself, diazepam, morphine, phencyclidine and phenobarbital were tested for generalization to the lacosamide stimulus. When lacosamide itself was tested, the pattern of responding was best described as random, underlining the difficulty the rats had reliably to distinguish lacosamide from saline. The generalization
studies with the comparison substances with known abuse and dependence liability are consistent with the weak lacosamide discriminative cue as the pattern of responding was essentially random at all doses. In conclusion, the discriminative stimulus produced by lacosamide in rats was not robust, nor clearly dose-dependent suggesting that the test substance is not likely to have subjective effects leading to abuse in man.

2) Further, lacosamide was investigated after oral (gavage) administration in the conditioned place preference test in the rat; morphine hydrochloride was used as reinforcing drug, and the vehicle was used as negative control. Contrary to morphine, lacosamide did not affect the time spent in the drug-paired compartment during the test session as compared with the vehicle
control. The number of crossing was not affected.

3) Furthermore, when lacosamide was compared to cocaine and physiological saline for its ability to maintain intravenous self-administration in rats, it didn’t demonstrate to maintain self-administration at all doses tested.

These results suggest that lacosamide is not likely to have positive reinforcing properties or abuse potential. The evaluation of the dependence potential of lacosamide

from: emea.europa.eu

I've been told by one of the people UCB had call me that the whole basis for scheduling is based on a few people who reported euphoria during the human trials stage of its development. There are many unscheduled pharmaceuticals that actually are addictive and reinforcing; tramadol, primidone and carisoprodol, for three quick off-the-top-of-my-head drugs.

As such, if I fail and it is scheduled, I will have delayed epileptic's access to a needed medication for no reason. I have to be especially prepared. If anyone is familiar with any research into any facet of issues related to abuse and dependence and lacosamide, I'd be especially interested. I believe I have combed the literature pretty well now, but it's very possible that I've missed something important.

I would like some information on what I need to know before this hearing, I'd be appreciative. I know this part doesn't really belong in ADD, but if I can get good answers to both aspects of it in one thread, that'd be best. Anyway, what can and can't I do? For instance, am I able to introduce expert testimony on the issue? I mean, if I had a PhD who was familiar with addiction and abuse, would I be able to ask him to comment on the risk this drug poses, ask questions, etc?

 

[flacky]

Have you mentioned that it doesn't activate any of the "usual" drug-of-abuse receptors such as GABA-A/B? (http://www.ncbi.nlm.nih.gov/pubmed/16620882)

 

[negrogesic]

^^^It is mentioned in the DEA proposal...

Hamilton, what you did is very interesting. If I was a drug company who had spent many millions in a developing a drug to potentially be held up by some "kid" (so to speak), I would be very upset. I would probably also be inclined to have someone come have a "conversation" with you. I don't see how a schedule V classification could pose any real problems for the drug company, while a one year setback certainly will...

I don't understand; are you going to the hearing?

I think tapentadol would have a been a more worthy cause...

 

[flacky]

Well, keeping it unscheduled would actually benefit the company by making it easier to prescribe, thus increasing sales. Well, not exactly easier to prescribe but the lack of scheduling gives doctors an incentive to prescribe it.

 

[libbyave]

Hammilton

well done you smug, self absorbed stupid b*****d. 3 - 12 months needless delay for a drug that I need urgently just to satisfy your pumped up sense of self importance - arent you a clever boy

You have no idea what you have done - real people with real families will die from failing to control seizures which lacosamide may wel have controlled.

Think about it for a minute - think about it really hard - while you pat yourself on the back and prepare an academic debate whose sole purpsoe seems to be proving how smart you are.

This drug has been thru all the required hurdles - its successfully being prescribed in europe (since October 2008) and you pop up and derail it - well done.

 

[flacky]

libbyave, what Hammilton is doing might make it EASIER for those real people to get prescribed this drug. Maybe you should do some hard thinking yourself.

 

[Enkidu]

But at the same time, those who need it could still get it really easily if it was schedule V. So I don't understand your logic?

 

[libbyave]

flacky - maybe you guys should try taking multiple anticonvulsants to the point that youve run out of options and then track DAILY for years the progress of new treatmemnts and wait patiently for their release, while your quality of life drops - and then you can give me some f****** advice.

This drug would be available NOW - its not and probably wont be for some time - beleive me hard thinking is something i spend alot of my time doing.

If this drug works and has a good ae profile real people with a real need will not have a problem getting it. Lyrica /Pregabalin is in classV and its being tossed around like candy. This may be a wonderful adventure for Hammilton, but there is a cost and its not to Hammilton.

 

[flacky]

If you're a physician and you have a choice between two anticonvulsants which are both Schedule V, you'll probably go with the one you have been using for years because you don't want to waste a prescription for a scheduled substance on something when you already know what works. If the choice is between Schedule V and Unscheduled, the choice is much more clear, no?

The fact is that doctors are becoming more cautious about throwing around Lyrica because the kids have started using it to get high. If we can delay the drug 12 months maximum to make sure that it's unscheduled, doctors will have a clear choice: an unabusable but completely effective method of treatment.

Come back to me when with your advice when you stop thinking about your personal case and start thinking about the waves who are undiagnosed and won't be able to get on this medication because doctors will be afraid to drop an "abusable" drug on them.

Seriously, you're a real piece of work.

 

[negrogesic]

If the choice is between Schedule V and Unscheduled, the choice is much more clear, no?

An even moderately decent physician will not choose a medication on the basis of its scheduling status, perhaps with the exception of opioids (schedule III versus II)...

Schedule V is hardly (although technically) a controlled substance. Many physicians care little about scheduling status, again, with the exception of CII and CIII opioids.

 

[flacky]

Yeah, agreed, but due to basic human nature, minor considerations such as this definitely have an effect. As a doctor, would you rather prescribe something generally recognized as abusable or generally recognized as unabusable?

 

[libbyave]

the waves who are undiagnosed and won't be able to get on this medication because doctors will be afraid to drop an "abusable" drug on them..

The above is simply not true.

- negrogesic got it spot on.

Epileptologists are poised waiting to prescibe it - and i dont mean in theory i mean absolutely in practice.

You are not knights in shining armor fighting the good fight - however you might want to rationalise this to yourselves.

 

[MONSTA!!]

/Subscribe

Awesome thread, Hamilton the epileptics are coming to get you!

 

[Hammilton]

I know, it's painful. I wonder how many other people paid by UCB will be joining in the next few days?

It all starts from the flawed assumption that this drug does something that no other drug can do. Not true. I'm pretty sure Mydocalm (Tolperisone) is available in the US, and is unscheduled.

But at the same time, those who need it could still get it really easily if it was schedule V. So I don't understand your logic?

I'm not entirely sure that is true. How many more prescriptions of Gabapentin do you suppose were written than for Lyrica? Hell, in 2003 it was still making 2.4 billion. Hell, in 2002, 94% of sales were off-label. You will never acheive those numbers in scheduled drug. Actually, if anyone can show me a scheduled drug that even remotely approached 50% off-label prescriptions, I will be amazed.

You are not knights in shining armor fighting the good fight - however you might want to rationalise this to yourselves.

Perhaps your heavier wallet is causing your brain to misfunction, because you're seriously ignoring the facts. When UCB's representatives first started contacting me, I had pretty much decided to drop the request. Then they said something really stupid that made me change my mind. They said that they were going to get the drug unscheduled in 2-3 years. How do they plan on doing this? Oh yeah, throwing money around. Aside from TFMPP which the DEA decided to just not schedule, I'm not aware of a single drug being unscheduled any other way. It's the only reason Carisoprodol isn't scheduled now. Look at the strange history of Stadol. Does anyone really think that Bristol-Myers Squibb wasn't behind that?

If they thought I'd find a corporation further corrupting our government to be a positive development, they were seriously confused.

The further efforts have really only solidified my reserve. Citizens were given these rights for a reason. It's not my fault that the laws were written in such a way that anyone excercising this right hinders patient access. That's not a reason for no one to use this right, it's a reason to adjust the law. There's no reason that a citizen wanting to take part in the rulemaking process hurts anyone, and even less reason they should be vilified for doing so. I don't feel bad at all, to tell you the truth, since I had nothing to do with the shape of the current laws.

I don't understand; are you going to the hearing?

I think tapentadol would have a been a more worthy cause...

Yes- of course, and WHAT? Until the laws are changed, we have to work within the framework of those laws. As they are currently written, I have a hard time arguing with tapentadol being scheduled or being put in schedule II. Less than CI, more than CIII. I wouldn't have had a rational basis to argue against it.

Lacosamide, on the other hand, has no proven abuse potential, and shouldn't be scheduled at all. Not CI CII CIII CIV CV or anything. Given that lacosamide has less abuse potential than some unscheduled drugs (carisoprodol, tramadol, primidone, etc), it's incredibly easy to prove that it should be unscheduled: because it actually should be.

An even moderately decent physician will not choose a medication on the basis of its scheduling status, perhaps with the exception of opioids (schedule III versus II)...

Schedule V is hardly (although technically) a controlled substance. Many physicians care little about scheduling status, again, with the exception of CII and CIII opioids.

Again, that doesn't seem to be borne out by the numbers. I'm looking at pregabalin vs. gabapentin, which have indications similar to lacosamide.

 

[flacky]

Hammilton basically summed up exactly what I meant about the key difference between Schedule V and Unscheduled drugs. There is actually a difference. Libbyave, just because you have a problem, that doesn't mean that everyone else should suffer in the long-term for your short-term relief. Seriously, what kind of sadist are you?

 

[Hammilton]

Libbyave, just because you have a problem, that doesn't mean that everyone else should suffer in the long-term for your short-term relief. Seriously, what kind of sadist are you?

Well, I wouldn't go that far. I can understand why some epileptics would be upset, and I don't fault them for that. I have a family member who has very bad epilepsy, had almost constant seizures for a time, eventually had to have brain surgery which massively cut down on his seizures.

Still, I didn't hear anyone complaining about the FDA taking too long with Vimpat (which, as I recall, was considered dead by many not that long ago). Or that the DEA was taking too long making a scheduling recommendation. These were all accepted as a part of the process. So is this.

 

[Hammilton]

Actually, it's all rather moot, my application for a hearing was denied as of today. They say they got a lot of comments after the commenting period closed, but I have no information regarding the substance of those comments.

Their basis for the rejection was the claim that I don't meet the standard set for an 'interested person.' I don't know that I agree with this decision, as the definition of an interested party is one that's easily met by anyone who has taken an interest. I need to take a look at what was actually intended by the definition, because absent that information, I can't see how anyone who wants to doesn't meet the definition.

I don't believe the ruling is appeal-able, which is fine. I'm disapointed that this will probably mean that UCB will end up throwing their money around in a year or two to accomplish the same end that I was looking for.

What's particularly odd about the ruling is that they state,

Preclinical studies indicated that lacosamide is selfadministered at rates higher than saline and partially mimics discrimitive stimulus effects to the schedule IV substances alprazolam and phenobarbital. In clinical trials, lacosamide produced subjective responses similar to alprazolam but these effects did not last as long as alprazolam.

But there are studies that show it doesn't produce or sustain self administration above saline, and I'm not aware of any that show what they're claiming. Of course, this could all be non-public stuff that I'll never see, which is unfortunate.

 

[libbyave]

Well thats excellent news - i will leave your forum in peace.

Contrary to what you suggest Im not associated with UCB in any way, nor do i ever want to be - I fundamentally dont trust drug companies at a very deep level.

If i was associated with UCB my comments would have been less of a rant and more designed to discredit you.

Anyway good luck and it was nice to meet you all.

 

[Hammilton]

So, you're not someone interested in this forum. That means you didn't just come across this thread while browsing. And the delay hasn't been in the media, so you didn't come here because of that. I feel pretty sure you're a UCB minion in some way or another, but admit it or not, it doesn't matter. I can't prove, you can't disprove.

Still, any reasonably intelligent epileptic ought to know that lacosamide isn't some drug panacea- there are perfectly suitable drugs already on the market, available, and unscheduled. Drugs with very similar activities.

Pretend that it was for a minute though. Does this mean that the process created for approving and scheduling drugs shouldn't be used? Should people say "oh yeah, let's just get it on the market as soon as possible and then leave it to the manufacturer to further corrupt our government by throwing money around to get the drug unscheduled?" I sure as hell don't think that's a good idea. Perhaps we should just get rid of the drug approval process altogether so people can access drugs as soon as possible. That sounds like a brilliant idea.

Seriously though, if anyone really wanted to access this drug before it was scheduled (and available) either two weeks ago or three years ago, they could have easily had it synthesized and measured out doses as such. It's not something beyond an intelligent adult's capabilities, it's not even illegal. It will be in a few weeks, now though.

 

[flacky]

Mods: Can you post libbyave's IP info? I bet a lookup will go back to some interesting results.