Question: I have a severe case of Restless Leg/Willis-Ekbom disease (RLS/WED). I have been on a variety of medications for it since 1990, most having lost their efficacy, and now currently on 1800mg of Gabapentin and 3mg of Neupro nightly.

In May/June of this year my legs got dramatically worse and I was essentially unable to sleep and in profound physical pain/distress night after night. This sort of thing has happened before, and it typically means (a) failure of one of my medications (a "Failure") or (b) something is interfering with one of my medications (an "Interference")

Figuring out the difference between a Failure and an Interference is critical to figuring out the appropriate treatment plan.

Specifically, a Failure means swapping out at least one medication (maybe more) and adding a new one, and then calibrating until I am out of distress. This process is slow, and typically due to withdrawal effects, involves more significant sleep disruption, pain and distress.

But if its an Interference, then the appropriate treatment may be to WAIT as long as three months for the impact of the interfering agent to leave my body and then see if the original medications are still working before deciding to change anything.

Just for example, when my legs when into acute distress in 2008, it took weeks to figure out that the Interference was caused by Celexa, because (for starters) it took over 2 months of being on Celexa to activate my RLS/WED enough to be clear I was having a profound RLS/WED reaction. Notably, it then took 2-3 months after stopping the Celexa for my legs to settle back down.

In my current situation, the only thing I could come up with was that I had changed, was that I started taking pregnenolone 2 months prior to onset of symptoms. As such, did a little research and very quickly found the following statement: "Pregnenolone may inhibit drugs used to increase GABA activity (e.g., Neurontin); these drugs are frequently used in the treatment of epilepsy and depression." (See, e.g., http://goo.gl/GphwZr) I found this exact same statement listed in connection with almost every OTC pregnenolone product on the market.

I thus immediately stopped the pregnenolone despite the otherwise VERY positive impact it was having on my energy/unknown autoimmune/chronic fatigue.

That said, my RLS/WED doctor very quickly dismissed the idea of a pregnenolone Interference. He said: "I am not that concerned about the effect of pregnenolone on Neurontin since Neurontin does not work on the GABA system. It was designed to work on the GABA system but it actually does not bind there so I don't think that is an issue."

He thus wants to treat me with a complicated regimen of medication changes that will take months of many sleepless/painful nights, starting with swapping Lyrica in for the Gabapentin (3 weeks to get to initial dose and taper the gabapentin, longer if a higher dose is needed), and then trying to reduce my Neupro (2 steps/2-4 weeks per mg).

At first I was inclined to do as he suggested, but the more I thought about it, I decided to do more research and maybe get a second opinion to make sure that this was not an Interference.

As it turns out, I think I may have found the research upon which the pregnenolone Interference theory is based. Please see below for that data. As promising as it looks for my proposition, its also WAY over my head, so I don't want to jump to conclusions.

With that as my introduction then, here are my 2 questions:

1. Is there science based evidence that supports the idea that pregnenolone inhibits Gabapentin/Neurontin?

2. Since Lyrica is pregabalin (which I presume means it works in the gaba system), does the same research suggest that pregnenolone would also inhibit Lyrica?

If the answer to 1 is yes, then I would think the best treatment plan would start with waiting for 3 months for the effects of it to leave my system.

If the answer to 2 is yes, then we have an even stronger case for waiting, because the replacement medication that may be inhibited as well. If it is inhibited, I would be at risk of them adjusting the dose to super high levels prematurely in order to get me relief. That would not only increase the risk of side-effects (of which I already have many from existing meds), but also reduce the long-term efficacy of one of the only medications I can still potentially use when either of my existing medications actually do fail.

By this I mean, I have already achieved tolerance and/or augmentation from all the dopaminergic agonists other than Neupro, and so after Lyrica (and possibly Horizant) my only options are benzos and opiods, something I very much don't want to get to, so I need to be extremely careful to preserve my options.

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RESEARCH

"Pregnenolone is an endogenous neurosteroid inhibits GABA-gated chloride currents by enhancing receptor desensitization.(4)"

http://www.lktlabs.com/images/custom/GABARelatedCompounds.pdf

Citation (4) is to a Journal of Neuroscience article entitled:

Pregnenolone Sulfate Modulates Inhibitory Synaptic Transmission by Enhancing GABAAReceptor Desensitization
Shen W, Mennerick S, Covey DF, Zorumski CF. J Neurosci. 20:3571-9 (2000).

For the abstract and full article see:
http://www.jneurosci.org/content/20/10/3571.abstract
http://www.jneurosci.org/content/20/10/3571.full.pdf+html

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Wikipedia:

Interestingly, unlike pregnenolone, pregnenolone sulfate is a negative allosteric modulatorof the GABAA receptor[4] as well as a positive allosteric modulator of the NMDA receptor.[5][6]

http://en.wikipedia.org/wiki/Pregnenolone#Lab_Synthesis
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"Lastly, because of pregnenolones anti-GABA, pro-NMDA action, persons known to suffer from epileptic seizures or who are taking an anti-seizure medication such as Dilantin, Depakote or Tegretol should probably only use pregnenolone with their doctors supervision."

http://intelegen.com/nutrients/pregnenolone_and_mental_function.htm

(Note: I have read glutamate has recently been implicated in RLS, and NMDA, it seems, is a glutamate receptor.)

Thank you for the thoughtful reply.

Just to clarify, one of the articles I read said that Pregnenolone sulfate works differently than pregnenolone.

See: Wikipedia:

"Interestingly, unlike pregnenolone, pregnenolone sulfate is a negative allosteric modulatorof the GABAA receptor[4] as well as a positive allosteric modulator of the NMDA receptor.[5][6] "

http://en.wikipedia.org/wiki/Pregnenolone#Lab_Synthesis

What I have been taking is pregnenolone.

Does this affect your answer at all?

Thanks!

Tremendous response. To make sure I actually understand it correctly, I want to try and clarify my question and also summarize what you have written. Please let me know where I am in significant error!

MY FACTS: Two months ago I had a dramatic worsening of my WED/RLS. It was bad enough so I was in unbearable pain and barely slept for nearly 2 months until they put me on Temazapam. I am now trying to determine whether my taking pregnenolone and DHEA inhibited my gabapentin (or Neupro), thus explaining my sudden increase in WED/RLS. In addition, given the positive effect I was getting from the Pregnenolone and DHEA on a separate condition (I have an "unknown autoimmune"/chronic fatigue problem), I was also wondering if Lyrica (the proposed substitute medication for my gabapentin) was likely to also be impacted by the DHEA & pregnenolone as well -- and thus, if not, whether I could possibly go back on DHEA and Pregnenolone after I have switched medications.

MY SUMMARY OF YOUR ANSWER:

Gabapentin enhances the effects of GABA.

Pregnenolone enhances GABA-A receptor activation.

However, at some point after ingestion (how long? 30 minutes?), pregnenolone ("P") is metabolized as pregnenolone sulfate ("PS"). <-----This is the part I was most unsure about and would like to understand.

Both PS and DHEA are antagonists of and thus inhibit GABA-A receptors.

As a result, generally speaking, the PS and DHEA I was taking likely conflicted with my Gabapentin, and once the Gabapentin was effectively negated, it was as if my WED/RLS was untreated.

Lyrica does not have the same conflict, and therefore it may be possible for me to go back on the P and DHEA after switching to Lyrica.

Is that a fair summary?

(Just as a follow-on note, I went off Temazepam and my symptoms are back to being much better.....yet I haven't changed any of my other medications. That, to me, is more evidence that the P and the DHEA were the culprits in what was happening.)

Thanks again for all your help. This will likely completely change my treatment plan.