Pain gone with AMBROXOL

pattismith

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My pains were worsening for some weeks, and so my mood disorders.( For 6 months, I had digestive issues and a lot of stress that may have triggered the problems)

Finally I found that Ambroxol could be helpful, it is cheap and not risky, so I started a few days ago and a kind of miracle happened. My pains vanished as soon as I started it.

Hard to believe that such a benign drug can be so powerful, let's see if the effect will keep going on the long run...

Ambroxol is a sodium channel blocker active on Nav1.8 in the dorsal root ganglia, and some studies suggest a positive effect for Fibromyalgia.

For the moment I take 15 mg three times a day.

I had to stop T3, it doesn't seem to match with it (first time I can withdraw from T3 for many months!)
I was totally sleepy and weak when taking them together.
 
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Iritu1021

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My pains were worseing for some weeks, and so my mood disorders.( I had digestive issues and a lot of stress that may have triggered the problems)

Finally I found that Ambroxol could be helpful, it is cheap and not risky, so I started a few days ago and a kind of miracle happened. My pains vanished as soon as I started it.

Hard to believe that such a benign drug can be so powerful, let's see if the effect will keep going on the long run...

Ambroxol is a sodium channel blocker active on Nav1.8 in the dorsal root ganglia, and some studies suggest a positive effect for Fibromyalgia.

For the moment I take 15 mg three times a day.

I had to stop T3, it doesn't seem to match with it (first time I can withdraw from T3 for many months!)
I was totally sleepy and weak when taking them together.
That's great news, glad to hear you're feeling better! Ambroxol also releases intracellular calcium from lysosomes - that's how I came across it when I posted about it originally in our T3/calcium thread - so can't exclude that intracellular calcium played some role in this as well.

How many days did it take to start working?
 
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pattismith

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That's great news, glad to hear you're feeling better! Ambroxol also releases intracellular calcium from lysosomes - that's how I came across it when I posted about it originally in our T3/calcium thread - so can't exclude that intracellular calcium played some role in this as well.

How many days did it take to start working?
Thank you for your participation on this thread @Iritu1021 .
It worked within the two hours after my first intake.

Our pathologies are probably induced by over activation of purinergic receptors by microbiome and intracellular infections.
P2X Purinergic receptors are ion channels, when they are activated, ions enter quickly into the cytoplam (Na, then Ca, K...).

If we don't have P2X blockers to test (Suramine is not available, nor PPADS), we just can try other ion channels modulators to see if they can help for one of the other cell type involved in our symptoms.

When my spinal pains were fixed with Azithromycin on the second day of the intake, I believed some intracellular bacterial infection was removed. This may be true because I had to do a long treatment to cure this pain definitively .
But this antibiotic family also have some P2X blockage property and so we can wonder if the effect is related to this effect...

However, these antibiotics and Ambroxol don't cure my muscle weakness, they increase it!

Let's see what effect I will have with a longer intake of Ambroxol...I hope to better tolerate it than I tolerate Macrolid antibiotics...


Hi @pattismith, may I ask what kind of pains you experienced? (For me it is mostly joint pains.)
Thank you for sharing and I'm happy that you found something that works for you!
over my 35 years of illness, I experienced several pain types, but the ones I have currently (that seems to be related in a way or the other to my gut) are neuropathic pains (they were diagnosed that way by a rheumatologist).

It is a burning sensation in muscles in my proximal hindlegs, mostly around my hips.
 

Wishful

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It's interesting how calcium keeps popping up in ME discussions. I'll follow this thread to find out if ambroxol continues to work for you (or if it's one of those things that only works a few times) and if it works for anyone else.
 

pattismith

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Here an interesting update about my Ambroxol trial.

It happens that even without T3, Ambroxol makes my brain very sleepy and my muscle weaked.

I took Idebenone (a drug that have already helped me in the past in association with it, and bingo! it rescued my brain within an hour, but not my muscles)

I did it two days to see if this effect can be reproduced and it does.

I investigated about what could explain these effects.

I can't find anything about Ambroxol induced sleepiness and weakness, so I may be special (I already know this!), but I found that Idebenone may be an ANO1 inhibitor, and that ANO1 activation in the brain induces artery vasocontriction. This means that ANO1 inhibition in the brain will probably induce vasodilatation, same as Nimodipine, a calcium channel blocker that have shown to help some ME/CFS patients here on PR!

Inhibition of ANO1/TMEM16A Chloride Channel by Idebenone and Its Cytotoxicity to Cancer Cell Lines

Abstract
The expression levels of anoctamin 1 (ANO1, TMEM16A), a calcium-activated chloride channel (CaCC), are significantly increased in several tumors, and inhibition of ANO1 is known to reduce cell proliferation and migration. Here, we performed cell-based screening of a collection of natural products and drug-like compounds to identify inhibitors of ANO1. As a result of the screening, idebenone, miconazole and plumbagin were identified as novel ANO1 inhibitors. Electrophysiological studies showed that idebenone, a synthetic analog of coenzyme Q10, completely blocked ANO1 activity in FRT cells expressing ANO1 without any effect on intracellular calcium signaling and CFTR, a cAMP-regulated chloride channel. The CaCC activities in PC-3 and CFPAC-1 cells expressing abundant endogenous ANO1 were strongly blocked by idebenone. Idebenone inhibited cell proliferation and induced apoptosis in PC-3 and CFPAC-1 cells, but not in A549 cells, which do not express ANO1.
These data suggest that idebenone, a novel ANO1 inhibitor, has potential for use in cancer therapy.

ANO1 inhibitors are potentially used to relax uterus:

Functional comparison of anoctamin 1 antagonists on human uterine smooth muscle contractility and excitability


Abstract
Background: Pre-term birth is a major health care challenge throughout the world, and preterm labor represents a potentially reversible component of this problem. Current tocolytics do not improve preterm labor beyond 48 h. We have previously shown that anoctamin 1 (ANO1) channel blockade results in relaxation of pre-contracted human uterine smooth muscle (USM). Three drug classes with reported medicinal effects in humans also have members with ANO1 antagonism. In this study, we compared the ability of representatives from these 3 classes to reduce human USM contractility and excitability.
Objective: This study sought to examine the comparative potency of 3 ANO1 antagonists on pregnant human USM relaxation, contraction frequency reduction, inhibition of intracellular calcium release and membrane hyperpolarization.
...
Conclusion:
While all 3 ANO1 antagonists attenuate pregnant human uterine tissue contractility and excitability, BB is the most potent tocolytic drug. Our findings may serve as a foundation for future structure-function analyses for novel tocolytic drug development.
Introduction...
One potential tocolytic target is the calcium-activated chloride channel (CaCC) family member anoctamin 1 (ANO1). CaCC currents have long been recognized as important modulators of smooth muscle excitability (7,8,9). These channels are voltage-gated and responsive to elevations in intracellular calcium levels, making them uniquely suited to participate in excito-mechanical coupling and action potential (AP) generation in smooth muscle tissues (7, 10)
...
Molecular identification of the ANO1 channel as a CaCC was not established until recently (17,18,19). The ANO1 channel is now known to play important roles in various cell types including airway and intestinal epithelial cells, smooth muscle cells, intestinal pacemaker cells, and sensory neurons (20,21,22,23)

Local coupling of TRPC6 to ANO1/TMEM16A channels in smooth muscle cells amplifies vasoconstriction in cerebral arteries

Abstract
Anoctamin-1 [ANO1, also known as transmembrane protein 16A (TMEM16A)] is a Ca2+-activated Cl− channel expressed in arterial myocytes that regulates membrane potential and contractility. Signaling mechanisms that control ANO1 activity in arterial myocytes are poorly understood.
In cerebral artery myocytes, ANO1 channels are activated by local Ca2+ signals generated by plasma membrane nonselective cation channels, but the molecular identity of these proteins is unclear. Arterial myocytes express several different nonselective cation channels, including multiple members of the transient receptor potential receptor (TRP) family. The goal of this study was to identify localized ion channels that control ANO1 currents in cerebral artery myocytes.
....
These data indicate that TRPC6 channels generate a local intracellular Ca2+ signal that activates nearby ANO1 channels in myocytes to stimulate vasoconstriction.



I have to look into puringergic receptors...
I guess there must be a chapter about it in your book, more and more scientific studies are released about the P2X receptors/channels, it's amazing to have all these new informations available about ion channels!
 
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Iritu1021

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I don't know about PR antagonists but uridine which would be a purinergic agonist is the next thing on my list to try. I'm trying to sort out if the improvement I had from lithium orotate might be due to orotate which may be a precursor to uridine - and uridine is becoming a very popular nootropic supplement right now and has been shown some efficacy in bipolar disorder.

But if any of my pain gets worse on it, it might support your theory in reverse testing.
 

pattismith

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I don't know about PR antagonists but uridine which would be a purinergic agonist is the next thing on my list to try. I'm trying to sort out if the improvement I had from lithium orotate might be due to orotate which may be a precursor to uridine - and uridine is becoming a very popular nootropic supplement right now and has been shown some efficacy in bipolar disorder.

But if any of my pain gets worse on it, it might support your theory in reverse testing.
Did you consider Lithium may be a P2X7 antagonist?

http://grantome.com/grant/NIH/Z01-MH002835-03

"Finally, we also found chronic (5-day) Li-treatment significantly blocked ATP-induced influx of Ca2+ in astrocytes. Our data demonstrated that P2X7 is expressed in astrocytes, and its expression levels can be regulated by chronic treatment of lithium at therapeutically relevant concentrations. Considering P2X7 receptor's role in the regulation of Ca2+ by ATP, this may be the molecular mechanism by which ATP-induced influx of Ca2+ can be blocked by lithium in astrocytes. Our data provide evidence showing that P2X7 receptor in astrocytes may be a therapeutic target for mood disorder treatments"
 

Iritu1021

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Did you consider Lithium may be a P2X7 antagonist?

http://grantome.com/grant/NIH/Z01-MH002835-03

"Finally, we also found chronic (5-day) Li-treatment significantly blocked ATP-induced influx of Ca2+ in astrocytes. Our data demonstrated that P2X7 is expressed in astrocytes, and its expression levels can be regulated by chronic treatment of lithium at therapeutically relevant concentrations. Considering P2X7 receptor's role in the regulation of Ca2+ by ATP, this may be the molecular mechanism by which ATP-induced influx of Ca2+ can be blocked by lithium in astrocytes. Our data provide evidence showing that P2X7 receptor in astrocytes may be a therapeutic target for mood disorder treatments"
No, I didn't know that - thank you! There seem to be so many ways in which lithium affects the CNS!

I'm pretty sure at this point that my issues are somehow calcium related. I think that lithium orotate did something to change my calcium flux, and I also began using gabapentin around the same time (initially just at night time to help increase slow wave sleep). I think that branched chain amino acids could be "a poor man's gabapentin" since they seem to bind to the same subunit of the calcium
channel. Have you tried pregabalin or gabapentin for your pain?
 

pattismith

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channel. Have you tried pregabalin or gabapentin for your pain?
Yes a doc gave me Gabapentin, I took it one day, and at around 5 PM I was in tears, without knowing why, it made me scared and I didn't keep it.

I also did a trial with Pregabalin, it was doing a good job on my pain, but too much sleepiness...I couldn't keep it more than a week.

What dosage of Lithium did you try?
 

Moof

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Lithium orotate definitely has a CNS effect – it gave me the worst RLS and allodynia pain that I'd ever experienced!! :eek:

I was referred to a neurologist, put on Parkinson's medication, was almost suicidal...and then heard a chance remark on a radio programme about medical doses of Lithium for bipolar disorder being well-known for causing severe, refractory RLS in some patients. I was taking such a tiny dose (1.5g, as opposed to the 100g someone might take for bipolar) that I assumed it couldn't possibly cause that much pain, but I stopped it anyway. The problem disappeared within 48 hours.

It was a horrible experience, and reminded me that supplements are far from benign. I stopped taking things that friends brought to the house for me in an attempt to be helpful, and now just stick to my B12 injections, occasional folate, and BCAAs. Lesson well and true learnt! :)
 

Iritu1021

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Yes a doc gave me Gabapentin, I took it one day, and at around 5 PM I was in tears, without knowing why, it made me scared and I didn't keep it.

I also did a trial with Pregabalin, it was doing a good job on my pain, but too much sleepiness...I couldn't keep it more than a week.

What dosage of Lithium did you try?
@pattismith, I couldn't tolerate lithium orotate - just like Moof before I went on levothyroxine. When I tried it with T3 it made me overstimulated and hyperthyroid, and when I tried it without any thyroid hormone, I would crash and had pain and worsening depression.

Once I've been on a good dose of T4 for a while, I began to lose my drug sensitivity so I was able to start with 2.5 mg per day and I worked up gradually to 30 mg per day but that caused too much T4 to T3 conversion (my T3 went from 3.0 to 4.0 and I was feeling hyperthyroid) so I backed down to 10 mg. I might increase up to 15 mg once I check my thyroid labs again.

It still made me worse for the first two weeks but once I got past that, it was like the skies have finally cleared for me - great brain clarity and stable mood.

If someone is not taking any thyroid, I would suggest lithium arginate or lithium aspartate by American Biologics which comes in doses of 50 mcg - at least to test it out. If ok then maybe switch to LO at 1.25 mg every other day and increase as tolerated.

Apparently, lithium arginate can penetrate inside the cell as well as orotate. I know you guys have Oligosol (gluconate) in France but I'm not sure it works quite the same way because its bound to inorganic salt. It will have more effect on plasma membranes - which might be good for your sodium and P2X7 channels but may not be able to reach into the cell and change ER calcium.
 

pattismith

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@pattismith

Apparently, lithium arginate can penetrate inside the cell as well as orotate. I know you guys have Oligosol (gluconate) in France but I'm not sure it works quite the same way because its bound to inorganic salt. It will have more effect on plasma membranes - which might be good for your sodium and P2X7 channels but may not be able to reach into the cell and change ER calcium.
Thank you @Iritu1021
We have Lithium citrate 1 mg (Granion) in France, which I have already tryed for a while, but can't remember if I felt any difference. Maybe I should try a bigger dose...
 

Iritu1021

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Thank you @Iritu1021
We have Lithium citrate 1 mg (Granion) in France, which I have already tryed for a while, but can't remember if I felt any difference. Maybe I should try a bigger dose...
This is similar to lithium carbonate which is used as prescription lithium, with the lowest therapeutic doses starting at around 30 mg of lithium. So yes, at 1 mg it probably would not do much, especially for intracellular effect since it's bound to an inorganic compound and doesn't penetrate BBB and plasma membrane as well.

With lithium orotate the lowest therapeutic doses are generally believed to start at 5 mg.

I've tried lithium carbonate 150 mg (which is about 20 mg of elemental lithium) and didn't like it. I didn't feel like I could push through the side effects with that one. But maybe at 5 - 10 mg it would be a different story. But to me, these two formulations felt like similar yet different drugs.

You don't have orotate or arginate forms in France?
 
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Iritu1021

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Looks, like calcium is involved in purinergic receptors too.

https://www.ncbi.nlm.nih.gov/pubmed/21911484
Calcium-dependent block of P2X7 receptor channel function is allosteric.
The results indicate that calcium in physiological concentrations acts as a negative allosteric modulator of P2X7R by decreasing the affinity of receptors for orthosteric ligand agonists, but not antagonists, and not by affecting the permeability dynamics directly or indirectly through Panx1 channels. We expect these results to generalize to other P2XRs.

and here: https://www.sciencedirect.com/science/article/pii/S0005273614001874?via=ihub
 

Moof

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Just another report on Ambroxol:

I'd never heard of it before, but coincidentally found some yesterday when round at my friend's house. She was clearing stuff from her bathroom ready to have it refitted, and I offered to box up the contents of her wall cabinet. She'd been given the drug in January for a stubborn cough and catarrh, and left the remaining tablets in the cupboard in case it came back. My leg muscles were sore from loading and unloading the wheelchair from the car, there were no contraindications on the leaflet that applied to me, so I asked if I could try one.

It worked pretty well, certainly enough to persuade me that it's worth keeping some in my cabinet for when I'm having a rough time with pain. I'll ask at the local pharmacy next time I'm collecting my meds, to see if you can get it in the UK without a prescription.
 

Moof

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Just as a postscript...after a second dose, courtesy of my friend (she gave me what's left of her tablets), I think I've fathomed out why Ambroxol works for me.

Much of my burning muscle pain after activity is caused by a weird involuntary tension in the small fibres. I got good results with gabapentin because it relaxed this tension, though I don't like taking it long-term. I'm pretty sure Ambroxol does the same thing; it doesn't make my muscles feel weak, as @pattismith reported, but they are relaxed in a way that they just can't without medication or immersion in warm water. The constant feeling of needing to pee has also gone, which is caused by the same phenomenon.

It's really irritating that I can't get these small fibres to relax without some kind of intervention – I've tried every technique under the sun, and I'm not even anxious or tense to begin with. Nothing doing, though! But anyway, I thought I'd add this in case it helps anyone else decide whether or not to give it a try.