Tolerance issues in general
Posted: Sun Sep 09, 2018 10:51 am
Be advised: this is only the personal perspective and opinion of a RLS patient like yourself. He is not (yet) a medical professional.
So here I want to offer some of my general observations I made in regards to treatment of RLS with medication. What I have to say is by no way complete description of the problem. However I think I now I have enough information and experience to make a more general statement that goes beyond my own personal situation.
I wish I could put it all in better English but unfortunately learning a new language was never my strong suit but I am trying my best here. Sometimes I just "forget" words. I think them but forget to write them down. Sorry for that.
So in my opinion, everyone who takes daily medication for RLS will sooner or later face the problem of either augmentation or tolerance.
I have no data for the U.S. but in Germany most patients with RLS, no matter how severe, get started on Levodopa (L-Dopa) together with a decarboxylase inhibitor to test if the patient is even responsive to dopaminergic treatment. At least here in Germany they use L-Dopa as some kind of test if somebody really has RLS. However the L-Dopa test is not 100% reliable.
Because the effects of L-Dopa are often not strong enough in moderate to severe cases and long term treatment with L-Dopa can cause severe side effects including fast augmentation most patients get a prescription for the classic RLS dopamine-agonists like Pramipexol (Mirapex in the U.S.) or Ropinirol. Rotigotine (the Neurpro patch) is also available but it seems that drug is only used when treatment with at least one oral dopamine agonists has failed. (*Pls note that L-Dopa is basically dopamine itself and is not classified as a dopamine agonists itself).
And here the big problems start. I would argue the data is insufficient however most of us with moderate to severe RLS will sooner or later augment on dopamine agonists. For some it is only a matter of days or weeks. Others seem to be able to tolerate them for a couple of years in low doses but only because they take regular breaks from the dopamine agonists. The 2nd issue is that once you have augmented on one dopamine agonists you will most likely augment on the other dopamine agonists too. And unfortunately much faster then on the 1st DA you tried.
For some going back to L-Dopa is an option but normally it is only a matter of time until they augment on L-Dopa, too. Patients who run into this problem seem to either increase their dose to deal with the enhanced symptoms and get stuck on high doses which will later result in a nasty withdraw or will just start and restart the DAs over and over again with poor sleep and poor quality of live.
So this is my first observation: the drugs who are described and advocated as 1st line treatment options in moderate to severe cases of RLS will, in many cases, only make the situation worse. And it is just a matter of time when this is happening. I don't know all the data and I am sure there are patients who happily life with DAs and L-Dopa for many years. However I don't know them and they don't seem to write in this particular forum. Please correct me if I am wrong.
Prescribing L-Dopa and DAs only seems to delay the inevitable, the use of alternatives. From reading treatment guidelines and the most common alternatives are
(1) opiods
(2) antiepileptics
(3) Benzodiazepines and other GABAnergic drugs
(4) i.V. iron infusion
(5) THC and other cannabinoids
And when you ask me, this is the point where the nightmare often really begins to start.
t Opioids are a highly effective treatment option for RLS, especially for the physical symptoms. The offer quick relief however there are unfortunately some problems associated with opioid treatment. The 1st would be that many doctors don't seem to know or belief that opioids can be an effective treatment for RLS but even when the patient can obtain a prescription for opioids, opioids often can cause hyper alertness and have stimulating effects together with their sedating properties. So the patient is free from his primary RLS symptoms but still can't sleep because the opioid itself is keeping him awake.
The 2nd big problem with opioids is, especially when you have the severe form of RLS which requires daily use of opioids or even round the clock treatment that you will run into tolerance problems. Especially in the U.S. the doctors now have strict limits when it comes to prescribing opioids and don't allow you to increase your dosage even though you would need a higher dose to manage your symptoms. There is no general consensus with dose is the appropriate limit for RLS but a equivalent of about 100 mg Morphine seems to be the maximum many doctors are willing to go now.
These two problems often lead to the addition of other drugs which all seem to have their separate tolerance issues (iron treatment excluded). Even when a medication works well for several years, unfortunately you are not safe. RLS is a dynamic disorder. Symptoms change and develop, simply because your brain changes, develops and ages. The intake of drugs who work in the central nervous system adds to that.
The antiepileptics Gabapentin and Pregabalin are often used to treat RLS. But to me it seems if effective, side effects associated with the treatment of antiepileptics either result in stopping the treatment or if the patients finds the side effect acceptable, the dosage needs to be increased over and over again. Up to a point where either side effects are forcing the patient or doctor to discontinue the the treatment or up to a point, where the patients rather accepts nasty side effects then no sleep during the night.
Antiepileptics are well known for their side effects and all the hopes doctors and patients put into them did not match the reality check. They work, sometimes, somehow but almost always not as expected and hoped for. And when there is a good response with a low rate of side effect, then unfortunately tolerance becomes much faster an issue then it normally would be.
So to deal with all the side effects from drug experiments and the withdraws and additional insomnia resulting from it, many doctors prescribe Benzodiazepines (Clonazepam, Diazepam, Lorazepam, Alprazolam, ...) and related drugs (Zopiclone, Zolpidem). Long term use unfortunately causes tolerance, dependence and will at some point result in a nasty withdraw when the drug is not stopped early enough.
To make my point, no matter which route you go, at some point a drug often simply stops working. RLS is a highly dynamic and extremely complex disorder in the nervous system. No matter what drug you feed that beast, it seems to adapt sooner or later when you have one of the more severe forms of RLS.
However doctors seem to except that once they found the right drug, it will just work for the time being, often not really realising how dynamic this disorder can be.
While mild forms of RLS are common, the more severe forms don't seem to be that prevalent. Also the drugs used for RLS are old and have been approved for other disorders like parkinson, epilepsy, chronic pain etc. ages and centuries ago. So there is no real interest from the industry how these drugs perform for RLS. The newer DAs and the combination of Oxycodone / Naloxone are rare exceptions because those drugs were still patented at the time they were approved for RLS. But nobody will invest drugs like Carbamazepine for RLS even though it can be highly effective with treating a broad spectrum of RLS symptoms, including hyper alertness caused by opioids and help to keep to opioid dose low simply because there is no money in it. Sadly one can become tolerant to the effects of Carbamazepine too as I had to experience.
If you want to treat your RLS in the proper way, then you need to figure out how all the substances who possibly work for RLS affect you and then find the combination that offers you the best quality of life. But make a plan what you will do when you run into tolerance issues. Speak about this problem with your doctor in advance. For example when antiepileptics are a great help for you, then you can add high-potent long acting Benzodiazepines like Clonazepam, stop the antiepileptics in a short period of time, take Clonazepam for 3-4 months, use Diazepam to have soft and slow withdraw from Clonazepam and then restart your old antiepileptic.
You can do similar stuff with opioids. (Using Benzodiazepines from time to time to do a partial withdraw from opioids). And even rotating opioids, like 1 year Oxycodone, 1 year Hydromorphone, 1 year Morphine can greatly help with keeping the dose low.
I use even weirder tricks to deal with tolerance issues and I thought about writing a complete treatment scheme for RLS when you run into tolerance issues but I am not sure if I am really qualified to do so and if this is the proper ethical way to publish the information I have. If you are interested in my personal history with RLS, I have a long (way too) long pharma diary in this forum.
And please consider iron treatment if you haven't done so already. There is good evidence that it really can help and keep in mind that all this is only my personal opinion.
So here I want to offer some of my general observations I made in regards to treatment of RLS with medication. What I have to say is by no way complete description of the problem. However I think I now I have enough information and experience to make a more general statement that goes beyond my own personal situation.
I wish I could put it all in better English but unfortunately learning a new language was never my strong suit but I am trying my best here. Sometimes I just "forget" words. I think them but forget to write them down. Sorry for that.
So in my opinion, everyone who takes daily medication for RLS will sooner or later face the problem of either augmentation or tolerance.
I have no data for the U.S. but in Germany most patients with RLS, no matter how severe, get started on Levodopa (L-Dopa) together with a decarboxylase inhibitor to test if the patient is even responsive to dopaminergic treatment. At least here in Germany they use L-Dopa as some kind of test if somebody really has RLS. However the L-Dopa test is not 100% reliable.
Because the effects of L-Dopa are often not strong enough in moderate to severe cases and long term treatment with L-Dopa can cause severe side effects including fast augmentation most patients get a prescription for the classic RLS dopamine-agonists like Pramipexol (Mirapex in the U.S.) or Ropinirol. Rotigotine (the Neurpro patch) is also available but it seems that drug is only used when treatment with at least one oral dopamine agonists has failed. (*Pls note that L-Dopa is basically dopamine itself and is not classified as a dopamine agonists itself).
And here the big problems start. I would argue the data is insufficient however most of us with moderate to severe RLS will sooner or later augment on dopamine agonists. For some it is only a matter of days or weeks. Others seem to be able to tolerate them for a couple of years in low doses but only because they take regular breaks from the dopamine agonists. The 2nd issue is that once you have augmented on one dopamine agonists you will most likely augment on the other dopamine agonists too. And unfortunately much faster then on the 1st DA you tried.
For some going back to L-Dopa is an option but normally it is only a matter of time until they augment on L-Dopa, too. Patients who run into this problem seem to either increase their dose to deal with the enhanced symptoms and get stuck on high doses which will later result in a nasty withdraw or will just start and restart the DAs over and over again with poor sleep and poor quality of live.
So this is my first observation: the drugs who are described and advocated as 1st line treatment options in moderate to severe cases of RLS will, in many cases, only make the situation worse. And it is just a matter of time when this is happening. I don't know all the data and I am sure there are patients who happily life with DAs and L-Dopa for many years. However I don't know them and they don't seem to write in this particular forum. Please correct me if I am wrong.
Prescribing L-Dopa and DAs only seems to delay the inevitable, the use of alternatives. From reading treatment guidelines and the most common alternatives are
(1) opiods
(2) antiepileptics
(3) Benzodiazepines and other GABAnergic drugs
(4) i.V. iron infusion
(5) THC and other cannabinoids
And when you ask me, this is the point where the nightmare often really begins to start.
t Opioids are a highly effective treatment option for RLS, especially for the physical symptoms. The offer quick relief however there are unfortunately some problems associated with opioid treatment. The 1st would be that many doctors don't seem to know or belief that opioids can be an effective treatment for RLS but even when the patient can obtain a prescription for opioids, opioids often can cause hyper alertness and have stimulating effects together with their sedating properties. So the patient is free from his primary RLS symptoms but still can't sleep because the opioid itself is keeping him awake.
The 2nd big problem with opioids is, especially when you have the severe form of RLS which requires daily use of opioids or even round the clock treatment that you will run into tolerance problems. Especially in the U.S. the doctors now have strict limits when it comes to prescribing opioids and don't allow you to increase your dosage even though you would need a higher dose to manage your symptoms. There is no general consensus with dose is the appropriate limit for RLS but a equivalent of about 100 mg Morphine seems to be the maximum many doctors are willing to go now.
These two problems often lead to the addition of other drugs which all seem to have their separate tolerance issues (iron treatment excluded). Even when a medication works well for several years, unfortunately you are not safe. RLS is a dynamic disorder. Symptoms change and develop, simply because your brain changes, develops and ages. The intake of drugs who work in the central nervous system adds to that.
The antiepileptics Gabapentin and Pregabalin are often used to treat RLS. But to me it seems if effective, side effects associated with the treatment of antiepileptics either result in stopping the treatment or if the patients finds the side effect acceptable, the dosage needs to be increased over and over again. Up to a point where either side effects are forcing the patient or doctor to discontinue the the treatment or up to a point, where the patients rather accepts nasty side effects then no sleep during the night.
Antiepileptics are well known for their side effects and all the hopes doctors and patients put into them did not match the reality check. They work, sometimes, somehow but almost always not as expected and hoped for. And when there is a good response with a low rate of side effect, then unfortunately tolerance becomes much faster an issue then it normally would be.
So to deal with all the side effects from drug experiments and the withdraws and additional insomnia resulting from it, many doctors prescribe Benzodiazepines (Clonazepam, Diazepam, Lorazepam, Alprazolam, ...) and related drugs (Zopiclone, Zolpidem). Long term use unfortunately causes tolerance, dependence and will at some point result in a nasty withdraw when the drug is not stopped early enough.
To make my point, no matter which route you go, at some point a drug often simply stops working. RLS is a highly dynamic and extremely complex disorder in the nervous system. No matter what drug you feed that beast, it seems to adapt sooner or later when you have one of the more severe forms of RLS.
However doctors seem to except that once they found the right drug, it will just work for the time being, often not really realising how dynamic this disorder can be.
While mild forms of RLS are common, the more severe forms don't seem to be that prevalent. Also the drugs used for RLS are old and have been approved for other disorders like parkinson, epilepsy, chronic pain etc. ages and centuries ago. So there is no real interest from the industry how these drugs perform for RLS. The newer DAs and the combination of Oxycodone / Naloxone are rare exceptions because those drugs were still patented at the time they were approved for RLS. But nobody will invest drugs like Carbamazepine for RLS even though it can be highly effective with treating a broad spectrum of RLS symptoms, including hyper alertness caused by opioids and help to keep to opioid dose low simply because there is no money in it. Sadly one can become tolerant to the effects of Carbamazepine too as I had to experience.
If you want to treat your RLS in the proper way, then you need to figure out how all the substances who possibly work for RLS affect you and then find the combination that offers you the best quality of life. But make a plan what you will do when you run into tolerance issues. Speak about this problem with your doctor in advance. For example when antiepileptics are a great help for you, then you can add high-potent long acting Benzodiazepines like Clonazepam, stop the antiepileptics in a short period of time, take Clonazepam for 3-4 months, use Diazepam to have soft and slow withdraw from Clonazepam and then restart your old antiepileptic.
You can do similar stuff with opioids. (Using Benzodiazepines from time to time to do a partial withdraw from opioids). And even rotating opioids, like 1 year Oxycodone, 1 year Hydromorphone, 1 year Morphine can greatly help with keeping the dose low.
I use even weirder tricks to deal with tolerance issues and I thought about writing a complete treatment scheme for RLS when you run into tolerance issues but I am not sure if I am really qualified to do so and if this is the proper ethical way to publish the information I have. If you are interested in my personal history with RLS, I have a long (way too) long pharma diary in this forum.
And please consider iron treatment if you haven't done so already. There is good evidence that it really can help and keep in mind that all this is only my personal opinion.