Are you taking anticholinergics?
It is clear that centrally acting anticholinergic drugs, which block so-called muscarinic receptors, are being used by many people with multiple sclerosis as DIY agents to promote remyelination. The scientific rationale for this practice is based on preclinical work in cell culture systems and animal models and one proof-of-concept study of clemastine in pwMS with previous optic neuropathy.
Is this practice wise? I say no. We need properly controlled large studies to confirm the results and show that clemastine and other drugs in this class are remyelinating, have a clinical effect that is meaningful and improve quality of life.
Why am I being so pessimistic? The problem is centrally-acting anticholinergic affect cognition. Oxybutynin, a first-generation CNS-penetrant anticholinergic, which is commonly prescribed for urinary frequency, reduces the average IQ of someone with MS by 7 points or half a standard deviation. This is a massive drop in cognitive function particularly if you already have cognitive impairment, which may be overt or hidden and is very common in pwMS.
I have been waging a war with many continence services who look after my patients who still use oxybutynin because it is cheap. There are many alternative newer anticholinergic agents that don’t penetrate the CNS or work on a different mechanism. So if you are on oxybutynin you need to switch drugs.
Lessons from the opicinumab phase 2 remyelination trial suggests that only a subset of pwMS are likely to benefit from a remyelinating agent. This is because not everyone with MS has demyelinated axons or nerve fibres that need remyelination. The estimate is that in pwMS with moderate disability (EDSS 2.0-5.5) only a third will benefit from a remyelinating agent. So if you are taking clemastine you may be taking a hit on your cognition when you don’t even know if you are one of those people who has a population of nerve fibres that are ready to be remyelinated.
For how long do you have to take a remyelination drug to achieve maximum benefit? Provided your MS is under control with an anti-inflammatory DMT and you are not demyelinating new axons you may only need a remyelination agent for a few weeks or months. Once you have stimulated remyelination and all the naked axons are remyelinated there is no need to continue taking the remyelination agent.
Please note these concepts about remyelination are based on animal models and early trials and are mostly hypothetical when it comes to pwMS.
Another worrying observation about anticholinergic drugs is that the impact on cognition may be irreversible and reduce your brain reserve. Several epidemiological studies have shown that in the general population 2-3 years of continuous anticholinergic exposure increases your risk of getting dementia by ~30%. Whether this is applicable to pwMS is at present unknown, but I can’t think of any reason why the MS brain would be less susceptible to anticholinergics; in fact, I suspect the MS brain may be more susceptible as pwMS have reduced brain and cognitive reserve.
So if you are taking off-label clemastine for its unconfirmed benefits in MS or another anticholinergic that is CNS penetrant my advice would be to stop taking them and to seek alternative cognition-friendly medication.
Please be aware that there are many drugs that have anticholinergic effects; the following website lists them. In addition, apart from blunting cognition the list of side effects attributable to anticholinergics includes the following:
- Dry mouth
- Difficulty in swallowing
- Constipation
- Paralytic ileus (paralysis of the bowl)
- Nausea or vomiting
- Increased heart rate
- Urinary retention
- Difficulty in urinating
- Blurred vision
- Dry eyes
- Exacerbation or precipitation of acute angle-closure glaucoma
- Decreased sweating
- Drowsiness or sedation
- Dizziness
- Hallucinations
- Deliriums
- Restlessness
- Irritability
- Nervousness
- Slurred speech
- Impaired concentration
- Confusion
- Memory impairment
Postscript 1: I have been asked which of the anticholinergics used for MS-related bladder dysfunction are the safest. The table below indicates that Trospium is by far the least CNS penetrant; is the least lipid-soluble and the most positively charged. It is clear that oxybutynin is the worst. Tolterodine, darifenacin and solifenacin are in between.
Source: Chancellor M, Boone T. Anticholinergics for overactive bladder therapy: central nervous system effects. CNS Neurosci Ther. 2012;18(2):167-174. doi:10.1111/j.1755-5949.2011.00248.x
Postscript 2: I have also been asked about what dose of drug X or drug Y is sufficient to cause anticholinergic cognitive effects. A good example on this list is Amitriptyline; just 10mg of Amitriptyline per day is sufficient.
Source: Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015;175(3):401-407. doi:10.1001/jamainternmed.2014.7663
#T4TD = Thought for the Day
CoI: nil in relation to this post
It seems you think urology specialist services hand out medication without considering the individual patient needs. It’s quite likely some of the side effects you’ve listed could be attributed to other treatments or co morbidities. In my experience those services have been caring, thorough and everything explained before any decision has been made.
Many in the UK still prescribe oxybutynin, which is what I am referring to. In the UK continence services are generally run by community-based nurses. They are not part of the urology services that are based in hospitals.
Well my urologist in the UK would probably disagree with you.
Morrow et al. Anti-cholinergic medications for bladder dysfunction worsen cognition in persons with multiple sclerosis. J Neurol Sci. 2018 Feb 15;385:39-44
Bladder dysfunction is common in persons with MS (PwMS), often due to detrusor muscle overactivity. Anticholinergic medications are considered the first line treatment for bladder dysfunction and are known to worsen cognition in healthy older adults and in persons with dementia. Yet, it is not known if these medications have the same effect on PwMS. Thus, the Objective of this prospective matched-cohort study was to determine if anticholinergic medications affect objective measures of cognition in PwMS. We recruited PwMS starting either oxybutynin or tolterodine (cases). Cases and controls were tested with the Brief International Cognitive Assessment for MS (BiCAMS) battery prior to starting anticholinergic medications and 12weeks later. The primary outcome was change on the Symbol Digit Modalities Test (SDMT) between groups; secondary outcomes were changes on the other BiCAMS measures. Analysis of Covariance with baseline measures as covariates to assess the significance of between group differences was performed at 12weeks. Forty eight PwMS starting anticholinergic medications and 21 matched PwMS controls were recruited. There was a significant difference (p<0.001) in the change on the cognitive measures over 12weeks between groups. The controls demonstrated improvement, consistent with practice effect, while the cases remained unchanged. This study demonstrates that anticholinergic medications may have a negative effect on cognition in PwMS; further confirmatory studies are needed.
It’s not the science I’m querying, it’s your sweeping generalisation about what care we receive in other UK hospitals.
Not sure about other NHS hospitals; I work in London. I still see a lot of patients with bladder dysfunction from around London who are still being prescribed oxybutynin; the reason because it is cheap. This is not urologists, they uncovered and have highlighted the issue, but continence services who are funded by CCGs and they do it for cost-saving reasons. A solution for this would be for the MHRA to take oxybutynin off the market by revoking its marketing authorisation, but that is only the tip of the iceberg as most of the anticholinergic burden is due to other drugs.
If we think we have a problem in MS you need to read the literature about this problem in the elderly. Anticholinergics are responsible not only for cognitive problems in the elderly but falls, fractures, constipation, faecal impaction, etc. The anticholinergic burden at a population level is a massive problem.
Thank you Prof G for these really informative blogs.
Would you consider Darifenacin for over active bladder relatively safe?
Darifenacin is an intermediate risk drug. I have added a postscript to the post (see above) to cover this question.
Interesting. Thank you very much for the information.
I notice amitriptyline is on the list, is 30mg daily enough to affect cognition at a meaningful level?
It was for
Yes, 10mg of amitriptyline is sufficient; as you know it is a potent anticholinergic. I have now added a postscript the blog post to deal with these sorts of questions (see above)
Kay & Ebinger. Preserving cognitive function for patients with overactive bladder: evidence for a differential effect with darifenacin. Int J Clin Pract 2008 Nov;62(11):1792-800.
Background: Antimuscarinic agents used in the treatment of overactive bladder (OAB) differ in their potential to impair cognitive function. It is hypothesised that low brain concentrations and relatively low selectivity for the M(1) muscarinic receptor may reduce the potential for adverse central nervous system (CNS) effects with darifenacin, compared with other antimuscarinics, particularly oxybutynin.
Methods: Cognitive function studies evaluating darifenacin, oxybutynin, tolterodine, solifenacin and/or trospium were identified from publications databases (Medline, Biosis and Embase) and congress abstracts. Preclinical studies and randomised controlled trials in adults were reviewed.
Results: Five randomised, double-blind, multiple-dose studies of cognitive function were identified. Oxybutynin was consistently associated with cognitive deficit (four studies), whereas darifenacin did not impair cognition (three studies). These findings were supported by data from sleep/attention and EEG studies. Tolterodine data were limited to one small study with each formulation. For solifenacin and trospium, there were no human studies evaluating memory, the cognitive function most vulnerable to CNS anticholinergics.
Conclusions: There is compelling evidence of cognitive impairment with oxybutynin, whereas darifenacin stands out by demonstrating no impairment of memory or other cognitive functions in three randomised, controlled trials. This may be attributed to the differences in physicochemical properties, efflux mechanisms and relative M(1) muscarinic receptor sparing. The risk of CNS impairment is of particular concern for vulnerable populations such as the elderly (a substantial proportion of the OAB population), and CNS-compromised neurogenic bladder patients such as those with multiple sclerosis or Parkinson’s disease.
Not sure how that posted?! 30 mg was enough for me. I also, three attempts later trying amitryptyline, found it was the cause of “relapses” of palinopsia. Ie I only had palinopsia when taking the drug LOL.
I’m curious whether extreme drug effects are due in part to a poorly functioning blood-brain barrier and if anything can be done about that. My BBB is officially shot; confirmed after extreme neuro adverse effects to resotran, which targets 5-HT4 receptors “specific” to the gut. Upon investigation, There are also receptors in the brain; I would assume that in a BBB healthy individual, it wouldn’t be an issue.
We still use amitriptyline in clinical practice for pain, but have largely replaced it with duloxetine which has a better evidence base in relation to pain, is less sedating and has very few anticholinergic side effects.
Duloxetine also has an emerging evidence base in migraine prophylaxis.
Kisler LB, Weissman-Fogel I, Coghill RC, Sprecher E, Yarnitsky D, Granovsky Y. Individualization of Migraine Prevention: A Randomized Controlled Trial of Psychophysical-based Prediction of Duloxetine Efficacy. Clin J Pain. 2019;35(9):753-765. doi:10.1097/AJP.0000000000000739
“Duloxetine also has an emerging evidence base in migraine prophylaxis”……..As a pwms who has suffered with daily chronic headache/migraine for the past 10 years, I can attest to the effectiveness of duloxetine. After trying various meds, I found the most relief with 30mg/daily Duloxetine and 400mg/daily Magnesium Oxide. Still need a rescue med every so often for bad migraines. Diet, water intake, exercise, stress reduction techniques, and sleep also help in reducing pain/symptoms.
The side-effects of centrally acting anticholinergics is certainly worth taking note in MS patients whose cognitive abilities (or lack thereof) are often under-reported, under-recognized or under-tested, to begin with.
However, the concept of remyelination is, in itself, an outmoded concept in my opinion. The brain is a 3D structure, like every other organ and in MS, it is not JUST a ‘peeling away’ of myelin alone that is at the heart of the disease. How about the scaffolding loss ? Axons are cut (transected), there is loss of cells, and so the ‘bones’ of the brain are gone too ! Why do we talk about myelin loss as it was just a layer of skin ? Even skin comes in many layers so I think we need to ALWAYS worry not just about drugs promoting remyelination or attempting to do so, but rather the fact that voxel loss is what underlies the pathology and therefore we need to address that too ! Simplistic explanations miss the point and the target and meanwhile there is no single drug that comes close to even replacing myelin loss. And then there is myelin loss in the cortex and deep gray nuclei……
Errata corrige…
Hi Prof. G, my name is Massimo and I am writing to you from Italy. I am currently taking Tysabri every 6 weeks EID (for 4 years) and everything is fine. But every now and then I have migraines and my doctor preventively prescribed the drug Laroxyl to prevent these migraines. In your article today you write that anticholinergic anticholinergic drugs can have negative effects on cognitive abilities and refer to a link where there is a list of anticholinergic drugs. Among these is AMITRIPTILINA which is the active substance of the drug Laroxyl. For 4 years I have been taking 8 drops every day. What do you suggest me? Do I stop taking this drug? I don’t really need it. As I said, I take it for migraines but at this point, given the dangers, I can also stop taking. Thank you very much Prof. G.
Hi Prof. G, my name is Massimo and I am writing to you from Italy. I am currently taking Tysabri every 6 weeks EID (for 4 years) and everything is fine. But every now and then I have migraines and my doctor preventively prescribed the drug Laroxyl to prevent these migraines. In your article today you write that anticholinergic anticholinergic drugs can have negative effects on cognitive abilities and refer to a link where there is a list of anticholinergic drugs. Among these is AMITRIPTILINA which is the active substance of the drug Laroxyl. I have been taking 8 drops every X for X years. What do you suggest me? Do I stop taking this drug? I don’t really need it. As I said, I take it for migraines but at this point, given the dangers, I can also stop taking.
Thank you very much Prof. G.
Massimo
You will need to discuss this with your HCP.
We still use amitriptyline in clinical practice for migraine but we have started to try duloxetine which has an emerging evidence base in relation to migraine prophylaxis.
Kisler LB, Weissman-Fogel I, Coghill RC, Sprecher E, Yarnitsky D, Granovsky Y. Individualization of Migraine Prevention: A Randomized Controlled Trial of Psychophysical-based Prediction of Duloxetine Efficacy. Clin J Pain. 2019;35(9):753-765. doi:10.1097/AJP.0000000000000739
Can I stop and replace it with another anti migraine drug? Do I have to stop it abruptly or do I have to scale the intake until I no longer take it? What other drug would you recommend for migraine. Thanks again Prof. G
I have been taking amitriptyline 30mg nocte for nerve pain for a very long while, have never managed to get below 20mg even with a very slow reducing dose before pain kicks in. Should I be asking my neuro for an alternative (gabapentin and pregabelin have too many unwanted side effects).
I went up to 40mg but have recently – carefully – reduced it to 30mg because I am struggling to lose any weight and wondered if that would help. I have come close many times to giving in to the pain and asking for gabapentin/pregablin but can’t risk the weight gain that many report. It would be good to find something else.
I have had a handful of patients who have found low-dose topiramate helpful with central pain syndromes and it is licensed for migraine prophylaxis. One advantage is that it an appetite suppressant and causes weight loss. The downside is that at high doses that are typically used for epilepsy topiramate is very sedating and affects cognition. At low doses (< 150-200mg per day) topiramate is usually well tolerated.
REQUEST OF PROFG:
The estimate is that in pwMS with moderate disability (EDSS 2.0-5.5) only a third will benefit from a remyelinating agent. So if you are taking clemastine you may be taking a hit on your cognition when you don’t even know if you are one of those people who has a population of nerve fibres that are ready to be remyelinated.
For how long do you have to take a remyelination drug to achieve maximum benefit? Provided your MS is under control with an anti-inflammatory DMT and you are not demyelinating new axons you may only need a remyelination agent for a few weeks or months. Once you have stimulated remyelination and all the naked axons are remyelinated there is no need to continue taking the remyelination agent.
Will you please expand on these aspect of remyelination and demyelination agents.
This is the first time I’ve been aware of these facts.
All prior knowledge I’ve gleaned has been about the efficacy (or not) of treatment as part of which seems to be the implicit assumption it’s essential for all PwMS to benefit from remyelination agents.
Nor have I been aware that continual use of agents may not be required.
If you will explain some of these complexities in more detail it’d be helpful.
Thanks
Is percutaneous tibial nerve stimulation (PTNS) for urinary frequency and incontinence more widely available now?
No, not yet. It also doesn’t work for everyone.
I was prescribed Solifenacin for my bladder urgency issues.
This was not effective so Mirabegron was added to my prescription, with the intention that I could eventually stop taking Solifenacin..
Is Mirabegron classed as an anticholinergic drug?
Are there any alternative neuropathic painkillers you could recommend? I currently take 50mg Nortriptyline for pain.