Your anticholinergic burden

Polypharmacy, which includes anticholinergic medications often comes with a high cost to the MS brain. Please think carefully before starting an anticholinergic.

Centrally acting anticholinergic drugs, which block so-called muscarinic receptors, are being used by many people with multiple sclerosis as do-it-yourself (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 people with multiple sclerosis (pwMS) with previous optic neuropathy. 

Is this practice wise? I would say no. We need properly controlled large studies to confirm these preliminary 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. 

Photo by Fakurian Design on Unsplash

Why am I being so pessimistic? The problem is centrally-acting anticholinergics, those that get into the brain, have an effect on 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 and particularly problematic if you already have cognitive impairment as a result of your MS. Please note cognitive impairment may be overt or hidden and is very common in pwMS.

I have been waging a war with many continence services that look after pwMS 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. 

It is likely that only a small subset of pwMS are likely to benefit from a remyelinating agent such as clemastine. This is because not everyone with MS has demyelinated axons or nerve fibres that need remyelination. I estimate that it will only be pwMS with moderate disability (EDSS 2.0-5.5) that may benefit from a remyelinating therapy. Why? If you have no disability how are you going to be able to assess an improvement in function? Hence these patients won’t be included in clinical trials and will be excluded from any marketing authorisation. On the other side of the spectrum if you are very disabled and have lost a large number of nerve fibres there may be too few surviving fibres to remyelinate. So if you are taking clemastine for its possible remyelinating effects 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 can be remyelinated.

Another question is 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 a remyelinating 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 to anticholinergics 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 an 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:

1. Dry mouth

2. Difficulty in swallowing

3. Constipation

4. Paralytic ileus (paralysis of the bowl)

5. Nausea or vomiting

6. Increased heart rate

7. Urinary retention

8. Difficulty in urinating

9. Blurred vision

10. Dry eyes

11. Exacerbation or precipitation of acute angle-closure glaucoma

12. Decreased sweating

13. Drowsiness or sedation

14. Dizziness

15. Hallucinations

16. Deliriums

17. Restlessness

18. Irritability

19. Nervousness

20. Slurred speech

21. Impaired concentration

22. Confusion

23. Memory impairment

I am often 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 sit in between the two extremes. The good news is that we have a relatively new class of drugs for MS-related bladder symptoms that work on the so-called adrenergic B3 receptor, which don’t have CNS side effects. Mirabegron is the first drug in this class to be licensed for bladder problems.

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

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; a small dose of 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

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.