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
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