Are you an anticholinergic zombie? 

A few months ago a 63-year-old MSer was admitted to hospital because of faecal impaction and overflow diarrhoea. She had had worsening constipation for years and was having intermittent diarrhoea due to liquification of stool from an overgrowth of bacteria in her colon, above a massive faecolith (a faecal rock). Her neurologist had her on a long-acting formulation of solifenacin for her neurogenic bladder and 50mg of amitriptyline to help her sleep at night. She had restless legs due to myelopathic pain and spasticity, which was helped by the amitriptyline. Could this be you? Or if you are an HCP do you recognise this patient? 

Faecolith and severe constipation

Her daughter had noticed that she had become increasingly forgetful over the last few months and had missed appointments and had started to repeat herself during casual conversation; often asking the same question during a short conversation. She also could not recall the name of her granddaughter, which was out of character and quite worrying. Her family had started to worry about whether, or not, she was developing dementia. 

During her admission to hospital, her solifenacin was replaced with mirabegron, a new class of drugs that work by stimulating the beta-3 receptor in the bladder wall, that is not associated with CNS side effects. Her amitriptyline was also stopped. Both of these were done to reduce the anticholinergic effects of these drugs on her bowels, which is constipation and on rare occasions faecal impaction. A day or two after these changes to her medication and the clear out of her bowels she woke up cognitively; she became animated and began to interact with her daughter and family members in a way that she had not done for years. She also stopped repeating herself. I identify this syndrome as the ‘Anticholinergic Zombie Syndrome’. Centrally acting anticholinergics have major cognitive side effects and in people with MS, who have reduced reserve, these can be severe. 

I have been developing the argument over the last few months that we should approach the management of MS holistically using the marginal gains philosophy developed by Sir Dave Brailsford when he initially started to manage the Team GB cycling team. 

“The whole principle came from the idea that if you broke down everything you could think of that goes into riding a bike, and then improved it by 1%, you will get a significant increase when you put them all together.” Dave Brailsford.

If you apply this to MS, i.e. break down everything we can think of that goes into improving MS outcomes, and then improving it by 1%, we will get a significant increase when we put them all together. This also means avoiding things that make MS worse. 

One particular factor that we know makes MS worse is exposure to anticholinergics. We use this class of drug mainly for bladder dysfunction, i.e. to reduce bladder irritability. The older the bladder drug the more likely it is to cross the blood-brain barrier and affect cognition. Oxybutynin, for example, reduces IQ or cognition by a half a standard deviation or 7 points. This is enough to make someone with MS-related cognitive impairment demented. 

However, many of the other drugs we prescribe to help MSers have anticholinergic effects off-target. These include the tricyclic antidepressants. As a class, these are used to help MSers with myelopathic pains and as sedatives. It is quite remarkable how often neurologists reach from the prescription pad to prescribe amitriptyline for their patients. I think it is time for us to step back from this practice. We now have other options. 

The remarkable thing is that in the general population exposure to anticholinergics increases your risk of developing dementia. The most recent population case-control study confirming this has just been published in JAMA. I suspect the MS brain is more vulnerable to the effects of anticholinergics and hence we may have inadvertently been exacerbating MS dementia. It is time for us to rethink how we manage the MS bladder and other symptomatic problems and avoid drugs with anticholinergic effects? 

Dare I suggest we should have zero-tolerance for anticholinergics and try and avoid them altogether? 

Coupland et al Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study. JAMA Intern Med. Published online June 24, 2019. doi:10.1001/jamainternmed.2019.0677

Question: Is the risk of dementia among persons 55 years or older associated with the use of different types of anticholinergic medication?

Findings: In this nested case-control study of 58 769 patients with a diagnosis of dementia and 225 574 matched controls, there were statistically significant associations of dementia risk with exposure to anticholinergic antidepressants, antiparkinson drugs, antipsychotic drugs, bladder antimuscarinics, and antiepileptic drugs after adjusting for confounding variables.

Meaning: The associations observed for specific types of anticholinergic medication suggest that these drugs should be prescribed with caution in middle-aged and older adults.

Importance: Anticholinergic medicines have short-term cognitive adverse effects, but it is uncertain whether long-term use of these drugs is associated with an increased risk of dementia.

Objective:  To assess associations between anticholinergic drug treatments and risk of dementia in persons 55 years or older.

Design, Setting, and Participants:  This nested case-control study took place in general practices in England that contributed to the QResearch primary care database. The study evaluated whether exposure to anticholinergic drugs was associated with dementia risk in 58 769 patients with a diagnosis of dementia and 225 574 controls 55 years or older matched by age, sex, general practice, and calendar time. Information on prescriptions for 56 drugs with strong anticholinergic properties was used to calculate measures of cumulative anticholinergic drug exposure. Data were analyzed from May 2016 to June 2018.

Exposures:  The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls (index date).

Main Outcomes and Measures  Odds ratios (ORs) for dementia associated with cumulative exposure to anticholinergic drugs, adjusted for confounding variables.

Results:  Of the entire study population (284 343 case patients and matched controls), 179 365 (63.1%) were women, and the mean (SD) age of the entire population was 82.2 (6.8) years. The adjusted OR for dementia increased from 1.06 (95% CI, 1.03-1.09) in the lowest overall anticholinergic exposure category (total exposure of 1-90 TSDDs) to 1.49 (95% CI, 1.44-1.54) in the highest category (>1095 TSDDs), compared with no anticholinergic drug prescriptions in the 1 to 11 years before the index date. There were significant increases in dementia risk for the anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24-1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57) all for more than 1095 TSDDs. Results were similar when exposures were restricted to exposure windows of 3 to 13 years (AOR, 1.46; 95% CI, 1.41-1.52) and 5 to 20 years (AOR, 1.44; 95% CI, 1.32-1.57) before the index date for more than 1095 TSDDs. Associations were stronger in cases diagnosed before the age of 80 years. The population-attributable fraction associated with total anticholinergic drug exposure during the 1 to 11 years before diagnosis was 10.3%.

Conclusions and Relevance:  Exposure to several types of strong anticholinergic drugs is associated with an increased risk of dementia. These findings highlight the importance of reducing exposure to anticholinergic drugs in middle-aged and older people.

CoI: multiple

12 thoughts on “Zombie”

  1. Great post.
    But we have to consider that as mirabegron can cause frequent UTI’s, is it the most suitable alternative bladder medication for those with MS?

    1. Mirabegron doesn’t cause UTIs itself; like all bladder antispasticity agents, it can reduce bladder emptying frequency and increase residual volume, which is the substrate for the UTIs. This is also a problem on the anticholinergics. All I am saying is mirabegron is an option if you want to get off anticholinergics.

  2. I use a Navina irrigation system. It’s electronic so doesn’t require hand grip. It’s changed things dramatically. I rarely take bladder meds. My bowel was worsening the bladder and now I can mostly manage without meds. Why do we have to Suffer the severity of bowel problems before we are offered these potentially life style changing devices ? I’m far more confident about going out and visiting family and friends without loo obsession

    1. I agree with you. We are also encouraging our patients to try an irrigation system earlier. The improvement it QoL can be quite extraordinary.

  3. Lots of food for thought there (haha). Great post and good to see some one tackling issues that too many people are reluctant to talk about

  4. Some DMTs can also worsen the quality of life of patients, but not all doctors address the problem (a recent example, Ocrevus can sometimes cause debilitating fatigue that does not resolve).
    Quality of life of MS patients is out of the disease targets unfortunately.

    1. Yes it can be. I’ve had side effects from all prescribed DMDs. Very unwell with gastric problems on Gilenya that just took over. So now I just manage my symptoms as positively as possible. Acceptance and joy in other things.

  5. Thanks for post. As usual, polypharmacy needs to be better monitored by physicians, pharmacists and patients in high risk populations, such as seniors and in MS.

    I thought that researchers were looking at a few of the anticholinergics, like solifenacin and benztropine, as possible remyelinating agents?

    I guess this would be counterintuitive as most anticholinergics are now being linked to dementia.

  6. Study conclusion references ‘strong’ anticholinergics.
    Please will you post as to which ones we as people with MS should be most cautious of and what viable alternatives are available.

    I’m taking Gabapentin and switched my antihistamine to Clemastin, as understand preliminary trials suggest it maybe of benefit with MS. Both these drugs facilitate my quality of sleep and this in turn benefits my QoL. It’s therefore equality pertient to ask – where is the balance best achieved between the benefits of the drugs and the detrimental impact?

    Most importantly, are there any anticholinergics that should be avoided at all costs by PwMS?

  7. Interesting post, thanks.

    Something for us all (patients, families, prescribers) to be aware of if taking an anticholinergic, even newer one like solifenacin.

    Imagine how common this must have been 30+ years ago in the pre Prozac days of high dose TCAs

  8. Yes please to the request for information on which anticholinergic agents are most potent/critical for pwMS to avoid.

  9. Re “I have been developing the argument over the last few months that we should approach the management of MS holistically using the marginal gains philosophy……” and “This also means avoiding things that make MS worse. ”
    It should go without saying that ” avoiding things that make MS worse” must also be applied in reverse i.e. avoiding MS related things that make other conditions worse or increase the risks of adverse events. I had a consultation about 18 months ago with a very arrogant urologist who gave me a script for Mirabegron and when I asked about the side effects he said it would probably put my blood pressure up by at least 10 points. When I commented that my cardiologist wouldn’t be very happy about that the urologist’s throwaway response was “Well, you’ll just have to increase your BP meds then, won’t you….”.
    The BP meds are not prescribed for me because I have lifestyle/ diet/ overweight/ cholesterol related increased or high blood pressure but because I suffered a very rare (and nearly fatal) cardiac event unrelated to lifestyle/ diet/ overweight/ cholesterol and my BP must be kept low to reduce ejection force from my heart and protect an aortic graft from damage. And Yes, the urologist knew all about this history.
    I am known to my pharmacist as “Side-Effects Central” due to my side-effect “over-reactions” to most medications e.g. two tablets in 24 hours of one common BP med put me in A&E with significant tachycardia. Even now, due to side-effects of asthma, dry cough and croaky voice, I’m on about a quarter of the usual dose of the only BP meds my body will tolerate – but my body reacts so strongly to meds that these supposedly not-even-therapeutic doses are keeping my BP within the target range. And Yes, the urologist knew all about this as well.
    So much for an holistic approach to patient care – and what made it worse that the urologist wasn’t some aged dinosaur specialist from a bygone era, but a YOUNG up-and-coming man you would not expect to be subscribing to the old “me doctor, you patient” ethos. So, my bladder problems continue to worsen while I’ve spent the past year on the waiting list to see one of the other urologists at my local hospital, and have no idea of how much longer I’ll have to wait. At least the guy I’m waiting to see, even though he is nearing retirement age, has a reputation of first rate patient care AND CARING (capitals intended………..).

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