Amitriptyline: the neurologist's dirty little secret

Are you taking amitriptyline? As someone with MS amitriptyline's side effect profile may not be in your best interests.

I entered medical school thinking I was going to become a psychiatrist. However, that changed within days of doing my first psychiatric rotation in a specialist inpatient unit, where almost all the patients had been admitted with psychotic disorders. The unit was morbidly quiet. All the patients spent their days in a zombified stupor. The psychiatrists’ dirty little secret was the class of drugs called neuroleptics or major tranquillisers; the pharmaceutical equivalent of a frontal lobotomy. 

Image created by Gemini Pro 3.0. It replaces a photo by Sharon McCutcheon on Unsplash, which is apparently now owned by a company. My apologies for using it. When I downloaded it from unsplash on the Sep 29, 2021, it was free to use.

I soon found out that pharmaceutical lobotomy was rife across medicine, and we were using small doses of neuroleptics widely in the geriatric population and on the surgical, medical and children’s wards. Low-dose chlorpromazine, haloperidol, sulpiride, thioridazine and pimozide were being dispensed to keep agitated and difficult-to-manage patients quiet. As a trainee neurologist, I used to see the consequences of this on the wards and in the clinic: drug-induced Parkinsonism, malignant neuroleptic syndrome, tardive dyskinesia, drug-induced dystonias, oro-facial-buccal dyskinesia, and acute dystonic reactions, to name a few. The orthopaedic surgeons were seeing the falls and fractures, and the general physicians were seeing the acute overdoses from these medications. 

Over time the over-prescribing of these medications was exposed and it is now very rare to see this class of medication prescribe long term and have largely been replaced by safer alternatives, for example, risperidone, olanzapine and quetiapine. 

We, neurologists, are no better than psychiatrists and also have a dirty little secret that is called amitriptyline. We tend to use amitriptyline for all sorts of problems including migraine headache, chronic daily headaches, chronic pain, insomnia and depression. It is quite remarkable how many patients with neurological conditions are on amitriptyline. 

Amitriptyline is the first tricyclic antidepressant that was developed in the 1950s. It is not used to treat depression anymore as the doses required for treating depression are far too sedating. However, it is because of the sedating effects of amitriptyline that it is so widely prescribed. We tend to use it at lower doses from 10mg to 75mg per day to manage neurological conditions. The problem with amitriptyline is that it is a dirty drug with potent central and peripheral anticholinergic effects, which affect cognition, cause dryness of the mouth, make constipation worse and have been associated with excessive daytime sedation. People on amitriptyline are far more likely to fall and have fractures. 

People with MS are far more susceptible to these anticholinergic effects, i.e. due to reduced cognitive reserve. There is little doubt amitriptyline clips cognition. The effect of amitriptyline on bowel function can be quite profound; one of my patients who was on 75mg at night of amitriptyline developed faecal impaction, ileus and perforated bowel and has subsequently required a colostomy. Thankfully, ileus is a rare complication of amitriptyline use.

We know that elderly people on amitriptyline, or other tricyclics, are at much greater risk of falls and fractures. I have little doubt that this applies to pwMS. Amitriptyline is also associated with hypotension (low blood pressure) and cardiac arrhythmias and interacts with many other drugs. 

It is recommended that an ECG should be performed prior to initiating amitriptyline to exclude a condition called long QT syndrome, which puts people at risk of cardiac arrhythmia. Although the latter is rare most doctors prescribe amitriptyline without doing an ECG. 

The worrying observation about anticholinergic drugs, including amitriptyline, 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 the anticholinergic effects of amitriptyline. I suspect the MS brain may be more susceptible as pwMS have reduced brain and cognitive reserve. 

So if you are taking amitriptyline 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; this 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

So if you are taking amitriptyline you should question whether you need it and whether or not it can be replaced with another drug with fewer anticholinergic effects. For example, I am now using duloxetine instead of amitriptyline for MS-related pain syndromes. 

I am also asked which of the anticholinergics used for MS-related bladder dysfunction are the safest. Trospium is by far the least CNS penetrant as it is the least lipid-soluble, the most positively charged and therefore does not cross the blood-brain barrier very well. Oxybutynin is the worst of the bladder drugs with tolterodine, darifenacin and solifenacin being in the grey zone.

I hope you find this helpful. For more detailed information on amitriptyline, I would recommend reading the Summary of Product Characteristics. 

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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.