Double-blind placebo-controlled study of the efficacy of oral terfenadine in the treatment of chronic fatigue syndrome, 1996, Steinberg et al

[Utsikt]

Double-blind placebo-controlled study of the efficacy of oral terfenadine in the treatment of chronic fatigue syndrome

Spoiler: Authors

Steinberg, Paul; McNutt, Bruce E.; Marshall, Paul; Schenck, Carlos; Lurie, Nicole; Pheley, Alfred; Peterson, Phillip K.

Abstract
(Line breaks added)

BACKGROUND:
There is no established treatment for chronic fatigue syndrome (CFS), an illness characterized by disabling fatigue exacerbated by physical activity. A variety of immunologic abnormalities have been reported, including a high incidence of atopy and hypoergy or anergy.

OBJECTIVE:
Because of anecdotal reports and uncontrolled trials showing antihistamine efficacy in CFS, we evaluated the clinical efficacy of the antihistamine terfenadine (60 mg twice daily) in a placebo-controlled study.

METHODS:
Thirty patients with CFS were enrolled in a 2-month, double-blind, placebo-controlled trial of terfenadine.

Participants underwent a battery of both immediate- and delayed-type hypersensitivity skin tests and completed a self-assessment questionnaire used to measure severity of symptoms, physical and social functioning, health perceptions, and mental health before each of six biweekly visits.

RESULTS:
Twenty-eight patients completed the trial. History of atopy and positive immediate skin test results were prevalent, 73% and 53%, respectively. No evidence for hypoergy or anergy after delayed-type hypersensitivity skin testing was found.

No therapeutic benefit from terfenadine could be detected in terms of symptom amelioration, improved physical or social functioning, health perceptions, or mental health. A high incidence of atopy in patients with CFS was confirmed.

CONCLUSION:
Although this trial involved a small number of patients, the results suggest that terfenadine is unlikely to be of clinical benefit in treating CFS symptoms.

Web | DOI | Journal of Allergy and Clinical Immunology

 

[Scarecrow]

Thanks, @Utsikt

A small study from 1996. I think the diagnostic criteria were fine. As you suggested on the histamine thread, it would have been preferable to exclude participants with allergies. It surprising how many of them had allergic rhinitis and/or a positive skin test.

Tefernadine, although an H1 antagonist, did not cause drowsiness. It may not have been too obvious to the participants if they were receiving the treatment or placebo. It was considered to have a limited ability to cross the blood brain barrier. So this increases confidence In the double blinded nature of the trial.

In a rapid response to this paper in the BMJ ( BMJ 2000; 320 doi: https://doi.org/10.1136/bmj.320.7243.1184 (Published 29 April 2000) ), the author noted When given to man in oral therapeutic doses terfenadine produced about 17% H1 receptor occupancy in the frontal lobe whereas the 1st generation antihistamine chlorpheneramine produced about 77% occupancy, citing the following study:

Yanai K, Ryu JH, Watanabe T, Iwata R, Ido T, Sawai Y, Ito K, Itoh M. Histamine H1 receptor occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography. Br J Pharmacology 1995; 116: 1649-1655

If tefernedine does not cross the BBB, then it's unlikely to be able to have any affect on brain fog and I would speculate that much of the fatigue of ME/CFS is associated with brain fog.

Also two months may be a very short time for any improvement in physical functioning even if the treatment had been effective.

 

[Utsikt]

It’s good to see that blinding might not have been an issue. Although unintended unblinding will favour the active arm, which would make the effect seem more positive.

If tefernedine does not cross the BBB, then it's unlikely to be able to have any affect on brain fog and I would speculate that much of the fatigue of ME/CFS is associated with brain fog.

Based on what?

Also two months may be a very short time for any improvement in physical functioning even if the treatment had been effective.

Why? The physical functioning of people with ME/CFS is primarily limited by how much they can do without PEM, not by the strength of their muscles, cardiovascular fitness etc.

 

[Utsikt]

I just noticed that the drug has been removed from most markets due to causing hearth issues in certain patients and when used with certain medications.

It was replaced by Allegra-D that has the same active component, but doesn’t require the liver to process it first.

 

[Kitty]

I just noticed that the drug has been removed from most markets due to causing hearth issues in certain patients and when used with certain medications.

It was replaced by Allegra-D that has the same active component, but doesn’t require the liver to process it first.

Yes, fexofenadine is now available over the counter in the UK. It's one of the antihistamines I use regularly for allergies, but up until two or three years ago it was prescription only.

 

[Scarecrow]

Based on what?

In the midst of even a moderate bout of brain fog, never once have I decided to go for a walk or scrub the floors instead. It could be argued that the aversion to physical exertion is related to reduced motivation but what is the reason for the reduced motivation? And having motivated myself to do anything at all, it better be a quick task or it will not get finished. Everything is just too much effort if the brain isn't functioning. At the milder end, a short walk or a light task is fine. I'm not claiming the fatigue of brain fog is the same as physical fatigue but it can be limiting all the same.

Why? The physical functioning of people with ME/CFS is primarily limited by how much they can do without PEM, not by the strength of their muscles, cardiovascular fitness etc.

Fundamentally, I disagree and not just due to brain fog.

Exercise intolerance, which by definition is not post exertional, affects physical functioning.

Orthostatic intolerance, which in my experience can provoke PEM, also affects physical functioning long before PEM strikes.

In 2024, three years after starting to manage histamine, I will still conscious of both. Perhaps they are related in a way that is not obvious.

Of course my treatment plan was probably far from ideal. Better treatments could lead to faster results but I have a hunch that there might be damage that takes longer to heal. If there is an autonomic connection, could it be related to nerve damage?

 

[Utsikt]

In the midst of even a moderate bout of brain fog, never once have I decided to go for a walk or scrub the floors instead. It could be argued that the aversion to physical exertion is related to reduced motivation but what is the reason for the reduced motivation? And having motivated myself to do anything at all, it better be a quick task or it will not get finished. Everything is just too much effort if the brain isn't functioning. At the milder end, a short walk or a light task is fine. I'm not claiming the fatigue of brain fog is the same as physical fatigue but it can be limiting all the same.

Nothing here explains why brainfog would be connected mechanistically to fatigue specifically. They frequently occur at the same time, but so do many other symptoms.

Fundamentally, I disagree and not just due to brain fog.

Exercise intolerance, which by definition is not post exertional, affects physical functioning.

Do people hit the limit for for exercise intolerance before they hit the limit for PEM? Perhaps the most mildly affected do. I never did when I was moderate and was told to exercise, but it might be different for others?

Orthostatic intolerance, which in my experience can provoke PEM, also affects physical functioning long before PEM strikes.

That’s a fair point.

To clarify: the prospect of PEM is in itself a limiting factor, not just the onset of PEM. I have to stop before my body stops me, because if I don’t I have to pay tomorrow.

Of course my treatment plan was probably far from ideal. Better treatments could lead to faster results but I have a hunch that there might be damage that takes longer to heal. If there is an autonomic connection, could it be related to nerve damage?

I’m not aware of any evidence of damage in ME/CFS.

 

[Scarecrow]

Nothing here explains why brainfog would be connected mechanistically to fatigue specifically. They frequently occur at the same time, but so do many other symptoms.

Perhaps it is simply individual experience that causes us to view things differently. I had to go shopping earlier, which has provoked my OI again. Consequently, I am very fatigued and as I sit here typing I am perceiving it as mostly mental rather than bodily fatigue but without brain fog. I feel ok about getting up to make dinner but it will need to be very simple so that I don't stand around and further worsen the situation. Most likely, I will have flu-like PEM tomorrow and then I really won't want to do anything but rest.

If I was sitting here right now with brain fog, it would be difficult to motivate myself to even make dinner other than say sticking some soup in the microwave because the mental effort involved would so limiting.

Do people hit the limit for for exercise intolerance before they hit the limit for PEM? Perhaps the most mildly affected do. I never did when I was moderate and was told to exercise, but it might be different for others?

That was certainly my experience when I was at my best between my early and late thirties.