Trial Report Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome...a randomised, double-blind, placebo-controlled, phase 3 trial, 2023, Ford

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https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01523-4/fulltext

Lancet. 2023 Oct 16:S0140-6736(23)01523-4.
doi: 10.1016/S0140-6736(23)01523-4. Online ahead of print.
Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial
Alexander C Ford 1, Alexandra Wright-Hughes 2, Sarah L Alderson 2, Pei-Loo Ow 2, Matthew J Ridd 3, Robbie Foy 4, Gina Bianco 2, Felicity L Bishop 5, Matthew Chaddock 6, Heather Cook 2, Deborah Cooper 4, Catherine Fernandez 2, Elspeth A Guthrie 4, Suzanne Hartley 2, Amy Herbert 3, Daniel Howdon 4, Delia P Muir 2, Taposhi Nath 2, Sonia Newman 7, Thomas Smith 2, Christopher A Taylor 2, Emma J Teasdale 5, Ruth Thornton 7, Amanda J Farrin 2, Hazel A Everitt 7; ATLANTIS trialists
Collaborators, Affiliations

• PMID: 37858323
  
• DOI: 10.1016/S0140-6736(23)01523-4

Free article
Abstract


Background: Most patients with irritable bowel syndrome (IBS) are managed in primary care. When first-line therapies for IBS are ineffective, the UK National Institute for Health and Care Excellence guideline suggests considering low- dose tricyclic antidepressants as second-line treatment, but their effectiveness in primary care is unknown, and they are infrequently prescribed in this setting.

Methods: This randomised, double-blind, placebo-controlled trial (Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment [ATLANTIS]) was conducted at 55 general practices in England. Eligible participants were aged 18 years or older, with Rome IV IBS of any subtype, and ongoing symptoms (IBS Severity Scoring System [IBS-SSS] score ≥75 points) despite dietary changes and first-line therapies, a normal full blood count and C-reactive protein, negative coeliac serology, and no evidence of suicidal ideation. Participants were randomly assigned (1:1) to low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months, with dose titration over 3 weeks (up to 30 mg once daily), according to symptoms and tolerability. Participants, their general practitioners, investigators, and the analysis team were all masked to allocation throughout the trial. The primary outcome was the IBS-SSS score at 6 months. Effectiveness analyses were according to intention-to-treat; safety analyses were on all participants who took at least one dose of the trial medication. This trial is registered with the ISRCTN Registry (ISRCTN48075063) and is closed to new participants.

Findings: Between Oct 18, 2019, and April 11, 2022, 463 participants (mean age 48·5 years [SD 16·1], 315 [68%] female to 148 [32%] male) were randomly allocated to receive low-dose amitriptyline (232) or placebo (231). Intention-to-treat analysis of the primary outcome showed a significant difference in favour of low-dose amitriptyline in IBS-SSS score between groups at 6 months (-27·0, 95% CI -46·9 to -7·10; p=0·0079). 46 (20%) participants discontinued low-dose amitriptyline (30 [13%] due to adverse events), and 59 (26%) discontinued placebo (20 [9%] due to adverse events) before 6 months. There were five serious adverse reactions (two in the amitriptyline group and three in the placebo group), and five serious adverse events unrelated to trial medication.

Interpretation: To our knowledge, this is the largest trial of a tricyclic antidepressant in IBS ever conducted. Titrated low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care across multiple outcomes, and was safe and well tolerated. General practitioners should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, with appropriate support to guide patient-led dose titration, such as the self-titration document developed for this trial.

Funding: National Institute for Health and Care Research Health Technology Assessment Programme (grant reference 16/162/01).


Informative thread by lead author:

 

Wouldn't the finding that an antidepressant had no effect on depression call the competency of everyone who's prescribed it, to treat depression, since the year dot, into question?

 

36% mean symptom improvement for the treatment arm versus 25% for the placebo isn't nothing, but it's not huge.

 

On a quick skim, this seems to be based on the results at 6 months based on a pre-specified exploratory analysis:



Results at 12 months look a bit different:

 

Figure 3
Key secondary outcome of SGA of relief of IBS symptoms at 6 months
SGA=subjective global assessment. IBS=irritable bowel syndrome. OR=odds ratio. HADS=Hospital Anxiety and Depression Scale. *All ORs were estimated using logistic regression adjusted for recruiting hub, IBS subtype, and HADS-depression score. Missing data were imputed via multiple imputation.

 

Mmm. Not much sleep tonight , so thoughts are a bit random .

Did they look at gut bacteria/ microbial balance prior ?
Seratonin is made in gut and anti depressants can affect gut bacteria.

Estrogen degradation can be affected by gut bacteria , so if female, ( who were in majority here ) I don't know that adding serotonin into the mix would be a good idea ( I literally don't know , tagging @Midnattsol who may )
Did titration account for menstrual cycles ?

Low dosage amitriptyline is used for many things though noone seems to know quite how it works - there seems to be the view that because it's a low dose it's safer . I don't know if there is any evidence for this .

What was the placebo used ?

 

No because the homeopathic dose prescribed in this trial (10 mg) is 10x lower than what’s needed to achieve an antidepressant effect.

 

Can’t really maintain blinding in placebo-controlled trials of tricyclics because they have such obvious characteristic side effects (dry mouth, drowsiness).

 

I know some people don’t like this and similar drugs but I’m happy I was offered it and believe it has helped me in a few different ways with my severe ME symptom complex:

Get 8.5-9 hours of a sleep a night (before trying it I was getting 5-6 hours a night; tried an SSRI and only got 4 hours a night)

Help with different types of pain:
- headaches
- IBS
- TMJ
- Muscle pain
Also I think it made me less light- and sound-sensitive and has taken the edge of lower mood episodes. I was never clinically depressed but my mood could drop maybe particularly when in PEM.

I have tried amitryptline but slept a bit less on it (7.5-8 hours a night) and felt a bit more drowsy on it. I prefer trimipramine.

 

I was prescribed Amitriptyline some years ago, and was started at 10mg, as far as I remember. It was prescribed for gut problems. It had to be increased up to 20mg - 25mg before I got any effect. It gave me a slight beneficial effect on pain, but also gave me one of the side effects listed in the Patient Information Leaflet. I got tachycardia, with a heart rate of 150, although it wasn't happening 24 hours a day. I had to come off the drug.

I was persuaded to go onto a different drug in the same family (Nortriptyline) which I was assured was far less likely to give me side effects. That was true to a small extent - my heart rate only rose to 135 beats per minute. *rolls eyes*

In the end my GP had to prescribe me real pain killers, which worked, and still do, several years later.

 

This I see as the key problem here. I suspect most people can tell if they are taking 30mg of amitriptyline.

It also highlights the problems of 'dose-titration' studies where patients are specifically on the outlook for side-effects. I see this being a major problem for any attempt at a low dose naltrexone study. There may be ways to do this and retain blinding but I think it needs extraordinarily careful design.

 

What a terrible way to make decisions. I know I'm an outlier in finding clinical trials to be generally useless, unless they have obvious dramatic benefits, but I don't see how such results can lead to a positive recommendation. It's such a trivial benefit for such a high cost that doesn't even add any understanding of the condition. Especially given the mess of confusion over having an entire category of drugs called antidepressants that more often than not don't even affect so-called depression, which itself is defined generically and so superficially as to be functionally useless.

Progress at this pace is not working. IBS has been known for decades, is still largely misattributed as some psychosomatic something or another, and this here is the result of a large and expensive trial. This whole approach is not even a good temporary step, it keeps polluting the discipline with bad information and misleading claims.

Entire new paradigms need to be developed to replace this BS. I don't get the lack of recognition for how so obviously pointless it all is.

 

Annoying. Hope it doesn’t happen here. Many years ago they got rid of the 10mg dosage so only available in 25mg (and maybe 50mg?).

 

You could probably achieve better blinding in tricyclic trials with an anticholinergic antihistamine serving as the placebo but they never do it.