July 18, 2024 • 38 mins
Ever wondered if a common supplement could help with endometriosis pain? In our latest episode, we dive into a listener-requested discussion on N-acetylcysteine (NAC). We explore NAC's potential to manage endometriosis-related pain, reduce endometrioma size, and improve fertility.
https://pubmed.ncbi.nlm.nih.gov/36981595/
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Introducer (00:02):
Welcome to the Dr Journal Club podcast, the show
that goes under the hood ofevidence-based integrative
medicine.
We review recent researcharticles, interview
evidence-based medicine thoughtleaders and discuss the
challenges and opportunities ofintegrating evidence-based and
integrative medicine.
Continue your learning afterthe show at www.
(00:23):
d rjournalclub.
com.
Dr. Joshua Goldenberg (00:31):
Please bear in mind that this is for
educational and entertainmentpurposes, only.
Talk to your doctor beforemaking any medical decisions,
changes etc.
Everything we're talking aboutthat's to teach you guys stuff
and have fun.
We are not your doctors.
Also, we would love to answeryour specific questions on
drjournalclub.
com.
You can post questions andcomments for specific videos,
(00:55):
but go ahead and email usdirectly at josh at
drjournalclub.
com.
That's josh at drjournalclub.
com.
Send us your listener questionsand we will discuss it on our
pod.
Hello and welcome to another DrJournal Club podcast with your
host, Josh and Adam.
We are back from.
(01:16):
I think.
We did a little bit of a hiatusfor July 4th weekend and the
amazing Michele, I think, sentus one of our super speedy
summary videos.
So we are back in the saddleagain.
I'm going to talk about NAC,n-a-c, known to his friends as
NAC, I guess.
Anyway, Adam, how you doing man?
What's the latest?
I haven't spoken to you in alittle bit.
Dr. Adam Sadowski (01:38):
I'm doing great.
Uh, I was in uh Portland, Maine, for Fourth of July.
Yeah, oh, very nice, yep yep,yep, awesome.
Dr. Joshua Goldenberg (01:43):
Was there for a little bit, did some fun
stuff there and then, on the wayback, visited.
Portland, maine, for 4th ofJuly.
Dr. Adam Sadowski (01:46):
Oh very nice.
Yep, yep, yep, yep, awesome.
Was there for a little bit, didsome fun stuff there.
Then, on the way back, visitedsome family in New Hampshire.
Dr. Joshua Goldenberg (01:51):
Very cool .
Dr. Adam Sadowski (01:52):
And then, yeah, it was a nice little
getaway.
How was your 4th?
Dr. Joshua Goldenberg (01:58):
Next time you're up in that part of Maine
you're going to have to hangout with Jacob Shore et al.
Do you know him?
No, oh, okay, I for some reasonI thought you guys were, you
were buddies, but I just uh.
Mark Davis, friend of the pod,was just up in Maine too and of
course had to do uh requiredkayaking with said doctor.
(02:19):
He's a huge kayaker and theymoved to Maine recently and
tried desperately to get us tomove to Maine because my mom
lives there and we were thinkingabout Portland during the
pandemic.
But it was just like I rememberthem sending me like houses and
it was like $800,000 for likean abode and it was just a
(02:39):
pandemic.
Even in Maine it was just likepandemic times.
Prices were insane and they'relike but think of the kayaking.
Anyway, okay, so I digress,let's, let's jump in.
So we have a, we have a requestfrom a listener, a dear listener
, for this paper.
So that's the selection andsometimes we pick stuff out.
Oftentimes you'll find stuffthat's being talked about in
(03:01):
some of the bigger journals orwe'll get sort of tips from
folks that on papers that havemade it out to the main media,
etc.
This is sometimes we getrequests from listeners, and
sometimes from doctors andsometimes from non doctors, for
just questions about papers thatthey've come across.
And it's good because I feellike folks that don't have the
medical background.
You look at a paper and you'relike, oh, this, this looks
(03:23):
interesting, looks legit, andyou know, understandably they
don't have the training to kindof take it apart.
So that's one of the services Ifeel like we offer is, while
we're geared to you know,doctors, I think we're also kind
of geared to the educated andinformed you know person at this
at the same point, and I feelthat way about my patients in
(03:44):
general.
So cool, so let's jump in anystarting questions about this.
So this is we'll put the link inthe show notes and I'm actually
going to write down link inlarge letters and send it to
Michele, because I always sayI'm going to send to Michele and
then I never send it toMichelle.
So this time is on a post itnote, so it's going to happen.
So this is about NAC forendometriosis-related pain and
(04:07):
endometriomas as well asfertility outcomes.
I do not do anything withendometriosis, I know very
little about it, and I've usedNAC and acetylcysteine when I
was in primary practice, mostlyfor like mucolytic effects, like
when people had colds and stuff.
So that was sort of like theextent of my background
(04:30):
knowledge.
So clinically I'm kind of aneophyte here.
How about you?
Have you used NAC a lot?
Have you played with it?
Do you see a lot ofendometriosis?
Dr. Adam Sadowski (04:38):
Yeah, so I am familiar with endometriosis.
It comes up quite a bit in theprimary care setting.
I'm familiar with it in that,in that regards.
With regards to NAC, myexperience has mostly been
around addiction, medicine withit and mental health related
(04:58):
things.
Oh yeah, there's someinteresting research there.
Dr. Joshua Goldenbe (05:01):
Interesting , oh okay.
Well, there's a chock full ofstuff that potentially used for
I feel like there might even beoncology outcomes for it.
Dr. Adam Sadowski (05:08):
I could be wrong about that, but it's also
a precursor to a more well-knownantioxidant known as
glutathione, and so that's kindof like.
The mechanism of action behindNAC is that it's a precursor to
glutathione, and so NAC isoftentimes used for things with
(05:29):
any sort of like inflammatoryconditions.
It has some you know reportedbenefits with regards to liver
health, and so it's used forthat.
This is not yeah, not medicaladvice.
By the way.
Yeah, none of this is not yeah,not medical advice by the way.
Dr. Joshua Goldenberg (05:46):
Yeah, none of this is we don't know
what we're talking about.
Don't listen to us.
Talk to your doctors.
We're just evidence experts.
We'll just, we'll break apartthe study, but talk to your own
doctors, guys.
Um, so that's it.
Yeah, I have seen it actuallyin a lot of protocols for liver
stuff and the glutathioneconnection makes sense.
My understanding is glutathioneis like apparently magic, but
(06:07):
it's very hard to getbioavailable and so like you try
to push it in other ways.
Is that kind of the rationalebehind?
Yeah, yeah, yeah, and it's uh,what, what cup is that?
Just just keep going, okay allright.
All right, I got distracted,squirrel, okay, anyway.
So yeah, so it's basically acheaper, bioavailable way of
(06:32):
pushing.
Glutathione andanti-inflammatory actions is one
proposed mechanism of actionand of course everything's
connected to inflammation, sopain and endometriosis makes
sense as well.
So I want to say, because thiswas recommended from someone who
doesn't have a background in inmedical science, I want to kind
of give my red flag thoughts asI read through it to kind of
(06:55):
help the reader that doesn'thave a lot of training in this
understand.
You know what are some thingsthat we look at, that kind of
like our ears jump up and belike what, and I don't know
about you.
But the first one that I saw waslike three sentences in in the
abstract, which was the primaryobjective of this prospective
(07:16):
single cohort study was toconfirm the effectiveness of NAC
in reducing endometriosisrelated pain and the size of
ovarian endometriomas.
So just that statement that thepurpose of this study is going
to confirm the effectiveness,all my bells and whistles went
off.
Like that is a very strongstatement.
(07:36):
My first thought was oh mygoodness, they must have in
science anyway.
It's a very strong statement.
They must have conflicts ofinterest and they must own all
the NAC production in the world.
I couldn't find any evidence ofthat, but that kind of language
is a red flag in and of itself.
And then to say that based upona cohort without a control, so
(07:58):
we use randomized control trialsto understand efficacy and
effectiveness right, and thisidea of looking at a single
cohort where you don't have anycontrol and that's going to
confirm the effectiveness andit's like our objective.
It doesn't matter what theresults are, it's not to see
what happens, our objective isto confirm this effectiveness.
So that was, at least for me.
That was my first kind of redflag, just like three sentences
(08:22):
in.
How did that get caught in yourcraw craw at all, or did you,
uh, anything else that youwanted to touch in on on that?
Dr. Adam Sadowski (08:28):
yeah, uh, there was.
There was one um, the, theconfirmatory component to it, um
, but I also recognize thatthese.
This was coming out of italy,so there may have been some
translation issues.
Dr. Joshua Goldenberg (08:41):
Uh, with regards to that, oh, you're
always kinder with that.
You always bring that with that.
You always bring that up.
That's a fair point.
Maybe it's a translation thing.
Dr. Adam Sadowski (08:48):
There's that.
But then also, you know, ifyou're going to be publishing in
an English written journal likeyou, better have someone who's
very fluent in the Englishlexicon where you know things
like these kind of languagenuances are not going to be
present.
Yeah, so there's.
You know, there these kind oflanguage nuances are not going
to be present.
Yeah, so there's.
You know there's kind of likethat onus on the authors or pay
(09:12):
a lot of money for someone to toprovide a very accurate um
translation.
So that's one thing.
Two is in in medical researchwe're very, you know, I would
say, almost never provingsomething.
It's.
It's really about disprovingsomething.
Dr. Joshua Goldenberg (09:31):
So right, or suggesting it's like the
strongest word we'll use yeah,and so it's like it's not so
much.
Dr. Adam Sadowski (09:40):
You know, when you're testing a hypothesis
, it's really about like, do wekind of, do we reject this
hypothesis or not?
It's not so much a confirmation.
Very few things in in scienceare like factual.
Um, I guess, if you will, now,there's certain things that that
are factual.
However, when it comes toresearch, especially early
(10:01):
research and stuff where there'sreally not a lot of evidence to
say you're confirming something, you better have the perfect
study.
Yeah.
Dr. Joshua Goldenberg (10:12):
Well, and studies like meta-analysis of
20 studies over 20,000 peopleover 20 years, Right.
Dr. Adam Sadowski (10:18):
But yeah, I like your idea and also they
mentioned it was a cohort, butan intervention was administered
, which was really weird.
Dr. Joshua Goldenberg (10:29):
Yeah.
Dr. Adam Sadowski (10:29):
Because with cohort studies you're really
just looking at an exposureYou're not necessarily
administering something andyou're just trying to see is
there an association to somesort of exposure?
Dr. Joshua Goldenberg (10:39):
Yeah, Okay, so my between the lines
here.
So this is really good, becauseyou can see how there's a lot
of nuance here and we're readingbetween the lines a lot, and
this is this is, uh, knowledgethat you know would not be, you
know, if you don't, if you'renot like read this stuff all day
(11:00):
long, um, so one is, everythingyou said is correct, and my
suspicion is they might havegotten pushback from the
reviewers saying that it was anintervention study, when you
know there was no actual controlgroup and so they had, they
were forced to call it a cohort,and so it does sound weird.
The other thing is, I thinkit's all from one clinic and it
(11:22):
might have been their clinic,and so maybe what they had
planned to do, which is thatthey have like a protocol, which
is that everyone that comes toour clinic, the first thing they
do is get NAC at this dose, andthen we're just going to kind
of measure that.
But yeah, I would be curious.
I think they did mention thatthey went through IRB, I believe
I'm sure they had to to getpublished, and that would have
(11:46):
been, you know, that would havebeen interesting, right, it's
like you would need permissionto give an intervention versus
just like observational innature.
So, yeah, that's a really goodpoint too.
It sounded very much like anintervention.
The results sounded the way theypresented.
The results sounded like anintervention.
But it's a cohort study andthey don't have any control.
So, yeah, lots of so a few redflags there, but I like your
(12:08):
idea, and one of the things welike to do on our podcast
although we do rag on stuff isto steel man as much as possible
.
So to steel man.
These authors maybe it was justa language issue that this sort
of nuance got lost or they werekind of overly enthusiastic
about NAC for non-financialreasons.
I didn't see any financialconnection there.
(12:29):
So, okay, well, let's jump in.
I'm ready to go into methodsand materials.
How about you?
Dr. Adam Sadowski (12:37):
Yeah well, they also did use some
background data saying thatresearch from their lab has
shown that in animal and humantissues that NAC has been able
to reduce the size ofendometrial tissue.
So that kind of set the stagefor then this study.
And they said the objective ofthis prospective observational
(12:59):
single cohort study was toconfirm the effectiveness of NAC
in reducingendometriosis-related pain, in
the size of endometriomas.
Dr. Joshua Goldenberg (13:10):
Yeah, so that's fair, so you know.
So basically it sounds likethey've done some benchtop and
animal research and they've seenthese effects and so in that
context they wanted to confirmthose effects in humans and to
do a cohort study would be areasonable first step compared
to a trial.
So if they're using confirm inthat way, I think that would
(13:31):
probably be the best way tosteel man that.
But yeah, I mean, most editors,I feel like in most respectable
journals, would be like allover this with red lines like
you can't say this sort of stuff, but anyway, okay.
So, yeah, so they did do thisbackground and, yep, like we
said, they recruited everybodyfrom one hospital.
So anyone that was referred toendometriosis outpatient service
(13:54):
of this hospital were enrolled.
So it seems like my suspicionis that these are folks from
that section and from thatdepartment and they were looking
to see, you know, objective andsubjective response to this NAC
approach.
I guess the dosing wasinteresting.
Dr. Adam Sadowski (14:13):
Well, before we get into that, yeah before we
get into that, they did gothrough an ethics committee.
So from an IRB standpoint, likeyou were saying earlier, they
did do that.
Dr. Joshua Goldenberg (14:26):
Good.
Dr. Adam Sadowski (14:27):
It was individuals between 18 to 45
years old with clinical surgicalhistological diagnosis of
endometriosis.
They were excluded if they werenot having any sort of menses
or if they were menopausal.
Dr. Joshua Goldenberg (14:43):
Right.
Dr. Adam Sadowski (14:43):
They had any sort of known adverse reactions
to NAC, which makes sense ifthey were currently receiving
any sort of hormonal treatment,because that is used in the
treatment of endometriosis, ifthey had any cancer or ongoing
pregnancy.
And then if they were using anysort of NSAIDs.
And there's a couple of reasonsthere.
One is because they werelooking at endometriosis-related
(15:04):
pain and so if they're onNSAIDs like ibuprofen, that
would interfere with painresults as well as if we're
thinking about anti-inflammatoryresponses, then that would
interfere if they were lookingat any sort of inflammatory
mediators.
Dr. Joshua Goldenberg (15:20):
That's a tough one.
I'm going to study now lookingat how we measure pain when,
like, if you have anintervention for pain and you
normally allow peoplequote-unquote rescue medication
like NSAIDs, you know if they're, if they have breakthrough pain
.
And it's a major issuemethodologically in how you
measure outcomes, because ofcourse, if you take an aspirin,
(15:43):
you you're going to feel better,and if your drug isn't working,
if the drug you're testing isnot working, you're going to
take more aspirin and then maybeyou're going to feel better.
So now the people that aretaking the drug are reporting
better outcomes, but maybe it'sjust it works less and you're
taking the NSAIDs.
So it's quite complicated andso it makes sense that they
would exclude them or at leasthave some limitations on the use
(16:04):
of rescue medications.
But then I think later andmaybe I hallucinated this
because I did kind of read thisin context of severe lack of
sleep that they mentioned thatthere was a decrease in NSAID
use in people over time, but Ithought it was an exclusion
criteria.
So I'm not sure, maybe I justmisread that.
We'll have to look again whenwe got there.
Dr. Adam Sadowski (16:23):
Well, let's get there when we get there.
Dr. Joshua Goldenberg (16:26):
Yeah.
Dr. Adam Sadowski (16:27):
From a treatment standpoint.
It was very oddly wordedbecause this was a three-month
study and they said quarterly.
Therapy with 600 milligrams ofNAC as three tablets a day for
three consecutive days of theweek was then administered for
three months, and so thatdoesn't make sense, because a
quarter of a year is threemonths.
Dr. Joshua Goldenberg (16:48):
Right.
Dr. Adam Sadowski (16:49):
But they're getting quarterly therapy for
three months and so that doesn'tmake sense.
And then so the way I read itwas they received three tablets
a day for three days straight,and then that was the
intervention.
Yeah, like, and it wasn'trepeated.
So it would be like monday,tuesday, wednesday, between,
(17:10):
let's say, between january andmarch, you were being studied.
Yeah, then I read that as likejanuary 1st, january 2nd and
january 3rd, you got threetablets of 600 milligrams nac
every single day for three days,so a total dose of like 1800
(17:30):
milligrams on a Monday, 1800milligrams the next day, 1800
milligrams the next day, andthen that was the intervention.
Dr. Joshua Goldenberg (17:39):
Look, the thing is we don't do this for
money.
This is pro bono and, quitehonestly, the mothership kind of
ekes it out every month or so,right, so we do this because we
care about this, we think it'simportant, we think that
integrating evidence-basedmedicine and integrative
medicine is essential and therejust aren't other resources out
there the moment.
(18:00):
We find something that does itbetter, we'll probably drop it.
We're busy folks, but right nowthis is what's out there.
Unfortunately, that's it, andso we're going to keep on
fighting that good fight.
And if you believe in that, ifyou believe in intellectual
honesty in the profession andintegrative medicine and being
an integrative provider andbringing that into the
integrative space, please helpus, and you can help us by
(18:22):
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If you're in need of continuingeducation credits, take our
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We have ethics courses,pharmacy courses, general
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Interact with us on socialmedia, listen to the podcast,
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These are all ways that you cansort of help support the cause.
Okay, so I read it totallydifferent.
(18:43):
So this speaks to like why thisis so important to get the
language right.
So, first of all, are we surethat's three tablets of 1600 of
600 or three tablets equals 600.
So they say 600 milligrams andthen in parentheses three
tablets.
So I don't know if that's threetablets of 600 or three tablets
made up 600.
So it's either two, it's either600 or 1800 milligrams.
(19:05):
That's like the first problem.
But NAC is usually dose prettyhigh, so I mean 1800 would be, I
think, pretty high, from atleast how I used to use it.
Dr. Adam Sadowski (19:14):
No, that's, that's pretty standard and in
research I've seen like around1600.
Dr. Joshua Goldenberg (19:19):
Yeah, Is that pretty standard?
Okay, all right.
So maybe that's that's three ofthose 600s.
But then I read it as three,three days on, four days off,
repeated every week for threemonths.
That's how I read that one.
Dr. Adam Sadowski (19:31):
Oh, I did not read it as that.
Dr. Joshua Goldenberg (19:33):
Yeah, and I think, if you go through that
in the discussion they talkabout the rationale for dosing,
which I actually reallyappreciated and was one of the
benefits of this paper.
I think that makes that beginsto make more sense as sort of
this pulsed approach, becauseapparently there's some sort of
absorption issue, like you stopabsorbing if you continuously
take it, and so they were tryingto maximize absorption
(19:55):
apparently by pulsing it in thisway, which I thought was an
interesting take.
But yeah, so anyway.
So we, so I think one of thetake homes are is well, so far
has been the importance oflanguage, and you and I have
completely different reads onhow this was dosed, based on the
opacity of this writing,unfortunately.
(20:15):
But okay, so I think it waspulsed for three months, you
think it was done for three days, and so maybe we'll see if we
can gather some more informationabout that.
And then they looked atoutcomes at the beginning and
then after three months oftreatment.
Dr. Adam Sadowski (20:31):
Yep, and the outcomes they looked at were
abnormal periods, pain withperiods, the size of the
endometrioma, specificallywithin the ovaries.
For those who don't know,endometriosis is
endometrial-like tissue that isnot present within the uterus,
(20:54):
and so you have basicallyuterine tissue not where it's
supposed to be, and so in thiscase they're looking at uterine
tissue within the ovaries.
And then they also looked atCA-125 levels, which I won't get
into.
I don't think that, for thesake of this study, that they're
clinically relevant, but maybesomeone else would argue
(21:15):
otherwise.
So I kind of looked over that.
I looked more so at the size ofthe endometriomas, dysmenorrhea
and dyspareunia, and theyestimated the size with the use
of transvaginal ultrasound,which is totally kosher in my
opinion, and they used the samesonographer every single time.
Yeah, yeah.
Pain was assessed through avisual analog scale.
(21:38):
So if you had you know like aruler from zero to 10, they
would say, okay, mark on thisruler, you know where your pain
is.
They would say, okay, mark onthis ruler, you know where where
your pain is.
And they had a 10 point scaleMild was considered one to four,
moderate five to seven andsevere eight to 10.
And then that was kind of it.
They didn't really get intothis physical analysis at all
and we have no idea if it waslike intention to treat or
(21:59):
anything like that.
They just kind of said, hey, wedid a pair T test and this and
that and our significant levelwas less than zero.
A paired t-test and this andthat in our significant level
was less than 0.05, but veryanemic statistical analysis
methodology.
Dr. Joshua Goldenberg (22:11):
Yeah, I like that phrase, so I agree
with all that I do want tomention brief.
I did want to touch on theCA-125.
So I'm familiar with that as anovarian cancer marker and it
was interesting to me that it'sused also in endometriosis and
that it's elevated endometriosis.
So I liked in theory, the ideaof using it as a tracking marker
(22:32):
, an objective tracking marker,I think.
My understanding is it's prettymuch garbage for diagnostic
purposes because it can beelevated in ovarian cancer and
endometriosis but not all thetime and so it isn't great to
diagnose it.
But I was curious about usingit as an objective marker of
improvement, with the theorythat it's related to the amount
of tissue.
(22:53):
So that was interesting to meas and to have an additional
objective marker, becauseotherwise you know you're
talking about subjectivelyreported outcomes and there's no
blinding.
Everybody knows they're takingthe NAC and you're talking about
, you know, pain with menses andpain with intercourse and these
are all subjectively reported.
However, we also have theultrasound which you point out,
(23:14):
which is an objective marker.
But I'll tell you, my wife is asonographer and the stories that
I hear, I mean it is a verysubjective quote, unquote
science, right, like verysubjective If, if the images are
, if the images are imperfect orthe patient wasn't prepped, or
the patient's in a bad position,or the the um, the mass is in
the wrong position, little likemillimeter differences happen
(23:37):
all the time in measurements andI personally I mean I, I don't
I'd like to see the studies onthis but I personally believe
there's a huge amount ofvariation in in how, the size of
the way things are read, andthere's no blinding here, of
course.
And so even though it's thesame operator, which is good
because that limits some of thatvariability, and assuming it's
the same machine, which alsointroduces variability, it's
(24:00):
just there's knowing that you'rein an intervention, you're
trying to see if it works, andyou're giving sort of like radio
, the classic studies onradiologists and how subjective
that that reporting is.
I think it's the same withsonographers.
So I am a little suspiciousabout that.
And so I really liked the CA 125.
Because I feel like that is atrue objective marker and in a
(24:21):
situation where you're notblinded, I was very interested
to see, because I don't believethat objective markers are
influenced by blinding, and so Iwas very interested to see that
.
I think that's all I have toadd about that Any comments or
criticisms or repudiations ofany of that.
Dr. Adam Sadowski (24:40):
Nope, nope, I think that that that's fine.
Dr. Joshua Goldenberg (24:43):
Yeah, okay, so we have our outcomes
here.
Okay, so let's jump intoresults.
You like to talk about what thepatients actually look like,
which is important.
I always skip over table one.
Dr. Adam Sadowski (24:57):
Yeah, they had 120 people within the study,
on average about 33 plus orminus seven years.
Mean BMI was 22 plus or minus 4.
28% had prior surgery forendometriosis.
87% used some sort of hormonaltreatment prior to the
recruitment process.
But they didn't mention like Ifthey were excluded or included
(25:22):
beyond a certain period of time.
So like was part of theexclusion criteria.
They just couldn't use any sortof hormonal treatment within
three months of recruitment oranything like that.
So that was a bit confusing.
Dr. Joshua Goldenberg (25:36):
Yeah.
Dr. Adam Sadowski (25:37):
And then they also looked at or excuse me
about a third had one pregnancyprior to recruitment.
Dr. Joshua Goldenberg (25:46):
Gotcha, yeah, and infertility was one of
the claimed things that theywere interested in.
And there and it was a, it wasa population in a decent amount
of pain.
I mean the.
The average VAS score wasalmost seven out of, you know, 0
to 10.
So these are people that werein a lot of pain, which makes
sense because these are allpeople referred to an
endometriosis center of ahospital, right, so sort of
(26:07):
tertiary referral.
So we would expect that thesewould be more severe patients.
Okay, so should we talk nowabout the actual results?
I like table two.
I thought that presented stuffpretty clearly.
Should we go through that one?
Dr. Adam Sadowski (26:21):
Yeah, sure.
So at the start, like you weresaying, the mean pain score for
painful periods was 7 plus orminus 2.
And then at the end of theintervention, so at the
three-month mark, it was a 5plus or minus 2.
So basically pain went down bytwo points, which was considered
(26:42):
statistically significant.
Pain with intercourse alsoimproved.
So at baseline it was six and ahalf plus or minus two and then
after three months it was fiveplus or minus two, and then
chronic pelvic pain at the startwas a seven plus or minus two
and then went down to a six plusor minus two.
(27:04):
Use of NSAIDs at the start wasabout 63% of the participant
population, which then went downto 53%, so a 10% reduction
there.
My assumption is that probablyduring the study they were not
supposed to be like atrecruitment, probably not
supposed to be daily users.
(27:25):
However, during the study theywere not supposed to be like at
recruitment, probably notsupposed to be daily users.
However, during the studyprobably were allowed to use it
as sort of like a quote unquoteemergency pain relief.
So you'll see that a lot inlike osteoarthritis studies
where you know they'll do likecurcumin versus placebo, but
both groups.
Like curcumin versus placebo.
(27:48):
But both groups, ideally priorto the start, are not using
NSAIDs.
However, during the study, ifthey need, like you know, acute
symptom, you know improvementare, they're not prohibited from
using NSAIDs.
Dr. Joshua Goldenberg (27:57):
Well, I mean, I would agree that that
would be the right way to do it.
But then, but the T0, thebaseline measure, says that 63%
of them were on NSAIDs.
And I've just reread thatexclusion criteria and it pretty
much says that was an exclusioncriteria.
That's another red flag.
So they claim that this is anexclusion criteria.
But 63% of the people atbaseline, as they were recruited
(28:19):
in, so normally, as you know,because you've run trials, like
the way this works is like youknow, you have your recruitment,
you pick them, you talk to themon the phone or they come in in
person.
You say, Are you on NSAIDs?
And they say no and then say,Okay, come in for your first
(28:40):
visit.
You know, a few days later, aweek later, and you're gonna do
your baseline, 63% of them aretaking NSAIDs.
I just feel like that isinteresting and suspicious.
That should, at the very least,be discussed, but was not.
So that's interesting to me.
Anyway, I'm gonna shut up now.
I think we still did.
You talk about the ovarian size, yet the endometrioma size size
(29:05):
, yet the endometrioma size no.
Dr. Adam Sadowski (29:06):
from baseline to the end of the study, the
size of the endometrium wasreduced by about three and a
half millimeters, which wasconsidered statistically
significant, and then also thelevels of CA-125, also reduced
by about 10, which wasconsidered statistically
significant.
Dr. Joshua Goldenberg (29:18):
Yeah, interesting.
So the results are like on itsface they look statistically and
clinically significant Painlevels are.
You know, it depends on thecondition, but usually we think
about a minimal importantdifference for pain outcomes to
be anywhere between like 1.2 or2 points on the VAS scale.
So that's kind of where thisstuff landed on average.
(29:38):
So, clinically significantresults you're seeing reduction
in objective markers like sizeof the endometrioma and serum
levels of CA-125.
And so you might say, okay,well, the objective markers, you
don't have to worry about theblinding issues and maybe you do
have to be more worried aboutthe pain levels, but there's no
control, so you're notcontrolling.
(29:59):
You know, yeah, blinding issue,but also like regression to the
mean and like everything else,the way disease works is has.
That has nothing to do withblinding.
It's just like when you getrecruited into a study you're at
the height of your symptompresentation.
Usually that's regression tothe mean, and then you know you
measure it later they're goingto be lower.
(30:20):
And because we don't have anycontrol group, we have no way of
saying is this what would havehappened to people who were not
given NAC?
In other words, was this didthis actually do anything?
So I mean one of the obviouslythe major issues with not having
a control group, but justwanted to say that out loud
because I know it was screamingin both of our heads.
Dr. Adam Sadowski (30:43):
Yeah, no, I think you brought up some some
valid points there and then thatwas kind of it for the study.
I didn't.
I didn't read the discussion atall.
It was a terrible study.
I'm sorry, that's just thefacts.
It was not a good study.
After I read the methods,honestly, I kind of you got
bored.
I glanced at the results but Iwas like this, this is so
(31:03):
terrible a study.
None of this is really.
This is just dumpster yeah, itis kind of dumpster at least it
wasn't funded well as far as Icould tell I guess that that you
know there was no funding here.
There was no.
Did you do a google search?
They didn't report anythingthey didn't report anything.
Dr. Joshua Goldenberg (31:20):
I didn't do a google search maybe I
should have.
I also didn't see that they hadthey registered the study
anywhere this is.
Dr. Adam Sadowski (31:27):
It was just a great example of like a
terrible study bad research.
Dr. Joshua Goldenberg (31:31):
Yeah, it was a great example of bad
research and also it's a goodexample of like, the importance
of language and reading betweenthe lines, um, and how, on its
face you would look at thatabstract, you'd be like, oh my
gosh, like this is gonna saveeverything and maybe it saves
everything.
But the point is we have noidea scientifically because of
the way this was designed andthen lots of questions that are
raised in its execution.
(31:51):
That makes things questionable.
Let me, okay and then look atthis.
So this is more.
I want to go through thediscussion because I think one
of the themes is like theimportance of language and how
that can give us red flags whenwe read this.
So let me just see here.
So here we go.
So in patients seekingpregnancy, the use of NAC can be
proposed.
(32:11):
In fact, NAC proved to beeffective and safe.
And you know, I just thelanguage is not what I'm used to
seeing in science and it seemsoverly blown conclusions from a
non-controlled, apparently notoptimally executed study, and so
(32:31):
again, those are just really.
Dr. Adam Sadowski (32:33):
Not.
Apparently it was not anexcellently.
It was a terribly executedstudy.
They didn't report any safetyoutcomes, so I don't know how
they can even claim safety.
So don't give them credit ifit's due.
It was a terrible study.
Dr. Joshua Goldenberg (32:50):
I thought we were steel manning.
Are we not steel manninganymore?
You're just done.
You're like dumpster, no moresteel manning.
Dr. Adam Sadowski (32:53):
So you can steel man, but let's also not,
let's not be overly nice.
It was not a good study at all.
Dr. Joshua Goldenberg (33:02):
It was not I, I would.
I would give this critical flawlevel.
Dr. Adam Sadowski (33:07):
The fact that even got published I'm
surprised.
Dr. Joshua Goldenberg (33:09):
Yeah, so I actually.
So that was one of the first.
I had the same thing.
I was like, how did this getpublished?
So I was curious about thejournal and you know is is this
a reputable journal or not?
Because there's just so manyred flags, that editorial red
flags that should have beencaught that I didn't see.
Um, oh, and you know what theydo delineate the dose better.
In when they're talking aboutdosing, they say the fraction,
(33:31):
fraction, nation into threedoses of 600 milligrams.
Okay, so that supports your1800 milligram total daily dose
argument.
Not three doses of 200 to getto 600, but three doses of 600
to get to 600, but three dosesof 600 to get to 1800 a day.
And yeah, basically they'regiving the rationale for pulsing
it based on plasma levels fromtheir previous work, which also
(33:55):
seems to be a bit of a stretchof their previous work is in
animals, but maybe, maybe therewere some humans in the study.
I didn't track those down andwhat else did I want to say?
Oh, they say everything's dueto inflammation.
You know, I know it makes sense, it is a good rationale and
probably everything is relatedto inflammation, but I sometimes
just roll my eyes, like whenyou read these studies, you're
like what's the proposedmechanism of action?
You're like inflammation.
(34:16):
It's like yeah exactly, exactly.
It solves all things, and yeah,so I was curious about that.
Dr. Adam Sadowski (34:23):
I've also noticed that, like publications
that have longer sectionsdedicated to mechanism of action
, when it becomes like aclinical study, the higher, like
that, the outcome is going tobe just like not important.
Dr. Joshua Goldenberg (34:39):
It's funny you say that I totally
have that same bias.
Yeah, I totally have the samebias and, like you're spending
so much time on mechanism,you're clearly a benchtop expert
, which is fine.
But now I'm curious about, like, the actual methods of the
clinical trial.
You might be too enamored.
Dr. Adam Sadowski (34:54):
Yeah, and it's like okay, are these
results, is like the magnitudeeven worthwhile, or are the
clinical outcomes like relevant,or is it going to be a terrible
study?
Dr. Joshua Goldenberg (35:04):
Yeah, I think that's not a terrible
proxy at all.
I have the same like intuitivesense about things.
What else, anything else?
I wanted to say no, we talkedabout the CA-125, yeah, and then
just the conclusion
Dr. Adam Sadowski (35:17):
Didn't even read it.
Dr. Joshua Goldenberg (35:18):
Yeah, it was just too rosy.
Dr. Adam Sadowski (35:21):
Don't even bother reading it.
Dr. Joshua Goldenberg (35:23):
Yeah, I would say um, I mean, based on
what they're saying.
These are important effects andthey are large effects and
clinically meaningful, or atleast they're clinically
meaningful.
What I would say is I don'ttrust a word of it.
That doesn't mean it doesn't dothat, it just means I have no
(35:44):
idea if that is just poorlyexecuted trial design or this is
what would happen withregression to the mean anyway.
And I can't answer thosequestions based on the reporting
in this study and the design ofthis study.
So I've got lots of feels aboutthis one and, yeah, I guess
probably one thing you could dois Google.
(36:05):
Is Google, all these authors?
You know they might just beresearchers in the NAC space and
just be like intellectuallyconflicted, which is which is
like that happens all the time.
Obviously you need experts.
You know doing, doing studies.
It's an issue in science.
But you could just read betweenthe lines Like these folks are
obviously super enamored withNAC, the design.
(36:29):
Read between the lines likethese folks are obviously super
enamored with nac, the design isset up to win.
I don't know.
I've just got all the feels andall the questions.
All right, that's that.
All right, we'll leave it atthat.
Dr. Adam Sadowski (36:33):
Cool
Dr. Joshua Goldenberg (36:33):
So thank you, dear listener, and thank
you for sending papers.
Please continue to send themour way.
We like discussing good papersand bad papers and how we can
differentiate, which is kind ofthe whole point of what the heck
we're trying to do here withthis podcast and with Dr Jerome
Club in general.
So thanks for listening and wewill see you next time.
(36:54):
If you enjoy this podcast,chances are that one of your
colleagues and friends probablywould as well.
Please do us a favor and letthem know about the podcast and,
if you have a little bit ofextra time, even just a few
seconds, if you could rate usand review us on Apple Podcast
or any other distributor, itwould be greatly appreciated.
It would mean a lot to us andhelp get the word out to other
people that would really enjoyyou.
content.
(37:14):
Thank youHey ya'll, this is Josh.
You know we talked about somereally interesting stuff today.
I think one of the things we'regoing to do that's relevant.
There is a course we have on DrJournal Club called the EBM
Boot Camp.
That's really meant forclinicians to sort of help them
understand how to criticallyevaluate the literature, etc.
Etc.
Some of the things that we'vebeen talking about today.
Go ahead and check out the shownotes link.
(37:36):
We're going to link to itdirectly.
I think it might be of interest.
Don't forget to follow us onsocial and interact with us on
social media at DrJournalClub.
Drjournalclub on Twitter.
We're on Facebook, we're onLinkedIn, etc.
Etc.
So please reach out to us.
We always love to talk to ourfans and our listeners.
If you have any specificquestions you'd like to ask us
(37:57):
about research evidence, being aclinician, etc.
Don't hesitate to ask.
Introducer (38:14):
Thank you for listening to the Doctor Journal
Club podcast, the show that goesunder the hood of
evidence-based integrativemedicine.
We review recent researcharticles, interview
evidence-based medicine thoughtleaders and discuss the
challenges and opportunities ofintegrating evidence-based and
integrative medicine.
Be sure to visit www.
drjournalclub.
com to learn more.
Welcome to the Dr Journal Club podcast, the show
that goes under the hood ofevidence-based integrative
medicine.
We review recent researcharticles, interview
evidence-based medicine thoughtleaders and discuss the
challenges and opportunities ofintegrating evidence-based and
integrative medicine.
Continue your learning afterthe show at www.
(00:23):
d rjournalclub.
com.
Dr. Joshua Goldenberg (00:31):
Please bear in mind that this is for
educational and entertainmentpurposes, only.
Talk to your doctor beforemaking any medical decisions,
changes etc.
Everything we're talking aboutthat's to teach you guys stuff
and have fun.
We are not your doctors.
Also, we would love to answeryour specific questions on
drjournalclub.
com.
You can post questions andcomments for specific videos,
(00:55):
but go ahead and email usdirectly at josh at
drjournalclub.
com.
That's josh at drjournalclub.
com.
Send us your listener questionsand we will discuss it on our
pod.
Hello and welcome to another DrJournal Club podcast with your
host, Josh and Adam.
We are back from.
(01:16):
I think.
We did a little bit of a hiatusfor July 4th weekend and the
amazing Michele, I think, sentus one of our super speedy
summary videos.
So we are back in the saddleagain.
I'm going to talk about NAC,n-a-c, known to his friends as
NAC, I guess.
Anyway, Adam, how you doing man?
What's the latest?
I haven't spoken to you in alittle bit.
Dr. Adam Sadowski (01:38):
I'm doing great.
Uh, I was in uh Portland, Maine, for Fourth of July.
Yeah, oh, very nice, yep yep,yep, awesome.
Dr. Joshua Goldenberg (01:43):
Was there for a little bit, did some fun
stuff there and then, on the wayback, visited.
Portland, maine, for 4th ofJuly.
Dr. Adam Sadowski (01:46):
Oh very nice.
Yep, yep, yep, yep, awesome.
Was there for a little bit, didsome fun stuff there.
Then, on the way back, visitedsome family in New Hampshire.
Dr. Joshua Goldenberg (01:51):
Very cool .
Dr. Adam Sadowski (01:52):
And then, yeah, it was a nice little
getaway.
How was your 4th?
Dr. Joshua Goldenberg (01:58):
Next time you're up in that part of Maine
you're going to have to hangout with Jacob Shore et al.
Do you know him?
No, oh, okay, I for some reasonI thought you guys were, you
were buddies, but I just uh.
Mark Davis, friend of the pod,was just up in Maine too and of
course had to do uh requiredkayaking with said doctor.
(02:19):
He's a huge kayaker and theymoved to Maine recently and
tried desperately to get us tomove to Maine because my mom
lives there and we were thinkingabout Portland during the
pandemic.
But it was just like I rememberthem sending me like houses and
it was like $800,000 for likean abode and it was just a
(02:39):
pandemic.
Even in Maine it was just likepandemic times.
Prices were insane and they'relike but think of the kayaking.
Anyway, okay, so I digress,let's, let's jump in.
So we have a, we have a requestfrom a listener, a dear listener
, for this paper.
So that's the selection andsometimes we pick stuff out.
Oftentimes you'll find stuffthat's being talked about in
(03:01):
some of the bigger journals orwe'll get sort of tips from
folks that on papers that havemade it out to the main media,
etc.
This is sometimes we getrequests from listeners, and
sometimes from doctors andsometimes from non doctors, for
just questions about papers thatthey've come across.
And it's good because I feellike folks that don't have the
medical background.
You look at a paper and you'relike, oh, this, this looks
(03:23):
interesting, looks legit, andyou know, understandably they
don't have the training to kindof take it apart.
So that's one of the services Ifeel like we offer is, while
we're geared to you know,doctors, I think we're also kind
of geared to the educated andinformed you know person at this
at the same point, and I feelthat way about my patients in
(03:44):
general.
So cool, so let's jump in anystarting questions about this.
So this is we'll put the link inthe show notes and I'm actually
going to write down link inlarge letters and send it to
Michele, because I always sayI'm going to send to Michele and
then I never send it toMichelle.
So this time is on a post itnote, so it's going to happen.
So this is about NAC forendometriosis-related pain and
(04:07):
endometriomas as well asfertility outcomes.
I do not do anything withendometriosis, I know very
little about it, and I've usedNAC and acetylcysteine when I
was in primary practice, mostlyfor like mucolytic effects, like
when people had colds and stuff.
So that was sort of like theextent of my background
(04:30):
knowledge.
So clinically I'm kind of aneophyte here.
How about you?
Have you used NAC a lot?
Have you played with it?
Do you see a lot ofendometriosis?
Dr. Adam Sadowski (04:38):
Yeah, so I am familiar with endometriosis.
It comes up quite a bit in theprimary care setting.
I'm familiar with it in that,in that regards.
With regards to NAC, myexperience has mostly been
around addiction, medicine withit and mental health related
(04:58):
things.
Oh yeah, there's someinteresting research there.
Dr. Joshua Goldenbe (05:01):
Interesting , oh okay.
Well, there's a chock full ofstuff that potentially used for
I feel like there might even beoncology outcomes for it.
Dr. Adam Sadowski (05:08):
I could be wrong about that, but it's also
a precursor to a more well-knownantioxidant known as
glutathione, and so that's kindof like.
The mechanism of action behindNAC is that it's a precursor to
glutathione, and so NAC isoftentimes used for things with
(05:29):
any sort of like inflammatoryconditions.
It has some you know reportedbenefits with regards to liver
health, and so it's used forthat.
This is not yeah, not medicaladvice.
By the way.
Yeah, none of this is not yeah,not medical advice by the way.
Dr. Joshua Goldenberg (05:46):
Yeah, none of this is we don't know
what we're talking about.
Don't listen to us.
Talk to your doctors.
We're just evidence experts.
We'll just, we'll break apartthe study, but talk to your own
doctors, guys.
Um, so that's it.
Yeah, I have seen it actuallyin a lot of protocols for liver
stuff and the glutathioneconnection makes sense.
My understanding is glutathioneis like apparently magic, but
(06:07):
it's very hard to getbioavailable and so like you try
to push it in other ways.
Is that kind of the rationalebehind?
Yeah, yeah, yeah, and it's uh,what, what cup is that?
Just just keep going, okay allright.
All right, I got distracted,squirrel, okay, anyway.
So yeah, so it's basically acheaper, bioavailable way of
(06:32):
pushing.
Glutathione andanti-inflammatory actions is one
proposed mechanism of actionand of course everything's
connected to inflammation, sopain and endometriosis makes
sense as well.
So I want to say, because thiswas recommended from someone who
doesn't have a background in inmedical science, I want to kind
of give my red flag thoughts asI read through it to kind of
(06:55):
help the reader that doesn'thave a lot of training in this
understand.
You know what are some thingsthat we look at, that kind of
like our ears jump up and belike what, and I don't know
about you.
But the first one that I saw waslike three sentences in in the
abstract, which was the primaryobjective of this prospective
(07:16):
single cohort study was toconfirm the effectiveness of NAC
in reducing endometriosisrelated pain and the size of
ovarian endometriomas.
So just that statement that thepurpose of this study is going
to confirm the effectiveness,all my bells and whistles went
off.
Like that is a very strongstatement.
(07:36):
My first thought was oh mygoodness, they must have in
science anyway.
It's a very strong statement.
They must have conflicts ofinterest and they must own all
the NAC production in the world.
I couldn't find any evidence ofthat, but that kind of language
is a red flag in and of itself.
And then to say that based upona cohort without a control, so
(07:58):
we use randomized control trialsto understand efficacy and
effectiveness right, and thisidea of looking at a single
cohort where you don't have anycontrol and that's going to
confirm the effectiveness andit's like our objective.
It doesn't matter what theresults are, it's not to see
what happens, our objective isto confirm this effectiveness.
So that was, at least for me.
That was my first kind of redflag, just like three sentences
(08:22):
in.
How did that get caught in yourcraw craw at all, or did you,
uh, anything else that youwanted to touch in on on that?
Dr. Adam Sadowski (08:28):
yeah, uh, there was.
There was one um, the, theconfirmatory component to it, um
, but I also recognize thatthese.
This was coming out of italy,so there may have been some
translation issues.
Dr. Joshua Goldenberg (08:41):
Uh, with regards to that, oh, you're
always kinder with that.
You always bring that with that.
You always bring that up.
That's a fair point.
Maybe it's a translation thing.
Dr. Adam Sadowski (08:48):
There's that.
But then also, you know, ifyou're going to be publishing in
an English written journal likeyou, better have someone who's
very fluent in the Englishlexicon where you know things
like these kind of languagenuances are not going to be
present.
Yeah, so there's.
You know, there these kind oflanguage nuances are not going
to be present.
Yeah, so there's.
You know there's kind of likethat onus on the authors or pay
(09:12):
a lot of money for someone to toprovide a very accurate um
translation.
So that's one thing.
Two is in in medical researchwe're very, you know, I would
say, almost never provingsomething.
It's.
It's really about disprovingsomething.
Dr. Joshua Goldenberg (09:31):
So right, or suggesting it's like the
strongest word we'll use yeah,and so it's like it's not so
much.
Dr. Adam Sadowski (09:40):
You know, when you're testing a hypothesis
, it's really about like, do wekind of, do we reject this
hypothesis or not?
It's not so much a confirmation.
Very few things in in scienceare like factual.
Um, I guess, if you will, now,there's certain things that that
are factual.
However, when it comes toresearch, especially early
(10:01):
research and stuff where there'sreally not a lot of evidence to
say you're confirming something, you better have the perfect
study.
Yeah.
Dr. Joshua Goldenberg (10:12):
Well, and studies like meta-analysis of
20 studies over 20,000 peopleover 20 years, Right.
Dr. Adam Sadowski (10:18):
But yeah, I like your idea and also they
mentioned it was a cohort, butan intervention was administered
, which was really weird.
Dr. Joshua Goldenberg (10:29):
Yeah.
Dr. Adam Sadowski (10:29):
Because with cohort studies you're really
just looking at an exposureYou're not necessarily
administering something andyou're just trying to see is
there an association to somesort of exposure?
Dr. Joshua Goldenberg (10:39):
Yeah, Okay, so my between the lines
here.
So this is really good, becauseyou can see how there's a lot
of nuance here and we're readingbetween the lines a lot, and
this is this is, uh, knowledgethat you know would not be, you
know, if you don't, if you'renot like read this stuff all day
(11:00):
long, um, so one is, everythingyou said is correct, and my
suspicion is they might havegotten pushback from the
reviewers saying that it was anintervention study, when you
know there was no actual controlgroup and so they had, they
were forced to call it a cohort,and so it does sound weird.
The other thing is, I thinkit's all from one clinic and it
(11:22):
might have been their clinic,and so maybe what they had
planned to do, which is thatthey have like a protocol, which
is that everyone that comes toour clinic, the first thing they
do is get NAC at this dose, andthen we're just going to kind
of measure that.
But yeah, I would be curious.
I think they did mention thatthey went through IRB, I believe
I'm sure they had to to getpublished, and that would have
(11:46):
been, you know, that would havebeen interesting, right, it's
like you would need permissionto give an intervention versus
just like observational innature.
So, yeah, that's a really goodpoint too.
It sounded very much like anintervention.
The results sounded the way theypresented.
The results sounded like anintervention.
But it's a cohort study andthey don't have any control.
So, yeah, lots of so a few redflags there, but I like your
(12:08):
idea, and one of the things welike to do on our podcast
although we do rag on stuff isto steel man as much as possible
.
So to steel man.
These authors maybe it was justa language issue that this sort
of nuance got lost or they werekind of overly enthusiastic
about NAC for non-financialreasons.
I didn't see any financialconnection there.
(12:29):
So, okay, well, let's jump in.
I'm ready to go into methodsand materials.
How about you?
Dr. Adam Sadowski (12:37):
Yeah well, they also did use some
background data saying thatresearch from their lab has
shown that in animal and humantissues that NAC has been able
to reduce the size ofendometrial tissue.
So that kind of set the stagefor then this study.
And they said the objective ofthis prospective observational
(12:59):
single cohort study was toconfirm the effectiveness of NAC
in reducingendometriosis-related pain, in
the size of endometriomas.
Dr. Joshua Goldenberg (13:10):
Yeah, so that's fair, so you know.
So basically it sounds likethey've done some benchtop and
animal research and they've seenthese effects and so in that
context they wanted to confirmthose effects in humans and to
do a cohort study would be areasonable first step compared
to a trial.
So if they're using confirm inthat way, I think that would
(13:31):
probably be the best way tosteel man that.
But yeah, I mean, most editors,I feel like in most respectable
journals, would be like allover this with red lines like
you can't say this sort of stuff, but anyway, okay.
So, yeah, so they did do thisbackground and, yep, like we
said, they recruited everybodyfrom one hospital.
So anyone that was referred toendometriosis outpatient service
(13:54):
of this hospital were enrolled.
So it seems like my suspicionis that these are folks from
that section and from thatdepartment and they were looking
to see, you know, objective andsubjective response to this NAC
approach.
I guess the dosing wasinteresting.
Dr. Adam Sadowski (14:13):
Well, before we get into that, yeah before we
get into that, they did gothrough an ethics committee.
So from an IRB standpoint, likeyou were saying earlier, they
did do that.
Dr. Joshua Goldenberg (14:26):
Good.
Dr. Adam Sadowski (14:27):
It was individuals between 18 to 45
years old with clinical surgicalhistological diagnosis of
endometriosis.
They were excluded if they werenot having any sort of menses
or if they were menopausal.
Dr. Joshua Goldenberg (14:43):
Right.
Dr. Adam Sadowski (14:43):
They had any sort of known adverse reactions
to NAC, which makes sense ifthey were currently receiving
any sort of hormonal treatment,because that is used in the
treatment of endometriosis, ifthey had any cancer or ongoing
pregnancy.
And then if they were using anysort of NSAIDs.
And there's a couple of reasonsthere.
One is because they werelooking at endometriosis-related
(15:04):
pain and so if they're onNSAIDs like ibuprofen, that
would interfere with painresults as well as if we're
thinking about anti-inflammatoryresponses, then that would
interfere if they were lookingat any sort of inflammatory
mediators.
Dr. Joshua Goldenberg (15:20):
That's a tough one.
I'm going to study now lookingat how we measure pain when,
like, if you have anintervention for pain and you
normally allow peoplequote-unquote rescue medication
like NSAIDs, you know if they're, if they have breakthrough pain
.
And it's a major issuemethodologically in how you
measure outcomes, because ofcourse, if you take an aspirin,
(15:43):
you you're going to feel better,and if your drug isn't working,
if the drug you're testing isnot working, you're going to
take more aspirin and then maybeyou're going to feel better.
So now the people that aretaking the drug are reporting
better outcomes, but maybe it'sjust it works less and you're
taking the NSAIDs.
So it's quite complicated andso it makes sense that they
would exclude them or at leasthave some limitations on the use
(16:04):
of rescue medications.
But then I think later andmaybe I hallucinated this
because I did kind of read thisin context of severe lack of
sleep that they mentioned thatthere was a decrease in NSAID
use in people over time, but Ithought it was an exclusion
criteria.
So I'm not sure, maybe I justmisread that.
We'll have to look again whenwe got there.
Dr. Adam Sadowski (16:23):
Well, let's get there when we get there.
Dr. Joshua Goldenberg (16:26):
Yeah.
Dr. Adam Sadowski (16:27):
From a treatment standpoint.
It was very oddly wordedbecause this was a three-month
study and they said quarterly.
Therapy with 600 milligrams ofNAC as three tablets a day for
three consecutive days of theweek was then administered for
three months, and so thatdoesn't make sense, because a
quarter of a year is threemonths.
Dr. Joshua Goldenberg (16:48):
Right.
Dr. Adam Sadowski (16:49):
But they're getting quarterly therapy for
three months and so that doesn'tmake sense.
And then so the way I read itwas they received three tablets
a day for three days straight,and then that was the
intervention.
Yeah, like, and it wasn'trepeated.
So it would be like monday,tuesday, wednesday, between,
(17:10):
let's say, between january andmarch, you were being studied.
Yeah, then I read that as likejanuary 1st, january 2nd and
january 3rd, you got threetablets of 600 milligrams nac
every single day for three days,so a total dose of like 1800
(17:30):
milligrams on a Monday, 1800milligrams the next day, 1800
milligrams the next day, andthen that was the intervention.
Dr. Joshua Goldenberg (17:39):
Look, the thing is we don't do this for
money.
This is pro bono and, quitehonestly, the mothership kind of
ekes it out every month or so,right, so we do this because we
care about this, we think it'simportant, we think that
integrating evidence-basedmedicine and integrative
medicine is essential and therejust aren't other resources out
there the moment.
(18:00):
We find something that does itbetter, we'll probably drop it.
We're busy folks, but right nowthis is what's out there.
Unfortunately, that's it, andso we're going to keep on
fighting that good fight.
And if you believe in that, ifyou believe in intellectual
honesty in the profession andintegrative medicine and being
an integrative provider andbringing that into the
integrative space, please helpus, and you can help us by
(18:22):
becoming a member on Dr JournalClub.
If you're in need of continuingeducation credits, take our
NANSEAC approved courses.
We have ethics courses,pharmacy courses, general
courses.
Interact with us on socialmedia, listen to the podcast,
rate our podcast, tell yourfriends.
These are all ways that you cansort of help support the cause.
Okay, so I read it totallydifferent.
(18:43):
So this speaks to like why thisis so important to get the
language right.
So, first of all, are we surethat's three tablets of 1600 of
600 or three tablets equals 600.
So they say 600 milligrams andthen in parentheses three
tablets.
So I don't know if that's threetablets of 600 or three tablets
made up 600.
So it's either two, it's either600 or 1800 milligrams.
(19:05):
That's like the first problem.
But NAC is usually dose prettyhigh, so I mean 1800 would be, I
think, pretty high, from atleast how I used to use it.
Dr. Adam Sadowski (19:14):
No, that's, that's pretty standard and in
research I've seen like around1600.
Dr. Joshua Goldenberg (19:19):
Yeah, Is that pretty standard?
Okay, all right.
So maybe that's that's three ofthose 600s.
But then I read it as three,three days on, four days off,
repeated every week for threemonths.
That's how I read that one.
Dr. Adam Sadowski (19:31):
Oh, I did not read it as that.
Dr. Joshua Goldenberg (19:33):
Yeah, and I think, if you go through that
in the discussion they talkabout the rationale for dosing,
which I actually reallyappreciated and was one of the
benefits of this paper.
I think that makes that beginsto make more sense as sort of
this pulsed approach, becauseapparently there's some sort of
absorption issue, like you stopabsorbing if you continuously
take it, and so they were tryingto maximize absorption
(19:55):
apparently by pulsing it in thisway, which I thought was an
interesting take.
But yeah, so anyway.
So we, so I think one of thetake homes are is well, so far
has been the importance oflanguage, and you and I have
completely different reads onhow this was dosed, based on the
opacity of this writing,unfortunately.
(20:15):
But okay, so I think it waspulsed for three months, you
think it was done for three days, and so maybe we'll see if we
can gather some more informationabout that.
And then they looked atoutcomes at the beginning and
then after three months oftreatment.
Dr. Adam Sadowski (20:31):
Yep, and the outcomes they looked at were
abnormal periods, pain withperiods, the size of the
endometrioma, specificallywithin the ovaries.
For those who don't know,endometriosis is
endometrial-like tissue that isnot present within the uterus,
(20:54):
and so you have basicallyuterine tissue not where it's
supposed to be, and so in thiscase they're looking at uterine
tissue within the ovaries.
And then they also looked atCA-125 levels, which I won't get
into.
I don't think that, for thesake of this study, that they're
clinically relevant, but maybesomeone else would argue
(21:15):
otherwise.
So I kind of looked over that.
I looked more so at the size ofthe endometriomas, dysmenorrhea
and dyspareunia, and theyestimated the size with the use
of transvaginal ultrasound,which is totally kosher in my
opinion, and they used the samesonographer every single time.
Yeah, yeah.
Pain was assessed through avisual analog scale.
(21:38):
So if you had you know like aruler from zero to 10, they
would say, okay, mark on thisruler, you know where your pain
is.
They would say, okay, mark onthis ruler, you know where where
your pain is.
And they had a 10 point scaleMild was considered one to four,
moderate five to seven andsevere eight to 10.
And then that was kind of it.
They didn't really get intothis physical analysis at all
and we have no idea if it waslike intention to treat or
(21:59):
anything like that.
They just kind of said, hey, wedid a pair T test and this and
that and our significant levelwas less than zero.
A paired t-test and this andthat in our significant level
was less than 0.05, but veryanemic statistical analysis
methodology.
Dr. Joshua Goldenberg (22:11):
Yeah, I like that phrase, so I agree
with all that I do want tomention brief.
I did want to touch on theCA-125.
So I'm familiar with that as anovarian cancer marker and it
was interesting to me that it'sused also in endometriosis and
that it's elevated endometriosis.
So I liked in theory, the ideaof using it as a tracking marker
(22:32):
, an objective tracking marker,I think.
My understanding is it's prettymuch garbage for diagnostic
purposes because it can beelevated in ovarian cancer and
endometriosis but not all thetime and so it isn't great to
diagnose it.
But I was curious about usingit as an objective marker of
improvement, with the theorythat it's related to the amount
of tissue.
(22:53):
So that was interesting to meas and to have an additional
objective marker, becauseotherwise you know you're
talking about subjectivelyreported outcomes and there's no
blinding.
Everybody knows they're takingthe NAC and you're talking about
, you know, pain with menses andpain with intercourse and these
are all subjectively reported.
However, we also have theultrasound which you point out,
(23:14):
which is an objective marker.
But I'll tell you, my wife is asonographer and the stories that
I hear, I mean it is a verysubjective quote, unquote
science, right, like verysubjective If, if the images are
, if the images are imperfect orthe patient wasn't prepped, or
the patient's in a bad position,or the the um, the mass is in
the wrong position, little likemillimeter differences happen
(23:37):
all the time in measurements andI personally I mean I, I don't
I'd like to see the studies onthis but I personally believe
there's a huge amount ofvariation in in how, the size of
the way things are read, andthere's no blinding here, of
course.
And so even though it's thesame operator, which is good
because that limits some of thatvariability, and assuming it's
the same machine, which alsointroduces variability, it's
(24:00):
just there's knowing that you'rein an intervention, you're
trying to see if it works, andyou're giving sort of like radio
, the classic studies onradiologists and how subjective
that that reporting is.
I think it's the same withsonographers.
So I am a little suspiciousabout that.
And so I really liked the CA 125.
Because I feel like that is atrue objective marker and in a
(24:21):
situation where you're notblinded, I was very interested
to see, because I don't believethat objective markers are
influenced by blinding, and so Iwas very interested to see that
.
I think that's all I have toadd about that Any comments or
criticisms or repudiations ofany of that.
Dr. Adam Sadowski (24:40):
Nope, nope, I think that that that's fine.
Dr. Joshua Goldenberg (24:43):
Yeah, okay, so we have our outcomes
here.
Okay, so let's jump intoresults.
You like to talk about what thepatients actually look like,
which is important.
I always skip over table one.
Dr. Adam Sadowski (24:57):
Yeah, they had 120 people within the study,
on average about 33 plus orminus seven years.
Mean BMI was 22 plus or minus 4.
28% had prior surgery forendometriosis.
87% used some sort of hormonaltreatment prior to the
recruitment process.
But they didn't mention like Ifthey were excluded or included
(25:22):
beyond a certain period of time.
So like was part of theexclusion criteria.
They just couldn't use any sortof hormonal treatment within
three months of recruitment oranything like that.
So that was a bit confusing.
Dr. Joshua Goldenberg (25:36):
Yeah.
Dr. Adam Sadowski (25:37):
And then they also looked at or excuse me
about a third had one pregnancyprior to recruitment.
Dr. Joshua Goldenberg (25:46):
Gotcha, yeah, and infertility was one of
the claimed things that theywere interested in.
And there and it was a, it wasa population in a decent amount
of pain.
I mean the.
The average VAS score wasalmost seven out of, you know, 0
to 10.
So these are people that werein a lot of pain, which makes
sense because these are allpeople referred to an
endometriosis center of ahospital, right, so sort of
(26:07):
tertiary referral.
So we would expect that thesewould be more severe patients.
Okay, so should we talk nowabout the actual results?
I like table two.
I thought that presented stuffpretty clearly.
Should we go through that one?
Dr. Adam Sadowski (26:21):
Yeah, sure.
So at the start, like you weresaying, the mean pain score for
painful periods was 7 plus orminus 2.
And then at the end of theintervention, so at the
three-month mark, it was a 5plus or minus 2.
So basically pain went down bytwo points, which was considered
(26:42):
statistically significant.
Pain with intercourse alsoimproved.
So at baseline it was six and ahalf plus or minus two and then
after three months it was fiveplus or minus two, and then
chronic pelvic pain at the startwas a seven plus or minus two
and then went down to a six plusor minus two.
(27:04):
Use of NSAIDs at the start wasabout 63% of the participant
population, which then went downto 53%, so a 10% reduction
there.
My assumption is that probablyduring the study they were not
supposed to be like atrecruitment, probably not
supposed to be daily users.
(27:25):
However, during the study theywere not supposed to be like at
recruitment, probably notsupposed to be daily users.
However, during the studyprobably were allowed to use it
as sort of like a quote unquoteemergency pain relief.
So you'll see that a lot inlike osteoarthritis studies
where you know they'll do likecurcumin versus placebo, but
both groups.
Like curcumin versus placebo.
(27:48):
But both groups, ideally priorto the start, are not using
NSAIDs.
However, during the study, ifthey need, like you know, acute
symptom, you know improvementare, they're not prohibited from
using NSAIDs.
Dr. Joshua Goldenberg (27:57):
Well, I mean, I would agree that that
would be the right way to do it.
But then, but the T0, thebaseline measure, says that 63%
of them were on NSAIDs.
And I've just reread thatexclusion criteria and it pretty
much says that was an exclusioncriteria.
That's another red flag.
So they claim that this is anexclusion criteria.
But 63% of the people atbaseline, as they were recruited
(28:19):
in, so normally, as you know,because you've run trials, like
the way this works is like youknow, you have your recruitment,
you pick them, you talk to themon the phone or they come in in
person.
You say, Are you on NSAIDs?
And they say no and then say,Okay, come in for your first
(28:40):
visit.
You know, a few days later, aweek later, and you're gonna do
your baseline, 63% of them aretaking NSAIDs.
I just feel like that isinteresting and suspicious.
That should, at the very least,be discussed, but was not.
So that's interesting to me.
Anyway, I'm gonna shut up now.
I think we still did.
You talk about the ovarian size, yet the endometrioma size size
(29:05):
, yet the endometrioma size no.
Dr. Adam Sadowski (29:06):
from baseline to the end of the study, the
size of the endometrium wasreduced by about three and a
half millimeters, which wasconsidered statistically
significant, and then also thelevels of CA-125, also reduced
by about 10, which wasconsidered statistically
significant.
Dr. Joshua Goldenberg (29:18):
Yeah, interesting.
So the results are like on itsface they look statistically and
clinically significant Painlevels are.
You know, it depends on thecondition, but usually we think
about a minimal importantdifference for pain outcomes to
be anywhere between like 1.2 or2 points on the VAS scale.
So that's kind of where thisstuff landed on average.
(29:38):
So, clinically significantresults you're seeing reduction
in objective markers like sizeof the endometrioma and serum
levels of CA-125.
And so you might say, okay,well, the objective markers, you
don't have to worry about theblinding issues and maybe you do
have to be more worried aboutthe pain levels, but there's no
control, so you're notcontrolling.
(29:59):
You know, yeah, blinding issue,but also like regression to the
mean and like everything else,the way disease works is has.
That has nothing to do withblinding.
It's just like when you getrecruited into a study you're at
the height of your symptompresentation.
Usually that's regression tothe mean, and then you know you
measure it later they're goingto be lower.
(30:20):
And because we don't have anycontrol group, we have no way of
saying is this what would havehappened to people who were not
given NAC?
In other words, was this didthis actually do anything?
So I mean one of the obviouslythe major issues with not having
a control group, but justwanted to say that out loud
because I know it was screamingin both of our heads.
Dr. Adam Sadowski (30:43):
Yeah, no, I think you brought up some some
valid points there and then thatwas kind of it for the study.
I didn't.
I didn't read the discussion atall.
It was a terrible study.
I'm sorry, that's just thefacts.
It was not a good study.
After I read the methods,honestly, I kind of you got
bored.
I glanced at the results but Iwas like this, this is so
(31:03):
terrible a study.
None of this is really.
This is just dumpster yeah, itis kind of dumpster at least it
wasn't funded well as far as Icould tell I guess that that you
know there was no funding here.
There was no.
Did you do a google search?
They didn't report anythingthey didn't report anything.
Dr. Joshua Goldenberg (31:20):
I didn't do a google search maybe I
should have.
I also didn't see that they hadthey registered the study
anywhere this is.
Dr. Adam Sadowski (31:27):
It was just a great example of like a
terrible study bad research.
Dr. Joshua Goldenberg (31:31):
Yeah, it was a great example of bad
research and also it's a goodexample of like, the importance
of language and reading betweenthe lines, um, and how, on its
face you would look at thatabstract, you'd be like, oh my
gosh, like this is gonna saveeverything and maybe it saves
everything.
But the point is we have noidea scientifically because of
the way this was designed andthen lots of questions that are
raised in its execution.
(31:51):
That makes things questionable.
Let me, okay and then look atthis.
So this is more.
I want to go through thediscussion because I think one
of the themes is like theimportance of language and how
that can give us red flags whenwe read this.
So let me just see here.
So here we go.
So in patients seekingpregnancy, the use of NAC can be
proposed.
(32:11):
In fact, NAC proved to beeffective and safe.
And you know, I just thelanguage is not what I'm used to
seeing in science and it seemsoverly blown conclusions from a
non-controlled, apparently notoptimally executed study, and so
(32:31):
again, those are just really.
Dr. Adam Sadowski (32:33):
Not.
Apparently it was not anexcellently.
It was a terribly executedstudy.
They didn't report any safetyoutcomes, so I don't know how
they can even claim safety.
So don't give them credit ifit's due.
It was a terrible study.
Dr. Joshua Goldenberg (32:50):
I thought we were steel manning.
Are we not steel manninganymore?
You're just done.
You're like dumpster, no moresteel manning.
Dr. Adam Sadowski (32:53):
So you can steel man, but let's also not,
let's not be overly nice.
It was not a good study at all.
Dr. Joshua Goldenberg (33:02):
It was not I, I would.
I would give this critical flawlevel.
Dr. Adam Sadowski (33:07):
The fact that even got published I'm
surprised.
Dr. Joshua Goldenberg (33:09):
Yeah, so I actually.
So that was one of the first.
I had the same thing.
I was like, how did this getpublished?
So I was curious about thejournal and you know is is this
a reputable journal or not?
Because there's just so manyred flags, that editorial red
flags that should have beencaught that I didn't see.
Um, oh, and you know what theydo delineate the dose better.
In when they're talking aboutdosing, they say the fraction,
(33:31):
fraction, nation into threedoses of 600 milligrams.
Okay, so that supports your1800 milligram total daily dose
argument.
Not three doses of 200 to getto 600, but three doses of 600
to get to 600, but three dosesof 600 to get to 1800 a day.
And yeah, basically they'regiving the rationale for pulsing
it based on plasma levels fromtheir previous work, which also
(33:55):
seems to be a bit of a stretchof their previous work is in
animals, but maybe, maybe therewere some humans in the study.
I didn't track those down andwhat else did I want to say?
Oh, they say everything's dueto inflammation.
You know, I know it makes sense, it is a good rationale and
probably everything is relatedto inflammation, but I sometimes
just roll my eyes, like whenyou read these studies, you're
like what's the proposedmechanism of action?
You're like inflammation.
(34:16):
It's like yeah exactly, exactly.
It solves all things, and yeah,so I was curious about that.
Dr. Adam Sadowski (34:23):
I've also noticed that, like publications
that have longer sectionsdedicated to mechanism of action
, when it becomes like aclinical study, the higher, like
that, the outcome is going tobe just like not important.
Dr. Joshua Goldenberg (34:39):
It's funny you say that I totally
have that same bias.
Yeah, I totally have the samebias and, like you're spending
so much time on mechanism,you're clearly a benchtop expert
, which is fine.
But now I'm curious about, like, the actual methods of the
clinical trial.
You might be too enamored.
Dr. Adam Sadowski (34:54):
Yeah, and it's like okay, are these
results, is like the magnitudeeven worthwhile, or are the
clinical outcomes like relevant,or is it going to be a terrible
study?
Dr. Joshua Goldenberg (35:04):
Yeah, I think that's not a terrible
proxy at all.
I have the same like intuitivesense about things.
What else, anything else?
I wanted to say no, we talkedabout the CA-125, yeah, and then
just the conclusion
Dr. Adam Sadowski (35:17):
Didn't even read it.
Dr. Joshua Goldenberg (35:18):
Yeah, it was just too rosy.
Dr. Adam Sadowski (35:21):
Don't even bother reading it.
Dr. Joshua Goldenberg (35:23):
Yeah, I would say um, I mean, based on
what they're saying.
These are important effects andthey are large effects and
clinically meaningful, or atleast they're clinically
meaningful.
What I would say is I don'ttrust a word of it.
That doesn't mean it doesn't dothat, it just means I have no
(35:44):
idea if that is just poorlyexecuted trial design or this is
what would happen withregression to the mean anyway.
And I can't answer thosequestions based on the reporting
in this study and the design ofthis study.
So I've got lots of feels aboutthis one and, yeah, I guess
probably one thing you could dois Google.
(36:05):
Is Google, all these authors?
You know they might just beresearchers in the NAC space and
just be like intellectuallyconflicted, which is which is
like that happens all the time.
Obviously you need experts.
You know doing, doing studies.
It's an issue in science.
But you could just read betweenthe lines Like these folks are
obviously super enamored withNAC, the design.
(36:29):
Read between the lines likethese folks are obviously super
enamored with nac, the design isset up to win.
I don't know.
I've just got all the feels andall the questions.
All right, that's that.
All right, we'll leave it atthat.
Dr. Adam Sadowski (36:33):
Cool
Dr. Joshua Goldenberg (36:33):
So thank you, dear listener, and thank
you for sending papers.
Please continue to send themour way.
We like discussing good papersand bad papers and how we can
differentiate, which is kind ofthe whole point of what the heck
we're trying to do here withthis podcast and with Dr Jerome
Club in general.
So thanks for listening and wewill see you next time.
(36:54):
If you enjoy this podcast,chances are that one of your
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Please do us a favor and letthem know about the podcast and,
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It would mean a lot to us andhelp get the word out to other
people that would really enjoyyou.
content.
(37:14):
Thank youHey ya'll, this is Josh.
You know we talked about somereally interesting stuff today.
I think one of the things we'regoing to do that's relevant.
There is a course we have on DrJournal Club called the EBM
Boot Camp.
That's really meant forclinicians to sort of help them
understand how to criticallyevaluate the literature, etc.
Etc.
Some of the things that we'vebeen talking about today.
Go ahead and check out the shownotes link.
(37:36):
We're going to link to itdirectly.
I think it might be of interest.
Don't forget to follow us onsocial and interact with us on
social media at DrJournalClub.
Drjournalclub on Twitter.
We're on Facebook, we're onLinkedIn, etc.
Etc.
So please reach out to us.
We always love to talk to ourfans and our listeners.
If you have any specificquestions you'd like to ask us
(37:57):
about research evidence, being aclinician, etc.
Don't hesitate to ask.
Introducer (38:14):
Thank you for listening to the Doctor Journal
Club podcast, the show that goesunder the hood of
evidence-based integrativemedicine.
We review recent researcharticles, interview
evidence-based medicine thoughtleaders and discuss the
challenges and opportunities ofintegrating evidence-based and
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Be sure to visit www.
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