I took part in a podcast recently at the invitation of John Wilks and Our Birth Journey a group John is linked to. Our conversation is on this link:
Antidepressants and Acetaminophen Use During Pregnancy
The title says Antidepressants and Acetaminophen (U.S. for Paracetamol). The original invite was to talk about Antidepressants and Pregnancy. The SSRI and related antidepressants along with anticonvulsants cause a range of birth defects including behavioral problems like Autism Spectrum Disorders (ASD). There are several previous RxISK posts on this stemming back a decade or so – which hinged on evidence that came to light when GlaxoSmithKline lost the Kilker Birth Defects trial. See:
- Lullaby
- Preventing Precaution
- Mumsnet
- Herding Women
- The Dark is for Mushrooms
- Autism Awareness Day: Antidepressants in Pregnancy
- Facts about Facs
After the invitation from John, evidence came my way that acetaminophen, aka paracetamol outside North America, and branded as Tylenol or Panadol and multiple other names, is also linked to birth defects and in particular ASD and is an anticonvulsant. With other anticonvulsants, notably valproate, strongly linked to birth defects and ASD, I suggested it should be included in the podcast and John agreed.
Almost immediately after finding paracetamol, aka acetaminophen, is an anticonvulsant, it also became evident that it acts on the serotonin reuptake site. Its benefits in pain may stem from effectively being a mild serotonin reuptake inhibitor rather than an NSAID analgesic like aspirin or ibuprofen, as was once thought.
The conversation with John focused on the use of medicines in pregnancy and fed into a question that is growing in salience – what is causing an apparent epidemic of autism spectrum disorders. Is the increase simply a change in diagnostic fashions or is something else going on?
Afterwards one of those attending from Germany or accessing the podcast, Bettina, got in touch and asked for more evidence linking paracetamol to birth defects/ASD. Her request suggested a series of posts covering Does Acetaminophen work, and then the Epidemiological, Pharmaco-epidemiological and Epigenomic data on this issue.
This post will cover the Does Paracetamol Work issue and following posts will cover the evidence for hazards.
Does Paracetamol Work?
In the 1970s, regulators reviewing over the counter (OTC) – analgesics like aspirin, ibuprofen and acetaminophen accepted they all worked even though there were no randomized controlled trials (RCTs) showing this. Nobel Prize winning research had just discovered that aspirin and other drugs in the group worked on the prostaglandin system. They were all viewed as being analgesic, anti-inflammatory and anti-pyretic (fever reducing). They were grouped as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).
Then it slowly became clear that paracetamol was not anti-inflammatory. The assumption for decades was its analgesic effects involved some other mechanism linked to prostaglandins like an action on Cox-2 enzymes as research on inhibiting these enzymes had led to Celebrex and the infamous Vioxx. Acetaminophen may have some mild Cox-2 actions – perhaps even enough to cause some problems – but in fact it has become clearer and clearer than we do not know how it works.
Knowing how acetaminophen works is one thing, but this is not the same as knowing that it does work and lots of readers of this post know that it does work just like I know ibuprofen works for me. We don’t need RCTs to tell us this. I also know that paracetamol does not work for me.
Am I mistaken? Well it turns out that the RCTs done on acetaminophen do not show it works. Groups like Cochrane who have reviewed all the trials they can find, which are much fewer than you might expect and of very poor quality, have concluded either that it doesn’t work or its effects are pretty minimal, less than we expect, perhaps mostly in the mind.
Maybe because paracetamol doesn’t work for me, I figured these interpretations saying RCTs show paracetamol doesn’t work are wrong. Confused?
The results we have from the RCTs that have been done can be read in 2 ways. One is that these drugs don’t work or barely work. The other way is that they work very well for some us and not at all for others – and if you average these effects we get a weak to no effect.
But the fact that there is a barely discernible effect on average allows companies to claim Acetaminophen works and everybody to say that if you need an analgesic during pregnancy that acetaminophen should be the first choice – even if you have rarely taken it before because you know in your bones it doesn’t work for you,
On my reading of the results half of those who end up taking it can only be harmed. On Cochrane’s reading everyone is likely to be harmed – if that is it causes harms.
This is very reminiscent of the RCT story for SSRI drugs. The trials done suggest these drugs have very weak, if any beneficial effects – effects that some claim are all in the mind. Effects that lots of those take the drugs and have good or bad outcomes know to a degree of reasonable certainty are not all in their minds.
The SSRI RCT data in my opinion are best interpreted as revealing that there are some people who get a beneficial effect from these drugs (not a cure) and some whom SSRIs do not suit – people who Arvid Carlsson found might do better smoking nicotine – See Restoring the Magic to Healthcare.
It has been interesting, therefore, to find that in the hunt to answer the question of how acetaminophen works, we have found out that it binds to the serotonin transporter site. And of course, SSRIs are used widely in pain clinics for analgesic purposes. Are they analgesic – the RCT data suggests maybe not but the best way to find out is to ask people on treatment.
It is worth going into RxISK’s Side Effect Search tool and mapping the profile of side effects or paracetamol against the profile for any SSRI. There is huge overlap down to adverse events like risk-taking. It looks very like acetaminophen, rather than being actually analgesic, blunts our emotional response to pain.
When the Fever Grows
So much for analgesia, what about acetaminophen’s antipyretic action? The good news for believers in acetaminophen is that in people who are severely ill with fevers caused by serious illnesses (not inflammation because remember it is not anti-inflammatory) that it can lower temperature by a degree centigrade or two – which is not to be sneezed at.
The RCTs that most convincingly showed this also showed that reducing temperature did not save lives or reduce stays in intensive care and that the same temperature reducing effects could be obtained by cold sponging. Cold baths and sponging was of course the traditional way to reduce temperature in the pre-Aspirin and pre-Acetaminophen era and as far as is known it works for everyone.
The Label (Quick Facts) on Acetaminophen tells you if Pregnant or Breast-Feeding consult a health professional before use. If you do consult someone, they are likely to look at you blankly wondering why you are asking them.
This warning seems to hinge on the idea that pregnant women are not terribly smart – which is not my experience. On average they probably do more research on medicines than any other group in society and are very sophisticated when it comes to assessing risks and the need at times to take risks.
The following posts will tell you more about the hazards of paracetamol that this warning conceals – more about the hazards than your healthcare professional is likely to know.
Jo Ann Cook says
Interesting to read at a time when I started questioning the extreme and disabling pain my husband was experiencing since he had a minor operation and began taking tylenol 500 up to 4000 a day.. Two weeks ago I queried on the net whether tylenol was associated with magnesium loss. The response was it can cause magnesium wasting disorder. My husband immediately quit all tylenol and began taking magnesium supplements for the short ter.m.. A week later he reported that the severe cramps in his leg had dissipated. He also has more energy. We intend to file a Health Canada adverse report.
Thank you.
Jo Ann
Anne-Marie says
Paracetamol never seems to work for me either. I prefer cocodamal for pain relief and temperatures myself. . I remember once having a very strange bug and a very high temperature and I was on seroxat and I tried every pain killer you could think of over the counter and nothing would bring my very hig temp down. I then went to the gp who prescribed very strong cocodamal and it worked straight away.
Peter Gøtzsche says
Don’t take paracetamol (acetaminophen) if you have a fever. See why on pp 73-4 in my book, “Survival in an overmedicated world: look up the evidence yourself.” Extracts:
I learned many years ago from a colleague in infectious diseases that this is a bad idea because the body’s immune defense becomes ten times more effective if the body temperature goes up a couple of degrees Celsius – a dramatic increase in efficiency …
A mechanism that can be seen all over the animal kingdom, that has likely been around for more than 600 million years, must have a very strong survival value, which even experimental studies have suggested.
What will you find when looking up systematic reviews of antipyretics? They lower the body temperature and perhaps have other small benefits like reducing headaches. But these are not important outcomes. When we have an infection, the most important thing is to survive, and the second most important thing is to cure the infection.
Therefore, do not consider the pros and cons of taking antipyretics, and ignore the usual nonsense: “Ask your doctor whether an antipyretic is right for you.” It is not right for anyone, not even for a reptile or an insect.
Dr. David Healy says
Peter makes an important point which is that fever has a function. But bodily reactions can go badly wrong and febrile convulsions in children can leave brain damage and affects a person for the rest of their life.
There are causes of raised temperatures other than infection and as a result raised temperatures which can be treated and may need treating without having to worry about compromising immune systems.
There were two points about the point made in the post – one of which is there have been traditional ways to lower fevers like cold baths/showers and sponging which can be turned to in both immune and non-immune cases.
The second point is that if paracetamol doesn’t work for you when you are not pregnant – and it does work for some – it is not going to start working when you are pregnant and as the next posts will show it is one thing to take risks if there is a benefit but taking risks of neurodevelopmental delay without getting a benefit doesn’t stack up.
At the end of the day, women who get pregnant are better placed to the make the right judgement call for them than P is
David
Anne-Marie says
Thank you for this it got me thinking about the time I had toothache and needed a root filling. I was on eurithimycin and still having toothache on my second visit to dentist. Numbing injection wasn’t working well either. I think the dentist was giving up on me because I couldn’t tolerate the pain when he tried to inject into the tooth. I thought I can’t live with this pain anymore and I didn’t want him to give up either so I begged him to just ignore me if I scream and just force that injection into the tooth. Well he wasn’t to happy with that but said he will try one more time and if unsuccessful he would have to stop and refer me to a dental hospital.
Well he tried again and I just held onto the seat with both my hands and screamed inside instead. In just two/three seconds he managed to inject the inside of the tooth and the pain instantly vanished. I was so relieved we all had a party to celebrate.
I said wow thats amazing while smiling and dribbling. He said it was so painful because your nerve is over excited because of the infection. He said no painkiller would relive me of this pain only antibiotics could do it. He cleaned out my roots and refilled my tooth.
It’s antibiotics that are the important drug for infections not paracetamol your right. I forget this myself sometimes.
Harriet Vogt says
I appreciated the genuine, non-paternalistic tone of your Our Birth Journey seminar –and it made sense in that context – reprised in this comment:
‘At the end of the day, women who get pregnant are better placed to the make the right judgement call for them than P is’.
But, unless women have listened to you, dug around in the research, read Peter’s book – or been fortunate to have an Aussie mother like mine – firmly of the view that, apart from serious disease, the body knew more about healing itself than ‘quacks or drug companies’ – the evidence suggests that many, even most pregnant women are in no position to make the right judgment for them.
Because – to use a perfectly apt term coined by Evan Wood – their judgment is founded in TRUISMS – not the truth about the risks of paracetamol/ APAP to the foetus. As usual, what starts as commercial messaging is slowly disseminated and embedded in the culture – so that what originates as a claim becomes a TRUISM. As you know better than anyone – there’s a lot of it about. I’ve even met critical thinking human beings who still believe the serotonin deficit garbage, it’s been so long embedded.
Any pregnant woman in the UK (parochial view), looking for reassuring authoritative guidance on the safety of paracetamol in pregnancy, might turn to the official NHS website – where she will find:
‘Paracetamol is the first choice of painkiller if you’re pregnant. It’s commonly taken during pregnancy and does not harm your baby.’
https://www.nhs.uk/medicines/paracetamol-for-adults/pregnancy-breastfeeding-and-fertility-while-taking-paracetamol-for-adults/
This will almost certainly be the TRUISM perpetuated by other health care professionals involved with pregnancy and childbirth – obstetricians, GPs, midwives etc. IF this pregnant woman then bothers to read the PIL – she’ll see this:
‘If necessary, paracetamol can be used during pregnancy. You should use the
lowest possible dose that reduces your pain and/or your fever and use it for the
shortest time possible.’
https://www.medicines.org.uk/emc/files/pil.5164.pdf
But given the fact that authoritative medical people have been relaxed about her taking paracetamol if she has even consulted them – and there’s no reason substantiating the caution – why should she worry? After all how dangerous is an OTC drug that’s sold for pennies in supermarkets? And surely the only known concern is overdose.
Ofc you know all this inside out – but the fact that In the US, they estimate APAP is used by up to 65% of pregnant women, worldwide, more than 50% – would seem to me to be evidence of lack of awareness of risk.
But the key point is, as ever, risk to human beings, in this case unborn ones, is defined by a sort of commercial scientism – rather than in terms of ethical precautionary principles – perfectly expressed in the Consensus statement you will know well:
‘We as a society should be able to take protective action when scientific evidence indicates a chemical is of concern, and not wait for unequivocal proof that a chemical is causing harm to our children.’
https://www.nature.com/articles/s41574-021-00553-7
I was really interested to learn that acetaminophen is also an anticonvulsant. This maybe makes sense of the one time I used paracetamol on one of my children, No 2 son aged about 18 months. We were in Italy on holiday and he developed chickenpox, a raging fever and started fitting. I regretted not holding my nerve – but he spent the rest of the time splashing about in cool baths laced with baking soda to calm the itching. The discovery that APAP also has some serotonin reuptake site involvement suggests, as you say, it may numb the senses and blunt the feelings of pain
This opens up another set of truisms – that drug molecules (or whatever you scientists call them) and actions are discrete and what they say they are. Clearly not. No wonder we mere mortals are confused. No wonder plenty of doctors seem pretty clueless too.
tim says
These additional drug reactions of paracetamol/acetaminophen are indeed fascinating and unexpected.
Is the anticonvulsant effect of sufficient intensity that withdrawal convulsions might occur in long term users???
Does the serotonergic action increase the risk of akathisia when paracetamol is taken in combination with SSRIs???
I wish RxISK had been available when I was taught pharmacology at medical school, many decades ago (1968 – 1974).
I have learned more invaluable pharmacology from RxISK, after retirement, than during half a century of studying and practising medicine.