Pregnancy: Acetaminophen or Paracetamol

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.