29 May 2019

Joining the dots on pregnancy nausea drug

Clinical Drugs Women

It started in her arm. One day Sophie* found herself holding her right arm in what she called a “T-rex” pose, bent at the elbow and wrist. She also found herself involuntarily doing strange things with her tongue and face.

Then came the agitation: she was jiggling her limbs constantly, couldn’t sit still for more than a minute, couldn’t concentrate on anything and certainly couldn’t sleep.

Two GPs, a psychologist and a psychiatrist had diagnosed her as having severe anxiety. Inpatient treatment had even been recommended.

In fact, Sophie was suffering from well-documented side effects of a drug commonly prescribed for morning sickness – metoclopramide (Maxolon) – and no-one made the connection.

No-one, except her hairdresser.

The Sydney lawyer was about seven weeks pregnant when her nausea turned into full-blown hyperemesis gravidarum.

“I was vomiting at least 20 times a day, dry retching,” she tells The Medical Republic. “I couldn’t keep down fluids. I was hardly eating.”

Her GP put her on metoclopramide, a dopamine D2 antagonist, at 10mg three times a day; and ondansetron (Zofran), a selective 5-HT3 receptor antagonist, also three times a day.

After continued vomiting and two near-miscarriages, she went to hospital for intravenous fluids, and then booked into the pregnancy day-stay program, where she would go every second day for IV fluids (the hyperemesis had forced her to take time off work).

Other women she met there were also on the same combination of anti-nausea medications.

But the hyperemesis continued.

Sophie was becoming familiar with hospital emergency departments, both for rehydration and repeat scripts. Each time she requested and received scripts for both drugs, with one exception. At an emergency clinic at a private hospital, there did appear to be some reservation about prescribing the metoclopramide.

“I asked for Maxolon, and one of the midwives there actually said, ‘Oh, you’re much better off with ondansetron, Maxolon is a really awful drug’, but she didn’t elaborate any further.”

Staying on top of the nausea and vomiting was proving incredibly difficult, but then a whole new set of challenging symptoms developed.

After about four weeks of both drugs, Sophie noticed the involuntary arm and facial movements and facial tremors. In retrospect, she was diagnosed as having developed a mild form of tardive dyskinesia – a known side-effect of prolonged metoclopramide use that can be irreversible.

Worse for Sophie was the psychomotor agitation known as akathisia.

“Whenever I was sitting down I got restless and I started jiggling my leg, which I hadn’t done before. Over time it got progressively worse. I also started to get restless arms and restless legs. I was taking [a sleeping pill] because I couldn’t sleep.

“It was awful. I increasingly had a sense of internal restlessness, and it got progressively worse, so I couldn’t concentrate on anything. I couldn’t read a book. I would try and watch an episode of a TV show and couldn’t sit still on the couch.

“People would try to have a conversation with me and I would just say ‘yep yep mm-hm yep’, not engage and be distracted.

“Then it got to the point where I couldn’t sit still to eat a meal. I had to get up and start pacing quite frequently. And I was still getting vomiting and nausea but not as severely as before, so I started cutting down on the ondansetron. I thought that was the more serious nausea medication.”

Her obstetrician thought this was anxiety because of the multiple threatened miscarriages. He again gave her scripts for metoclopramide and ondansetron and referred her to a psychologist. The psychologist agreed she had severe anxiety and needed a GP referral to a psychiatrist. All these practitioners were aware she was on metoclopramide and ondansetron.

The psychiatrist prescribed quetiapine, and suggested she might need inpatient psychiatric treatment.

By now, Sophie says, the anxiety was very real. She did not want to be alone, and was experiencing dark thoughts.

“I was terrified because of what was happening to me. I felt like I was completely losing my mind and I was out of control.

“I didn’t want my pregnancy any more, I had had enough. I thought, if this is what it’s like I don’t want anything to do with it.”

It was a haircut, of all things, that saved her from this downwards spiral. Sophie was in the salon and had to keep getting up and pacing in between having bits of hair cut. While doing this she asked the patient hairdresser whether she’d experienced any restlessness or anxiety while pregnant.

The hairdresser told Sophie that she’d been prescribed some anti-nausea medication for her morning sickness, which had made her anxious, nervous and restless, but that all stopped when she stopped taking it.

Sophie and her husband turned to Google and found numerous complaints of similar symptoms from women on pregnancy forums and mummy blogs.  “A lot of the women said ‘I had this horrible experience when I went on it, I felt really anxious and restless, I couldn’t do anything. One woman said ‘I just cleaned the house constantly because I couldn’t sit still’, and I thought oh my god, that sounds like me!”

The forums are also full of reports from women who say they experienced unpleasant psychological effects, though some found it helped where nothing else did. On the drugs.com ratings site, 24% of users rate it a 10 (the best) while 53% rate it a one (the worst), with only a scattering in between.

One very poignant comment on the site stated: “I thought I was going crazy. It started off as feeling restless and unable to be concentrate, developing into nightmares and really dark thoughts. It was terrifying.”

In the medical literature there are numerous articles linking metoclopramide with tardive dyskinesia.

In fact, 10 years ago the US Food and Drug Administration issued this warning: “Treatment with metoclopramide can cause tardive dyskinesia, a serious movement disorder that is often irreversible. The risk of developing tardive dyskinesia increases with duration of treatment and total cumulative dose.

“Metoclopramide therapy should be discontinued in patients who develop signs or symptoms of tardive dyskinesia. There is no known treatment for tardive dyskinesia. Treatment with metoclopramide for longer than 12 weeks should be avoided in all but rare cases where therapeutic benefit is thought to outweigh the risk of developing tardive dyskinesia.”

It said that although the link had not been extensively studied, one published study reported a tardive dyskinesia prevalence of 20% among patients treated with metoclopramide for at least 12 weeks.

The FDA also approved a medication guide for patients, telling them to “Call your doctor right away if you get movements you cannot stop or control, such as: lip smacking, chewing, or puckering up your mouth; frowning or scowling; sticking out your tongue; blinking and moving your eyes; shaking of your arms and legs”.

The Therapeutic Goods Administration’s list of indications for metoclopramide include short-term nausea and vomiting associated with “intolerance to essential drugs possessing emetic properties; uraemia; radiation sickness; malignant disease; postoperative vomiting; labour; infectious diseases”. It does not include hyperemesis gravidarum.

In 2015, the TGA updated its product information on metoclopramide to include warnings about extrapyramidal disorders including tardive dyskinesia, saying the drug should not be used for more than 12 weeks except in extreme cases.

But Sophie, who had been on metoclopramide for 12 or 13 weeks by now, had never seen these warnings or been told to look out for strange, involuntary movements.

“I just stopped taking the Maxolon immediately and within 24 hours I had already noticed a significant improvement, and in 48 hours a huge improvement,” Sophie says.

“I went back and saw the psychiatrist, and she said ‘you are a completely different person’, and was very apologetic. My GP was shocked, my obstetrician was shocked – he said ‘Maxolon is a very mild drug, we prescribe it regularly’.

“No one seemed to have heard of it. My family GP looked up her system, and found where it said it could cause restlessness, anxiety, tardive dyskinesia.

“But my prescription just came in a small bottle with no warning other than ‘may cause drowsiness, don’t operate heavy machinery’.

“I never got a leaflet.”

Metoclopramide was the 250th-most prescribed medicine in the US in 2016, with 1.9 million prescriptions, according to the ClinCalc DrugStats database.

Gynaecologist Stephen Lane, president of the National Association for Specialist Obstetricians and Gynaecologists, says he prescribes metoclopramide regularly to pregnant women.

“I’m comfortable with the side effect profile and safety in pregnancy: Category A, safe in pregnancy,” Dr Lane tells The Medical Republic. “Dyskinetic reactions are rare but distressing. Most obstetricians continue to prescribe it for hyperemesis.”

Category A means a drug has been taken “by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed”.

This says nothing as to the safety or side-effects for the mother.

Ondansetron, a newer drug with a different action that has never been associated with extrapyramidal side effects, is a category B1, meaning it has been taken by a limited number of pregnant women with no observed adverse effects on the fetus.

Obstetrician Bernadette White, speaking on behalf of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, says metoclopramide is “reasonably commonly prescribed”.

“Once you get that more severe [hyperemesis] you really do have to do something about it,” she tells The Medical Republic.

“For women in whom simpler things are not effective, I would say Maxolon often would be, certainly in my experience, a first-line of treatment because it has been around for a very long time and it’s regarded as a really safe thing to take in pregnancy.

“That said, there are a small number of women who do get troublesome, usually reversible side-effects from it like twitchiness or just feeling something isn’t quite right. I would’ve thought most people would know that there is a small risk of those extrapyramidal side-effects and generally you would stop the treatment if someone complained of anything suggestive of that.

“So it sort of surprises me to think [Sophie] would develop those sort of symptoms and not have it recognised. That would be disappointing.”

Dr White says there are not many alternatives to metoclopramide, with prochlorperazine (Stemetil) having an even worse side-effect profile.

Ondansetron is not PBS-listed, except for radiotherapy cancer patients, so it can be very expensive.

“If you’re not getting it through a public hospital pharmacy, where often it will be a little cheaper, it can be very expensive. On the other hand, it’s more effective than Maxolon. A lot of people will try Maxolon just because it’s been around for so long, a lot of people are pretty comfortable with using it.

“But if it’s not effective, a lot of people would then go on to use ondansetron as a next option. The patients usually, by the time they get to that stage, they’re prepared to pay for it even though it is quite expensive.”

Dr White says ever since the thalidomide scandal, the safety of the fetus has been paramount when prescribing in pregnancy: “People are very cautious.”

She said it’s “a good question” whether to warn women about the possible side-effects of metoclopramide.

“I probably wouldn’t routinely tell people that they might get side-effects – I suspect a lot of people don’t. On the other hand, I would have thought most people would be aware that if a person does start to get those symptoms – and people who are going to get it, will often get it straight away – that you would normally advise people to stop.

“Having been an obstetrician for a very long time and prescribed Maxolon for many, many women, it’s not a side-effect I’ve ever encountered or even heard of someone getting. It’s not to say it doesn’t, but I’d say it’s very rare.”

The TGA says that in the 30 years to 2014 it received 2190 adverse event case reports associated with metoclopramide, including nine cardiac arrests and over 100 cases of extrapyramidal disorders including tardive dyskinesia. This suggests the rate is much lower than the 20% the FDA cites, if the drug is regularly prescribed for prolonged use.

Dr White said while she would not stop prescribing metoclopramide, doctors had to monitor the signs and be prepared to discontinue the drug immediately. This includes GPs, who may not have prescribed the drug themselves and therefore won’t have seen the alert on their software.

“I’d still say I think Maxolon is a reasonable thing to prescribe for women, but doctors need to be aware that if a patient complains of little symptoms, even though they may seem quite trivial and hard to explain like, ‘My mouth feels funny’ or ‘My jaw feels funny’, you stop it at that point.

Dr White does find at least one part of Sophie’s story dispiritingly familiar: the part where the young woman’s symptoms are dismissed as anxiety.

“You know, it’s a common story of symptoms not being taken seriously – ‘Ah, you’re just worried or you’re anxious or something,’ instead of someone listening and saying, ‘Hang on, I wonder if those symptoms are related to the fact you’re taking a drug that is known to have those potential side effects?’”

Happily, Sophie is now feeling well and heading into the last leg of her pregnancy with no more dark thoughts.

“It’s coming up soon now,” she says. “I’m in the third trimester, which is a great relief. I’m like, oh gosh, it’s been a rough ride but now I feel like I’m on the home stretch.”

*Not her real name

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