Did the TGA bungle the scheduling of pregabalin?

When pregabalin misuse first caught the eye of the TGA a few years back, Australian Doctor asked Professor Ric Day what the watchdog could do to stop people overdosing on one of the country’s most widely prescribed medications.

A respected clinical pharmacologist, his response was simple. “The horse has already bolted,” he said.

The gabapentinoid, first registered for use in 2005, has for much of its life, been a mere blip at the very edge of the therapeutic radar.

But its massive growth as a relatively safe pain management option for doctors sometimes faced with prescribing opioid alternatives has had significant consequences.

In recent years pregabalin has been implicated in suicides and both intentional and accidental overdoses, especially when ingested with fentanyl or benzodiazepines.

A study published in Addiction last year found that the drug was a factor in 77 deaths in NSW between 2013 and 2016.

And last year forensic toxicologists in Queensland began routinely screening for pregabalin in post-mortems, suspicious it could be present in car-crash victims.

The TGA’s response has been to launch its own review into the safety of the drug.

Perth GP Dr Amanda Stafford wrote at the time that it was long overdue given that its misuse had been known on a “grand scale” for some time.

“As someone who works with street homeless patients, I can say that pregabalin is highly appreciated for its powerful anxiolytic properties.

“Since we don’t want to prescribe benzos for anxiety, since the new antipsychotics are expensive unless you scam the PBS with a diagnosis of bipolar type 1 and since we don’t want to spend the money to fix broken, shitty lives, we have an epidemic of PBS-subsidised pregabalin use.”

A tragic situation, one whose damage may be difficult to reverse, but was any of this predictable when it was first registered as a therapeutic good?

The TGA was originally asked to approve pregabalin by Pfizer, the company with the then-exclusive patented brand Lyrica.

Australian Doctor has learnt that among the masses of paperwork produced in analysing its efficacy and safety was a segment called ‘abuse potential’.

It was just seven lines long and focused on one piece of research labelled Study 098.

This was a single-centre, five-arm crossover study of 15 subjects with known drug and alcohol use disorders in the US, who took pregabalin 200mg, pregabalin 450mg, diazepam 15mg, diazepam 30mg and a placebo, with a washout period of at least five days between each drug.

It used the Multiple Choice Procedure (MCP), an established method of assessing a drug’s abuse potential by asking participants to compare pairs of substances (Drug A versus Drug B, or Drug A versus Drug C, or Drug B versus Drug C).

The TGA wasn’t impressed.

According to the TGA’s confidential analysis back then, obtained by Australian Doctor under Freedom of Information laws, it concluded that the MCP used “failed to differentiate placebo and the test drugs and thus could not assess the reinforcing effects of pregabalin”.

And that was it.

The paper wasn’t any good.

The TGA’s overall conclusion before approving pregabalin was: “Considering the severity of the diseases being treated and the need for new drugs, pregabalin offers a relatively safe and effective option.”

From that point on, the drug grew in popularity, particularly after its PBS listing in 2013.

The PBAC, which had assessed its cost-effectiveness when deciding whether the drug should be listed, did touch upon the safety issues but only to state that “the data presented did not suggest that there are substantial differences in safety for pregabalin versus amitriptyline or gabapentin”.

What is notable is that across the Pacific another regulator, the FDA, was looking at Study 098 very differently from the TGA, at least at first.¹

The US watchdog acknowledged the flaws, saying it failed to differentiate between diazepam and placebo which undermined the rationale of using diazepam as a comparator drug of abuse.

But it took seriously the subjective reports from the participants themselves. The majority of the subjects with drug and alcohol use disorders identified both pregabalin 200mg and diazepam 15mg as sedatives by their obvious effects on them.

Pregabalin 450mg had “more stimulant-like effects” than diazepam 30mg but resembled the benzodiazepine with regards to whether users felt “high”, the FDA noted.

“I believe this study with all its flaws … suggests that pregabalin has a potential for euphorigenic activity in susceptible populations,” the then-deputy director of the FDA’s centre for drug evaluation and research concluded.

“There is another aspect of the study that bears comment.

“A drug with potent euphoric properties (as the high dose of pregabalin appears to have in this study) would have less of an abuse liability if that ‘high’ was paired consistently with a ‘low’.”

The ‘low’ was a reference to the unpleasant comedown associated with many stimulants.

“This was not the case for pregabalin, and euphoria in many of the drug and alcohol abusers was not consistently coupled to any dysphoric signals.”

Unlike the TGA, the FDA in its findings made explicit reference to the adverse event reports from patients being treated for diabetic peripheral neuropathy or epilepsy that could indicate abuse potential.

It saw that the euphoria experienced as an adverse event — the combined numbers of patients who felt ‘high’, ‘stoned’, ‘elation’, ‘elevated mood’, or ‘drugged’ — was 3.7%, compared with 0.5% of those who received placebo.

At the time, Pfizer argued that the effects of pregabalin were similar to other drugs that were not controlled drugs in the US at the time: clonidine, pseudoephedrine, dextromethorphan, tramadol and pregabalin’s cousin, gabapentin.

The response from the FDA was that many of these drugs were being abused, correctly predicting that tramadol would eventually be made a controlled drug.

It concluded there was a “consistent, credible case that pregabalin possesses substantial potential risk for abuse”.

But then despite these dire-sounding warnings, the FDA suddenly backed down from its original plan to schedule the new drug as Category 4, alongside alprazolam and diazepam.

The reason?

In several short-term trials and one eight-month study, patients were assessed for withdrawal symptoms after ceasing pregabalin.

The results found some evidence of a withdrawal syndrome — insomnia, headache and diarrhoea were all reported — but less severe than the classic discontinuation syndrome linked to benzodiazepines.

This led the FDA to warn that pregabalin’s abuse potential was less about dependence, whether from long-term use or not, but “intermittent, acute use illicitly”.

So it was made schedule Category 5, a prescription drug but at the lowest end of controls alongside low-dose codeine.

Should the TGA have taken a harder line when pregabalin first appeared? Did it misread the signs?

Hindsight is easy. The evidence was severely limited.

Pfizer says abuse-related adverse events from pregabalin are still frequently linked to patients with some kind of abuse history – whether of drugs, alcohol or nicotine.

“We continue to work diligently with health officials to ensure the appropriate prescribing and use of pregabalin, and we recommend physicians carefully evaluate patients for history of drug abuse and observe them for signs of misuse or abuse,” the company told Australian Doctor.

The TGA says it’s currently working with pregabalin manufacturers – many more than just Pfizer now the drug is generic – on warnings about the drug’s misuse potential.

However, drug policy researcher Dr Barbara Mintzes (PhD), from the University of Sydney, says there are some lessons for the TGA today.

Firstly, she says the TGA could have asked Pfizer to redo Study 098 if the results weren’t usable.

“This was a small and likely a short-term study,” she says. “It’s certainly not a major expense.”

However, she stresses that for the vast majority of drugs, different regulators around the world end up going down different paths, even if they have the same data in front of them.

Dr Mintzes is coauthor on a study that looked at safety warnings issued by drug regulators in Australia, the US, the UK and Canada, and concluded only 7% of warnings were uniform between the four countries.²

“There are major differences in how regulators judge the same evidence and whether or not doctors and patients receive a warning — depending on where they happen to live.”

One thing that could help address the variation is having regulators publish all the information provided by pharma companies when approving a new drug, she says, including the full results of Study 098, which the TGA still keeps in a locked cabinet.

Drug regulators in Europe and Canada now make “the full thousands of pages” of pre-market clinical study reports publicly available, says Dr Mintzes.

But although the TGA publishes summaries of pre-trial evidence, documents called AUSPARs, it continues to “fall short” in terms of releasing full clinical study reports.

“Often this is the only place that evidence — such as the ‘euphoria’ results the FDA has described — would be found.

“There have been enormous gains in terms of public access to the research evidence but we still fall short when it comes to safety information.

“This is an example of a study which should have been published.”

The TGA told Australian Doctor it was not considering any changes to what information it releases to the public.

Many pharmaceutical companies present the TGA with the same studies they use in Europe, it said, where under European policy they are published in full.

The TGA’s review of pregabalin has been completed.

The watchdog had previously flagged a number of possible responses, ranging from recommendations for more prescriber education to the drug’s up-scheduling.

But as yet, its intentions still remain a little unclear.

References on request, contact [email protected]u