Chronological timeline of milestones
| Year | Milestone | Significance |
|---|---|---|
| 1990 | Chemical synthesis of Pregabalin (S-3-isobutyl GABA) | Invented by Richard Bruce Silverman at Northwestern University as a lipophilic GABA analogue. |
| 2000 | Pfizer acquires Parke-Davis / Warner-Lambert | Pfizer takes over global clinical trial development and commercialization. |
| 2004 | First regulatory approvals in Europe (EMA) | Lyrica approved for peripheral neuropathic pain and adjunctive focal epilepsy. |
| 2005 | US FDA approval | Approved in the United States for diabetic neuropathy and post-herpetic neuralgia. |
| 2006 | European approval for Generalised Anxiety Disorder (GAD) | Becomes one of the few non-antidepressant, non-benzodiazepine licensed treatments for GAD in the UK. |
| 2014 | Expiry of basic substance patent in the UK | Generic manufacturers begin manufacturing for epilepsy and GAD indications. |
| 2018 | UK Supreme Court second medical use patent ruling | Landmark ruling opens the door to full generic prescribing for pain across the NHS. |
| 2019 | UK reclassifies Pregabalin as a Schedule 3 Controlled Drug | Home Office implements strict prescription controls (Class C) to reduce misuse and overdose deaths. |
| 2021 | MHRA issues respiratory depression safety warning | Highlights risk of life-threatening breathing suppression when combined with opioids or sedatives. |
| 2022 | MHRA issues first-trimester pregnancy safety update | New safety warnings regarding slightly elevated congenital malformation risks based on Nordic study data. |
1990: Discovery and synthesis at Northwestern University
In the late 1980s, medicinal chemist Professor Richard Bruce Silverman and research associate Ryszard Andruszkiewicz at Northwestern University in Evanston, Illinois, sought to design molecules that could cross the blood-brain barrier and inhibit the enzyme GABA aminotransferase, with the goal of increasing inhibitory GABA levels in the brain to stop epileptic seizures.
They synthesized a series of 3-substituted GABA derivatives. One enantiomer, (S)-3-(aminomethyl)-5-methylhexanoic acid, showed exceptional anticonvulsant activity in animal models. Although researchers later discovered that the molecule did not actually act via GABA transaminase—binding instead to voltage-gated calcium channels—the compound was licensed to Parke-Davis (later acquired by Pfizer in a $90 billion merger in 2000) and entered clinical trials under the code CI-1008, later named pregabalin.
2004–2006: European authorization and the Lyrica era
In July 2004, the European Medicines Agency (EMA) granted marketing authorization for Lyrica across the EU and UK for peripheral neuropathic pain and as an adjunctive treatment for focal epilepsy. In 2006, the licensed indications were expanded to include central neuropathic pain and generalised anxiety disorder (GAD).
Lyrica rapidly became one of the world’s best-selling pharmaceutical products, generating over $5 billion in annual global sales for Pfizer, and generating over $1 billion in royalties for Northwestern University, which funded major biomedical research infrastructure.
2014–2018: The landmark UK patent litigation
The expiry of Pfizer’s original substance patent in 2014 triggered one of the most significant legal battles in UK patent history:
- The "Skinny Label" dilemma: Pfizer’s primary compound patent expired in 2014, allowing generic manufacturers to sell pregabalin for epilepsy and anxiety. However, Pfizer maintained a "second medical use patent" covering the treatment of pain until July 2017.
- NHS prescribing guidance: Because UK doctors routinely prescribe medicines by generic chemical name on NHS electronic systems, pharmacists were unknowingly dispensing cheaper generic capsules for pain indications, infringing Pfizer’s secondary patent.
- The Supreme Court Decision (2018): In Warner-Lambert Company LLC v Generics (UK) Ltd [2018] UKSC 56, the UK Supreme Court ruled that Pfizer’s secondary patent claims for neuropathic pain were invalid for lack of plausibility. This landmark decision opened the market to unrestricted generic competition, saving the NHS tens of millions of pounds annually.
2019: Reclassification as a UK Controlled Drug
As generic pregabalin became inexpensive and widely prescribed across the UK between 2014 and 2018, public health data revealed an alarming trend:
- Prescription numbers surged dramatically, exceeding 6 million NHS prescriptions per year.
- Data from the Office for National Statistics (ONS) showed a steep increase in drug-related deaths where pregabalin was detected at post-mortem, predominantly alongside diverted or prescribed opioids and benzodiazepines.
- The Advisory Council on the Misuse of Drugs (ACMD) warned the UK Home Secretary that pregabalin was being diverted into illicit prison and street markets for its sedative and euphoric properties.
On 1 April 2019, the Home Office officially placed Pregabalin and gabapentin into Schedule 3 of the Misuse of Drugs Regulations 2001 and designated them Class C Controlled Drugs under the Misuse of Drugs Act 1971. This introduced mandatory 28-day prescription expiry limits, prohibited routine repeat dispensing, and made unauthorized possession a criminal offence.