Pregabalin is a 3-substituted analogue of gamma-amino butyric acid (GABA) and a compound related to Pfizer's hugely successful antiepileptic drug gabapentin. (Source: ABPI)
Formulae for the drugs Pregabalin and Gabapentin.
At high doses gabapentin has proven effective against neuropathic pain induced by diabetic neuropathy and postherpetic neuralgia. (Source: ABPI)

In July 2004, Pfizer secured Europe-wide approval for Lyrica (pregabalin) for use in the management of peripheral neuropathic pain, as well as adjunctive therapy in the treatment of partial epileptic seizures.

Subsequently, in December 2004 the company gained US Food and Drug Administration (FDA) approval for use of Lyrica (pregabalin) in neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia, making it the first FDA-approved treatment for the neuropathic pain states.

Lyrica (pregabalin) was also reviewed by the FDA as an adjunctive treatment for partial epileptic seizures in adults. In June 2005, the FDA granted approval to market Lyrica for adjunctive treatment of partial epileptic seizures in adults. In June 2007, Lyrica became the first drug to be approved by the FDA for the treatment of fibromyalgia.

“Lyrica is seen as an important successor now that gabapentin is facing the threat of generic competition.”

In September 2009, Pfizer was found guilty of misbranding drugs with the aim to defraud or mislead. A subsidiary of the company was promoting four drugs, including Lyrica, for uses not approved by the FDA. Pfizer received a fine of $2.3bn. In addition, the company will have to enter a corporate integrity agreement.

A successor to gabapentin

First marketed in 1983, gabapentin (Neurontin) has been one of Pfizer’s top-performing drugs. Lyrica (pregabalin) is seen as an important successor now that gabapentin is facing the threat of generic competition.

Both drugs share a similar mechanism of action: binding to calcium channels and modulating calcium influx as well as influencing GABergic neurotransmission. This mode of action translates into anti-epileptic, analgesic and anxiolytic effects.

As it is more potent than gabapentin, Lyrica (pregabalin) achieves efficacy at lower doses. This increases its therapeutic index with respect to gabapentin and should lead to fewer dose-related side effects. Clinical studies with Lyrica (pregabalin) have been carried out on over 10,000 patients worldwide.

Clinical studies with Lyrica (pregabalin) in epilepsy

Gabapentin is approved worldwide for adjunctive treatment of patients with partial epilepsy. As it is not metabolised (and so does not alter the pharmacokinetics of co-administrated drugs) it is a good candidate for use in combination with other antiepileptic medications.

Clinical studies with oral Lyrica (pregabalin) suggest it is at least as effective as gabapentin as adjunctive therapy in patients refractory to one or more conventional antiepileptic drugs. In large-scale, placebo-controlled studies of 12 weeks’ duration, add-on therapy with oral Lyrica (pregabalin) reduced seizure frequency by up to 75%. In these studies, doses of Lyrica (pregabalin) ranged from 150mg to 600mg daily.

Clinical studies with Lyrica (pregabalin) in neuropathic pain and anxiety disorder

Neuropathic pain is chronic pain that arises from damage to sensory nerves. It can include:

  1. Pain arising from trapped or compressed nerves
  2. Drug-induced nerve damage
  3. Diabetic neuropathy
  4. Post-herpetic pain
  5. Phantom limb syndrome following limb amputation
  6. Peripheral neuropathy
  7. Fibromyalgia

Neuropathic pain generally does not respond to treatment with opioid or non-steroidal anti-inflammatory drugs (NSAIDs). At high doses, gabapentin has proven effective against neuropathic pain induced by diabetic neuropathy and postherpetic neuralgia.

Data from clinical studies show that Lyrica (pregabalin) shares this analgesic effectiveness. Efficacy has been demonstrated in a number of clinical studies, including those in patients with diabetic neuropathy and fibromyalgia. Treatment of neuropathic pain is seen as the drug’s leading indication.

“Treatment of neuropathic pain is seen as the drug’s leading indication.”

A double-blind, placebo-controlled monotherapy study in 529 patients with fibromyalgia, for example, showed that eight weeks’ treatment with Lyrica (pregabalin) 150mg to 450mg per day produced significantly greater reductions in pain compared with placebo, as well as improving sleep quality and fatigue.

Pain, sleep disturbances and fatigue are core symptoms of fibromyalgia, which has proved an extremely difficult condition to treat.

Data from a series of Phase II and III placebo-controlled clinical studies in over 1,200 patients with generalised anxiety disorder suggested that Lyrica (pregabalin) was effective for this disabling disorder. In comparison with venlafaxine, pregabalin provided more rapid relief of psychic and somatic symptoms.

In comparison with alprazolam (a benzodiazepine), Lyrica (pregabalin) appeared equally effective in reducing somatic symptoms. Overall, these findings showed that Lyrica (pregabalin) combined the benefits of antidepressants and benzodiazepines. It appeared at least as rapid as benzodiazepines against somatic symptoms while providing more rapid control of psychic symptoms than antidepressants.

Marketing commentary

Once generic manufacture of gabapentin is approved, sales of Pfizer’s Neurontin are likely to fall dramatically. Encouraging physicians to switch patients from Neurontin to Lyrica (pregabalin), if approved, will be an important strategy in minimising the impact of generic competition.

Lyrica (pregabalin) is as effective as Neurontin, but at lower doses, which translates to fewer side effects. Thus, it is well placed to capture Neurontin’s market share. Through the successful launch of follow-on products, Pfizer has maintained leadership in other CNS areas, such as the market for antidepressants.

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