Pregabalin An Overview Dr. Shaun Greene

What is Pregabalin? Gabapentinoid used for the Rx of epilepsy + neuropathic pain Trade name in Australia = Lyrica Analgesic, anticonvulsant, anxiolytic, sleep modulator Pharmaceutical Benefits Scheme (PBS): Refractory neuropathic pain not controlled by other drugs

Gabapentinoids: derivatives of GABA (gamma-aminobutyric acid)

Pharmacodynamics What does Pregabalin do to the body? Binds to neuronal voltage gated calcium channels (VGCCs) Inhibits calcium conductance through VGCCs Increases the expression of L-glutamic acid decarboxylase (GAD) GAD is an enzyme utilised to synthesize GABA Pregabalin does not bind to GABA receptors or form GABA

Pharmacokinetics What does the body do to Pregabalin? Active absorption from gastrointestinal tract (no saturation) 90% bioavailable, food may delay absorption Active transport across the blood-brain-barrier into CNS 98% eliminated unchanged in urine Half-life 6-7 hours

History: International First synthesised in 1990, Northwestern University, Illinois USA Created originally as an anticonvulsant Approved for use by FDA and European Union in 2004 Epilepsy, diabetic neuropathy, post herpetic neuralgia

History: Australia 2004: Therapeutic Goods Administration Treatment of neuropathic pain in adults and as adjunctive therapy in adults with partial seizures with or without secondary generalisation 2011: Pharmaceutical Benefits Advisory Committee (PBAC) Reject: Initial and continuing treatment of neuropathic pain Uncertain cost effectiveness

History: Australia 2012: Pharmaceutical Benefits Advisory Committee (PBAC) The PBAC recommended the listing of pregabalin on the PBS as an Authority Required (Streamlined) benefit for the treatment of refractory neuropathic pain not controlled by other drugs on the basis of acceptable cost-effectiveness compared with placebo in patients dissatisfied with their current pain relief.

Indications for use in Australia Diagnosis Pregabalin PBS approved? Refractory neuropathic pain not controlled by other Rx  Acute pain X Pain of non-neuropathic origin Fibromyalgia Generalised anxiety disorder Insomnia Epilepsy

Prescribing Information Tablet strengths: 25mg, 75mg, 150mg, 300 mg PBS streamlined - 56 tablets - General patient charge $40.30

Evidence for Benefit: Neuropathic pain Moderate-quality evidence shows pregabalin 300-600 mg daily has an important effect on pain in some people with moderate or severe neuropathic pain after shingles, or due to diabetes. Diagnosis Pregabalin Placebo Post-herpetic neuralgia 3/10 pain  ≥ 50% 5/10 pain  ≥ 33% 2/10 pain  ≥ 50% 3/10 pain  ≥ 33% Diabetic neuropathy 3.5/10 pain  ≥ 50% 5.5/10 pain  ≥ 33% 2.5/10 pain  ≥ 50% 4.5/10 pain  ≥ 33% Stroke / trauma neuropathic pain - Small benefit HIV neuropathic pain - No evidence of effect

Evidence for Benefit: Neuropathic pain Moderate-quality evidence shows pregabalin 300-600 mg daily has an important effect on pain in some people with moderate or severe neuropathic pain after shingles, or due to diabetes. Adverse effects Pregabalin Placebo Side effects 6/10 5/10 Dizziness or sleepiness 1/3 Serious adverse effects Rare Stopped taking because of side effects 1/10

Evidence for Benefit: Neuropathic pain Helpful for some people with chronic neuropathic pain Not possible to know beforehand who will benefit / who won’t Current knowledge suggests that a short course of treatment (perhaps four weeks) is the best way of telling Some people will derive substantial benefit with pregabalin; more will have moderate benefit, but many will have no benefit.

Evidence for Benefit: Fibromyalgia Cochrane: High quality evidence that pregabalin at daily doses of 300-600 mg produces a large fall in pain in about 1 in 10 people with moderate or severe pain from fibromyalgia. Pain reduction comes with improvements in other symptoms, in quality of life, and in ability to function. Number needed to treat (NNT) = 11

Evidence for Benefit: Generalised Anxiety Disorder Pregabalin superior to placebo for amelioration of symptoms The anticonvulsants gabapentin and pregabalin showed moderate-quality evidence of a clinical response

Evidence for Benefit: Other Conditions Acute pain or chronic non-neuropathic pain: no evidence

Adverse Effects with Therapeutic Doses Reported by at least 3% of patients: Dizziness Drowsiness Blurred vision Fatigue Weight gain Dry mouth Headache Impaired balance Peripheral oedema

Potential for Misuse Evidence suggests gabapentinoids possess potential for abuse, particularly in individuals with a history of opioid abuse, and reports of such abuse are increasingly being documented.

Effects in Overdose  CNS: dizziness, agitation, delirium, headache, myoclonus, coma, tremor, fasciculations, ataxia Other: ECG abnormalities, GI upset, kidney injury, cardiac failure Care is supportive Death is unlikely following lone Pregabalin OD

Lethality in Overdose? Frequently found with opioids, benzodiazepines, antidepressants Less lethal than opioids and tricyclic antidepressants taken alone Aust: UK:

VPIC Pregabalin Enquiries

Summary: Pregabalin Gabapentinoid approved for Rx of neuropathic pain + epilepsy Increasing prescription rates in Australia Moderately effective for a minority of patients Carries significant risk of misuse Increasing involvement in multi-drug fatal ODs Number need to treat (NNT) 8 Number need to harm (NNH) 14