1. Pregabalin An Overview
Dr. Shaun Greene

2. 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

3. Gabapentinoids: derivatives of GABA (gamma-aminobutyric acid)

4. 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

5. 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

6. 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

7. 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

8. 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.

9. 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

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

11. Evidence for Benefit: Neuropathic pain
Moderate-quality evidence shows pregabalin 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

12. Evidence for Benefit: Neuropathic pain
Moderate-quality evidence shows pregabalin 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

13. 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.

14. Evidence for Benefit: Fibromyalgia
Cochrane: High quality evidence that pregabalin at daily doses of 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

15. 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

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

17. 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

18. 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.

19. 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

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

21. VPIC Pregabalin Enquiries

22. 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