Lyrica® for the Off-Label Treatment of Trigeminal Neuralgia

1. Lyrica® for the Off-Label Treatment of Trigeminal Neuralgia Stephanie PiemontesePharm D. Candidate, 2010University of Pittsburgh School of Pharmacy

2. Objectives: • Describe symptoms of trigeminal neuralgia • List current treatments for trigeminal neuralgia • Describe indications and MOA of Lyrica® • Review clinical studies of Lyrica® used in treatment of trigeminal neuralgia • Compare safety and cost data of treatments • Discuss how Lyrica® may be used in treatment of trigeminal neuralgia

3. What is Trigeminal Neuralgia? • Trigeminal Neuralgia (TGN) is defined as sudden, usually unilateral, severe brief stabbing, recurrent episodes of pain in the distribution of one or more branches of the trigeminal nerve.1 • Also called tic douloureux due to the fact that the pain can be so excruciating that facial muscle spasms can be seen.2

4. Opthalmic Zone 1st branch (V1) Maxillary Zone 2nd branch (V2) Common Trigger Areas Mandibular Zone3rd branch (V3)

5. Facts about TGN… • Annual incidence rate of 4-5 people per 100,0002 • Most frequently seen neuralgia in the elderly2 • Females are more commonly affected than males3 • Age of onset is generally over 40-50 years of age3

6. Progression of TGN… • Initial Stage: • occurs intermittently • remissions lasting as long as weeks to months • Later Stage: • remissions become increasingly shorter • eventually may experience continuous dull ache in addition to episodic acute pain

7. Types of TGN… • There are 2 types of TGN • Classic • more common • “idiopathic” or “primary” • most cases are result of vascular compression where the trigeminal nerve enters into the pons2 • Symptomatic • less common • “secondary” • structural abnormality offending the nerve • cases include multiple sclerosis (MS), tumors and basilar artery aneurysm or ectasia4

8. TGN and MS • The association of TGN and MS is well established • MS is seen in 2-4% of patients with TGN4 • Common denominator in patients with TGN and MS is the involvement of plaques in the TG nerve entry zone in the pons4 • Plaques in other parts of the brain do not necessarily lead to TGN • Reports of vascular compression in MS patients

9. TGN pain can be precipitated by: • Simple touch • Washing or shaving • Cold wind • Eating, chewing, or tooth brushing • Talking, smiling or grimacing

10. Diagnosis of TGN • Routine neuroimaging (CT, MRI) is not a reliable means of identifying all patients with TGN1 • Clinical diagnosis dependent on accurate patient history • Patients often have difficulty in conveying the characteristics of their pain • Other rare cranial neuralgias can produce pain identical to that of TGN, but differ from TGN by the location of the pain4 • Glossopharyngeal neuralgia • Neuralgia of nervusintermedius • Neuralgia of the superior laryngeal nerve • Occipital neuralgia

11. Pathophysiology • Not fully elucidated, but evidence points to the trigeminal nerve rather than the CNS • TG ganglion undergoes unique pathological changes • Demylenative lesions of trigeminal nerve fibers appear to set up ectopic impulses and ephapses • may dis-inhibit pain pathways in the spinal trigeminal nucleus2 • Demylenation and remylenation at the trigeminal root at the site of compression4

12. Pathophysiology • Slowly evolving process that leads to increased excitability in some of the trigeminal afferents and subsequently leading to inappropriate facial painful sensations4 • Compression by blood vessel or tumor • Alteration of neural functions by MS plaque

13. Current Treatments for TGN • Pharmacotherapy

14. Current Treatments for TGN • Surgical Options4 • Microvascular decompression • Radiofrequency gangliolysis • Glyercolgangliolysis • Balloon compression • Stereotactic radiosurgery • Peripheral neurectomy • Cryotherapy • Nerve block • Alternative Therapies • Acupuncture • Cobra venom • Botulinum Toxin • Topical Capsacin

15. Lyrica® (pregabalin): FDA approved indications and dosages

16. Lyrica®: Mechanism of Action • Exact MOA is unknown • Binds with high affinity to the alpha2-delta site in the CNS tissues10 • An auxiliary subunit of voltage-gated calcium channels • Studies in genetically modified mice suggest this subunit may be involved in pregabalin’s antiocieptive and antiseizure effects10

17. Lyrica®: Mechanism of Action • Pregabalin is a structural derivative of GABA, • But it does not bind to GABAA or GABAB, benzodiazepine, serotonin, or dopamine receptors10 • Nor does it effect uptake of GABA, dopamine, serotonin, or noradrenaline • Pregabalin does not block sodium receptors and is not active at opiate receptors10 • In vitro, pregabalin reduces the calcium-dependent release of several neurotransmitters possibly by modulation of the channel function10 • glutamate, norepinephrine, and substance P

18. Geriatric Use of Lyrica® • In controlled studies of Lyrica® in treatment of fibromyalgia, 106 patients were 65 years old or older10 • The adverse reaction profile was similar across the age groups; • However, the following adverse reactions were more frequent in patients 65 years of age or older: >dizziness >blurred vision >balance disorder >tremor >confusional state >abnormal coordination >lethargy

19. Clinical Studies • Published literature about the usefulness of pregabalin in TGN is thin • “Efficacy of pregabalin in the treatment of trigeminal neuralgia” • Obermann M, et al. Cephalagia. 2008 • Prospective, open-label study • Objective was to evaluated the efficacy of pregabalin 150-600 mg/day in 53 patients with TGN ± concomitant facial pain • Exclusion criteria • Additional severe medical or psychiatric illness • Pregnant or lactating women • Taking TCAs, opioids, SSRIs, SNRIs, phenothiazines, antiarrhythmics, pteridine, macrolides + antihistamines • Previous TGN medications were d/c prior to treatment with pregabalin • Therapy could be intensified with carbamazepine or lamotrigine after 8 weeks if patients did not have complete pain relief with pregabalin alone • TGN pain was completely suppressed in 25% of the patients and was reduced by at least 50% in 49% of the patients

20. Clinical Studies • “Trigeminal Neuralgia Treated With Pregabalin in Family Medicine Settings: Its Effect on Pain Alleviation and Cost Reduction” • Pérez et al. J ClinPharmacol. 2009. • 65 patients naïve to pregabalin with refractory neuropathic pain due to TGN • pregabalin alone or as add-on to patients’ current treatment for 12 weeks

21. “Trigeminal Neuralgia Treated With Pregabalin in Family Medicine Settings: Its Effect on Pain Alleviation and Cost Reduction” • Objective: • To compare the effect of 2 patterns of pregabalin treatment, add-on and monotherapy, on pain and • The use of health care resources, productivity measures, and the associated costs in a subgroup of patients with TGN. • Methods: • Study Design: • Secondary analysis of a multicenter, observational, prospective 12-week study

22. “Trigeminal Neuralgia Treated With Pregabalin in Family Medicine Settings: Its Effect on Pain Alleviation and Cost Reduction” • Methods: • Study population: • Male and female patients > 18 years old • Diagnosis of neuropathic pain secondary to TGN • Refractory pain to previous course of analgesia • Chronic pain > 6 months • DN4 neuropathic pain questionnaire score > 4 (scale 0-10) • Naïve to pregabalin

23. “Trigeminal Neuralgia Treated With Pregabalin in Family Medicine Settings: Its Effect on Pain Alleviation and Cost Reduction” • Methods: • Measurement of Variables • Pain severity was measured at baseline and was recorded weekly in a diary • Assessed using the DN4 and a visual analog scale (VAS) of the Short Form McGill Pain Questionnaire • Cumulative days without or with mild pain (VAS < 40 mm) were calculated • Health care resource utilization during the 12 week period were taken from the patient’s clinical record • Lost work day equivalents (LWDE) were calculated using the following equation: • LWDE = W1 + W2 (1-P) • W1 = # days within previous 3 months patient unable to work • W2 = # days within previous 3 months patient able to work through pain • 1-P = percentage or work disability • P = percentage of work effectiveness

24. “Trigeminal Neuralgia Treated With Pregabalin in Family Medicine Settings: Its Effect on Pain Alleviation and Cost Reduction” • Results: • 36/65 patients received pregabalin monotherapy and 29/65 received pregabalin as add-on therapy with other drugs • Patients in the add-on therapy group scored significantly higher on the DN4 and had lower work productivity at baseline • DN4 score of 7.3 vs. 6.2 (p=0.017) • The most frequent drugs being used were: • NSAIDS 38% • Antiepileptic drugs 22% • Acetaminophen 19%

25. “Trigeminal Neuralgia Treated With Pregabalin in Family Medicine Settings: Its Effect on Pain Alleviation and Cost Reduction” • Results: • Average doses of pregabalin monotherapy and add-on group were 196 ± 105 mg/day and 234 ± 107 respectively • At completion of the study 60% of patients’ baseline pain had been reduced by at least 50% • No significant different reported between 2 groups (64% in monotherapy vs. 54% in add-on (p = 0.413)

27. “Trigeminal Neuralgia Treated With Pregabalin in Family Medicine Settings: Its Effect on Pain Alleviation and Cost Reduction” • Results: • LWDEs decreased from 32 to 12 in the monotherapy group and from 52 to 20 in the add-on group • 62% reduction in LWDEs in the whole population • Decrease in health care resource utilization across all categories

28. Comparison of Safety Data

29. Comparison of Costs of TGN Treatments Price data taken from drugstore.com

30. Should Lyrica® be covered for use in patients with TGN? • Current evidence suggests that pregabalin may be useful in mono-therapy and combination therapy for treatment of TGN; • However, the amount of that evidence is very small. • Lyrica® has similar side effects as other commonly used medications for TGN

31. Should Lyrica® be covered for use in patients with TGN? • The cost of therapy per month is higher for Lyrica® than most other TGN therapies. • Lyrica® should not be used as first-line therapy for TGN. • Better studied, equally safe, less expensive alternatives • Could consider using Lyrica® after patients have failed other agents. • Prior Authorization?

32. References • Gronseth G, Cruccu J, Argoff C, et al. Practice Parameter: The diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): Report on the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societes. Neurology. 2008; 71:1183-90. • Ward T, Levin M. Facial Pain: Trigeminal Neuralgia. In: Warfield C, Bajwa Z. Principles and practice of pain medicine. 2nd ed. New York: McGraw-Hill; 2004: 246-47. • Wray D. Pain and Neurological Disorders: Organic facial pain syndromes. In: Textbook of General and Oral Medicine. 1st ed. Edinburgh; New York:Churchill Livingstone; 1999:229-300. • Nurmikko TJ, Eldridge PR. Trigeminal neuralgia – pathophysiology, diagnosis and current treatment. Br J Anaesth. 2001;87:117-32. • Attal N, Cruccu G, Haanpaa M, et al. ENFS guidelines on pharmacological treatment of neuropathic pain. European Journal of Neurology. 2006; 13:1153-69. • Gilron I, Booher S, Rowan J. Max M. Topiramate in trigeminal neuralgia: a randomized, placebo-controlled multiple crossover pilot study. ClinNeurpharmacol. 2001:24(2):109-112.

33. References • Sindrup S, Jensen T. Pharmacotherapy of Trigeminal Neuralgia. Clin J of Pain. 2002:18(1): 22-27. • Cheshire W. Defining the role for gabapentine in the treatment of trigeminal neuralgia: A retrospective study. J Pain. 2002:3(2):223-230. • Obermann M, Yoon M, Sensen K, et al. Efficacy of pregabalin in the treatment of trigeminal neuralgia. Cephalagia. 2008:28(2):174-81. • Lyrica package insert. New York, NY: Pfizer Inc; 2009 April. • Topiramate package insert. Titusville, NJ. Ortho-McNeil Neurologics;2009 May. • Gabapentin package insert. Peapack, NJ. Greenstone; 2009 May. • Pimozide package insert. Sellersville, PA: Teva Pharmaceuticals; 2008 January. • Topiramate package insert. Titusville, NJ. Ortho-McNeil Neurologics;2009 May. • Gabapentin package insert. Peapack, NJ. Greenstone; 2009 May.