Pregabalin (Lyrica©) for the Management of Pain Associated with Trigeminal Neuralgia

PREGABALIN (LYRICA©) FOR THE OFF-LABEL TREATMENT OF PAIN ASSOCIATED WITH TRIGEMINAL NEURALGIAEd Paiewonsky

PharmD Candidate Class of 2012

University of Pittsburgh School of Pharmacy

[email protected]

September 26, 2011

Objectives

Discuss the epidemiology and pathophysiology of trigeminal neuralgia

Identify patient symptoms associated with trigeminal neuralgia

List pharmacological and non-pharmacological treatment options currently used in practice

Explain the current role of pregabalin in trigeminal neuralgia based upon evidence available in the literature

Case Study

PP is a 51 yo female presenting with sharp, bilateral, and intermittent facial pain, currently controlled; s/p two microvascular decompression surgeries (1992 & 2002) on R & L side for tx of typical and atypical trigeminal neuralgia, respectively

PMH: Non-contributory FHx: Non-contributory Meds: topiramate 300 mg orally BID Allergies: carbamazepine, phenytoin (documented toxic

epidermal necrolysis); gabapentin (intolerable drowsiness, confusion)

SHx: (+)Social EtOH; (-) tobacco, quit in 2010

Case Study

PP is currently interested in trying another agent for the management of her pain due to side effects from topiramate Complains of memory issues and cognitive decline She heard Lyrica© could be used for her condition

Her physician calls and asks for your recommendation

What is trigeminal neuralgia? Trigeminal neuralgia (TN), also referred to as “Tic

Doloureux”, is a form of neuropathic pain Characterized by an abrupt onset of pain

characterized as: Severe Sharp Brief Intermittent and recurrent

Generally unilateral in nature TN is the most common form of craniofacial pain

thatis neuropathic in origin

Elias WJ et al. Curr Pain Headache Rep. 2002;6:115-124.Pėrez C et al. Cephalalgia. 2009;29:781-790.

Epidemiology

Annual incidence 4-5 patients per 100,000 Highest incidence between 50 & 70 years of age

90% of cases occur after age 40 More prevalent in women then men

1.5-2:1 ratio Estimated 2% of multiple sclerosis patients

complain of TN Roughly 15,000 new cases annually in the United

States Most cases are sporadicvan Kleef M et al. Pain Practice. 2009;9:252-259.Rozen TD. Neurol Clin. 2004;22:185-206.Katusic S et al. Neuroepidemiology. 1991;10:276-281.Obermann M et al. Expert Review of Neuropathics. 2009;7:323-329.Rozen TD et al. Wolff's Headache and Other Head Pain. Oxford University Press, 2001.Fleetwood IG et al. J Neurosurg. 2001;95:513-517.

Pathophysiology

Proximal compression of the trigeminal nerve close to the brain stem by a twisted, dilated, and/or distended blood vessel Leads to a mechanical twist or compression of the

nerve fibers, secondary demyelination This demyelination is probably due to ischemic damage

Changes lower excitability threshold of the affected fibers Promotes inappropriate ephaptic impulse propagation

High frequency discharges result, followed by a brief period of latency Marinkovic S et al. Headache. 2007;47:1334-1339.

Burchiel KJ. J Neurosurg. 1980;53:674-683.Forssell H et al. Neurology. 2007;69:1451-1459.

Trigeminal Nerve

Pain is limited to one or more distributions of the trigeminal (5th Cranial) nerve

V1 (Ophthalmic) only: 4% V2 (Maxillary) only: 17% V3 (Mandibular) only: 15% V2 + V3: 32% V1 + V2: 14% V1 + V2 + V3: 17%

Rozen TD. Neurol Clin. 2004;22:185-206.

Two Types of Trigeminal Neuralgia

Classic (Essential or Idiopathic) Absence of clinically relevant neurological

deficit

Symptomatic Pain indistinguishable from that of classic TN

but caused from a demonstrable structural lesion

Obermann M et al. Expert Review of Neuropathics. 2009;7:323-330.

Symptoms

Character/Severity Sharp or shooting Electric or lightning Terrifying Unbearable Moderate to Severe

Timing Paroxysmal Acute onset < 2 minutes per attack

Can be only a few seconds Periods of complete

remission Can last weeks to months

Site Unilateral

97% of cases Along trigeminal nerve

branches Not common along the first

division

Precipitating Factors Light touch to the area Spontaneous in nature May have trigger points Certain tasks

i.e. Teeth brushing, chewing Rarely affects sleep

Zakrzewska JM. Expert Opin. Pharmacother. 2010;11:1239-1254.Obermann M et al. Expert Review of Neuropathics. 2009;7:323-330.

Non-Pharmacologic Options

Considered to be second-line after failure of pharmacologic management Either single agent or combination regimens

Two Types

Destructive: ablative; nerve function is intentionally & selectively destroyed

Nondestructive: nerve is decompressed to preserve the original function

Obermann M et al. Expert Review of Neuropathics. 2009;7:323-330.

Non-Pharmacologic Options Gasserian ganglion percutaneous techniques

All destructive Include:

Radiofrequency thermocoagulation (RFT) Balloon compression Percutaneous glycerol rhizolysis (PGR)

Success Rates: Initial: 90% 12 months: 68-85% 36 months: 54-64% 60 months: 50%

Adverse Events: Sensory loss (50%), dysethesias (6%) Low mortality from the procedure

Obermann M et al. Expert Review of Neuropathics. 2009;7:323-330.Zakrzewska JM et al. Pain. 1999;79:51-58.


Microvascular Decompression Craniectomy to evaluate nerve for vascular

compression near the entrance to the brain stem Compressive arteries and veins are repositioned with

stents while some veins are electrocoagulated and divided

Outcomes: Initial: 90% 12 months: 80% 36 months: 75% 60 months: 73%

Adverse Events: 0.2-0.5% mortality associated with surgery 4% suffer from CSF Leakage, infarcts, or hematomas Aseptic meningitis (11%), sensory loss (7%), hearing loss (10%)

Obermann M et al. Expert Review of Neuropathics. 2009;7:323-330.Barker FG 2nd et al. N Eng J Med. 1996;334:1077-1082


Gamma knife radiosurgery Produces lesions by means of focused gamma

radiation

Aimed at proximal trigeminal root

Pain relief can take up to one month to occur

Efficacy: Pain relief at 12 months was 69% and at 36 months decreased

to 50% At 3 months pain relief is noted around 75%

Gronseth G et al. Neurology. 2008;71:1183-1190.

Pharmacologic Therapy

Considered first-line Carbamazepine is the drug of choice for

pain control in this population Only FDA-Approved drug for trigeminal

neuralgia Dosed 100 – 200 mg PO BID initially &

titrated upward by 200 mg daily increments as tolerated Average maintenance dose: 600 – 800 mg daily Max recommended is 1,200 mg

Gronseth G et al. Neurology. 2008;71:1183-1190.Tegretol® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2011.


Carbamazepine Adverse Effects: Toxic epidermal necrolysis and Stevens-Johnson

Syndrome Aplastic anemia Agranulocytosis Suicidal ideation Dizziness Drowsiness Nausea Vomiting Liver failure Chronic Heart Failure

Gronseth G et al. Neurology. 2008;71:1183-1190.Tegretol® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2011.


Other first-line agents: Oxcarbazepine

Not FDA-approved indication 600-1800 mg/day Better safety profile than carbamazepine

Second-line agents: Not as clear; add-on or switch to different entity entirely Drugs include:

Gronseth G et al. Neurology. 2008;71:1183-1190.Beydoun A. Pharmacotherapy. 2000;20:152-158.Obermann M et al. Expert Review of Neuropathics. 2009;7:323-330.

Lamotrigine Botulinum toxin type APhenytoin SummatriptanClonazepam PimozideGabapentin TizanidineTopiramate ValproateBaclofen Pregabalin

Lamotrigine Botulinum toxin type APhenytoin SummatriptanClonazepam PimozideGabapentin TizanidineTopiramate ValproateBaclofen Pregabalin

Pregabalin (Lyrica©)

First approved in December 2004 by the FDA to treat neuropathic pain associated with diabetic peripheral neuropathy (DPN) and postherpetic neuralgia (PHN)

Structurally related to GABA

Mechanism of Action: Exact mechanism has not been elucidated Binds with high affinity to the alpha2-delta site (an

auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues

GABA

pregabalin

Lyrica© [package insert]. New York, NY: Pfizer Inc; 2011.



FDA-Approved Indications & Dosages Neuropathic pain associated with diabetic peripheral

neuropathy (DPN) 150 mg/day divided TID; titrate up to a max of 300 mg/day within 1 week

Post herpetic neuralgia (PHN) 150 mg/day divided BID – TID; titrate up to a max of 300 mg/day within 1

week Total max daily dose beyond 1 week is 600 mg/day

Adjunctive therapy for adult patients with partial onset seizures 150 mg/day divided BID – TID; max daily dosage of 600 mg/day

Fibromyalgia 150 mg/day divided BID; titrate up to a max of 300 mg/day within 1 week Total max daily dose beyond 1 week is 450 mg/day



Adverse Events:


- Dizziness- Somnolence- Dry Mouth- Edema- Blurred Vision- Weight Gain- Thinking Abnormalities:

- Difficulty with concentration/attention

- Dizziness- Somnolence- Dry Mouth- Edema- Blurred Vision- Weight Gain- Thinking Abnormalities:

- Difficulty with concentration/attention


Warnings/Precautions:


- Angioedema- Hypersensitivity reaction- Increased seizure frequency if rapidly discontinued- Increased risk of suicidal thoughts- Peripheral edema- Dizziness & somnolence may affect ability to operate machinery- Pregnancy Category C- Schedule V controlled substance

- Angioedema- Hypersensitivity reaction- Increased seizure frequency if rapidly discontinued- Increased risk of suicidal thoughts- Peripheral edema- Dizziness & somnolence may affect ability to operate machinery- Pregnancy Category C- Schedule V controlled substance


Pharmacokinetics: Absorption:

Oral bioavailability ≥90% Cmax: 1.5 hours

Distribution: No protein binding 0.5 L/kg VD

Metabolism: Negligible metabolism; 90% unchanged in urine No CYP P450 interactions

Excretion: T1/2: 6.3 hours


Summary

Trigeminal neuralgia A painful disorder characterized by the

sporadic, sudden onset, of neuropathic pain that generally passes quickly

Compression and ischemic damage to the 5th cranial nerve is thought to be the cause

Treatment options include anticonvulsants, with carbamazepine being the only FDA-approved medication, or surgery

Pregabalin (Lyrica©) Pregabalin is an alpha2-delta binder which

possesses analgesic and anticonvulsant properties and is approved to treat neuropathic pain and prevent seizures

Efficacy of Pregabalin in the Treatment of

Trigeminal Neuralgia

Obermann M, Yoon MS, Sensen K et al.

Cephalalgia.2008;28:174-181.

Study Design

Prospective, open-label, single-center, uncontrolled, non-randomized trial

Obermann M et al. Cephalalgia. 2007;28:174-178.

Study Objectives

Prospectively assess the efficacy of pregabalin in relieving pain related to trigeminal neuralgia Evaluate in patients with and without

concomitant facial pain

Rationale: Clinical trials have demonstrated that

pregabalin is effective in treating other forms of neuropathic pain


Inclusion Criteria

Diagnosis of trigeminal neuralgia according to the International Classification of Headache Disorders (ICHD-II) criteria

Classical or symptomatic TN was permitted


ICHD-II Diagnostic Criteria

A. Paroxysmal attacks of pain lasting from a fraction of a second to 2 minutes, affecting one or more divisions of the trigeminal nerve and fulfilling criteria B & C

B. Pain has at least one of the following characteristics: Intense, sharp, superficial or stabbing Precipitated from trigger areas or trigger factors

C. Attacks are stereotyped in the individual patient D. There is no clinically evident neurological

damage E. Not attributed to another disorderLance J et al. The international classification of headache disorders 2nd edition. Cephalalgia. 2004; 24; Suppl 1:9-160.

Exclusion Criteria Pregnancy or lactation Other severe medical or psychiatric conditions Patients on the following medications:

Tricyclic antidepressants Opioids Serotonin/Norepinephrine Reuptake Inhibitors Phenothiazines Antiarrythmic agents Pteridine Antihistamines and macrolide antibiotics in

combination


Patient Enrollment & Assessment Recruited from a tertiary headache clinic

from August 2004 through May 2006

Examined by a board-certified neurologist

ECG & Diagnostic MRIs at baseline

Blood work included: Hematology, Chemistries, Endocrinology, and

UrineObermann M et al. Cephalalgia. 2007;28:174-178.

Primary Outcomes

Number of patients free of pain at 8 weeks Measured by a standardized daily pain diary

Verbal Rating Scale (VRS) for pain 0 = no pain through 10 = worst possible pain

Number of attacks per day

Number of patients with > 50% reduction of pain from baseline and attack frequency reduction >50% of baseline at 8 weeks


Secondary Outcomes

Sustained pain relief after 12 months Using the VRS previously described


Treatment Protocol

Previous neuropathic medications were stopped

Pregabalin dose was initiated at 75 mg/day and titrated up to a maximum of 600 mg/day Max increase of 75mg/week weeks 1-2 Increases of 150 mg/week beginning week 3 Titration based on pain relief


Treatment Protocol

Additional antineuropathic medications were allowed after week 8 if patients did not respond or wanted to intensify therapy

Aspirin for myocardial infarction prophylaxis & up to 3000 mg/ day of acetaminophen was permitted


Protocol Map


Statistics – Symptom Reduction Analysis of variance (ANOVA) for repeated

measures was used to assess symptom reduction VRS-pain scale scores at baseline, 4-weeks,

and 8-weeks Ordinal data

Attack frequency per day at baseline, 4-weeks, and 8-weeks Continuous data

ANOVA appropriate for continuous data


Statistics-Subgroup Analysis

Chi-square test was used to detect differences in the number of responders between the subgroups Concomitant facial pain No concomitant facial pain

Number of patients = 53 Type of Data = Nominal Done at 8 weeks and 1 year


Results-Demographics

Total of 53 patients enrolled in the study Mean age: 62.7 years old Female: 30 patients Baseline VRS: 8.4 ±1.3 Attacks per day: 14.2 ± 18.9 Episodic TN: 33 patients Concomitant facial pain: 14 patients


Results-Primary Outcomes


Pain Free at 8

weeks

Pain Reduction >50% and Attack

Frequency Reduction >50%

Non-Responde

rs

Number of

Patients

(%)

13

(25%)

26

(49%)

14

(26%)

Mean Daily Dose = 269.8 mg

Results – Symptom Reduction


OutcomePregabalin Group

(n=53)

ANOVA P-value(Baseline vs. 4-

weeks vs. 8-weeks)

VRS-pain score (baseline)

8.4 ±1.3 ---

# Attacks/day at (baseline)

14.2 ±18.9 ---

VRS-pain score (4-weeks)

Value not reported P < 0.001

# Attacks/day at (4-weeks)

Value not reported P = 0.001

VRS-pain score (8-weeks)

Value not reported P < 0.001

# Attacks/day at (8-weeks)

Value not reported P <0.001

Results – Secondary Outcomes

11 of 13 with complete pain response had sustained pain relief at 1 year

21 of 26 with >50 % reduction received additional medications and were pain free at the 6 months visitAdd on medications were

carbamazepine (18) and lamotrigine (3)


Results – Follow-Up

Non-responders, n=14

10 discontinued pregabalin within the first 8 weeks Switched to carbamazepine or lamotrigine

4 continued on pregabalin 300 mg/day with either carbamazepine or lamotrigine


Results – Subgroup Analysis

Concomitant Facial Pain (n=14) At 8 weeks follow up:

7 of 14 patients responded32 of 39 patients without respondedχ2 = 5.4; P = 0.02

At 12 months follow up: 9 of 14 responded 35 of 39 without concomitant facial pain (after

add on therapy)χ2 = 4.7; P = 0.03


Results – Safety

Adverse events reported in 22 patients (53%) Most common:

Dizziness (10 patients – 19%) Somnolence (8 patients – 15%) Headache (2 patients – 4%) Peripheral edema (1 patient – 2%) Dry mouth (1 patient – 2%)

Six patients prematurely stopped pregabalin due to severity in the first 8 weeks (11%)


Author’s Conclusion

Pregabalin might be effective in treating TN symptoms

Study design and low patient numbers make it difficult to know the extent of the benefit

Concomitant facial pain appears to be a predictor of poor treatment response

Patients did have a significant response being treated with pregabalin therapy warranting further studies


Trial Critique: Strengths

High number of patients accrued given prevalence of disease

Follow-up over the course of a year

First to look prospectively at pregabalin for this indication


Trial Critique: Weaknesses

Not blinded or controlled Lacked a placebo-controlled or current standard of

care comparison group

Open-label design introduces potential bias

Patients accrued from a tertiary referral center

Not a random population

May have downplayed benefit since the population was already refractory to treatment


Trial Critique: Weaknesses

Flawed statistical tests

Not a random sample

ANOVA was not appropriate for VRS-pain reduction

VRS-pain score is ordinal data

Mean daily dose for the first 8 weeks was misleading Doses were intentionally lower during the titration

period which lasted as long as 4 weeks in some patients


Other Literature

“Trigeminal neuralgia treated with pregabalin in family medicine settings: its effect on pain alleviation and cost reduction”

Citation: Pérez C, Saldaña MT, Navarro A, et al. J Clin

Pharmacol. 2009;49:582-590.

Other Literature

Secondary analysis of a subgroup of TN patients from a larger prospective 12-week, multicenter, observational study

Objective: Compare add-on versus monotherapy with

pregabalin in this sub-group of patients

Pérez C, Saldaña MT, Navarro A, et al. J Clin Pharmacol. 2009;49:582-590.

Other Literature

n = 65 pregabalin-naïve patients Monotherapy (n = 36) Add-on therapy (n = 29)

Outcomes: Pain score reduction Health care resources Productivity measures Associated costs


Other Literature

Results Significant reduction in pain scores, health

care resources, and number of Lost Workdays Equivalents (LWDEs)

Additional cost of pregabalin was compensated by a reduction in: Health care costs (P < 0.001) Indirect costs (P <0.001)


Other Literature

Author’s conclusion: Pregabalin as monotherapy or in combination

is effective in pain management in patients with TN and reduces the cost of illness

Strengths: Prospective study

Weaknesses: Secondary analysis Open-label, non-randomized, observational

study


Conclusion

The evidence is currently not strong enough to recommend using pregabalin in TN patients Could consider in refractory cases looking

to avoid surgery Important to consider that these positive

results are from poorly conducted studies with lots of potential bias Two, uncontrolled, open-label, non-randomized

trials

Case Study

PP is a 51 yo female presenting with sharp, bilateral, and intermittent facial pain, currently controlled; s/p two microvascular decompression surgeries (1992 & 2002) on R & L side for tx of typical and atypical trigeminal neuralgia, respectively

PMH: Non-contributory FHx: Non-contributory Meds: topiramate 300 mg orally BID Allergies: carbamazepine, phenytoin (documented toxic

epidermal necrolysis); gabapentin (intolerable drowsiness, confusion)

SHx: (+)Social EtOH; (-) tobacco, quit in 2010

Case Study

PP is currently interested in trying another agent for the management of her pain due to side effects from topiramate Complains of memory issues and cognitive decline She heard Lyrica© could be used for her condition

Her physician calls and asks for your recommendation

Case Study Recommendation Strong evidence in favor of pregabalin in

this patient population is not available An adverse effect of pregabalin is

thinking abnormalities Specifically difficulty with

concentration/attention Given the evidence available and the

similar adverse event profiles, I would not recommend a trial with pregabalin at this time

Questions?

Ed Paiewonsky

PharmD Candidate Class of 2012

University of Pittsburgh School of Pharmacy

[email protected]

September 26, 2011

Health & Medicine

Pregabalin (Lyrica©) for the Management of Pain Associated with Trigeminal Neuralgia