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

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The document discusses the use of pregabalin (Lyrica©) for off-label treatment of trigeminal neuralgia, a condition characterized by sudden, severe facial pain. It reviews the epidemiology, pathophysiology, and current treatment options, with a focus on pharmacological therapies, primarily highlighting carbamazepine as the FDA-approved drug and discussing pregabalin's efficacy. A case study is included to illustrate a patient seeking alternative management due to side effects from other medications.

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PREGABALIN (LYRICA©) FOR THE OFF-LABEL TREATMENT OF PAIN ASSOCIATED WITH TRIGEMINAL NEURALGIA Ed Paiewonsky PharmD Candidate Class of 2012 University of Pittsburgh School of Pharmacy esp13@pitt.edu 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 that is 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 sporadic van 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  Site  Sharp or shooting  Unilateral  Electric or lightning  97% of cases  Terrifying  Along trigeminal nerve branches  Unbearable  Not common along the first division  Moderate to Severe  Timing  Precipitating Factors  Light touch to the area  Paroxysmal  Spontaneous in nature  Acute onset  May have trigger points  < 2 minutes per attack  Can be only a few seconds  Certain tasks  i.e. Teeth brushing, chewing  Periods of complete remission  Can last weeks to months  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.
Non-Pharmacologic Options  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
Non-Pharmacologic Options  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  OnlyFDA-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.
Pharmacologic Therapy  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.
Pharmacologic Therapy  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: Lamotrigine Botulinum toxin type A Phenytoin Summatriptan Clonazepam Pimozide Gabapentin Tizanidine Topiramate Valproate Baclofen Pregabalin 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.
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 GABA  Mechanism of Action: pregabalin  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 Lyrica© [package insert]. New York, NY: Pfizer Inc; 2011.
Pregabalin (Lyrica©)
Pregabalin (Lyrica©)  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 Lyrica© [package insert]. New York, NY: Pfizer Inc; 2011.
Pregabalin (Lyrica©)  Adverse Events: - Dizziness - Somnolence - Dry Mouth - Edema - Blurred Vision - Weight Gain - Thinking Abnormalities: - Difficulty with concentration/attention Lyrica© [package insert]. New York, NY: Pfizer Inc; 2011.
Pregabalin (Lyrica©)  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 Lyrica© [package insert]. New York, NY: Pfizer Inc; 2011.
Pregabalin (Lyrica©)  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 Lyrica© [package insert]. New York, NY: Pfizer Inc; 2011.
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 Obermann M et al. Cephalalgia. 2007;28:174-178.
Inclusion Criteria  Diagnosis of trigeminal neuralgia according to the International Classification of Headache Disorders (ICHD-II) criteria  Classical or symptomatic TN was permitted Obermann M et al. Cephalalgia. 2007;28:174-178.
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 disorder Lance 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
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 Urine Obermann 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
Secondary Outcomes  Sustained pain relief after 12 months  Using the VRS previously described Obermann M et al. Cephalalgia. 2007;28:174-178.
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 Obermann M et al. Cephalalgia. 2007;28:174-178.
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 Obermann M et al. Cephalalgia. 2007;28:174-178.
Protocol Map Obermann M et al. Cephalalgia. 2007;28:174-178.
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 Obermann M et al. Cephalalgia. 2007;28:174-178.
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 Obermann M et al. Cephalalgia. 2007;28:174-178.
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 Obermann M et al. Cephalalgia. 2007;28:174-178.
Results-Primary Outcomes Pain Reduction >50% Pain Free at Non- and Attack Frequency 8 weeks Responders Reduction >50% Number of 13 26 14 Patients (25%) (49%) (26%) (%) Mean Daily Dose = 269.8 mg Obermann M et al. Cephalalgia. 2007;28:174-178.
Results – Symptom Reduction ANOVA P-value Pregabalin Group Outcome (Baseline vs. 4-weeks vs. (n=53) 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
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 visit  Add on medications were carbamazepine (18) and lamotrigine (3) Obermann M et al. Cephalalgia. 2007;28:174-178.
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 Obermann M et al. Cephalalgia. 2007;28:174-178.
Results – Subgroup Analysis  Concomitant Facial Pain (n=14)  At 8 weeks follow up:  7 of 14 patients responded  32 of 39 patients without responded  χ2 = 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
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%) Obermann M et al. Cephalalgia. 2007;28:174-178.
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 Obermann M et al. Cephalalgia. 2007;28:174-178.
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 Obermann M et al. Cephalalgia. 2007;28:174-178.
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 Obermann M et al. Cephalalgia. 2007;28:174-178.
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 Obermann M et al. Cephalalgia. 2007;28:174-178.
Other Literature  “Trigeminal neuralgia treated with pregabalin in family medicine settings: its effect on pain alleviation and cost reduction”  Citation:  PérezC, 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 Pérez C, Saldaña MT, Navarro A, et al. J Clin Pharmacol. 2009;49:582-590.
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) Pérez C, Saldaña MT, Navarro A, et al. J Clin Pharmacol. 2009;49:582-590.
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 Pérez C, Saldaña MT, Navarro A, et al. J Clin Pharmacol. 2009;49:582-590.
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 esp13@pitt.edu September 26, 2011

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

  • 1. PREGABALIN (LYRICA©) FOR THE OFF-LABEL TREATMENT OF PAIN ASSOCIATED WITH TRIGEMINAL NEURALGIA Ed Paiewonsky PharmD Candidate Class of 2012 University of Pittsburgh School of Pharmacy esp13@pitt.edu September 26, 2011
  • 2. 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
  • 3. 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
  • 4. 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
  • 5. 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 that is neuropathic in origin Elias WJ et al. Curr Pain Headache Rep. 2002;6:115-124. Pėrez C et al. Cephalalgia. 2009;29:781-790.
  • 6. 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 sporadic van 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.
  • 7. 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.
  • 8. 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.
  • 9. 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.
  • 10. Symptoms  Character/Severity  Site  Sharp or shooting  Unilateral  Electric or lightning  97% of cases  Terrifying  Along trigeminal nerve branches  Unbearable  Not common along the first division  Moderate to Severe  Timing  Precipitating Factors  Light touch to the area  Paroxysmal  Spontaneous in nature  Acute onset  May have trigger points  < 2 minutes per attack  Can be only a few seconds  Certain tasks  i.e. Teeth brushing, chewing  Periods of complete remission  Can last weeks to months  Rarely affects sleep Zakrzewska JM. Expert Opin. Pharmacother. 2010;11:1239-1254. Obermann M et al. Expert Review of Neuropathics. 2009;7:323-330.
  • 11. 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.
  • 12. 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.
  • 13. Non-Pharmacologic Options  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
  • 14. Non-Pharmacologic Options  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.
  • 15. Pharmacologic Therapy  Considered first-line  Carbamazepine is the drug of choice for pain control in this population  OnlyFDA-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.
  • 16. Pharmacologic Therapy  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.
  • 17. Pharmacologic Therapy  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: Lamotrigine Botulinum toxin type A Phenytoin Summatriptan Clonazepam Pimozide Gabapentin Tizanidine Topiramate Valproate Baclofen Pregabalin 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.
  • 18. 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 GABA  Mechanism of Action: pregabalin  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 Lyrica© [package insert]. New York, NY: Pfizer Inc; 2011.
  • 20. Pregabalin (Lyrica©)  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 Lyrica© [package insert]. New York, NY: Pfizer Inc; 2011.
  • 21. Pregabalin (Lyrica©)  Adverse Events: - Dizziness - Somnolence - Dry Mouth - Edema - Blurred Vision - Weight Gain - Thinking Abnormalities: - Difficulty with concentration/attention Lyrica© [package insert]. New York, NY: Pfizer Inc; 2011.
  • 22. Pregabalin (Lyrica©)  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 Lyrica© [package insert]. New York, NY: Pfizer Inc; 2011.
  • 23. Pregabalin (Lyrica©)  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 Lyrica© [package insert]. New York, NY: Pfizer Inc; 2011.
  • 24. 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
  • 25. Efficacy of Pregabalin in the Treatment of Trigeminal Neuralgia Obermann M, Yoon MS, Sensen K et al. Cephalalgia. 2008;28:174-181.
  • 26. Study Design  Prospective, open-label, single-center, uncontrolled, non-randomized trial Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 27. 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 28. Inclusion Criteria  Diagnosis of trigeminal neuralgia according to the International Classification of Headache Disorders (ICHD-II) criteria  Classical or symptomatic TN was permitted Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 29. 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 disorder Lance J et al. The international classification of headache disorders 2nd edition. Cephalalgia. 2004; 24; Suppl 1:9-160.
  • 30. 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 31. 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 Urine Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 32. 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 33. Secondary Outcomes  Sustained pain relief after 12 months  Using the VRS previously described Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 34. 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 35. 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 36. Protocol Map Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 37. 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 38. 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 39. 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 40. Results-Primary Outcomes Pain Reduction >50% Pain Free at Non- and Attack Frequency 8 weeks Responders Reduction >50% Number of 13 26 14 Patients (25%) (49%) (26%) (%) Mean Daily Dose = 269.8 mg Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 41. Results – Symptom Reduction ANOVA P-value Pregabalin Group Outcome (Baseline vs. 4-weeks vs. (n=53) 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 42. 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 visit  Add on medications were carbamazepine (18) and lamotrigine (3) Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 43. 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 44. Results – Subgroup Analysis  Concomitant Facial Pain (n=14)  At 8 weeks follow up:  7 of 14 patients responded  32 of 39 patients without responded  χ2 = 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 45. 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%) Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 46. 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 47. 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 48. 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 49. 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 Obermann M et al. Cephalalgia. 2007;28:174-178.
  • 50. Other Literature  “Trigeminal neuralgia treated with pregabalin in family medicine settings: its effect on pain alleviation and cost reduction”  Citation:  PérezC, Saldaña MT, Navarro A, et al. J Clin Pharmacol. 2009;49:582-590.
  • 51. 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.
  • 52. 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 Pérez C, Saldaña MT, Navarro A, et al. J Clin Pharmacol. 2009;49:582-590.
  • 53. 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) Pérez C, Saldaña MT, Navarro A, et al. J Clin Pharmacol. 2009;49:582-590.
  • 54. 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 Pérez C, Saldaña MT, Navarro A, et al. J Clin Pharmacol. 2009;49:582-590.
  • 55. 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
  • 56. 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
  • 57. 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
  • 58. 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
  • 59. Questions? Ed Paiewonsky PharmD Candidate Class of 2012 University of Pittsburgh School of Pharmacy esp13@pitt.edu September 26, 2011

Editor's Notes

  • #2: My rationale for selecting this topic is that a close family member of mine was diagnosed with the condition when I was young. As per the case presentation, the pain symptoms have been adequately controlled however she complains of adverse events related to topiramate therapy Given her past pharmacologic failures I wanted to look into the literature and see if there was any good evidence available to support a trial with pregabalin.
  • #3: BY THE END OF THIS PRESENTATION YOU WILL BE ABLE TO [SLIDE]
  • #4: Intolerable droswiness despite adequate titration and length of therapeutic trial
  • #6: The term “Tic Doloureux” was coined in 1756 and means “painful jerking” Reported in ancient literature as early as 980 AD in Arabic text, treatment for TN has been documented as early as 1677 by Locke who used sulphuric acid, applied topically to the face, to try and cure the Dutchess of Northumberland from the disease which he described as “a fit of violent and exquisite torment that extended over the right side of her face and mouth” Intermittent and recurrent ; it has been described as “the worst pain in the world” by Dr. Peter Jannetta, the physician who pioneered microvascular decompression surgery, a treatment option for TN Generally one-sided in nature although it has occurred bilaterally in some TN patients
  • #7: Most cases are sporadic meaning there does not appear to be a genetic or familial link to the disease Approximately 2% of multiple sclerosis patients complain of TN and this appears to be related to the demyelniation of the nerves associated with MS. I will discuss how this relates to TN shortly
  • #8: Pathophysiology is not well understood eph·ap·tic: adj :  relating to or being electrical conduction of a nerve impulse across an ephapse without the mediation of a neurotransmitter
  • #11: Periods of complete remission UNLESS ATYPICAL WHERE CONSTANT, DULL BACKRGOUND PAIN PERSIST Quality of life can be greatly reduced because, over-time, the remission periods can shorten and patients will avoid eating or other simple tasks for fear of setting off the attack
  • #13: Radiofrequency thermocoagulation rhizotomy, which creates a lesion by application of heat Mechanical balloon compression, which uses a Fogarty catheter to compress the gasserian ganglion Chemical (glycerol) rhizolysis, which involves the injection of 0.1 to 0.4 mL of glycerol into the trigeminal cistern Dysethesia =&gt; abnormal sensations as a result of the nerve damage
  • #14: Electrocoagulation: a therapeutic destructive form of electrosurgery in which tissue is hardened by the passage of high-frequency current from an electric cautery device. Hematoma: localized swelling filled with blood resulting from a break in a blood vessel.
  • #15: Aimed at proximal trigeminal root because t argeting the gasserian ganglion produced poor results
  • #16: Surgical interventions should be considered in those refractory to pharmacologic therapy
  • #17: TEN and SJS in 1 to 6 per 10,000 new users; IN COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B*1502, AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING TREATMENT WITH TEGRETOL. PATIENTS TESTING POSITIVE FOR THE ALLELE SHOULD NOT BE TREATED WITH TEGRETOL UNLESS THE BENEFIT CLEARLY OUTWEIGHS THE RISK Aplastic anemia : body cant produce enough RBCs due to damage to the bone marrow Agrnulocytosis: depletion of leukocytes (WBCs), specifically neutrophils
  • #19: Structurally related to: the inhibitory neurotransmitter gamma- aminobutyric acid While pregabalin is a structural derivative of GABA, it does not bind directly to GABAA, GABAB, or benzodiazepine receptors this binding is thought to be involved in the anti-nociceptive and antiseizure effects
  • #20: This is an image of and excitatory, glutamatergic synapse. Red dots represent glutamate. Presynaptic targets diminishing glutamate release include the VG-Ca 2+ channels targeted by pregabalin. Other drugs which act here are also used to treat TN off-label and include lamotrigine and gabapentin
  • #22: Occurred in greater than or equal to 5% of patients and twice the placebo Withdraw lyrica over a minimum of 1 week
  • #24: Because pregabalin is not bound to plasma proteins this clearance rate indicates that renal tubular reabsorption is involved. Pregabalin elimination is nearly proportional to creatinine clearance (CLcr) In comparison, Tegretol is 76% protein bound and has CYP 3A4 implications; it is an auto-inducer of its own metabolism Given that patient population usually affected by TN is the elderly, a drug like pregabalin, with no CYP 450 interactions, minimal metabolism, and no protein binding, hence an elimination rate proportional to CrCl, is a potentially attractive agent from a safety standpoint.
  • #27: Published in 2007 in Cephalagia
  • #30: This criteria is for classical TN. The difference in diagnostic criteria for symptomatic TN is that D &amp; E are replaced with: “ D. A causitive lesion, other than vascular compression has been demonstrated by special investigations &amp;/or posterior fossa exploration”
  • #31: Phenothiazines Antiarrythmic agents Pteridine Antihistamines and macrolide antibiotics in combination DUE TO PROARRYTHMIC PROPERTIES OF THESE MEDICATIONS
  • #33: This diary was completed on a daily basis for weeks 1-8 then 4 weeks prior to each follow up session
  • #38: In terms of baseline statistics, the Study was not randomized and there was only one treatment group so Intent-to-treat analysis and baseline statistical differences between groups do not apply in this study
  • #39: This test was appropriate. The data being analyzed was nominal data (Did they respond, Y or N?) The number of patients exceeded 40 so a Fischer’s exact test would not have been appropriate
  • #40: VRS range was 4-10 Frequency of Attack was 2-100 Looked at episodic vs symptomatic vs TNcp
  • #41: Mean daily dose was not very informative because a titration schedule was used; it would have been more beneficial to present the numbers of patients at each dosage level at the 8 week point
  • #42: Did not report specific numbers of patients or the groups from which these patients came from Again, ANOVA was not appropriate to compare data from a VRS-scale because this is ordinal data and ANOVA should be reserved for continuous data
  • #43: Range of 150-600 mg/day Other 2 had mild recurrent attacks at 7 &amp; 9 months respectively but refused additional medications
  • #46: Dizziness and somnolence were commonly reported in the titration phase but resolved after 2 weeks in most patients (19 of 22  86%) Severity was dose-dependent; the 600/d group (only 2 patients) had peripheral oedema, dry mouth, and headache
  • #47: This is a concern across all TN treatments and may not be correlate with the efficacy of pregabalin in the majority of patients with TN and no concomitant pain
  • #49: By not blinding the study, the Author;s introduce a great deal of potential bias into this study. The benefit of pregabalin could be overestimated due to this bias Patients accrued from a tertiary referral center this introduces potential selection bias because these patients could be considerably more refractive to treatment than the typical, newly diagnosed TN patient (only 3 patients had not tried at least one other medication out of the 53 in the study prior to enrollment);, the internal validity is also compromised bc you do not have two groups equal at baseline to compare an intervention like you would in a randomized, placebo-controlled trial.
  • #50: ANOVA requires that the group is a random sample from the population of interest **ANOVA only should be used with continuous data, such as number of attacks per day.
  • #55: Short Form McGill Pain Questionairre
  • #57: Intolerable droswiness despite adequate titration and length of therapeutic trial
  • #59: Given her past therapeutic failures and complicated disease course, combined with the lack of evidence for pregabalin in TN, I would not recommend trying it in this patient. The cognitive ADE’s appear similar between the two agents, further pushing me to recommend that a trial with this agent would not benefit the patient, especially since her pain is controlled.