Executive Summary Pregabalin (Lyrica by Pfizer) Formulary Review

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1 Executive Summary Pregabalin (Lyrica by Pfizer) Formulary Review Lyrica (pregabalin) is a new prescription medication indicated for use in painful diabetic peripheral neuropathy (DPN), post-herpetic neuralgia, and as adjunct therapy for partial seizures. Off-label uses of pregabalin include generalized anxiety disorder (for which the FDA denied the application), fibromyalgia, and dental pain. This review will focus on the treatment of DPN. Pregabalin is pharmacologically similar to gabapentin, another agent used in these indications. Pregabalin and gabapentin bind to the same receptor, and elicit the same response. Pregabalin is six times more potent than gabapentin. Four randomized placebo-controlled studies demonstrated the efficacy of pregabalin in relieving painful diabetic peripheral neuropathy. Regimens of 300 mg daily (given bid or ) achieved a greater than 50% reduction in pain in about 0-50% of patients, with a corresponding NNT=-5. Common side effects of pregabalin use include dizziness and somnolence. Weight gain and peripheral edema are also fairly common, especially when given with a thiazolidinedione, an agent commonly prescribed for diabetics. In pregabalin trials of DPN, the Numbers Needed to Treat (NNTs) ranged from -5 to achieve a 50% reduction in pain over 5 to 12 weeks of treatment. The pregabalin NNTs are similar to those measured in trials of other agents treating DPN. In addition to clinical trials, the older agents have extensive treatment experience for the treatment of DPN and other neuropathic pain conditions. There are no trials available to determine the effectiveness of pregabalin in the long-term treatment of DPN. Pregabalin (sold as the brand Lyrica ) is more expensive than the majority of other agents used to treat these disease states, such as amitriptyline, nortriptyline, gabapentin, carbamazepine, and phenytoin. The following table illustrates approximate costs for one patient to achieve a positive outcome using 300 mg daily. Disease State NNT (average) Duration Cost ($) Outcome DPN 6-8 weeks % reduction in pain score Because there are no studies comparing pregabalin with existing agents, and pregabalin offers no clinically significant safety advantages to gabapentin, and the cost of pregabalin exceeds that of other agents, there is no compelling reason to add pregabalin to the formulary at this time for the treatment of DPN. Use should be limited for patients with DPN who have either failed a trial of formulary alternatives or have a contraindication. Page 1 of 8

2 Pregabalin (Lyrica by Pfizer) Formulary Review Key Questions: 1. Is pregabalin more effective than current therapy in the treatment of diabetic peripheral neuropathy? 2. Is pregabalin safer than currently used agents such as gabapentin and TCAs? 3. Does pregabalin offer increased value compared with currently used agents?. Should pregabalin be added to the formulary? 5. Are there any restrictions that should be placed on pregabalin usage? Indications Pregabalin is approved by the FDA for the following indications: Painful Diabetic Peripheral Neuropathy (DPN) Post-Herpetic Neuralgia Adjunct therapy for Partial Seizures This review will focus on the use of pregabalin for DPN. Off-Label Uses The FDA denied approval for the use of pregabalin in generalized anxiety disorder. Studies have been performed evaluating the use of pregabalin in social anxiety disorder, fibromyalgia, and dental pain. Brief Overview of Diabetic Peripheral Neuropathy Peripheral neuropathy is a common complication of diabetes mellitus estimated to affect 20-2% of patients with diabetes. Other estimates place the amount of patients suffering from painful diabetic neuropathy at more than 3 million. 1 The exact cause of the neuropathy is unknown. Painful diabetic neuropathy often presents as burning or aching pain, with allodynia (super-sensitivity) also common. Pain generally starts at the distal ends of the limbs (fingers and toes) and progresses toward the torso. Diabetic neuropathy can lead to numbness in the limbs, ulcerations, and eventual amputation if not controlled. Prevention involves strict glucose control. High cholesterol, tobacco use, hypertension, and excessive alcohol use accelerate progression of the disease. Control of these factors slows the onset and development of DPN. Treatment involves a variety of pharmaceutical agents 2,3,. The Fourth International Conference on the Mechanisms and Treatment of Neuropathic Pain designated tricyclic anti-depressants (TCAs), gabapentin, opioids, tramadol, and the 5% lidocaine patch as first line agents. These agents were chosen because of positive results in multiple randomized controlled trials. Since publication, the SNRI duloxetine has been FDA approved for neuropathic pain. According to the Conference, choice between the first-line agents should take into account the cost of the agent, as well as the effects of side effects on the patient. They recommend caution in the use of TCAs in elderly patients due to anticholinergic side effects and adverse cardiac events. In addition, gabapentin, tramadol and opioids must be used cautiously in older patients due to side effects affecting cognitive and motor skills. Tramadol and opioids also carry a risk of dependence. Gabapentin and TCAs are considered to have a slower onset of pain relief, due to the need for titration of these drugs. The Conference does not make any statements concerning the relative efficacy between the first-line agents. Clinical Pharmacology Pregabalin is a structural analog of GABA, similar to gabapentin. It binds to the 2- protein, which is associated with voltage-gated calcium channels. Binding at this site reduces calcium influx at nerve terminals, and reduces the release of several neurotransmitters, including glutamate, norepinephrine, and substance P. This activity results in analgesic, anxiolytic, and anticonvulsant effects. Pregabalin is six times more potent than gabapentin in 2- binding. Pregabalin does not show activity at GABA receptors, and it does not affect uptake or degradation of GABA.5. Page 2 of 8

3 Pharmacokinetics (5,6) Parameter Pregabalin Gabapentin Route Oral Oral Time to Peak 1 hour 1.5- hours Bioavailability 90% 60% Absorption Linear Saturated (F=33% for 1200 mg q8hr) T1/ hrs 5-7 hrs Metabolism Negligible Negligible Elimination Renal (92-99%) Renal (76-81%) Fecal (10-23%) Protein Bind None <3% Food Effect Time to peak prolonged, no change in AUC Slight increase in AUC, Cmax The main difference between pregabalin and gabapentin relating to pharmacokinetics is that pregabalin has linear absorption whereas gabapentin has saturable absorption, for which the clinical implications are uncertain. Clinical Efficacy Four randomized, placebo-controlled studies were reviewed for evidence of efficacy in diabetic peripheral neuropathy The studies enrolled adult patients with HbA1C<11% and a minimum of a 6-12 month history of symmetric peripheral pain in the distal extremities. There were approximately 80 patients per treatment group in the studies, and trials lasted from 5-12 weeks. Primary endpoints included mean pain score and the percentage of patients achieving a 50% reduction in pain. Pain score improvements >30% are considered clinically relevant. About 0-50% of patients in the pregabalin groups receiving 300 mg daily experienced a 50% reduction in pain. Mean pain scores decreased about points on an 11 point scale. NNTs ranged from -5 to achieve a 50% reduction in pain over 8 to 15 weeks of treatment. Pregabalin has not been directly compared to gabapentin or TCAs. The pregabalin NNTs are similar to data from separate trials of these agents for treating DPN. In addition to clinical trials, the older agents have extensive treatment experience for the treatment of DPN and other neuropathic pain conditions. There are no trials to determine the effectiveness of pregabalin in the long-term treatment of DPN. The FDA review panel faulted the Lesser and Rosenstock studies for using a flawed intent to treat policy in the statistical review. The studies each used a Last Observation Carried Forward (LOCF) method for analysis. Thus, when a patient discontinues the study, the last pain scores recorded are used as the final pain scores for that patient. This can overestimate efficacy, as a patient may experience pain relief, but be unable to continue taking the drug due to an adverse event. The FDA recommends a Baseline Observation Carried Forward (BOCF) method for patients discontinuing due to an adverse event. The FDA did perform statistical analysis of the data from the Lesser and Rosenstock trials and found efficacy for the pregabalin regimens of 300 mg or more daily. 11 Pain score data and responder rate were similar to the values reported using the LOCF method. The Richter and Freynhagen studies also used the LOCF method, but were not included in the FDA review package. Another observation is that the Lesser and Rosenstock studies excluded patients that had failed a previous trial of gabapentin for pain relief. Because gabapentin acts at the same receptor site as pregabalin, this exclusion may result in overestimating the overall efficacy of pregabalin when applied to the general population. Page 3 of 8

4 Adverse Effects (5,6) Adverse Effect Pregabalin Gabapentin Placebo Dizziness 23-29% 7-17% 5% Somnolence 13-16% 19% 3% Peripheral Edema 9-12% 2% 2% Asthenia -7% n/a 2% Weight Gain -6% reported 0% Adverse effect data was taken from package inserts and post-marketing data, not from a head to head comparison of pregabalin and gabapentin. The majority of adverse effects were dose-dependant. 5 Percentages shown were for the 300 mg to 600 mg per day range, which corresponds with clinical efficacy. The majority of the adverse effects were qualified as mild to moderate, and dropout rates due to adverse effects ranged from 10-30%, with higher doses resulting in higher dropout rates. Allergies and Interactions 5 Pregabalin is not an inducer, inhibitor, or substrate of the CYP-50 system. There are no known drugdrug interactions involving pregabalin. Concurrent use of pregabalin with a thiazolidinedione (rosiglitazone, pioglitazone) results in an increased risk of weight gain and peripheral edema. Warnings/Precautions/Contraindications 5 Withdrawal of Antiepileptic Drugs: As with all antiepileptic medications, abrupt withdrawal may result in increased seizure frequency. In addition, patients also experienced insomnia, nausea, headache, and diarrhea following abrupt withdrawal. Withdraw pregabalin over a course of at least 1 week. Tumorigenic potential: Pregabalin trials in mice resulted in a high incidence of hemangiosarcoma. It is not known how this translates to a human population. Dizziness/Somnolence: Patients need to be counseled concerning the risks of driving while taking pregabalin. Ophthalmological Effects: There is an increased risk of blurred vision with pregabalin use. Weight Gain and peripheral edema: There is an increased risk of weight gain and peripheral edema with pregabalin use. This risk was increased with concurrent use of a thiazolidinedione. Other effects: CK elevation, ECG changes, Decreased Platelet count. Dosage and Administration 5 Diabetic Peripheral Neuropathy: Pregabalin can be given with or without food. Dosing should be initiated at 50 mg, and can be increased to 100 mg within one week. Doses above 300 mg/day are poorly tolerated, and have not been found to improve outcomes. Pregabalin is renally cleared so the following adjustments should be made in patients with renal failure: Creatinine Clearance (ml/min) Total Pregabalin Daily Dose (mg/day) Dose Regimen BID or TID BID or TID QD or BID < QD Supplementary dose following hemodialysis mg mg (One time dose) Page of 8

5 Cost Drug Strength/Quantity AWP-15% or Usual Daily Cost of 30 Day MAC* Dose Supply ($) Lyrica 100 mg capsule mg Gabapentin 600 mg tablet mg mg tablet mg Nortriptyline 50 mg capsule mg q hs 3.60 Tramadol 50 mg tablet mg qid AWP based on Redbook 2006 and MAC based on Oregon State generic Maximum Allowable Cost pricing 3/2006. The cost to get one response to treatment (50% reduction in pain scores) is $1180. This calculation is based on the clinical trial NNT of for 2 months of treatment. Conclusions and Recommendations 1. Is pregabalin more effective than current therapy in the treatment of diabetic peripheral neuropathy? Pregabalin has been proven effective compared to placebo in clinical trials for the treatment of diabetic peripheral neuropathy. There are no trials available comparing pregabalin with current standard therapies. Since two of the four pregabalin trials excluded patients who failed previous gabapentin treatment and gabapentin and pregabalin have similar mechanisms of actions, patients who have already failed gabapentin are likely to be non-responders to pregabalin. A trial comparing pregabalin with gabapentin as well as with other available agents would be helpful to determine its place in therapy. At this time, pregabalin cannot be judged more effective than current therapy. 2. Is pregabalin safer than currently used agents such as gabapentin and TCAs? While pregabalin has not been directly compared with either of these agents, there is no compelling reason to believe that pregabalin will have a safer profile than gabapentin. 3. Does pregabalin offer increased value compared with currently used agents? Pregabalin has not been proven superior to currently used agents based on efficacy and safety and it has higher cost.. Should pregabalin be added to the formulary? As there are no trials showing pregabalin s superiority to other agents, and other agents have a longer history of use, pregabalin should not be added to the formulary at this time. Pregabalin should require a prior authorization. 5. Are there any restrictions that should be placed on pregabalin usage? Yes prior authorization should be required. Criteria for authorization includes: a. Age 18 years or older and b. Diagnosis of DPN and c. Contraindication or previous trial and failure of at least two formulary agents, including gabapentin and a TCA, resulting in inadequate efficacy or discontinuation based on side effects and d. Any previous treatment with gabapentin should be discontinued prior to starting pregabalin. e. Apply a quantity limit of 300mg per day and approve for 3 months f. Follow-up documentation of effectiveness of treatment with at least a 50% reduction in pain before approving continued therapy. Page 5 of 8

6 Ref/Study Design Rosenstock 25 center Design: MC,DB, PG,PC Lesser 5 center Design: MC,DB, PG,PC Patient Population Inclusion Criteria M/F >18 yo DM Type 1 or 2 Sym. Pain in Dist. Ext. for 1-5 yrs. pain diaries completed during baseline week with average pain on 11-point Likert scale Exclusions: pregnant, lactating, HbA1C>11%, ClCr<60mL/min, failure of gabapentin >1200 mg/day to treat pain, low WBC, PLT, neurologic disorders not related to DPN Study also excluded use of pain meds except for APAP Pt. Characteristics (St Dev.): Avg Age = 60 yo (11.) 56% Male 87.7% White 87% Type II DM 96% on anti-dm med 37% on insulin 80% on oral med Mean Duration of DM = 9. y (10.3) Inclusion Criteria M/F >18 yo DM Type 1 or 2 Sym. Pain in Dist. Ext. for 1-5 yrs. pain diaries completed during baseline week with average pain on 11-point Likert scale Exclusions: pregnant, lactating, HbA1C>11%, ClCr<60mL/min, failure of gabapentin >1200 mg/day to treat pain, low WBC, PLT, neurologic disorders not related to DPN Study also excluded use of pain meds except for APAP Pt. Characteristics (St Dev.): Avg Age = 60 yo (10.5) 60% Male 9% White 91% Type II DM 95% on anti-dm med 2% on Insulin 73% on oral meds ClCr = 98.1 ml/min (30.5) Drug Regimens n Duration End Points Results (CI / p-value) ARR PLA 69 8 weeks Primary: Mean Pain Score (Baseline/Conclusion) PLA (6.1/5.3) 75 PGB (6.5/.0) p = PGB 100 mg PLA PGB 25 mg (75mg/day) PGB 100 mg (300mg/day) PGB 200 mg (600mg/day) weeks (1 week titration period for 600 mg/day group) Mean Pain Score (avg. of last 7 daily diaries) % Responders (Reduction of >50% pain score to baseline) Secondary: SF-MPQ Daily Sleep Interference Score PGIC CGIC SF-36 POMS Primary: Mean Pain Score (avg. of last 7 daily diaries) % Responders (Reduction of >50% pain score to baseline) Secondary: SF-MPQ Daily Sleep Interference Score PGIC CGIC SF-36 POMS % Responder PLA 1.5% PGB 0% (p=0.001) SF-MPQ (VAS-Pain Conclusion) PLA PGB 0.83 (p=0.0002) PGIC (% reporting improvement) PLA 39% PGB 67% (p=0.00) Withdrawal Rates Due to AE s: PLA 3% PGB 11% Other Secondary Results: Results from the Sleep scores, CGIC, SF-36, and POMS all showed significant improvement for the PGB group over PLA Mean Pain Score (Baseline/Conclusion) PLA (6.6/5.06) PGB 75mg/day: (6.7/.91) p= PGB 300mg/day: (6.2/3.8) p= PGB 600mg/day: (6.2/3.6) p= % Responder PLA 18% PGB 300mg/day 6% (p=0.001) PGB 600mg/day 8% (p=0.001) SF-MPQ (VAS-Pain Conclusion) PLA 53.9 PGB 75mg/day 9.7 (p=0.297) PGB 300mg/day 37. (p=0.0001) PGB 600mg/day 3.8 (p=0.0001) PGIC (% much or very much improved) PLA 2.2% PGB 75mg/day Not Given PGB 300mg/day 55.7% (p=0.001) PGB 600mg/day 69.2% (p=0.001) Withdrawal Rates Due to AE s: PLA 3.1% PGB 75mg/day 2.6% PGB 300mg/day 3.7% PGB 600mg/day 12.2% 25.5% 28% 8% 28% 30% % 9.1% NNT/ NNH Comments Study required 70 patients per group to provide >90% power, lowers internal validity Excluding patients who have failed gabapentin may result in reduced external validity, as PGB and gabapentin share the same mechanism No titration phase may result in higher withdrawal rates due to early adverse effects Excluding pain meds improves internal validity, but may reduce external validity as this will not be general practice in the public Study required 80 patients per group to provide 90% power, lowers internal validity Titration phase of 1 week for the 600mg/day group. Excluding patients who have failed gabapentin may result in reduced external validity, as PGB and gabapentin share the same mechanism Excluding pain meds improves internal validity, but may reduce external validity as this will not be general practice in the public PLA group had more Type I DM patients than the PGB groups, may influence internal validity if there is a difference in pain response between Type I and Type II patients. Other Secondary Results: PGB 300mg/day and PGB 600 mg/day showed statistical superiority to PLA in the Sleep score, CGIC, and SF-36. PGB 300 mg/day showed significant superiority to PLA in the POMS tension/anxiety domain Abbreviations: PLA Placebo, PGB Pregabalin, MC - Multi Center, DB - Double blinded, PG - Parallel Group, PC - Placebo Controlled, ARR - Absolute Risk Reduction, NNT - Number Needed to Treat, CI Confidence Interval, DM Diabetes Mellitus, WBC White Blood Cell, PLT Platelets, DPN Diabetic Peripheral Neuropathy, SF-MPQ Short Form McGill Pain Questionnaire, SF-MPQ VAS Visual Analog Scale (0-100 scale of pain), PGIC Patient Global Impression of Change, CGIC Clinical Global Impression of Change, POMS Profile of Mood States Page 6 of 8

7 Ref/Study Design Richter 29 center Design: MC,DB, PG,PC Patient Population Inclusion Criteria M/F >18 yo DM Type 1 or 2 Sym. Pain in Dist. Ext. for 1-5 yrs. pain diaries completed during baseline week with average pain on 11-point Likert scale Exclusions: pregnant, lactating, HbA1C>11%,, neurologic disorders not related to DPN, serious medical conditions Study also excluded use of pain meds except for APAP Pt. Characteristics (St Dev.): Avg Age = 57 yo 60% Male 8% White 91% Type II DM HbA1c = 8.2 (1.) 9% on anti-dm med Drug Regimens n Duration End Points Results (CI / p-value) ARR PLA 82 6 weeks (2 Primary: Mean Pain Score (Baseline/Conclusion) week PLA (6.9/5.8) 79 titration PGB 150mg/day: (6.5/.9) p= period) PGB 600mg/day: (6.7/.3) p= PGB 50 mg (150mg/day) PGB 200 mg (600mg/day) 82 Mean Pain Score (avg. of last 7 daily diaries) % Responders (Reduction of >50% pain score to baseline) Secondary: SF-MPQ Daily Sleep Interference Score PGIC CGIC SF-36 POMS % Responder PLA 1% PGB 150mg/day 18% (non significant) PGB 600mg/day 39% (p=0.002) SF-MPQ (VAS-Pain Conclusion) PLA PGB 150mg/day (p=0.2058) PGB 600mg/day 3.38 (p=0.0002) PGIC (% reporting improvement) * estimates, as reported only in graphical form PLA 7% PGB 150mg/day 56% PGB 600mg/day 85% Withdrawal Rates Due to AE s: PLA.7% PGB 150mg/day 2.5% PGB 600mg/day 8.5% Other Secondary Results: PGB 600mg/day showed significant improvement compared to PLA in Sleep scores, CGIC, and the SF-36 bodily pain component % 25% 9% 38% 3.8% NNT/ NNH 27 Comments Study used doses greater than 300mg/day, the max as recommended by FDA. Study required 80 patients per group to provide 90% power 2 week titration phase for each PGB arm Including patients who have tried gabapentin increases external validity Excluding pain meds improves internal validity, but may reduce external validity as this will not be general practice in the public PLA group consisted of more Type I diabetes patients than the PGB groups (16.5% vs 8.9% and 2.%). Could influence internal validity of study if there is a difference in pain response due to DM diagnosis. Freynhagen 60 center Design: MC,DB, PG,PC Inclusion Criteria M/F >18 yo Diagnosis of DPN: (DM Type 1 or 2 Sym. Pain in Dist. Ext. for at least 6 months) Or Diagnosis of PHN: (Pain present for 3 months after healing of herpes zoster rash) Pain worse than 0mm on the 100mm VAS of the SF-MPQ Exclusions: pregnant, lactating, HbA1C>11%,, ClCr<60mL/min,unstable or clinically significant medical conditions Study also excluded use of pain meds except for APAP Pt. Characteristics (St Dev.): Avg Age = 62 yo (11.1) 5% Male 97.6% White 73.6% DPN 83% Type II DM Mean Duration DM = 13.5 yr (9.) 26.3% PHN Mean Duration PHN = 37 months (1.9 PLA PGB Flexdose PGB 300 mg bid (600mg/day) weeks (1 week titration in 600mg/day group; weekly titration in flexible dose group) Primary: Mean Pain Score (avg. of last 7 daily diaries) % Responders (Reduction of >50% pain score to baseline) Secondary: Daily Sleep Interference Score PGIC MOS-Sleep There was no significant improvement in the POMS for either PGB dose. Mean Pain Score (Baseline/Conclusion) *estimates, as final values given only in graphical format PLA (6.7/.7) PGB flexdose (7.0/3.3) p<0.013 PGB 600mg/day (7.1/3.3) p<0.001 % Responder PLA 2.2% PGB flexdose 8.2% (p<0.001) PGB 600mg/day 52.3% (p<0.001) PGIC (% reporting improvement) * estimates, as reported only in graphical form PLA 8% PGB flexdose 73% (p<0.01) PGB 600mg/day 70% (p<0.01) Withdrawal Rates Due to AE s: PLA 7.7% PGB flexdose 17% PGB 600mg/day 25% Other Secondary Results: Both PGB groups significantly improved Sleep scores and the MOS-Sleep scale over PLA 2% 28.1% 25% 22% 9.3% 17.3% Study used doses greater than 300mg/day and bid dosing instead of as recommended by FDA. Very high withdrawal rates, overall for each group was: 6.2% 3.8% 37.9% Average dose in flex-dose group was 50mg/daily Predominantly Caucasian population Excluding pain meds improves internal validity, but may reduce external validity as this will not be general practice in the public Including patients who have tried gabapentin increases external validity Abbreviations: PLA Placebo, PGB Pregabalin, MC - Multi Center, DB - Double blinded, PG - Parallel Group, PC - Placebo Controlled, ARR - Absolute Risk Reduction, NNT - Number Needed to Treat, CI Confidence Interval, DM Diabetes Mellitus, WBC White Blood Cell, PLT Platelets, DPN Diabetic Peripheral Neuropathy, SF-MPQ Short Form McGill Pain Questionnaire, SF-MPQ VAS Visual Analog Scale (0-100 scale of pain), PGIC Patient Global Impression of Change, CGIC Clinical Global Impression of Change, POMS Profile of Mood States Page 7 of 8

8 References: 1. Schmader KE. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clinical Journal of Pain. 2002;18: Dworkin R, Backonja M, Rowbotham M, et al. Advances in Neuropathic Pain. Archives of Neurology. 2003;60: Vinik A. Use of antiepileptic drugs in the treatment of chronic painful diabetic neuropathy. J Clin Edocrinol Metab. 2005;90(8): Cochrane Database Syst Rev Jul 20;(3):CD Prescribing Information for Lyrica. Accessed on October 3, Drugdex Drug Evaluations: Gabapentin. Micromedex Healthcare Series. (Accessed April 20, 2006 at 7. Lesser H, Sharma U, LaMoreaux L, et al. Pregabalin relieves symptoms of painful diabetic neuropathy. Neurology. 200;63: Rosenstock J, Tuchman M, LaMoreaux L, et al. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain. 200;110: Richter R, Portenoy R, Sharma U, et al. Relief of Painful Diabetic Peripheral Neuropathy With Pregabalin: A Randomized, Placebo-Controlled Trial. The Journal of Pain. 2005;6(): Freynhagen R, Strojek K, Griesing T, et al. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomized, double-blind, multicentre, placebo-controlled trial of flexible and fixed-dose regimens. Pain. 2005;115: FDA Medical Review of Lyrica. Accessed March 31, Page 8 of 8