Brian Kahan, D.O. FAAPMR, DABPM, DAOCRM, FIPP Center for Pain Medicine and Physiatric Rehabilitation 2002 Medical Parkway Suite 150 Annapolis, MD 1630 Main Street Suite 215 Chester, MD 410-571-9000 www.4-no-pain.com
Common complication of diabetes Affects somatic, sensory and autonomic nerves Common symptoms include Dysethesias Burning Spontaneous shock like sensations Allodynia
Three theories Microvascular disease of the vasa nervorum causing demyelination Damage of nerve fibers due to free radicals affecting dorsal root ganglion Mitochondrial damage in nerves
Mechanisms of Neuropathic Pain: Peripheral Sensitization Inflammatory signaling molecules trigger Na + channel phosphorylation Lower activation threshold Larger current when activated Gene transcription altered at dorsal root ganglia and dorsal horn neurons Upregulation of vanilloid receptor 1 Upregulation of SNS/PN3 Na + channels Heat sensitivity Lower firing threshold Woolf, Salter. Science.. 2000;288:1765 ;288:1765-1768.
Mechanisms of Neuropathic Pain: Central Sensitization Peripheral nociceptor inputs trigger molecular changes in central neurons Modification of GABA, glycine receptors NMDA and AMPA receptor activation Long-lasting changes may result from Altered receptor expression Inhibitory interneuron death Reduce effect of inhibition Lower firing threshold GABA = -aminobutyric acid; NMDA = N-methyl-D-aspartate; AMPA = -amino-3-hydroxyl-5-methyl-4-isoxazolepropionate. Woolf, Salter. Science.. 2000;288:1765 ;288:1765-1768.
Distal Symmetric Polyneuropathy Result of sensory nerve damage Large (A / ) fibers Small (A and C) fibers Most patients have mixed neuropathy Large- and small-fiber symptoms Sock-and-glove distribution very common Vinik.. In: Diabetes and Carbohydrate Metabolism.. 2002.
Distal Symmetric Polyneuropathy: Small Fiber First: pain and hyperalgesia Later: loss of sensitivity Heat/Cold Light touch/pinprick Autonomic symptoms Predisposes to diabetic foot disease Electrophysiology may not detect nerve damage Vinik.. In: Diabetes and Carbohydrate Metabolism.. 2002.
Distal Symmetric Polyneuropathy: Large Fiber Sensory and/or motor nerves Feet usually affected first Vibration perception Position sense (proprioception) Deep-seated gnawing/aching pain Muscle wasting (hammertoes) May interfere with activities of daily living Abnormalities readily detected by electromyography Vinik.. In: Diabetes and Carbohydrate Metabolism.. 2002.
Leads to increase production substance P Activation of NMDA receptors Extended depolarization of membrane Increased sodium and calcium influx
Pregabalin: Pharmacology
Pregabalin Binds to the 2 - Subunit of Voltage-Gated Ca 2+ Channels in the Central Nervous System Pregabalin Presynaptic α 2 - subunit Presynaptic α 2 - subunit Ca 2+ channel Ca 2+ channel Neurotransmitters Neurotransmitters Postsynaptic Postsynaptic Schematic representation of pregabalin s proposed mechanism of action Pregabalin selectively binds to 2 - subunit of calcium channels Modulates calcium influx in hyperexcited neurons Reduces neurotransmitter release Pharmacologic effect requires binding at this site The clinical significance of these observations in humans is currently unknown Taylor. CNS Drug Rev. 2004;10:183-188. 188.
Voltage-Gated Calcium Channel Structure Voltage-Gated Calcium Channel Structure
Importance of 2 - Subunit Modulation R217A mutation in the 2 - subunit Reduced [ 3 H]-pregabalin binding in the dorsal horn Eliminated analgesic effect of pregabalin Did not affect response to morphine Field et al. Presented at: 23rd Annual Scientific Meeting of the American Pain Society; 2004.
Pregabalin Mechanism of Action Not Related to GABA Name pregabalin based on chemical structure Named before mechanism of action was elucidated Pregabalin does not* Interact with GABA A or GABA B receptors Convert into GABA or GABA agonist Inhibit GABA uptake or degradation Alter brain concentration of GABA Block Ca 2+ channels *The clinical relevance of these results is not known. Fink et al. Neuropharmacology. 2002;42:229-236; 236; Lyrica (pregabalin) Capsules CV [package insert]. New York, NY: Pfizer Inc; 2005.
Pregabalin Is Not a Calcium Channel Blocker Ion channel Ion channel PREGABALIN α 2 α 2 CCB EXTRACELLULAR EXTRACELLULAR α 1 α 1 δ Cell membrane α 1 α 1 δ Cell membrane Ca 2+ influx blocked β INTRACELLULAR Ca 2+ influx attenuated β INTRACELLULAR Ca 2+ channel blockers (CCBs) bind to 1 subunit of L-type calcium channels and directly block the pore CCBs prevent movement of Ca 2+ CCBs work in the peripheral vascular smooth muscle and relax arteries to reduce systemic blood pressure Pregabalin binds to the 2 - subunit and modulates the influx of Ca 2+ into the cell in hyperexcited neurons Pregabalin works at brain and spinal cord synapses that have Ca 2+ channels, but does not alter vascular or cardiac function Pregabalin modulates Ca 2+ channels (does not block) Triggle. Cleve Clin J Med.. 1992;59:617-627; 627; Taylor. CNS Drug Rev. 2004;10:183-188; 188; Data on file. Pfizer Inc, New York, NY.
Pregabalin Pharmacokinetic Profile Variable Absorption Bioavailability PK 150-600 mg/d Exposure Plasma half-life Steady state Protein binding Metabolized Renal excretion Characteristics T max 1.5 h 90% Linear Dose proportional (C max and AUC) 6.3 h 24-48 h No No 90% unchanged Clinical Relevance Rapid No food effect Dose proportional Predictable levels Predictable levels BID or TID dosing Fast dose adjustment Predictable levels Predictable levels Removed by dialysis Adjust in renal impairment Lyrica (pregabalin) Capsules CV [package insert]. New York, NY: Pfizer Inc; 2005.
Pregabalin and Gabapentin Pharmacology Facts FDA-approved pain indication Mechanism of action Pharmacokinetic profile Oral bioavailability Dose potency for PHN Dosing (PHN) Time to effective dose (PHN) Pregabalin Neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia 2 - ligand Selectively binds to the α 2 - site in CNS tissues Linear Plasma concentration is dose proportionate 90% all doses Effective at 150 mg/d Dose range from 150 mg/d to 600 mg/d* BID or TID CO 2 H NH 2 1 day Effective starting dose of 150 mg/d Gabapentin Postherpetic neuralgia 2 - ligand Selectively binds to the 2 - site in CNS tissues Nonlinear Plasma concentration increases disproportionately to dose 60% 900 mg 47% 1200 mg 34% 2400 mg 33% 3600 mg Effective at 1800 mg/d No additional benefit at higher doses TID CH 2 NH 2 CH 2 CO 2 H 9 or more days Titrate to effective dose of 1800 mg/d *Some patients with PHN may benefit from up to 600 mg/d given after 2 to 4 weeks of treatment with 300 mg/d. Adverse events may increase with dose. CNS = central nervous system. Lyrica (pregabalin) Capsules CV [package insert]. New York, NY: Pfizer Inc; 2005; Neurontin (gabapentin) [package insert]. New York, NY: Pfizer Inc; 2004.
Steady State Plasma Pregabalin Concentration ( g/ml) Pregabalin Steady-State Pharmacokinetics Steady-State Plasma Pregabalin Concentration ( g/ml) 10 8 6 4 2 0 Pregabalin 75 mg/d (q8h) (n=8) Pregabalin 300 mg/d (q8h) (n=6) Pregabalin 600 mg/d (q8h) (n=11) Pregabalin 600 mg/d (q12h) (n=8) 0 2 4 6 8 10 12 600 mg/d pregabalin given BID or TID results in similar steady-state plasma pregabalin levels Data on file. Pfizer Inc, New York, NY. Time (Hours) Dosage adjustment is recommended for patients with reduced renal function (creatinine clearance 60 ml/min) and in those undergoing hemodialysis.
Pregabalin C max (µg/ml) g/ml) Pregabalin Absorption Is Proportional Across the Dose Range 12 10 8 6 4 2 0 Mean Individual 0 150 300 450 600 Pregabalin Daily Dose (mg/d) Solid line is the line of regression going through the origin. Data on file. Pfizer Inc, New York, NY.
Pregabalin Relieves Symptoms of Painful Diabetic Neuropathy: A Randomized Controlled Trial Lesser H et al. Figure reproduced with permission, from Lesser H et al. Neurology.. 2004:63:2104-2110. 2110.
Percent of Patients Percent of Patients Pregabalin: Percentage of Patients With 50% Reduction in Pain in Painful DPN* 50 P=.001 vs placebo P=.001 vs placebo 40 30 20 10 0 Placebo (n=97) Pregabalin 75 (n=77) Pregabalin 300 (n=81) Pregabalin 600 (n=82) *Last observation carried forward (LOCF) analysis. All pregabalin doses in mg/d. Lesser et al. Neurology.. 2004;63:2104 ;63:2104-2110; Data on file. Pfizer Inc, New York, NY.
Pregabalin for the Treatment of Painful Diabetic Peripheral Neuropathy: A Double-Blind, Placebo-Controlled Trial Rosenstock J et al. Figure reproduced with permission, from Rosenstock J et al. Pain.. 2004;110:628-638. 638.
Mean Pain Score* Mean Pain Score* Pregabalin Effect on Mean Weekly Pain Scores in Painful DPN 10 9 8 7 6 5 4 3 2 1 0 *Least squares means calculated from the model. P.01 Rosenstock et al. Pain.. 2004;110:628 ;110:628-638. Placebo (n=70) Pregabalin 300 mg/d (n=76) 0 1 2 3 4 5 6 7 8 End Weeks Point (LOCF)
Percent of Patients Percent of Patients Pregabalin: Percentage of Patients With 50% Reduction in Pain in Painful DPN* 50 40 P=.001 vs placebo 30 20 10 0 Placebo (n=70) *Last observation carried forward (LOCF) analysis. All pregabalin doses in mg/d. Rosenstock et al. Pain.. 2004;110:628 ;110:628-638. Pregabalin 300 (n=76) Patients taking pregabalin should be counseled that dizziness and d somnolence may impair their ability to perform potentially hazardous tasks such as driving or operating complex machinery until they have sufficient experience with pregabalin to determine its effect on cognitive and motor function.
Percent of Patients Improved Percent of Patients Improved 56986.03621747.03695408.0960268.0672849.038430.1568570.196021.1539761.1798602.1798602.15301392.13973.15049304.175824.15102354.123874.15264205.1390725.1542715.142715.1831427.1543018.125698.18430139.1671569.140.2828430.269860.2527151.2973142.28168572.2643013.2472843.2013973.2397314.25698654.25.2301345.2702685.25013926.2414276.2571517.2126857.2430139.2142710.384301.367284.38435.396026.3239736.34698607.36947.301397.371569.3502680.427150.45728490.4139731.483142.4543013.43618763.43682524.4957284.43970935.4693595.427156.45414271.5694102.525892.58026852.54653782.5290613.5672843.582843.5142715.56986.57860268.5428430.61698602.613973.671564.642715.6139736.6831427.65867847.6808967.629097.6401218.6261238.6823458.68934578.625698.69860.7973142.7528482.7685723.75986073.7397314.76857284.7242715.78986026.7456986.7126857.75430139.784301.8039731.86314271.84698602.82973142.8268572.89602630.867284.85986026.8301397.871569.8502680.9427150.95728490.9139731.9698602.9268572.9872843.94397314.957284.920235.9182185.9245036.9308976.9460927.952387.9685728.901501780.012471.013843.016986.0192417.0129837.015367.018187.018218.014738.0170268.01508098.0145919.01572849.01079.0154750.18430.18430.1469860.184301.1239731.1614271.19602.165062.1212542.1863462.1425382.186203.1638123.129043.1841063.13973.12715.18906.1242056.130596.167847.120897.1382748.15698.1320459.139410.2179860.21283142.21497314.2192685.2126857.21685728.2125698.2181569.2148430.3154301.3129061.3193812.3168572.318284.312365.3161876.31397.3139731.4143013.4154353.415693.4156934.4167284.4130795.41646217.4195728.4151201340.51402680.51603921.514271.5151512.5126852.51527103.513843.51239783.51430134.51631474.5142715.51317475.51381236.516986.5170268.518430.61359190.61398602.619602.61501392.613973.612715.61402685.6186026.6127156.61656986.6141427.6169860.7184301.7126857.7130139.7154301.81756981.81468572.8170263.818284.8196026.8161876.8136537.81397.813978.812569.8120.9148430.9169860.9184301.9139731.9143013.917943.91206953.9132483.9146804.9159434.91621854.9167284.91569865.917156.9195728.914271.023843.0213973.02497314.0267284.02857284.0242715.026986.0256857.0270268.028430.12715.1241427.125698.1297314.247284.2857284.242715.282715.212685.230139.242710.3254301.32581231.329061.3256981.3293812.32521742.3268572.323.32308093.328284.3296026.32524946.3261876.32598607.3236537.32563467.321397.32502638.3213978.3251429.32569.32527150.4239731.4243013.427156.4295728.425214271.523892.52353782.523843.5242715.5254306.526986.5267237.5278737.5218418.5270268.5258430.629602.62501392.6213973.62715.6241427.625698.6279860.7257151.7283142.7297314.72362174.7237825.7212685.7230139.7254301.8256981.8268572.828284.82569.82527150.9239731.9230181.9243142.92632762.9243013.925693.9267284.9242715.9242715.92602685.9286026.927156.9254757.923658.92598659.9274750.034941.0314271.0353782.0369204.0342715.0317475.0381236.036986.0370268.0345919.031079.038430.139602.1313973.132715.139736.1341427.1316187.1380938.135698.1367289.1379860.2326857.230139.230589.2379540.354301.3568572.38284.396026.3501397.32569.3527150.439731.43230181.4343142.43632762.4343013.435693.4367284.437156.4395728.4314271.53892.5353782.53843.5342715.5356986.5370268.539602.63468572.6382843.63297314.63657284.632715.6341427.63543018.635698.63569860.7383142.73597314.7312685.73213926.73414276.7361517.7326857.7390618.7365378.730139.7354301.8368572.838284.8396026.831397.832569.8364080.934591.9343013.9318763.9382524.9367284.932045.93795.937156.9395728.9314271.043843.04530134.042715.046986.049602.1413973.1451564.142715.141427.145698.14320459.1439410.2479860.2497314.2412685.2426857.2468572.348284.3496026.3461876.3436537.341397.347156.483147.495728.46058.435249.45414271.54243013.547284.54602685.54831427.5470268.54572849.548430.649602.6476.64621.7412685.745107.7490618.7430139.74379540.84619061.8468572.8470263.848284.841397.8413978.842569.843013.94318763.9438524.9467284.947156.9495728.940574750.054941.0514271.053843.0542715.056986.0570268.0513973.152715.1539736.1541427.15698.15320459.1539410.2579860.2512685.2526857.254301.358284.357505.352365.3596026.352569.3539731.4543013.4567284.4569865.457156.4512471.5259592.53843.56986.58430.6596021.659602.6513973.651564.652715.65698.6579860.7583142.7597314.75.7512685.7514276.7526857.7590618.7565378.7530139.754301.8568572.8570263.858284.8596026.852569.8539731.9543013.9567284.9595728.956058.9535249.950614271.063843.0642715.06986.0670268.068430.1696021.169602.162715.1639736.1641427.16543018.165698.1697314.2612685.2626857.2630139.2654301.3656981.368572.368284.361397.362569.3639731.4698602.46268572.4682843.46497314.467284.467156.468572.37)714=n( obecalp96932.1579243.18264.1785945.1398256.1673537.1281818.1862809.14174289.16160.21979431.248302.23507272.24865143.25131014.293974.280716.2128457.265298.25234169.2303030.3537190.340861.35419632.3587503.38618463.36848324.3408284.3219145.34906.3857956.380917.313231.48578412.46025792.4561083.42018264.454545.43123416.46291386.49360257.42539028.4560898.4876859.4346409.460520.59630450.52328580.590671.58593941.5128181.54869212.5745742.514562.52723803.5631043.5109173.5215875.5421587.549358.56829.53719.5606060.65674921.6743891.68063.6928374.67516.650176.635037.61097.694948.679809.654869.6397420.7528380.758241.798102.7129062.735913.7589873.710834.742158.7545459.74158750.8175161.836462.8289892.843.8686763.830204.893634.82470174.8490505.8549395.8973475.851806.82052346.868676.87152517.84718257.81383097.849728.8541568.82080309.89546049.8612879.837510.934350.909090.95682.919363.9231405.9520375.9378146.95347017.941697.95484848.953719.98503.0123283.014834.0163584.0181735.01485.01294046.0141296.018347.01601748.01214059.01817350.1420751.13062.1636363.124964.152075.127516.1490356.1616496.1831637.167.1281918.1407068.16209.1847349.174389.105240.21235101.21365061.21495912.21526872.2165673.219693.213435.21671276.212908.216749.214580.314132.3171282.31202143.313204.31462954.31592815.3162375.3163636.31537.3147019.3139740.4121581.4195940.418264.412496.4130678.4173979.4146280.51749581.5162982.5184207.515317.512048.5190909.516879.5137640.61751.6151323.6139825.6151249.6198970.7136712.717353.7120414.71434374.7164235.71894195.7135056.71265907.716867.71252028.71409178.7165329.718168620.81215870.81461031.8128181.813483.8140595.8156108.816280.91578412.9194124.91826.917438.9139742.02567454.02616.02597467.029768.0258179.0283470.126784.127465.1243526.1212496.1280367.1259138.12809.1296969.1265830.234701.23671.271542.250413.253714.26025.2569326.272727.275038.24839.2191730.325041.3251291.32408342.32654592.32801743.32854592.321743.3267893.32735.323067.324969.32742070.4245371.42168672.4271083.429397.421602.52314.5238916.5210786.5275757.5234628.52413598.52581469.526030.628264.6213505.6243465.6237326.62404286.62534147.6264597.625958.62414509.62823159.624279.62451340.72860980.7289431.72698081.721862.7237272.7274014.7212845.7259586.7272727.72495867.7261908.72832158.7265298.72839.72402579.72625610.82848750.827190.82780904.8240917.82129820.92483.9254545.9270257.9257358.9286859.92589160.0392561.03439742.0387503.032314.0368594.0315875.034719.0317050.13208901.13861.1346872.13598682.13629543.1369404.137245.134086.1381818.13504132.23646.2358750.327621.39591.36462.3.3204.370174.393215.361735.3930595.3263636.358676.380917.313067.3456108.379248.348.325792.43724.438785.436037.4379321.5391735.5314059.5365030.6320751.63843891.6349082.6346363.6315234.6383105.6352075.6321936.639707.636867.6374389.638091.7359693.731306.7350147.7397878.735610.8347190.83818181.8326462.83601743.8357924.83563636.8389248.832652.93483.9384124.93231405.9367685.932496.930678.9346280.0452982.0478594.0457195.0484207.04587508.0490909.04593210.14751.1450912.141323.1418193.1425064.14329825.149795.1456.14537.1451249.1467841.24560252.247353.24576854.2489165.2412579.245921.3496052.343483.3471625.341936.3456108.348412.4581813.494124.4597425.41826.47017.48397.4230678.476859.423140.54539742.545454.5491735.54838916.54284207.54621587.54768.549082.6437814.647465.6412496.642809.6434701.74640413.746025.7472727.74839.74594041.841743.843067.8487685.9425427.946268.9405319540.0593731.05256381.056592.05874572.05193123.05403763.05712314.052314.05725615.05438916.05141327.054628.0521549.05236081.15496892.15657614.15818435.158256.1598256.15160.2543974.259586.2565298.257190.3597503.353534.3572185.3510917.357658.35949.353231.45483.454545.45391386.45639028.45976859.45634690.5291432.59173.521587.597420.7504132.7520834.7542158.758750.856462.8570174.859676.85348.8519090.95682.959363.9531405.9563719.956020.0679321.0657272.068503.0691735.068347.0674389.1657680.268091.2658392.269693.2651908.264132.3610292.368063.3657924.3626894.3694765.363636.3676937.36479248.36182649.3695940.463781.4670523.4618264.4657305.4649735.4650575.4670316.46536056.46286.46567527.46367.4659808.464838.4630678.4684207.56751.670912.641323.6126524.639825.64537.651249.6497420.76834701.7628091.7627272.767353.76589165.76867.7642158.76839.76235610.867190.8628181.8646462.86801743.86257924.8693215.8640595.86543896.8656108.8659409.86280.9671813.96490826.9610839.9639742.07516.0783470.1758671.179082.17592483.176784.1741535.17824975.17243526.17652176.171717.17480367.1789808.17219458.173809.1750413.2797154.2735985.272727.2761908.27565298.27802579.27458750.375041.372735.379397.476030.6737272.7)061=n( yad/gm 051 nilabagerp497618.374891.4398392.4313983.437484.4351085.4238169.45176251.515343.56737074.52469795.5191527.580927.56016028.54023868.52030619.547369.589410.6951950.678601.690432.6323163.6584.692078.680920.7627571.742823.72619084.78536.78536.72428.74762510.81701602.8749693.862687.8503061.96135782.92857414.9589145.931296.96734697.946329.9890130.01235831.0169542.0143503.01568953.0193414.01519864.014325.0156975.0194236.0120786.0165367.01296938.01820619.0146329.017860.145952.183054.12146.160238.147312.2169043.21291864.2124595.2179.21623401.3125132.3187853.3126945.3164047.31370408.31686768.31398.3169019.31303139.314121.4128305.41815835.41612375.41419706.41416246.41376.4180217.41607647.41404187.41201618.418058.4158.41267219.4142049.41682769.4184549.418120.51270940.5143670.51695301.51858031.5121851.51283581.5146212.5160932.5181762.51795263.51410854.513435.515846.5196938.5135030.6165751.61289482.61214.6198397.617571.715432.714172.7152813.71563.71591414.718164.71565905.715275.7190847.7139839.716023.8163874.81260575.819207.8179380.91603061.9124632.91879213.91413983.9156564.913748.91092.0296016.027329.0250473.123757.124731.280915.26709.2374382.3247123.329840.4291832.4284724.423816.4261908.4248091.5286183.525275.524976.526367.5287858.52459.5240541.62853.6265717.624290.72804731.7267571.7247312.7219152.728092.72842823.72463.72485404.725724.729084.726268.727242.821534.8259526.82365986.82671357.82987618.820408.8251049.823670.92658431.9280262.9213983.92456496.9289.9243503.03686016.030619.035079.0380520.13506970.131431.135681.1381342.131792.131393.13584.1379385.1393976.132078.1370160.2369281.232513.235724.2372510.39785.34248.369690.435153.4373874.4369506.4328237.43541.5386251.53638091.534092.53271762.5343503.53805343.53676183.5348914.53210854.5381694.5320786.536878.5345952.632146.6364867.63276598.63920.7385404.7326945.83648676.83270408.83139.834121.9389213.9328305.936496.9358.9343670.0467171.0481762.046263.0420854.045846.0496938.04620619.0426329.04896860.1430541.147312.14695843.1428574.1450306.143176.1467137.14932597.14203958.1456329.1434789.141463.24636394.24268026.2490847.24613578.2424520.347921.345415.34676836.34209567.34721398.3453020.485741.418472.432073.456564.470165.494656.43748.471830.541092.5458914.54670745.54203476.5435108.547329.5412381.64634013.6426734.6498465.642146.6485717.64298397.6462078.6465649.642823.74675404.74219084.7484275.748536.742907.74637268.742510.84863861.8468123.8482374.8460506.8463727.8469458.84632.9484724.9423816.940586183.056367.05685098.05218710.1540541.15853.1527625.1567176.25861417.25675657.25489897.25293148.25838.25802629.25616869.2542010.354350.3598703.3543265.3597618.3561049.35242170.4574891.45696523.4529254.451085.4538169.452750.576251.590842.515343.584.6579385.6593976.651847.6532078.6570160.7519152.75631973.75263605.759536.75857176.7562907.75490847.75262687.75753428.756709.75439839.7520179.7572510.8572510.85876750.856801.85494241.85209481.851372.85817962.85621213.85435453.859693.85365064.85671425.8598785.85304156.8510517.853687.8589145.9528237.956329.9543503.06359863.065234.06971694.0629795.06504326.0620786.067860.1683054.160238.1647312.26841652.265892.26469043.2627383.2687524.2681864.2695015.264035.2624595.264627.26278948.26179.2625270.3649761.36362.3687853.3626945.364047.3697618.36231398.36864969.36408540.464121.46395673.4640136.46580.4681762.56510854.565846.5696938.5635030.6839270.64351.645751.626102.675242.6879482.683723.6497963.61214.6328574.634935.6940306.626.6572037.698397.652328.616258.67918.6319.696049.65079.6149.67820.7631850.7694780.765861.767571.7673702.76281932.7689072.76297203.7689543.760463.76212893.7681034.76428164.7636394.7634525.765275.767921.869207.86518657.864318.86568568.8693029.86519479.864920.9679380.9656564.9694656.963748.961092.0752914.0794906.073797.07989.0712081.1754073.1790365.173757.17565649.174731.2780915.276709.278169.276190.3720781.374282.376873.3782374.37865.372146.373727.37643197.37959458.37275819.37581289.378540.472141.474632.476023.4784724.4760745.47239186.4761908.4748091.5760813.5729254.5725275.57540726.575186.57590637.5726097.57541548.57698.572459.57635030.67278601.67802381.6745952.67853.67292134.67407625.676126.6735717.674290.76462.7296353.729084.743675.767176.781767.76268.70509.7414749.7128989.78230.87536470.8724071.8794951.87658102.87242.87597892.872353.87548704.873264.87598615.8724175.8759526.8768207.872687.87859458.87492139.873670.97658431.97280262.9713983.9737484.9751085.97576.97907.971468.9738169.9752750.0876251.0863092.08204503.0867183.08431854.0853435.08686016.0820786.085367.08969308.0830619.086089.08285160.1853431.18431702.181792.18639424.1826125.1893976.181847.1832078.1856569.1870160.2856329.4862687.78)362=n( yad/gm 03 nilabagerp85782.5951293.565.56819026.5272686.58536157.549618.535328.51918639.5258219.53157540.6471201.65386451.651902.6547268.65245981.743615.731348.7694809.72658379.78512930.84575401.853961.8376872.869783.8237694.8723051.942174.93095135.9650685.925046.92989496.954947.929308.96458219.9787120.0127031.0171492.01415754.019026.013487.01749.01.19734.13106.17467.146378.175289.15190.215152.2137814.21547.215809.219170.31592532.3196893.3165616.312438.319250.41686512.4180973.414.418905.4161575.4125046.418507.4182968.4186230.51316141.51345052.5184953.51572686.5170310.617893.61762305.6146.616038.616439.6168651.7162023.7160746.715603.81685904.81615815.8154726.8158097.8152459.8150182.9148706.914217.9146439.914162.024285.027396.02436157.02138.0230519.0238142.12396954.126576.124598.12.20945.23867.2647489.216202.321063.3214925.3212658.3210381.42638.42524361.526782.521492.5284953.5248424.52094.523195.5260807.529618.5297341.6295074.6293797.623609.6252510.7281421.728502.7275782.7282963.7289054.7287.7284958.728149.72820.8285401.82952731.8283961.82716202.82692532.82579762.8245603.823.821063.8296893.8273134.8271857.8279480.92563842.926714.9284245.92376.929308.9246439.9263560.03754013.0345.0315608.0357540.1354721.1351902.1358092.135273.135396.1341620.2345981.2349253.2347976.234560.3.3106.39689.3051.437313.4325046.434217.4369109.4386230.534361.5321492.5350304.5368915.5329026.531749.534650.6367561.6315472.6313106.631829.637185.731547.735809.73598170.8392532.8396893.8390265.8397346.8394527.8391708.8398.8396512.9326423.93534.9384245.9382968.9346439.930463560.0427031.0480691.04349314.04608136.0476948.0474671.147893.1472305.1468651.246384.2464018.24818578.2467149.243560.34298170.3452731.3450464.349035.3438795.342746.3416137.3458097.34749530.40182.4141625.4217.437108.4601989.40890.549831.547971.549502.54162.549203.541343.549383.548424.54735.547246.5436157.545328.5470310.6497341.6415472.6432504.6436814.6430237.642850.7426583.743615.7460746.7487.745809.742930.8451841.8480752.841063.843404.84658434.84182964.84724035.8475195.84127256.84868317.84761638.8432057.8471638.84713798.8416910.942376.94058623.05791094.05495356.0519618.0593089.0585782.2589054.2583416.2587.258149.25340951.35609673.357495.3571857.3575129.35305030.4549301.4573842.453753.453264.4561575.45390486.45620397.4569109.45398010.562891.56782.564013.561293.568374.565.59817.5328.57540.651902.65273.659535.65396.657268.6545981.7543615.75734167.7543560.85136152.8537694.853106.8535328.8583468.8532509.8580649.85396989.858720.9536860.9584901.953051.952174.9525046.9529308.9523769.9527031.064361.0680691.06782.064162.0621492.068623.0654953.0631293.0618424.0625754.06519026.0613487.0676948.0630519.0693089.0657540.161.1619734.1617467.165190.263814.2632725.261636.261547.269170.3696893.3690265.3694527.369250.46586512.4680973.4684245.468507.4686230.5675782.5638424.56419026.5696198.5670310.67893.6762305.646.616038.6439.681421.769452.7626583.7643615.760746.767827.764018.761298.768379.765603.8650813.8656963.862153.86572373.86534193.8695904.8654724.86954.8650464.861284.8656305.8625815.8657635.863845.86589275.864195.86592906.8654726.8618296.8671857.8635328.8698.8652459.8650182.9646439.964285.07536157.0730519.072.2726583.2720945.27684306.27259756.27814217.274867.2753128.2728578.2787149.2763560.37498170.37252731.3716202.379762.373.3796893.3750464.3714925.37343836.37672747.3712658.375129.3739689.379250.475671.4710381.478905.47638.474361.5758012.57652.5754303.5741053.57528693.571534.572094.5748635.57865385.57252036.57639676.5726327.5740307.579618.5712160.674503.67176945.6793797.6723609.6752510.781421.785782.789054.71674.7652105.7493625.723515.7675.7808106.7649626.7480256.7276.763207.7894727.7636257.787.784958.78149.7820.8785401.872681.87479762.87176943.873134.87303045.87632946.87961857.875129.879480.97563842.9787913.976714.9765837.9769109.9763560.08523131.0892791.0852362.08612923.08796163.08471493.0815624.0821954.08506194.08280425.089565.08630985.08315126.089356.08764686.0859817.0861437.0828728.084328.08418639.08219.0857540.1851902.185273.185396.18547268.1841620.28606080.28270531.2835981.284042.2874892.2849253.2892615.2847976.284560.3898170.3852731.38616202.38479762.383.3837694.383106.3835328.3839689.3837313.4834343.48641373.48458204.4870373.487204.48684234.48491264.48209194.4816125.481315.4825046.4823769.4829026.5826056.5863086.584017.58257937.5864967.586197.5867828.58485858.582928.5819.581749.5870310.6834870.6897341.6851902.6815472.68912403.68293.68736363.6864393.6850324.68672524.68374284.68281215.68198145.686175.6813106.68601829.68209452.7896185.78494809.7892532.8)32=n( yad/gm 06 nilabagerp Pregabalin: Patients Achieving Various Levels of Pain Relief* 100 90 80 70 60 Placebo (n=70) Pregabalin 300 mg/d (n=76) 50 40 30 20 10 0 > 0 10 20 30 40 50 60 70 80 90 100 Percent Improvement in Pain From Baseline *Baseline observation carried forward (BOCF) analysis. Lyrica (pregabalin) Capsules CV [package insert]. New York, NY: Pfizer Inc; 2005.
Pregabalin Dosing If needed, may increase to 300 mg/d within 1 week Patients with PHN who tolerate pregabalin may benefit from up to 600 mg/d after 2 to 4 weeks of treatment with 300 mg/d Dosage adjustment may be necessary in patients with renal insufficiency, based on creatinine clearance Pregabalin may be taken with or without food Adverse events may increase with dose Lyrica (pregabalin) Capsules CV [package insert]. New York, NY: Pfizer Inc; 2005.