Gabapentin Does Not Improve Analgesia Outcomes For Total Joint Replacement Manyat Nantha-Aree, MD
Objective n Preliminary results of MOBILE study in total hip and knee arthroplasty
Background n Gabapentin= 1-(aminomethyl)cyclohexane acetic acid: n Is an amino acid n Has a structural analogue of gammaaminobutyric acid (GABA) n The cellular mechanisms of pharmacological actions of gabapentin remains incompletely described
Mechanistic Hypotheses of Gabapentin Pharmacology 1,2 n Selectively activate the presynaptic heterodimeric GABA B receptors (GABA B1a and GABA B2 subunits) on glutamatergic terminals 3 n Selectively enhance the NMDA current at GABAnergic interneurons
n n n Selectively bind to the α 2 δ subunit of spinal N-type Ca 2+ channels which is very likely the analgesic action target of gabapentin Block AMPA-receptor-mediated transmission in the spinal cord Activate ATP-sensitive K + channels
Pharmacokinetic n Following oral administration, peak plasma concentrations are observed within 2-3 hrs n Absolute bioavailabilty of a 300 mg dose of gabapentin capsules is ~ 0.59 n Food has no effect on the rate or extent of absorption n < 3% of gabapentin is bound to plasma proteins n Initial distribution volume = 0.6 L/kg n Not metabolized in humans n Excretion as unchanged drug solely by glomerular infiltration n Elimination half-life = 5-7 hrs
n Originally gabapentin was developed for the treatment of spasticity n Anticonvulsant activity n Antinociceptive activity in various animal models n Treatment of epilepsy, various pain settings especially neuropathic pain, etc
In animal models: n Gabapentin does not block physiological pain n Effective against hypersensitivity (allodynia, hyperalgesia) induced by tissue damage or neuropathy 4
Gabapentin in Pain Management. Anesth Analg; 2000; 91: 680-7. J Mao, LL C. 18 n The efficacy and indications of gabapentin for postoperative pain treatment are being established n Lacking of consensus with regard to the dosage and indications in postoperative pain treatment, side effect profiles, and comparisons between gabapentin and other pain medications
Preoperative Gabapentin for Postoperative Analgesia: a Metaanalysis. CAN J ANESTH 2006; 3(5): 461-9. RK Seib, J Paul n 8 Trials, 663 subjects, 7 surgeries: abdominal/vaginal hysterectomy, mastectomy/lumpectomy, cholescystectomy, lumbar discectomy/ spinal fusion
Reference No. of patients/ surgery Methodology/ Intervention Gabapentin dosing regimen Primary analgesic Outcome measures Dierking et al, 2004 20 80 Abdominal hysterectomy RCT Gabapentin or placebo 1200 mg gabapentin1 hr preop, then 600 mg q 8 hr for 3 doses PCA morphine n Pain scores at rest & on mobilization n Incidence of side effects n Morphine consumption n Gabapentin plasma levels Dirks et al, 70 2002 12 Mastectomy RCT Gabapentin or placebo 1 hr before surgery 1200 mg gabapentin PCA morphine n Pain scores at rest & on mobilization n Incidence of side effects n Morphine consumption Fassoulaki et al, 67 2002 11 Radical mastecomy & lumpectomy RCT Gabapentin, mexiletin or plaebo 400 mg gabapentin or 200 mg mexiletine tid beginning the night before surgery x 10day IM acetaminophen, propoxyphene, and codeine n Pain scores at rest & on mobilization n Analgesia consumption n Time to first analgesic requirement Pandey et al, 459 2004 15 Laparoscopic cholecystectomy RCT Gabapentin, tramadol or placebo 2 hr before surgery 300 mg gabapentin or 100 mg tramadol IV fentanyl on demand n Pain scores at rest n Incidence of side effects n Fentanyl consumption n Preop anxiety Pandey et al, 56 2004 16 Lumbar discoidectomy RCT Gabapentin or placebo 2 hr before surgery 300 mg gabapentin IV fentanyl on demand n Pain scores n Incidence of side effects n Fentanyl consumption Rosarius et al, 75 2004 10 Vaginal hysterectomy RCT Gabapentin or oxazepam 2.5 hr prior to surgery 1200 mg gabapentin or 15 mg oxazepam PCA fentanyl n Pain scores at rest n Incidence of side effects n Fentanyl consumption Turan et al, 50 2004 16 Spinal surgery RCT Gabapentin or placebo 1 hr before surgery 1200 mg gabapentin PCA morphine n Pain scores n Incidence of side effects n Morphine consumption Turan et al, 50 2004 13 Abdominal hysterectomy RCT Gabapentin or placebo 1 hr befor surgery 1200 mg gabapentin PCA tramadol n Sitting & supine pain scores n Incidence of side effects n Tramadol consumption
Outcome Results Evidence Pain at rest Pain with activity Analgesia consumption Nausea Sedation Pruritis Dizziness Lightheadedness WMD = -11.9 WMD = -11 WMD = -13.7 OR = 1.1 NS OR = 2.5 NS OR = 0.3 NS OR = 1.0 NS OR = 1.0 NS + + + 8 Trials, 663 Subjects, 7 Surgeries: abdominal//vaginal hysterectomy, mastectomy/ lumpectomy, cholecystectomy, lumbar discectomy/spinal fusion
MOBILE Study: n Primary question: Does consecutive doses of gabapentin reduce postoperative morphine consumption following total joint arthroplasty? n Secondary question: Does Gabapentin decrease Morphinerelated side effects?
Study protocol n Randomized, double blind, control trials n 2 separated trials (hip and knee) n Population: THA and TKA n Single and primary joint replacement n Age 19-90 n Juravinski hospital n Exclusion criteria: 1. Allergic to study medications 2. Chronic pain syndrome 3. Abnormal liver or kidney function 4. Contraindication to spinal anesthesia 5. Unable to use PCA
2 Hour preoperative period n Gabapentin group 1. Gabapentin 600 mg PO 2. Acetaminophen 1000 mg PO 3. Ketorolac 30 mg IV n Control group 1. Placebo PO 2. Acetaminophen 1000 mg PO 3. Ketorolac 30 mg
Intraoperative period n Spinal anesthesia with isobaric or hyperbaric bupivacaine with fentanyl 20 mcg n No other opioids given n No skin infiltration (LA)
Outcomes: Total hip arthroplasty
Table 1: Baseline characteristics and medical history THA Gabapentin (n=44) Placebo (n=48) Age (yr) 60.40 (9.43) 60.08(8.81) Sex (female) 18 (40.91 %) 23 (47.92 %) Weight (kg) 87.8 (18.88) 82.4 (14.71) Height (cm) 171.36 (11.78) 171.62 (10.08) BMI 29.87 (5.6) 27.96 (4.34) ASA 1 0 (0) 0 (0) ASA 2 18 (45%) 29 (70.23%) ASA 3 20 (50%) 12 (29.27%) ASA 4 2 (5%) 0 (0) ASA 5 0 (0) 0 (0)
Comorbidities Gabapentin (n=44) Placebo (n=48) Arthritic change ++ : - OA 43 (100%) 47 (97.92%) - RA 0 (0) 9 (0) - Other 0 (0) 1 (2.08%) CAD 2 (4.55%) 1 (2.08%) HTN 21 (47.73%) 17 (35.42%)
Comorbidities Gabapentin (n= 44) Placebo (n= 48) Smoker 10 (22.73%) 12 (25%) COPD 0 (0) 3 (6.25%) CVD 1 (2.27%) 0 (0) OSA 1 (2.27%) 1 (2.08%) Asthma 4 (9.09%) 1 (2.08%) Diabetes 3 (6.82%) 3 (6.25%) n n n Data are mean, (SD) for interval data and number, (%) for categorical data + 4 missing values in Gabapentin gr and 7 missing values in placebo gr ++ 1 missing value in Gabapentin gr
Table 2: Morphine consumption (mg) Morphine consump. (mg) Gabapentin (n=45) Placebo (n=48) Treatment effect (95% CI) P-value PACU 3.18 (0.97) 4.55 (1.07) -1.36 (-4.26, 1.53) 0.351 DAY 1 18.58 (2.05) 25.02 (1.99) -6.44 (-12.12, -0.76) 0.027 DAY 2 23.19 (2.81) 23.28 (2.92) -0.09 (-8.17, 7.99) 0.982 Cumulative 48 hrs 42.26 (4.16) 48.49 (4.14) -6.23 (-17.92, 5.46) 0.292
Fig.2: Side effects 100 90 80 70 60 50 40 30 20 10 0 Gabapentin Placebo N/V Sedation Pruritis Dizziness Visual disturbance LOS (days)
Pain score Gabapentin (n=45) Placebo (n=48) Treatment effect (95% CI) p-value PACU- rest 0.64 (0.24) 0.55 (0.21) 0.09 0.777 PACU- movement 0.47 (0.35) 1.28 (0.77) -0.80 0.337 At rest- POD 1 2.51 (0.24) 2.38 (0.29) 0.13 0.733 At rest- POD 2 2.07 (0.35) 1.37 (0.19) 0.70 0.075 At rest- POD 3 1.88 (0.360 1.21 (0.24) 0.67 0.116 Movemt.- POD 1 5.27 (0.50) 5.20 (0.47) 0.07 0.923 Movemt.- POD 2 3.98 (0.46) 3.77 (0.48) 0.21 0.758 Movemt.- POD 3 3.26 (0.5) 2.77 (0.45) 0.5 0.457 Wt.bearing- POD1 Wt.bearing- POD2 9.42 (0.45) 9.66 (0.40) -0.24 0.692 5.33 (0.54) 5.35 (0.52) -0.02 0.978 Wt.bearing- POD3 4.29 (0.42) 3.86 (0.49) 0.43 0.511
Outcomes Gabapentin (n= 45) Placebo (n= 48) Treatment effect (95%CI) p-value Satisfaction (goodexcellent) - POD 1 Satisfaction (goodexcellent) - POD 2 Satisfaction (goodexcellent) - POD 3 ROM- flexion (degree) 3.34 (0.68) 3.38 (0.81) -0.04 0.801 3.32 (0.88) 3.42 (0.74) -0.10 0.562 3.13 (0.94) 3.51 (0.66) 0.37 (-0.71, -0.03) 0.034 93.56 (18.8) 95.68 (9.97) -2.12 0.51- LOS (days) 4.93 (1.7) 4.22 (1.39) 0.7 (0.05, 1.35) 0.035
Hemodynamic outcomes SBP < 90 mmhg Gabapentin (n=45) Placebo (n= 48) Treatment effect (95%CI) p-value Intraop. 21 (48.84%) 14 (31.82%) 2.05 0.108 PACU 8 (18.18%) 4 (8.89%) 2.28 0.208 OR 5 (11.36%) 8 (17.39%) 0.61 0.419 POD 1 11 (25%) 7 (15.56%) 1.81 0.271 POD 2 2 (4.55 %) 2 (4.26%) 1.07 0.946 POD 3 0 0 N/A Overall 27 (62.79%) 19 (466.34%) 1.95 0.132
Hypertension (SBP >160 mmhg) Gabapentin Placebo Treatment effect Intraoperative 0 (0.00) 0 (0.00) N/A p-value PACU 0 (0.00) 0 (0.00) N/A OR 0 (0.00) 0 (0.00) N/A Day 1 1 (2.27) 0 (0.00) N/A #0.299 Day 2 1 (2.27) 2 (4.26) 0.52 (0.05, 5.98) 0.602 Day 3 0 (0.00) 2 (4.35) N/A #0.167 Overall 2 (4.65) 3 (6.82) 0.67 (0.11, 4.20) 0.666
Bradycardia (HR < 55) Gabapentin Placebo Intraoperative 6 (15.00) 12 (26.09) PACU 14 (35.00) 20 (42.55) OR 2 (5.00) 2 (4.35) Treatment effect p-value 0.50 (0.17, 1.49) 0.212 0.3 (0.30, 1.73) 0.472 1.16 (0.16, 8.62) 0.886 Day 1 0 (0.00) 2 (4.26) N/A #0.187 Day 2 3 (7.50) 0 (0.00) N/A #0.056 Day 3 0 (0.00) 0 (0.00) N/A Overall 17 (42.50) 25 (54.35) 0.62 (0.26, 1.46) 0.274
Tachycardia (HR > 100) Gabapentin Placebo Intraoperative 3 (7.50) 2 (4.35) Treatment effect p-value 1.78 (0.28, 11.25) 0.538 PACU 1 (2.50) 0 (0.00) N/A #0.276 OR 3 (7.50) 2 (4.35) Day 1 9 (23.08) 5 (10.64) Day 2 10 (25.64) 5 (10.64) Day 3 9 (23.68) 4 (8.51) Overall 19 (48.72) 12 (26.09) 1.78 (0.28, 11.25) 0.538 2.52 (0.77, 8.28) 0.128 2.90 (0.90, 9.36) 0.076 3.33 (0.94, 11.86) 0.063 2.69 (1.08, 6.68) 0.033
Bradypnea (RR < 10) Gabapntin Placebo Treatment effect Intraoperative 0 (0.00) 0 (0.00) N/A P-value PACU 0 (0.00) 2 (4.17) N/A #0.181 OR 0 (0.00) 0 (0.00) N/A Day 1 0 (0.00) 0 (0.00) N/A Day 2 0 (0.00) 0 (0.00) N/A Day 3 0 (0.00) 0 (0.00) N/A Overall 0 (0.00) 2 (4.17) #0.181
Hypoxemia (Sp02 <90%) Gabapentin Placebo Treatment effect p-value Intraoperative 0 (0.00) 1 (2.13) N/A #0.353 PACU 0 (0.00) 0 (0.00) N/A OR 0 (0.00) 0 (0.00) N/A Day 1 1 (2.38) 0 (0.00) N/A #0.282 Day 2 1 (2.38) 1 (2.08) 1.15 (0.07, 18.91) 0.924 Day 3 0 (0.00) 2 (4.17) N/A 0.186 Overall 2 (5.13) 4 (8.70) 0.57 (0.10, 3.28) 0.527
Summary (THA) n Baseline characteristics and medical history are similar among Gabapentin and Placebo group n There is no clinical significant in amount of morphine consumption between 2 groups n There is no difference found in side effects, ROM, hypotension, bradycardia, bradypnea, and hypoxemia between 2 groups
Outcomes: Total knee arthroplasty
Table 1: Baseline characteristics and medical history Gabapentin group Placebo group P-value (n = 44) (n = 41) *Age (years) 61.92 (6.58) 64.46 (5.95) Sex (female) 27 (61.36) 25 (60.98) *Weight (kg) 94.24 (20.82) 89.95 (17.48) *Height (cm) 167.74 (9.62) 168.83 (10.06) BMI 33.36 (6.05) 31.53 (5.43) ASA 1 1 (2.44) 1 (2.86) ASA 2 14 (34.15) 11 (31.43) ASA 3 25 (60.98) 22 (62.86) ASA 4 1 (2.44) 1 (2.86) ASA 5 0 (0.00) 0 (0.00)
Co-morbidities Arthritic change: Gabapntin (n=44) Placebo (n=41) Osteoarthritis 42 (95.45) 41 (100.00) Rheumatoid arthritis 1 (2.27) 0 (0.00) Past medical history: Other 1 (2.27) 0 (0.00) p-value Coronary artery disease 2 (4.55) 3 (7.32) 0.587 Hypertension 24 (54.55) 18 (43.90) 0.327 Smoker 6 (13.64) 9 (21.95) 0.315 COPD 1 (2.27) 3 (7.32) 0.272 Cerebral vascular disease 2 (4.55) 0 (0.00) 0.167 Sleep apnea 3 (6.82) 6 (14.63) 0.242 Asthma 4 (9.06) 4 (9.76) 0.916 Diabetes 7 (15.91) 2 (4.88) 0.099 Data are mean (SD) for interval data and number (%) for categorical data. * Interval data + 3 missing values in Gabapentin group and 6 missing values in placebo group
Morphine consumption Morphine consumption (mg) Gabapenti n group (n = 45) Placebo group (n = 50) Treatment effect (95% CI) p-value PACU 7.53 (1.70) 5.29 (1.46) Day 1 28.42 (3.54) 25.41 (2.46) Day 2 31.38 (4.92) 29.44 (3.59) Cumulative at 48 hours 57.76 (7.84) 55.16 (5.10) 2.25 (-2.20, 6.69) 0.318 3.01 (-5.53, 11.54) 0.485 1.93 (-10.06, 13.93) 0.749 2.61 (-15.68, 20.88) 0.778
Outcomes Gabapentin (n=45) Placebo (n=50) Treatment effect (95% CI) p-value Pain score at discharge from PACU At rest 1.70 (0.44) 0.69 (0.27) 1.01 (0.004, 2.02) 0.049 with passive movement 2.00 (0.88) 0.50 (0.28) 1.50 (-0.09, 3.09) 0.064 Pain scores at rest Day 1 2.70 (0.31) 2.15 (0.27) 0.55 (-0.27, 1.37) 0.185 Day 2 1.74 (0.21) 1.52 (0.23) 0.22 (-0.40, 0.83) 0.482 Day 3 2.45 (0.39) 1.91 (0.36) 0.54 (-0.52, 1.60) 0.312 Pain scores with passive movement Day 1 5.13 (0.45) 4.27 (0.47) 0.86 (-0.44, 2.16) 0.193 Day 2 3.50 (0.34) 3.96 (0.47) -0.55 (-1.61, 0.69) 0.432 Day 3 3.63 (0.44) 3.30 (0.43) 0.33 (-0.90, 1.56) 0.593 Pain scores with weight barring Day 1 9.48 (0.44) 8.23 (0.56) 1.25 (-0.18, 2.68) 0.086 Day 2 5.49 (0.50) 5.65 (0.53) -0.16 (-1.61, 1.30) 0.831 Day 3 4.35 (0.42) 3.95 (0.44) 0.40 (0.79, 1.58) 0.508 Patient satisfaction good to excellent Day 1 3.11 (0.71) 3.18 (0.81) -0.07 (0.38, 0.25) 0.665 Day 2 3.18 (0.76) 3.14 (0.88) 0.05 (-0.30, 0.39) 0.795 Day 3 3.21 (0.77) 3.19 (0.73) 0.02 (-0.30, 0.35) 0.887
Side effects 100 90 80 70 60 50 40 30 20 10 0 Gabapentin Placebo N/V Sedation Pruritis Dizziness Visual disturbance LOS (day)
Side effects and morbidity Gabapentin (n= 45) Placebo (n=50) Treatment effect (95% CI) p-value Nausea/Vomiting: Mild to Severe 30 (68.18) 39 (81.25) 0.49 (0.19, 1.26) 0.152 Moderate to Severe 20 (40.82) 25 (51.02) 0.66 (0.30, 1.47) 0.312 Severe 10 (20.41) 8 (16.33) 1.31 (0.47, 3.67) Sedation: Mild to Severe 31 (73.81) 24 (55.81) 2.23 (0.89, 5.56) 0.085 Moderate to Severe 10 (20.41) 7 (14.58) 1.50 (0.52, 4.34) 0.452 Severe 4 (8.16) 3 (6.12) 1.36 (0.29, 6.44) 0.696 Pruritis: Mild to Severe 17 (42.50) 20 (44.44) 0.92 (0.39, 2.18) 0.857 Moderate to Severe 0 (0.00) 6 (12.24) N/A #0.011 Severe 0 (0.00) 2 (4.08) N/A #0.153 Dizziness / lightheadedness 26 (60.47) 27 (58.70) 1.08 (0.46, 2.51) 0.865 Visual disturbance 9 (22.50) 7 (16.28) 1.49 (0.50, 4.48) 0.474 Death 0 (0.00) 0 (0.00) N/A
Outcomes Gabapentin (n=45) Placebo (n=50) Treatment effect (95% CI) p-value Knee range of motion at discharge (degree): Flexion 97.98 (19.91) 105.11 (15.42) -7.13 (-14.52, 0.26) 0.059 Extension 3.57 (5.24) 2.96 (4.16) 0.62 (-1.38, 2.61) 0.540 Hospitalizatio n(days): *Length of stay (days) 4.02 (1.28) 4.39 (1.76) -0.34 (-1.01, 0.29) 0.275
Hypotension (SBP < 90 mmhg) Gabapentin (n=45) Placebo (n=50) Treatment effect (95% CI) p-value Intraoperative 8 (17.39) 4 (8.70) PACU 10 (22.22) 6 (13.33) OR 4 (8.89) 8 (17.02) Day 1 2 (4.35) 3 (6.67) Day 2 2 (4.35) 1 (2.13) 2.21 (0.62, 7.93) 0.224 1.86 (0.61, 5.64) 0.274 0.48 (0.13, 1.71) 0.254 0.64 (0.10, 4.00) 0.630 2.09 (0.18, 23.89) 0.553 Day 3 0 (0.00) 0 (0.00) N/A Overall 19 (41.30) 17 (37.78) 1.16 (0.50, 2.69) 0.731
Hypertension (SBP >160 mmhg) Gabapentin (n=45) Placebo (n=50) Treatment effect (95% CI) p-value Intraoperative 0 (0.00) 1 (2.17) N/A #0.315 PACU 2 (4.44) 3 (6.38) 0.68 (0.11, 4.29) 0.683 OR 0 (0.00) 1 (2.17) N/A #0.315 Day 1 2 (4.35) 1 (2.13) Day 2 1 (2.17) 2 (4.26) Day 3 4 (8.70) 4 (8.51) Overall 7 (15.56) 6 (13.04) 2.09 (0.18, 23.89) 0.553 0.50 (0.04, 5.71) 0.577 1.02 (0.24, 4.36) 0.975 1.23 (0.38, 3.99) 0.732
Bradycardia (HR < 55) Gabapentin (n=45) Placebo (n=50) Treatment effect (95%CI) p-value Intra-operative 12 (27.27) 14 (31.82) PACU 13 (30.23) 20 (45.45) OR 3 (6.82) 5 (11.36) 0.80 (0.32, 2.01) 0.641 0.52 (0.22, 1.25) 0.146 0.57 (0.13, 2.55) 0.463 Day 1 0 (0.00) 1 (2.27) N/A 0.315 Day 2 0 (0.00) 0 (0.00) N/A Day 3 0 (0.00) 0 (0.00) N/A Overall 19 (43.18) 24 (54.55) 0.63 (0.27, 1.50) 0.287
Tachycardia (HR > 100) Gabapentin (n=450 Placebo (n=50) Intra-operative 1 (2.27) 1 (2.27) PACU 1 (2.33) 1 (2.27) Treatment effect (95%CI) p-value 1.00 (0.06, 16.51) >0.999 1.02 (0.06, 16.91) 0.987 OR 6 (13.64) 0 (0.00) N/A #0.011 Day 1 4 (9.09) 3 (6.82) Day 2 8 (18.18) 5 (11.36) Day 3 9 (20.45) 5 (11.36) Overall 14 (32.56) 10 (22.73) 1.37 (0.29, 6.50) 0.695 1.73 (0.52, 5.79) 0.371 2.01 (0.61, 6.57) 0.250 1.64 (0.63, 4.25) 0.307
Bradypnea (RR < 10) Gabapentin (n=45) Placebo (n=50) Treatment effect (95% CI) p-value Intra-operative 0 (0.00) 0 (0.00) N/A PACU 0 (0.00) 1 (2.13) N/A #0.336 OR 0 (0.00) 0 (0.00) N/A Day 1 0 (0.00) 0 (0.00) N/A Day 2 0 (0.00) 0 (0.00) N/A Day 3 0 (0.00) 0 (0.00) N/A Overall 0 (0.00) 1 (2.13) N/A #0.336
Hypoxemia (Sp02 < 90%) Gabapentin (n=45) Placebo (n=50) Treatment effect Intraoperative 0 (0.00) 0 (0.00) N/A PACU 0 (0.00) 0 (0.00) N/A (95% CI) p-value OR 0 (0.00) 1 (2.13) N/A #0.331 Day 1 0 (0.00) 2 (4.26) N/A #0.166 Day 2 0 (0.00) 2 (4.26) N/A 0.166 Day 3 0 (0.00) 1 (2.17) N/A 0.325 Overall 0 (0.00) 5 (10.87) N/A 0.026 Data are mean (SD) for interval data and number (%) for categorical data. Treatment effect was reported as difference between Gabapentin group and placebo group for interval data, and odds ratio for categorical data * patient with length of stay of 63 days was excluded as outlier # From chi-squred test
Summary (TKA) n Patients were similar between 2 groups n There was no difference in morphine consumption between 2 groups n Side effects, ROM, hospitalization, hypotension, bradycardia, bradypnea, and hypoxemia were similar between 2 groups