Gabapentin Does Not Improve Analgesia Outcomes For Total Joint Replacement. Manyat Nantha-Aree, MD

Transcription

1 Gabapentin Does Not Improve Analgesia Outcomes For Total Joint Replacement Manyat Nantha-Aree, MD

2 Objective n Preliminary results of MOBILE study in total hip and knee arthroplasty

3 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

4 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

5 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

6 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

7 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

8 In animal models: n Gabapentin does not block physiological pain n Effective against hypersensitivity (allodynia, hyperalgesia) induced by tissue damage or neuropathy 4

9 Gabapentin in Pain Management. Anesth Analg; 2000; 91: 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

10 Preoperative Gabapentin for Postoperative Analgesia: a Metaanalysis. CAN J ANESTH 2006; 3(5): RK Seib, J Paul n 8 Trials, 663 subjects, 7 surgeries: abdominal/vaginal hysterectomy, mastectomy/lumpectomy, cholescystectomy, lumbar discectomy/ spinal fusion

11 Reference No. of patients/ surgery Methodology/ Intervention Gabapentin dosing regimen Primary analgesic Outcome measures Dierking et al, 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, 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, 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, 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, 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, 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, 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, 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

12 Outcome Results Evidence Pain at rest Pain with activity Analgesia consumption Nausea Sedation Pruritis Dizziness Lightheadedness WMD = WMD = -11 WMD = OR = 1.1 NS OR = 2.5 NS OR = 0.3 NS OR = 1.0 NS OR = 1.0 NS Trials, 663 Subjects, 7 Surgeries: abdominal//vaginal hysterectomy, mastectomy/ lumpectomy, cholecystectomy, lumbar discectomy/spinal fusion

13 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?

14 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 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

15 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

16 Intraoperative period n Spinal anesthesia with isobaric or hyperbaric bupivacaine with fentanyl 20 mcg n No other opioids given n No skin infiltration (LA)

17 Outcomes: Total hip arthroplasty

18 Table 1: Baseline characteristics and medical history THA Gabapentin (n=44) Placebo (n=48) Age (yr) (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) (11.78) (10.08) BMI (5.6) (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)

19 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%)

20 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

21 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) (-4.26, 1.53) DAY (2.05) (1.99) (-12.12, -0.76) DAY (2.81) (2.92) (-8.17, 7.99) Cumulative 48 hrs (4.16) (4.14) (-17.92, 5.46) 0.292

22 Fig.2: Side effects Gabapentin Placebo N/V Sedation Pruritis Dizziness Visual disturbance LOS (days)

23 Pain score Gabapentin (n=45) Placebo (n=48) Treatment effect (95% CI) p-value PACU- rest 0.64 (0.24) 0.55 (0.21) PACU- movement 0.47 (0.35) 1.28 (0.77) At rest- POD (0.24) 2.38 (0.29) At rest- POD (0.35) 1.37 (0.19) At rest- POD ( (0.24) Movemt.- POD (0.50) 5.20 (0.47) Movemt.- POD (0.46) 3.77 (0.48) Movemt.- POD (0.5) 2.77 (0.45) Wt.bearing- POD1 Wt.bearing- POD (0.45) 9.66 (0.40) (0.54) 5.35 (0.52) Wt.bearing- POD (0.42) 3.86 (0.49)

24 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) (0.88) 3.42 (0.74) (0.94) 3.51 (0.66) 0.37 (-0.71, -0.03) (18.8) (9.97) LOS (days) 4.93 (1.7) 4.22 (1.39) 0.7 (0.05, 1.35) 0.035

25 Hemodynamic outcomes SBP < 90 mmhg Gabapentin (n=45) Placebo (n= 48) Treatment effect (95%CI) p-value Intraop. 21 (48.84%) 14 (31.82%) PACU 8 (18.18%) 4 (8.89%) OR 5 (11.36%) 8 (17.39%) POD 1 11 (25%) 7 (15.56%) POD 2 2 (4.55 %) 2 (4.26%) POD N/A Overall 27 (62.79%) 19 (466.34%)

26 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) 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

27 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) (0.30, 1.73) (0.16, 8.62) 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

28 Tachycardia (HR > 100) Gabapentin Placebo Intraoperative 3 (7.50) 2 (4.35) Treatment effect p-value 1.78 (0.28, 11.25) 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) (0.77, 8.28) (0.90, 9.36) (0.94, 11.86) (1.08, 6.68) 0.033

29 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

30 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) Day 3 0 (0.00) 2 (4.17) N/A Overall 2 (5.13) 4 (8.70) 0.57 (0.10, 3.28) 0.527

31 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

32 Outcomes: Total knee arthroplasty

33 Table 1: Baseline characteristics and medical history Gabapentin group Placebo group P-value (n = 44) (n = 41) *Age (years) (6.58) (5.95) Sex (female) 27 (61.36) 25 (60.98) *Weight (kg) (20.82) (17.48) *Height (cm) (9.62) (10.06) BMI (6.05) (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)

34 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) Hypertension 24 (54.55) 18 (43.90) Smoker 6 (13.64) 9 (21.95) COPD 1 (2.27) 3 (7.32) Cerebral vascular disease 2 (4.55) 0 (0.00) Sleep apnea 3 (6.82) 6 (14.63) Asthma 4 (9.06) 4 (9.76) Diabetes 7 (15.91) 2 (4.88) 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

35 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 (3.54) (2.46) Day (4.92) (3.59) Cumulative at 48 hours (7.84) (5.10) 2.25 (-2.20, 6.69) (-5.53, 11.54) (-10.06, 13.93) (-15.68, 20.88) 0.778

36 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) with passive movement 2.00 (0.88) 0.50 (0.28) 1.50 (-0.09, 3.09) Pain scores at rest Day (0.31) 2.15 (0.27) 0.55 (-0.27, 1.37) Day (0.21) 1.52 (0.23) 0.22 (-0.40, 0.83) Day (0.39) 1.91 (0.36) 0.54 (-0.52, 1.60) Pain scores with passive movement Day (0.45) 4.27 (0.47) 0.86 (-0.44, 2.16) Day (0.34) 3.96 (0.47) (-1.61, 0.69) Day (0.44) 3.30 (0.43) 0.33 (-0.90, 1.56) Pain scores with weight barring Day (0.44) 8.23 (0.56) 1.25 (-0.18, 2.68) Day (0.50) 5.65 (0.53) (-1.61, 1.30) Day (0.42) 3.95 (0.44) 0.40 (0.79, 1.58) Patient satisfaction good to excellent Day (0.71) 3.18 (0.81) (0.38, 0.25) Day (0.76) 3.14 (0.88) 0.05 (-0.30, 0.39) Day (0.77) 3.19 (0.73) 0.02 (-0.30, 0.35) 0.887

37 Side effects Gabapentin Placebo N/V Sedation Pruritis Dizziness Visual disturbance LOS (day)

38 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) Moderate to Severe 20 (40.82) 25 (51.02) 0.66 (0.30, 1.47) 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) Moderate to Severe 10 (20.41) 7 (14.58) 1.50 (0.52, 4.34) Severe 4 (8.16) 3 (6.12) 1.36 (0.29, 6.44) Pruritis: Mild to Severe 17 (42.50) 20 (44.44) 0.92 (0.39, 2.18) 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) Visual disturbance 9 (22.50) 7 (16.28) 1.49 (0.50, 4.48) Death 0 (0.00) 0 (0.00) N/A

39 Outcomes Gabapentin (n=45) Placebo (n=50) Treatment effect (95% CI) p-value Knee range of motion at discharge (degree): Flexion (19.91) (15.42) (-14.52, 0.26) Extension 3.57 (5.24) 2.96 (4.16) 0.62 (-1.38, 2.61) Hospitalizatio n(days): *Length of stay (days) 4.02 (1.28) 4.39 (1.76) (-1.01, 0.29) 0.275

40 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) (0.61, 5.64) (0.13, 1.71) (0.10, 4.00) (0.18, 23.89) 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

41 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) 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) (0.04, 5.71) (0.24, 4.36) (0.38, 3.99) 0.732

42 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) (0.22, 1.25) (0.13, 2.55) Day 1 0 (0.00) 1 (2.27) N/A 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

43 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) > (0.06, 16.91) 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) (0.52, 5.79) (0.61, 6.57) (0.63, 4.25) 0.307

44 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

45 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 Day 3 0 (0.00) 1 (2.17) N/A Overall 0 (0.00) 5 (10.87) N/A 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

46 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

47