|Year : 2016 | Volume
| Issue : 1 | Page : 7-12
A comparative study between oral pregabalin and gabapentin in prolongation of postoperative pain relief after spinal anesthesia
Swarup Pal1, Sugata Dasgupta1, Soma Mukhopadhyay1, Arunima Chaudhuri2
1 Departments of Anaesthesiology and Critical Care Medicine, RG Kar Medical College and Hospital, Kolkata, West Bengal, India
2 Department of Physiology, Burdwan Medical College and Hospital, Burdwan, West Bengal, India
|Date of Web Publication||7-Jan-2016|
Dr. Arunima Chaudhuri
Krishnasayar South, Borehat, Burdwan - 713 102, West Bengal
Source of Support: None, Conflict of Interest: None
Background: Preemptive analgesia involves the introduction of an analgesic regimen before the onset of noxious stimuli, with the goal of preventing sensitization of the nervous system to subsequent stimuli that could amplify pain. Aims: To compare the efficacy of pregabalin and gabapentin as preemptive analgesics in surgery below the umbilicus under spinal anesthesia. Materials and Methods: This study was conducted in a time span of 1 year in a tertiary care hospital of eastern India after obtaining institutional ethical clearance and informed consent of the subjects. Sixty-two patients were randomly allocated to two groups using an online randomizer. Group G (n = 31) received single dose of gabapentin 1,200 mg and Group P (n = 31) received a single dose of pregabalin 300 mg. the parameters were studied for comparing the quality of intraoperative and postoperative analgesia and sedation and complications. Results: In the 24 h of postoperative period, the mean visual analogue scale (VAS) scores at rest of Group P was always significantly lower than those of Group G. In Group G (gabapentin group) rescue analgesic was given after 9.41 ± 1.84 h while in Group P (pregabalin group), rescue analgesic was required after 15.38 ± 3.52 h. In Group G subsequent rescue analgesic was required in only three cases while in Group P, subsequent rescue analgesic was required in only two cases. In the pregabalin group, the incidence of somnolence and dizziness was significantly less than the other group. Conclusion: Single oral dose of pregabalin (300 mg) given preoperatively provides better postoperative pain control and decreases postoperative rescue analgesic consumption compared to a single dose of gabapentin (1,200 mg).
Keywords: Complications, gabapentin, pregabalin, preemptive analgesia
|How to cite this article:|
Pal S, Dasgupta S, Mukhopadhyay S, Chaudhuri A. A comparative study between oral pregabalin and gabapentin in prolongation of postoperative pain relief after spinal anesthesia. Indian J Pain 2016;30:7-12
|How to cite this URL:|
Pal S, Dasgupta S, Mukhopadhyay S, Chaudhuri A. A comparative study between oral pregabalin and gabapentin in prolongation of postoperative pain relief after spinal anesthesia. Indian J Pain [serial online] 2016 [cited 2020 Jul 13];30:7-12. Available from: http://www.indianjpain.org/text.asp?2016/30/1/7/173435
| Introduction|| |
Postoperative pain is not purely nociceptive in nature, and may consist of inflammatory, neurogenic, and visceral components.  Surgical stimulation leads to sensitization of the dorsal horn neurons, which are associated with augmentation of pain. 
Preemptive analgesia, an evolving clinical concept, involves the introduction of an analgesic regimen before the onset of noxious stimuli, with the goal of preventing sensitization of the nervous system to subsequent stimuli that could amplify pain. Surgery offers the most promising setting for preemptive analgesia because the timing of noxious stimuli is known. When adequate drug doses are administered to appropriately selected patients before surgery, intravenous opiates, local anesthetic infiltration, nerve block, subarachnoid block, and epidural block offer benefits that can be observed as long as 1 year after surgery. ,,,
Anticonvulsants and tricyclic antidepressants were conventionally used for neuropathic pain. Gabapentin, a structural analogue of gamma-aminobutyric acid (GABA), introduced in 1994 as an antiepileptic drug and later used for chronic pain conditions such as neuropathic pain,  diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome,  exerts its effects by binding with alpha 2 delta subunit of presynaptic voltage gated Ca 2+ channels  and has antinociceptive, antihyperalgesic, and antiallodynic properties. 
Several studies have shown the effectiveness of gabapentin as an agent for acute postoperative pain relief resulting in reduced postoperative analgesic requirement in abdominal hysterectomy,  spinal surgery,  radical mastectomy,  and laparoscopic cholecystectomy. 
Pregabalin, another analogue of GABA that shares some characteristics with its predecessor gabapentin, however with superior pharmacokinetic profile,  introduced in 2004 already has an established role in the treatment of peripheral neuropathic pain associated with diabetes mellitus and postherpetic neuralgia. On review of the recent literatures, pregabalin showed evidence that it might be efficacious in relieving acute pain similar to gabapentin ,, although there is a relative paucity of studies comparing them.
In view of the above observations, the present study was designed as randomized, double-blinded, parallel group, open label trial to compare the efficacy of pregabalin and gabapentin as preemptive analgesics in surgery below the umbilicus under spinal anesthesia.
| Materials and Methods|| |
This randomized double-blinded prospective study was conducted in a time span of 1 year in a tertiary care hospital of eastern India after obtaining institutional ethical clearance and informed consent of the subjects.
Patients of both sexes in the age group of 20-50 years having body weight 50-70 kg and with physical status American Society of Anesthesiologists (ASA)-I and ASA-II undergoing infraumbilical surgeries under spinal anesthesia were included.
As calculated from a previous study  to get a clinically relevant difference in the duration of postoperative analgesia, we needed 31 patients in each group with a power of study 80% at 95% confidence interval (alpha = 0.05). Total number of patients = 62; they were randomly allocated in two groups using an online randomizer. Group G (n = 31) received a single dose of gabapentin 1,200 mg; Group P (n = 31) received a single dose of pregabalin 300 mg.
Patients with uncontrolled or labile hypertension, allergic to the study drugs, pregnant and lactating women, patients with psychiatric illness, hepatic impairment, or renal impairment, and patients having any contraindication to spinal anesthesia were excluded.
The parameters studied for comparing the quality of intraoperative and postoperative analgesia and sedation:
- Visual analogue scale (VAS)  between 0 cm and 10 cm; 0 = no pain; 10 = most severe pain
- Time lapsed after operation when the patient needs rescue analgesic for sedation: Filos' numerical scale
Scale 1 = awake and nervous
Scale 2 = awake and relaxed
Scale 3 = sleepy but easy to awake
Scale 4 = sleepy and hard to awake
The parameters studied for comparing adverse effects: Dizziness/somnolence; diplopia; vomiting [the severity of PONV will be graded on a 4-point ordinal scale; (0 = no nausea/vomiting; 1 = mild nausea; 2 = moderate nausea; 3 = severe nausea with vomiting)]; confusion (assessed by asking time, place, person); urinary retention in a noncatheterized patient; respiratory depression [defined as ventilatory frequency <8 bpm and oxygen saturation <90% without oxygen supplementation].
Patients in Group G (n = 31) received a single dose of gabapentin 1,200 mg, whereas in the Group P (n = 31), patients were administered pregabalin 300 mg per oral 1 h prior to the administration of spinal anesthesia. No other premedication was instituted.
A day before the scheduled operation the patients were visited preoperatively in their wards for preanesthetic checkup. A thorough clinical history was obtained. They were physically examined, laboratory investigations were reviewed and details about VAS  (0-10 cm) was explained on the day before operation. The patients were also explained about the procedures of spinal anesthesia and postoperative pain relief and all queries and doubts were answered to get their confidence and support. A pharmacologist of our institution not involved in this study prepared the drug containing bags, each containing four hard gelatin capsules. Ingroup G, the bag contained four 300 mg hard gelatin capsules of gabapentin belonging to one particular pharmaceutical company; in group P the bag contained four 75 mg hard gelatin capsules of pregabalin belonging to the same pharmaceutical company (size and shape looked similar). The medication was given to the patient by an anesthesiologist not involved in the study 1 h before the induction of anesthesia.
Routine monitoring in the form of noninvasive blood pressure amplifier (NIBP), pulse oximetry, and electrocardiogram (ECG) were instituted on arrival in operation theater. All the patients were preloaded with 10 mL/kg lactated Ringer's solution before being administered spinal anesthesia. Spinal anesthesia was instituted with 3 mL of 0.5% bupivacaine (15 mg) at L 3 - L 4 /L 4 - L 5 level. Fluid administration was continued intraoperatively and hypotension, if any, was treated with fluid replacement and intravenous (IV) mephentermin, and this whole procedure was conducted by another anesthetist.
Pain was assessed postoperatively by VAS in the immediate postoperative period and every 2 h thereafter, which was explained to the patient during the preoperative visit. When patient was shifted to the ward anesthesiologists, unaware that premedication was responsible for charting the pain score by VAS scale. Pain charting was done separately and anesthetic chart was not attached with the case sheet, so the observer was not able to assess to which group the patient belonged.
Any patient with VAS score of more than 3 received diclofenac 1 mg/kg intramuscularly. Time since spinal anesthesia to the first dose of analgesic and total dose of analgesic in the first 24 h was recorded. Any complications such as dizziness, somnolence, diplopia, vomiting, confusion, respiratory depression, pain, and urinary retention were recorded in the first 24-h postoperative period.
The computer software Statistical Package for the Social Sciences (SPSS) version 16 (SPSS Inc. Released 2007, SPSS for Windows, version 16.0. Chicago, Illinois, USA) was used for analysis of data. For all analyses, probability values (P value) <0.05* were considered as statistically significant and P values <0.01 ** were considered as statistically highly significant.
| Results|| |
Sixty-two patients, of either sex, aged 20-50 years, belonging to ASA grades I and II, and scheduled to undergo infraumblical surgeries were included in this prospective, randomized, double-blinded, parallel group, open label study. All the groups were comparable in respect to demographic data, ASA physical status, the mean duration of surgery, and the type of surgeries performed. Maximum number of participants belonged to the age group of 40 years and above. The male-female ratio was 1:1.38.
In the 24 h of postoperative period, the mean VAS scores at rest of Group P was always significantly lower than those of Group G. The time to first dose of rescue analgesic was compared between the groups. In Group G (gabapentin group), rescue analgesic was given after 9.41 ± 1.84 h while in Group P (pregabalin group) rescue analgesic was required after 15.38 ± 3.52 h. In Group G subsequent rescue analgesic was required in only three cases while in Group P, subsequent rescue analgesic was required in only two cases. In the pregabalin group, the incidence of somnolence (12.90%) and dizziness (9.68%) were significantly less than the other group (gabapentin group -22.59% and 19.35%, respectively) while the incidences of nausea and vomiting were absent in both the groups. The groups did not vary with respect to the average time required for the surgical maneuver as shown in [Table 1].
|Table 1: Distribution of participants as per duration of surgery (N = 62)|
Click here to view
The study groups had a significant variation in the time interval after surgery when the VAS score was found to be 3 or more signaling the need of rescue analgesic. In Group P, the time interval was more compared to Group G as shown in [Table 2]. The time required for the administration of the rescue analgesic postoperatively was found to be significantly earlier in case of Group G compared to Group P. That means that pregabalin showed prolonged postoperative analgesia compared to gabapentin [Table 3].
|Table 2: Distribution of participants as per the time elapsed after of surgery when VAS score was more than 3 (N = 62) |
Click here to view
|Table 3: Distribution of participants according to the time of administration of rescue analgesic after surgical maneuver, i.e., postoperative analgesia time after giving preemptive pregabalin or gabapentin (N = 62)|
Click here to view
| Discussion|| |
Management of pain and its complications in the postoperative period still is a major challenge. Preemptive analgesia is a treatment that prevents establishment of the altered sensory processing that amplifies postoperative pain. Preincisional analgesia has been shown to be more effective in the control of postoperative pain by protecting the central nervous system from deleterious effects of noxious stimuli and resulting allodynia, and increased pain. Gabapentin and pregabalin have antiallodynic and antihyperalgesic properties useful for treating neuropathic pain and may also be beneficial in acute postoperative pain. ,,,
In some of the studies conducted with pregabalin as preemptive analgesic, like minor gynecological surgery involving the uterus by Peach et al.  in 2007, day-case gynecological laparoscopic surgery by 2008 Jokela et al.,  and laparoscopic cholecystectomy by Agarwal et al.,  a single dose of 100-150 mg was used. The present study was different from these studies in the analgesic effect of pregabalin. The pain scores in the placebo group of the earlier studies mentioned were substantially low and the dose of pregabalin in the present study would have been subtherapeutic as laminectomy, discectomy, and instrumentation are much more painful procedures. Therefore, the present study used a single preemptive 300 mg dose of pregabalin. The duration after operation when rescue analgesic was required was 15.38 ± 3.52 h in the case of pregabalin and 9.41 ± 1.84 h in the case of gabapentin, which was statistically and significantly lower in the case of gabapentin. Subsequent dose required in the case of pregabalin was 6.45% and in the case of gabapentin was 9.68%.
In a study conducted by Saraswat et al.,  time to rescue analgesic was 8.98 ± 5.38 h for the gabapentin group, which was significantly less (P value <0.001) than the pregabalin group (14.17 ± 6.67 h), whereas the total dose of rescue analgesic (mg) in the 24-h postoperative period was 62.5 ± 28.43 mg for pregabalin, being lower than 5 ± 23.99 mg for gabapentin, and was statistically not significant between the groups.
The requirement of subsequent number of rescue analgesic doses in the 24 h of postoperative period between the groups have shown that in Group G (gabapentin group) and Group P (pregabalin group), it was only for 3/0/0 and 2/0/0 (1 dose/2 doses/3 doses) patients, respectively. This finding is in agreement with the results of the study conducted by Saraswat et al.  where the number of doses in 24 h (0 dose/1 dose/2 doses) in the gabapentin group was 2/26/2 and for the pregabalin group was 4/25/1 (no discernible difference between the two groups).
Peach et al.  in 2007 conducted the study in 90 women having minor gynecological surgery involving the uterus. Patients received either oral pregabalin 100 mg or placebo approximately 1 h before surgery, whereas in our study 300 mg pregabalin was used in infraumblical surgery under spinal anesthesia. There was no significant difference between the groups regarding pain experienced in the recovery room or thereafter or for recovery room fentanyl requirement (42% group pregabalin versus 27% group placebo, P value = 0.12) or the quality of recovery at 24 h postoperatively.
Agarwal et al.  in 2008 evaluated the efficacy of a single preoperative dose of 150 mg pregabalin when given 1 h before surgery for attenuating postoperative pain and fentanyl consumption after laparoscopic cholecystectomy compared to the placebo. Our study in contrast used 300 mg dose of pregabalin and that too in infraumblical surgery. Postoperative pain (static and dynamic) was assessed by a 100 mm VAS and the subjects received patient-controlled IV fentanyl analgesia during the postoperative period while in our study only static scores were measured and diclofenac was used as rescue analgesic. Result of the study revealed that postoperative pain (static and dynamic) and postoperative patient-controlled fentanyl consumption were reduced in the pregabalin group compared with the placebo group (P < 0.05).
Sahu et al. in 2010  conducted a study to evaluate the role of pregabalin in reducing postoperative pain and rescue analgesic demand in patients undergoing infraumbilical surgeries under spinal anesthesia. In Group I placebo capsules 12 h before surgery and 1 h before surgery and in Group II, pregabalin capsules (150 mg) 12 h before surgery and 1 h (150 mg) before surgery were used. After giving anesthesia, the patients were assessed every 2 h for 24 h for pain score by VAS scale, blood pressure (BP), pulse rate, respiratory rate, rescue analgesics demand (injection tramadol IV), and side effects if any. In our study, only one preemptive dose of 300 mg pregabalin or 1200 mg gabapentin was used instead of two doses at 12 h intervals. Postoperative respiratory rate was not seen in our study and rescue analgesic used was diclofenac. Patients in the pregabalin group had significantly lower mean VAS postoperatively and lower rescue analgesic consumption than the placebo group (I) (P < 0.05), which were nearly similar to our results.
In studies by Saraswat et al.  patients in Group G were given a single dose of gabapentin 1,200 mg, whereas in Group P, the patients were administered pregabalin 300 mg 1 h prior to the administration of spinal anesthesia, which was similar to our study. Pain was assessed by VAS immediately after operation and every 2 h thereafter, time since spinal anesthesia to the first dose of analgesic (diclofenac) and total dose of analgesic in the first 24 h was recorded, similar to our study. The total postoperative analgesic time was 8.98 h in Group G, whereas 14.17 h in Group P (HS, P < 0.001) and total dose of analgesics in the first 24 h was 62.5 mg in Group P and 72.5 mg in Group G and was not significant (P > .05). In our study, total postoperative analgesic time was 9.41 ± 1.84 h in Group G, whereas it was 15.38 ± 3.52 h in Group P.
Gajraj  reviewed the phamacology of pregabalin and found that somnolence (29.2%) and dizziness (22.2%) were the most common side effects, which were similar to our study but the percentage incidence was much lower (12.90% and 9.68%).
The incidences of nausea and vomiting were not found in our study. Turan et al.  showed that the use of oral gabapentin given preoperatively in patients of spinal surgery showed a significant reduction in the incidence of vomiting (P < 0.05) compared to the placebo. No incidence of nausea/vomiting in the gabapentin and pregabalin groups in our study might be attributed to the fact that very little rescue analgesic was required in these groups. Another cause might be the antiemetic action of gabapentinoids that has already been established.
Peach et al.  in 2007 conducted a study in 90 women having minor gynecological surgery involving the uterus. Patients received either oral pregabalin 100 mg or placebo approximately 1 h before surgery, whereas in our study 300 mg pregabalin was used in infraumblical surgery under spinal anesthesia. In their study, incidences of posthospital discharge lightheadedness, visual disturbance, and difficulty with walking were significantly higher in the pregabalin group but in our study, somnolence and dizziness were significantly less than the gabapentin group.
In 2008 Jokela et al.  conducted a study to evaluate the control of pain after perioperative administration of pregabalin 300 or 600 mg, compared with diazepam 10 mg in patients undergoing laparoscopic hysterectomy. In contrast, our study was on infraumblical surgery where only 300 mg pregabalin and no 600 mg dose was used; and gabapentin was used instead of diazepam. The incidences of dizziness (70% vs 35%; P = 0.012), blurred vision (63% vs 14%; P = 0.002), and headache (31% vs 7%; P = 0.041) were higher in the P600 group than in the D10 group. Side effects such as somnolence (12.90%) and dizziness (9.68%) were significantly less in the pregabalin group than the gabapentin group (somnolence: 22.59%, dizziness: 19.35%) in our study but not in the high magnitude as 70% (dizziness) and 63% (blurred vision) in their study. Thus, it may be said in conclusion that a 300 mg dose is better suited than 600 mg as used in their study to reduce the incidence of side effects.
Agarwal et al. evaluated the efﬁcacy of a single preoperative dose of 150 mg pregabalin when given 1 h before surgery for attenuating postoperative pain and fentanyl consumption after laparoscopic cholecystectomy compared to placebo. Ours in contrast used 300 mg dose of pregabalin and that too in infraumblical surgery. Side effects were similar in both the groups in their study but in ours, side effects were less in the pregabalin group.
Sahu et al.  evaluated the role of pregabalin in reducing postoperative pain and rescue analgesic demand in patients undergoing infra umbilical surgeries under spinal anesthesia. 300 mg of pregabalin was associated with less side effects in this study, which was similar to our study.
| Conclusion|| |
In conclusion, a single oral dose of pregabalin (300 mg) given preoperatively provides better postoperative pain control and decreases postoperative rescue analgesic consumption compared to a single dose of gabapentin (1,200 mg). So it can be postulated that pregabalin may effectively be used as a part of the multimodal analgesic approach to prevent acute postoperative pain, much like gabapentin, which already has an established role.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kong VK, Irwin MG. Gabapentin: A multimodal perioperative drug? Br J Anaesth 2007;99:775- 86.
Turan A, Kaya G, Karamanlioglu B, Pamukcu Z, Apfel CC. Effect of oral gabapentin on postoperative epidural analgesia. Br J Anaesth 2006;96:242-6.
Bennett MI, Simpson KH. Gabapentin in the treatment of neuropathic pain. Palliat Med 2004;18:5-11.
van de Vusse AC, Stomp-van den Berg SG, Kessels AH, Weber WE. Randomised controlled rial of gabapentin in Complex Regional Pain Syndrome type 1 [ISRCTN84121379]. BMC Neurol 2004;4:13.
Luo ZD, Calcutt NA, Higuera ES, Valder CR, Song YH, Svensson CI, et al
. Injury type-specific calcium channel alpha 2 delta-1 subunit up-regulation in rat neuropathic pain models correlates with antiallodynic effects of gabapentin. J Pharmacol Exp Ther 2002;303:1199-205.
Rose MA, Kam PC. Gabapentin: Pharmacology and its use in pain management. Anaesthesia 2002;57:451-62.
Turan A, Karamanlioğlu B, Memiº D, Usar P, Pamukçu Z, Türe M. The analgesic effects of gabapentin after total abdominal hysterectomy. Anesth Analg 2004;98:1370-3, table of contents.
Turan A, Karamanlioğlu B, Memiº D, Hamamcioglu MK, Tükenmez B, Pamukçu Z, et al
. Analgesic effects of gabapentin after spinal surgery. Anesthesiology 2004;100:935-8.
Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H, Dahl JB. A randomized study of the effects of single dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology 2002;97:560-4.
Pandey CK, Priye S, Singh S, Singh U, Singh RB, Singh PK. Preemptive use of gabapentin significantly decreases postoperative pain and rescue analgesic requirements in laproscopic cholecystectomy. Can J Anaesth 2004;51:358-63.
Ben-Manachem E. Pregabalin Pharmacology and its relevance to clinical practice. Epilepsia 2004;45(Suppl 6):13-8.
Hill CM, Balkenohl M, Thomas DW, Walker R, Mathé H, Murrary G. Pregabalin in patients with postoperative dental pain. Eur J Pain 2001;5:119-24.
Reuben SS, Buvanendran A, Kroin JS, Raghunathan K. The analgesic efficacy of celecoxib, pregabalin, and their combination for spinal fusion surgery. Anesth Analg 2006;103:1271-7.
Saraswat V, Arora V. Preemptive gabapentin vs pregabalin for acute postoperative pain after surgery under spinal anaesthesia. Indian J Anaesth 2008;52:829.
Tiippana EM, Hamunen K, Kontinen VK, Kalso E. Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety. Anesth Analg 2007;104:1545-56, table of contents.
Van Elstraete AC, Tirault M, Lebrun T, Sandefo I, Bernard JC, Polin B, et al
. The median effective dose of preemptive gabapentin on postoperative morphine consumption after posterior lumbar spinal fusion. Anesth Analg 2008;106:305-8, table of contents.
Rusy LM, Hainsworth KR, Nelson TJ, Czarnecki ML, Tassone JC, Thometz JG, et al
. Gabapentin use in pediatric spinal fusion patients: A randomized, double-blind, controlled trial. Anesth Analg 2010;110:1393-8.
Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: A double-blind, placebo-controlled trial. Pain 2004;110:628-38.
Paech MJ, Goy R, Chua S, Scott K, Christmas T, Doherty DA. A randomized, placebo-controlled trial of preoperative oral pregabalin for postoperative pain relief after minor gynecological surgery. Anesth Analg 2007;105:1449-53, table of contents.
Jokela R, Ahonen J, Tallgren M, Haanpää M, Korttila K. A randomized controlled trial of perioperative administration of pregabalin for pain after laparoscopic hysterectomy. PAIN 2008;134:106-12.
Agarwal A, Gautam S, Gupta D, Agarwal S, Singh PK, Singh U. Evaluation of a single preoperative dose of pregabalin for attenuation of postoperative pain after laparoscopic cholecystectomy. Br J Anaesth 2008;101:700-4.
Sahu S, Sachan S, Verma A, Pandey HD, Chitra. Evaluation of pregabalin for attenuation of postoperative pain in below umbilical surgeries under spinal anaesthesia. J Anaesth Clin Pharmacol 2010;26:167-71.
Gajraj NM. Pregabalin: Its pharmacology and use in pain management. Anesth Analg 2007;105:1805-15.
Pandey CK, Sahay S, Gupta D, Ambesh SP, Singh RB, Raza M, et al
. Preemptive gabapentin decreases postoperative pain after lumbar discoidectomy. Can J Anesth 2004;51:986-9.
[Table 1], [Table 3]