SPINE Volume 39, Number 6, pp E363-E368 ©2014, Lippincott Williams & Wilkins
RANDOMIZED TRIAL
Postoperative Pain and Long-Term Functional Outcome After Administration of Gabapentin and Pregabalin in Patients Undergoing Spinal Surgery Gurjeet Khurana, MD,* Parul Jindal, MD,* Jagdish P. Sharma, MD,* and Krishan K. Bansal, MS, MCh†
Study Design. Prospective, double-blind study, randomized control trial. Objective. To evaluate and compare the analgesic efficacy, adverse effects, and clinical utility of gabapentin and pregabalin in postoperative pain management, long-term functional outcome, and quality of life in patients undergoing spinal surgery. Summary of Background Data. Patient outcome after lumbar discectomy for radicular low back pain is variable and the benefit is inconsistent. The most common persistent symptoms are pain, motor deficit, and decreased functional status. Methods. This study was conducted in 90 patients belonging to the 18 to 75 age group of either sex undergoing spinal surgery under general anesthesia. Group A received 300 mg of gabapentin, group B received 75 mg of pregabalin, whereas group C received placebo 1 dose 1 hour before surgery and 8 hourly for 7 days, thereafter. The outcome of postoperative static and dynamic pain and functional outcome was recorded using 3 questionnaires—visual analogue scale, Prolo functional and economic score, Oswestry Disability Index score from preoperative period to 3 months postoperatively. Results. Among the 3 groups, subjects receiving pregabalin showed consistently reduced static and dynamic pain intensity and also required lesser amount of rescue drug throughout the postoperative period. There was statistically significant difference (P < 0.05) in the Prolo score and Oswestry Disability Index score at all time intervals between group B and group C. Although, significant difference in the functional outcome between group A and group B was seen at 3 months.
From the Departments of *Anesthesiology; and †Neurosurgery, Himalayan Institute of Medical Sciences, HIHT University, Swami Ram Nagar, Dehradun, India. Acknowledgment date: August 6, 2013. First revision date: November 8, 2013. Second revision date: December 3, 2013. Acceptance date: December 16, 2013. The device(s)/drug(s) is/are FDA-approved or approved by corresponding national agency for this indication. No funds were received in support of this work. No relevant financial activities outside the submitted work. Address correspondence and reprint requests to Parul Jindal, MD, Department of Anesthesiology, Himalayan Institute of Medical Sciences, HIHT University, Swami Ram Nagar, Dehradun, India; E-mail: [email protected] DOI: 10.1097/BRS.0000000000000185 Spine
Conclusion. Preoperative pregabalin administration is associated with less pain intensity and improved functional outcomes 3 months after lumbar discectomy followed by gabapentin and then placebo. Key words: pregabalin, gabapentin, functional outcome, postoperative pain, lumbar discectomy, Prolo score, Oswestry Disability Index score, visual analogue scale. Level of Evidence: 2 Spine 2014;39:E363–E368
P
erioperative pain relief is the aim of anesthesia. Pain is now regarded as the fifth vital sign and has ill effects on particularly all the systems. With the decrease in morbid adverse events after surgery, patient satisfaction with perioperative care is assuming more importance. Postoperative pain differs from other types of pain in that it is usually transitory with progressive improvement during a relatively short time course. This renders the condition more easily amenable to therapy than is the case for chronic pain.1 Major spinal surgery causes severe postoperative pain that can persist up to 3 days, thus hampering convalescence. Although opioids have been the mainstay of postoperative management, they are not free from adverse effects. Multimodal analgesia with its benefit of superior pain relief is now the cornerstone of postoperative pain management. Adding an antineuropathic analgesic improves postoperative pain by preventing the development of central sensitization. The mechanism of action of gabapentin and its successor, pregabalin is likely mediated by binding to the 21 subunits of the presynaptic voltage-gated calcium channels, which are upregulated in the dorsal root ganglia and spinal cord after surgical trauma. Gabapentin may produce antinociception by inhibiting calcium influx via these channels, and subsequently inhibiting the release of excitatory neurotransmitters (e.g., substance P, calcitonin gene-related peptide) from the primary afferent nerve fibers in the pain pathway.2 Pregabalin has a more favorable pharmacokinetic profile, including dose-independent absorption.3,4 Gabapentin and pregabalin have antiallodynic and antihyperalgesic properties useful for treating neuropathic pain.5 These properties may also be beneficial in acute postoperative pain.2 The primary aim was to compare the improvement in pain score preoperatively to 72 hours postoperatively in www.spinejournal.com
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RANDOMIZED TRIAL patients who were given gabapentin, pregabalin, or placebo. Secondary objectives included a comparison of predefined measures of pain and pain-related function up to 3 months postoperatively.
MATERIALS AND METHODS The study was performed in accordance with the ethical standards of the same institute. Informed consent was obtained from each subject at recruitment. This prospective, randomized, double-blind study was conducted in the department of anesthesiology in conjunction with the department of neurosurgery on 90 patients of either sex belonging to the 25 to 72 age group. Inclusion criteria were patients with chronic low back pain persisting up to 6 months in spite of alternative therapies and on radiological intervention diagnosed with intervertebral disc prolapse without ligament hypertrophy posted for lumbar discectomy; minimum visual analogue scale score (VAS) at recruitment, 40 mm; and American Society of Anesthesiologists physical status I, II. Patients excluded from the study were patients with history of previous back surgery, history of gastric ulcers or intestinal bleeding, known allergy to the drugs under study, patients with serious medical problems within the last 6 months including myocardial infarction (heart attack), congestive heart failure, stroke, deep vein thrombosis, pulmonary embolism, kidney disease as evidenced by the need for dialysis or kidney transplant, history of seizure or other neurological disorders, patients intending to become pregnant or who are pregnant or nursing during the projected course of treatment, and those who were taking gabapentin or pregabalin for other medical purposes. According to computer-generated random allocation in this double-blind study, group A received 300 mg of gabapentin, group B received 75 mg of pregabalin, whereas group C received placebo; 60 minutes preoperatively and 8 hourly for 7 days postoperatively. The medication was prescribed according to instructions in a sealed, opaque envelope by an anesthesiologist with no further involvement in the study. Preoperatively, on the evening before surgery (time 0), all patients completed 3 questionnaires in the presence of one of the investigators. These were as follows: • VAS pain at rest and on movement • Oswestry Disability Index (ODI)6 • Modified Prolo economic and functional score.7 With standard hemodynamic monitors in place (electrocardiogram, heart rate, pulse oximeter oxygen saturation, and noninvasive blood pressure, capnography, and temperature monitoring), anesthesia was induced with 2 μg/kg of fentanyl and 2 to 4 mg/kg of propofol, followed by 0.1 mg/kg of vecuronium, to facilitate tracheal intubation and ventilation. Anesthesia was maintained using isoflurane to maintain end tidal concentration 1 to 1.5 minimum alveolar concentration and vecuronium and fentanyl as clinically indicated. At the time of skin closure 75 mg of diclofenac sodium was administered intravenously. Neuromuscular E364
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Gabapentinoids: Postop Pain and Outcome • Khurana et al
block was reversed with 0.5 μg/kg of neostigmine and glycopyrrolate and patient was shifted to postanesthesia care unit. Postoperatively pain score, hemodynamics, oxygen saturation respiratory rate, sedation and side effects like nausea, vomiting, dizziness, dry mouth, general fatigue, somnolence, itching, headache, and urinary retention and requirement of analgesic postoperatively was observed. VAS score at rest was assessed at 0, 3, 6, 12, 24, 36, 48, and 72 hours postoperatively, whereas VAS score at movement was assessed after 6 hours of strict bed rest when the patient was able to perform a 90° logroll while in bed. At any given time, if the VAS score was more than 30 mm, the patient was given 1 to 2 mg/kg of tramadol intravenously. Sedation score was measured using a numerical score (1: completely drowsy, 2: awake but drowsy, 3: asleep but responsive to verbal command, 4: asleep but responsive to tactile stimulus, 5: asleep but not responsive to any stimulus). Then, the 3 questionnaires were filled at 7 days, 21 days, and 3 months by the same recorder who was not involved further in the study. Modified Prolo score was interpreted as: 2 to 4, poor; 5 to 6, fair; 7 to 8, good; and 9 to 10, excellent. ODI score was first calculated as total score/50 × 100 = % disability and was interpreted as: 0% to 20%, minimal; 21% to 40%, moderate; 41% to 60%, severe; 61% to 80%, crippled; and 81% to 100% bedridden.
Statistical Analysis In a pilot study conducted in the department, we observed the number of tramadol doses required to be 8.4 ± 0.48. We anticipated a decrease in the number of analgesic doses required after adding the pharmacological modality to be 18%. On the basis of these values and accepting α = 0.05 and β = 0.8 and using a 1-tail the sample size was 24 so to be conservative we enrolled 30 patients in each group. Data were analyzed for the difference between the groups using the nonparametric Kruskal-Wallis test. The association of the variables among the 3 groups was analyzed by the χ2 test of association. The difference among the same group for the postoperative period was analyzed using the Friedman test for repeated measure.
RESULTS Demographic Data and Operative Period There was no significant difference in the demographic, preoperative scores and operative details among all the groups (Table 1). Most of the patients experienced radicular pain radiating to the unilateral limb. The intraoperative hemodynamic parameters mean arterial pressure, heart rate, and saturated arterial oxygen pressure were similar in all the 3 groups at all measured intervals.
Acute Postoperative Period No patient was withdrawn from the study because of severe pain requiring additional analgesic beyond the recommended March 2014
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Gabapentinoids: Postop Pain and Outcome • Khurana et al
TABLE 1. Demographic Profile, Operative Details, and Analgesic Requirement in Postoperative
Period of the 3 Groups
Group A
Group B
Group C
49 ± 10.4
46.9 ± 10.1
47.1 ± 10.7
22:8
24:6
22:8
Height (cm)
161.8 ± 9.19
160.2 ± 5.18
160.1 ± 6.18
Weight (kg)
72.7 ± 9.16
71.6 ± 11.38
70.16 ± 11.01
23:7
22:8
24:6
5 (16.6%)
3 (10%)
3 (10%)
3 (10%)
2 (6.67%)
2 (6.67%)
2 (6.67%)
0
1 (3.33%)
3 (10%)
1 (3.33%)
1 (3.33%)
Smoker
5 (16.6%)
5 (16.67%)
4 (13.3%)
Previous surgery
4 (13.3%)
4 (13.3%)
3 (10%)
3 (10%)
1 (3.33%)
(10%)
28:2
27:3
27:3
2.8 ± 1.7
2.8 ± 1.6
2.8 ± 1.8
4:20:6
3:17:10
3:20:7
104.3 ± 34.4
94.66 ± 25.01
107.7 ± 34.9
Rescue drug given after (hr)
10.7 ± 4.9
11.8 ± 3.7
5.6 ± 2.3*
No. of doses given
6.3 ± 1.4
5.6 ± 1.2
8±1.1*
Age (yr) Sex (male:female)
ASA grade (I:II) Comorbid conditions Diabetes mellitus Hypertension Diabetes + hypertension Alcoholic
Others Site of pain, back + leg:leg Duration of pain (mo) Site of surgery, L3–L4:L4–L5:L5–S1 Operating time (min)
*Significant difference P < 0.05. ASA indicates American Society of Anesthesiologists.
protocol. There was no significant difference in intensity of pain preoperatively among all the 3 groups. Throughout the postoperative period the static and dynamic pain showed consistently reduced pain intensity. Postoperative pain static and dynamic was significantly less in groups A and B as than in group C. Overall, more patients in groups A and B had lower pain scores than in group C (Figures 1, 2). The total postoperative analgesic duration (time from end of surgery to the requirement of first dose of rescue drug) was 11.8 ± 3.7 hours in group B, whereas it was 10.7 ± 4.9 hour in group A, which was insignificant (P = 0.16), but in comparison with group C (5.6 ± 2.3 hr), there was significant difference (P = 0.0001). There was significant difference (P < 0.0001) in the number of doses of rescue analgesia administered between placebo and groups A and B (Table 1).
Functional Outcome VAS score, modified Prolo score, and ODI score was less at 3 months postoperatively compared with preoperative scores in all patients. At 3 months postoperatively, a larger proportion of patients who received pregabalin (43.3%) than those who received placebo (6.6%) had an excellent outcome, Spine
defined as Prolo score 9 or more (Table 2). Preoperatively, most patients in groups A, B, and C had scored 3, 4 points on ODI scale but at the end of 3 months the patients had improved functional scores with majority patients scoring 0, 1 points in groups A, B, whereas the majority of patients in the placebo group had scored 1, 2. Although 90% of subjects in group B had improved ODI score 20% or less, only 53.3% had the best scores in placebo groups (Table 3). Preoperatively, most of the subjects 64 (71.1%) were wary of traveling. However, after 3 months, 14 (46.6%) subjects in placebo group avoided traveling as compared with 7 (20.3%) in group B. Pregabalin had more pronounced clinical effect as compared with gabapentin but was statistically nonsignificant until 21 days, but a statistically significant difference was observed at 3 months (P < 0.01). We observed a statistically significant difference between pregabalin and placebo on all the days of observation (P < 0.01; P < 0.00; P < 0.00).
Complications The overall incidence of complications was 28.8% (26), but the nature was mild to moderate. Most of the complications occurred in the immediate postoperative period, within www.spinejournal.com
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Gabapentinoids: Postop Pain and Outcome • Khurana et al
DISCUSSION
Dynamic pain at different me intervals 80
Mean VAS Score
70 60 50
Group A
40
Group B
30
Group C
20
*
*
10 0 0
6 hr
12 hr
24 hr
Figure 1. Mean VAS score for static pain at different time intervals of the 3 groups. *Statistically significant difference (P < 0.05) on comparing group C with group A and group B. †Statistically significant difference (P < 0.05) on comparing group A and group B. VAS indicates visual analogue scale.
24 hours from surgery. All the complications were transient and were managed conservatively. Sedation and nausea were the common side effects in groups A and B, but there was no significant difference between the 2 groups. No other side effects such as ataxia, urinary retention, visual disturbances, and headache were noted in either group. Respiratory depression was not noted in any patient (Table 4).
Follow-up From the immediate postoperative period till the patient was discharged, patient’s compliance was excellent as documented by the nursing charts and the patient pro forma that was duly filled by the unbiased anesthetist who was not included in evaluation of the data. Thereafter, the same anesthesiologist conducted telephonic interviews at regular intervals. It was observed that subjects belonging to groups A and B did not require any additional analgesia than prescribed, whereas subjects in group C required supplement analgesia in the form of nonsteroidal anti-inflammatory drugs.
Static pain at different time interval
60
Mean VAS Score
50 40
Group A Group B
30
Group C 20
* *
10
*
*
*
* †
†
0 0
3 hr
6 hr
12 hr 24 hr 36 hr 48 hr 72 hr
7d
21 d 3 mo
Figure 2. Mean VAS score for static pain at different time intervals of the 3 groups. *Statistically significant difference (P < 0.05) on comparing group C with group A and group B. †Statistically significant difference on comparing group A and group B. VAS indicates visual analogue scale.
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Acute pain management is challenging in patients after spinal surgery. As compared with other surgical procedures postoperative pain in spinal surgery may have different pathophysiology due to pre- and perioperative nerve damage. Postoperative pain in this situation is best managed using a multimodal approach. Gabapentinoids may be especially valuable when used as an adjunct in a multimodal analgesic approach by not only decreasing the opioids consumption but also decreasing the incidence of transition to chronic pain.8 Several studies have elaborated the antiallodynic and antihyperalgesic properties useful for neuropathic pain and suggested that these drugs may be considered for acute perioperative period.2,9–12 This male preponderance can be attributed to the fact that larger population in our state is living mainly in hilly areas. Males of this region are devoted to the farming activities and are laborers lifting heavy weights, hence many workmen in this area engage in activity that involves strain or trauma of lumbar spine. Although the primary concern of the study was to compare gabapentin and pregabalin, we included placebo to compare the individual drugs effectively with the control. In this study, we have administered 75 mg of pregabalin and 300 mg of gabapentin considering that pregabalin is 2½ times more potent than gabapentin.13,14 Most of the studies14,15 have given a single dose, whereas 1 study has included them for 48 hours.16 However, in our study we have given the gabapentinoids for 7 days including the preoperative dose to avoid decreased effect over time. Our results showed that a combination of gabapentinoids with diclofenac sodium showed improved analgesia and functional outcome compared with diclofenac sodium alone after spinal surgery. The acute postoperative analgesic effects of gabapentin and pregabalin in spinal surgery revealed that these drugs (1) decreased postoperative pain scores in the early postoperative period, (2) decreased postoperative tramadol consumption throughout the study period, and (3) both gabapentin and pregabalin reduced movement-evoked pain as compared with placebo, and this speeds the functional postoperative recovery. It has been documented that many patients continue to experience pain 3 months after lumbar discectomy surgery.17 The development of chronic postsurgical pain has attracted increased attention and with central sensitization as a prerequisite, gabapentinoids with its ability to attenuate secondary hyperalgesia in pain models, is an interesting alternative.18 Burke and Shorten,17 in their study, have emphasized that central neuroplasticity is induced by perioperative, intraoperative, and postoperative nociceptive inputs. Neuroplasticity can manifest as inhibitory or excitatory effects and can vary with time.17–19 A study evaluating neuroplasticity in patients undergoing back surgery concluded that, without analgesia, neuroplastic changes after surgery are predominantly inhibitory for the first 24 hours and excitatory at 5 days after surgery.20 Pregabalin, a membrane stabilizer, may decrease perioperative central sensitization and subsequent persistent pain.17 There have been contrasting observations in the literature available regarding long-term benefits of gabapentinoids. March 2014
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Gabapentinoids: Postop Pain and Outcome • Khurana et al
TABLE 2. Comparison of Prolo Scores at Different Time Intervals Between the 3 Groups Prolo Score Presurgery
7d
21 d
3 mo
Group A
Group B
Group C
Group A
Group B
Group C
Group A
Group B
Group C
Group A
Group B
Group C
2–4
29
29
30
6
6
10
4
1
8
0
0
0
5–6
1
1
0
16
13
18
13
15
19
3
3
13
7–8
0
0
0
8
11
2
13
9
3
24
14
8
9–10
0
0
0
0
0
0
0
5
0
3
13
9
Prolo score: 2 to 4, poor; 5 to 6, fair; 7 to 8, good; 9 to 10, excellent.
TABLE 3. Comparison of Oswestry Disability Index Scores at Different Time Intervals Between the
3 Groups
Oswestry Disability Index Scores Group A
Group B
Group C
Preop
7d
21 d
3 mo
Preop
7d
21st Day
3 mo
Preop
7d
21 d
3 mo
0%–20%, minimal
0
0
5
17
0
0
11
27
0
0
1
16
21%–40%, moderate
0
1
25
13
0
0
17
3
0
0
28
14
41%–60%, severe
15
27
0
0
15
29
2
0
15
29
1
0
61%–80%, crippled
15
2
0
0
15
1
0
0
15
1
0
0
81%–100%, bedridden
0
0
0
0
0
0
0
0
0
0
0
0
Preop indicates preoperative.
Burke and Shorten17 have reported that preoperative administration of pregabalin improves long-term functional outcome, but in striking contrast, Gianesello et al15 have demonstrated that there is no difference in the outcome but the perception of subjects’ overall health status was better in pregabalin group as compared with placebo. They hypothesized that patients who received pregabalin in the preoperative period had less pain, good memory, and less perioperative stress that may have led to the greater confidence in the subjects, which continued over the time. In our study, we observed that patient receiving gabapentinoids had better economical and functional status after 7 and 21 days. There
TABLE 4. Comparison of the Incidence of
Complications Between the 3 Groups Group A
Group B
Sedation
4
3
Vertigo
2
2
Nausea
2
4
1
Numbness
2
0
3
Vomiting
1
0
2
Spine
Group C
was no statistically significant difference among groups A and B at 7 and 21 days but had significant difference at 3 months indicating that the economic and functional status had improved significantly in pregabalin group. Both the gabapentinoids have a demonstrated great efficacy in terms of quality of life after spine surgery with pregabalin having an edge over gabapentin. Similar to a previous study, we too observed that pregabalin resulted in an increase in pain tolerance threshold at 24 hours in both lower limbs with the magnitude of this increase being greater in the asymptomatic lower limb. This difference in pain perception threshold between groups may represent an antihyperalgesic effect of pregabalin.17 The strength of this study was that the analgesic efficacy of gabapentinoids has been assessed for 72 hours postoperatively. Because of its linear pharmacokinetics, pregabalin in repeated doses has shown to improve analgesia much more than gabapentin and placebo. The other positive feature in the study is all the surgical procedures were conducted at a single center, collection of the questionnaire was by a single blinded investigator. The limitations of the study was lack of information about the use of analgesic drugs 3 months after surgery and no usage of patient-controlled analgesia because it was not available at that time. www.spinejournal.com
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RANDOMIZED TRIAL CONCLUSION Preoperative pregabalin administration is associated with less pain intensity and improved functional outcomes 3 months after lumbar discectomy followed by gabapentin and then placebo.
➢ Key Points Perioperative administration of gabapentinoids reduces early static and dynamic pain.Findings of the study suggest that in postoperative pain management, gabapentin, and pregabalin are the preferred alternatives in multimodal analgesia. Gabapentinoids effectively reduce the opioid consumption and opioid-related adverse effects after surgery. At the time of the interviews, perceived current health status of all patients was better than before surgery. However, at 3 months, pregabalin has more pronounced effect on economic and functional improvement as compared with gabapentin.
References
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Gabapentinoids: Postop Pain and Outcome • Khurana et al
6. Fairbank JC, Pynsent PB. The Oswestry Disability Index. Spine 2000;25:2940–52. 7. Vitzthum HE, Dalitz K. Analysis of five specific scores for cervical spondylogenic myelopathy. Eur Spine J 2007;16:2096–103. 8. Iohom G, Abdalla H, O’Brien J, et al. The associations between severity of early postoperative pain, chronic postsurgical pain and plasma concentration of stable nitric oxide products after breast surgery. Anesth Analg 2006;103:995–1000. 9. Fassoulaki A, Triga A, Melemeni A, et al. Multimodal analgesia with gabapentin and local anesthetics prevents acute and chronic pain after breast surgery for cancer. Anesth Analg 2005;101: 1427–32. 10. Gilron I, Orr E, Tu D, et al. A placebo-controlled randomized clinical trial of perioperative administration of gabapentin, rofecoxib and their combination for spontaneous and movement-evoked pain after abdominal hysterectomy. Pain 2005;113:191–200. 11. Turan A, White PF, Karamanlioglu B, et al. Gabapentin: an alternative to the cyclooxygenase-2 inhibitors for perioperative pain management. Anesth Analg 2006;102:175– 81. 12. Ittichaikulthol W, Virankabutra T, Kunopart M, et al. Effects of pregabalin on postoperative morphine consumption and pain after abdominal hysterectomy with/without salpingo-oophorectomy: a randomized, double-blind trial. J Med Assoc Thai 2009;92: 1318–23. 13. Wesche D, Bickbraden H. A pharmacokinetic comparison of pregabalin and gabapentin. Pain 2005;6:S29. 14. Ghai A, Gupta M, Hooda S, et al. A randomized controlled trial to compare pregabalin and gabapentin for postoperative pain in abdominal hysterectomy. SJA 2011;5:252–6. 15. Gianesello L, Pavoni V, Barboni E, et al. Perioperative pregabalin for postoperative pain control and quality of life after major spinal surgery. J Neurosurg Anesthesiol 2012;24:121–6. 16. Kim JC, Choi YS, Kim KN, et al. Effective dose of perioperative oral pregabalin as an adjunct to multimodal analgesic regimen in lumbar spinal fusion surgery. Spine 2011;36:428–33. 17. Burke SM, Shorten GB. Perioperative pregabalin improves pain and functional outcome 3 months after lumbar discectomy. Anesth Analg 2010;110:1180–5. 18. Woolf CJ, Chong MS. Preemptive analgesia treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993;77:362–79. 19. Turan A, Karamanlioglu B, Memis D, et al. Analgesic effects of gabapentin after spinal surgery. Anesthesiology 2004;100:935–8. 20. Wilder-Smith OH, Tassonyi E, Crul BJ, et al. Preoperative back pain is associated with diverse manifestations of central neuroplasticity. Pain 2002;97:189–94.
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Postoperative Pain and Long-Term Functional Outcome After Administration of Gabapentin and Pregabalin in Patients Undergoing Spinal Surgery Gurjeet Khurana, MD,* Parul Jindal, MD,* Jagdish P. Sharma, MD,* and Krishan K. Bansal, MS, MCh†
Study Design. Prospective, double-blind study, randomized control trial. Objective. To evaluate and compare the analgesic efficacy, adverse effects, and clinical utility of gabapentin and pregabalin in postoperative pain management, long-term functional outcome, and quality of life in patients undergoing spinal surgery. Summary of Background Data. Patient outcome after lumbar discectomy for radicular low back pain is variable and the benefit is inconsistent. The most common persistent symptoms are pain, motor deficit, and decreased functional status. Methods. This study was conducted in 90 patients belonging to the 18 to 75 age group of either sex undergoing spinal surgery under general anesthesia. Group A received 300 mg of gabapentin, group B received 75 mg of pregabalin, whereas group C received placebo 1 dose 1 hour before surgery and 8 hourly for 7 days, thereafter. The outcome of postoperative static and dynamic pain and functional outcome was recorded using 3 questionnaires—visual analogue scale, Prolo functional and economic score, Oswestry Disability Index score from preoperative period to 3 months postoperatively. Results. Among the 3 groups, subjects receiving pregabalin showed consistently reduced static and dynamic pain intensity and also required lesser amount of rescue drug throughout the postoperative period. There was statistically significant difference (P < 0.05) in the Prolo score and Oswestry Disability Index score at all time intervals between group B and group C. Although, significant difference in the functional outcome between group A and group B was seen at 3 months.
From the Departments of *Anesthesiology; and †Neurosurgery, Himalayan Institute of Medical Sciences, HIHT University, Swami Ram Nagar, Dehradun, India. Acknowledgment date: August 6, 2013. First revision date: November 8, 2013. Second revision date: December 3, 2013. Acceptance date: December 16, 2013. The device(s)/drug(s) is/are FDA-approved or approved by corresponding national agency for this indication. No funds were received in support of this work. No relevant financial activities outside the submitted work. Address correspondence and reprint requests to Parul Jindal, MD, Department of Anesthesiology, Himalayan Institute of Medical Sciences, HIHT University, Swami Ram Nagar, Dehradun, India; E-mail: [email protected] DOI: 10.1097/BRS.0000000000000185 Spine
Conclusion. Preoperative pregabalin administration is associated with less pain intensity and improved functional outcomes 3 months after lumbar discectomy followed by gabapentin and then placebo. Key words: pregabalin, gabapentin, functional outcome, postoperative pain, lumbar discectomy, Prolo score, Oswestry Disability Index score, visual analogue scale. Level of Evidence: 2 Spine 2014;39:E363–E368
P
erioperative pain relief is the aim of anesthesia. Pain is now regarded as the fifth vital sign and has ill effects on particularly all the systems. With the decrease in morbid adverse events after surgery, patient satisfaction with perioperative care is assuming more importance. Postoperative pain differs from other types of pain in that it is usually transitory with progressive improvement during a relatively short time course. This renders the condition more easily amenable to therapy than is the case for chronic pain.1 Major spinal surgery causes severe postoperative pain that can persist up to 3 days, thus hampering convalescence. Although opioids have been the mainstay of postoperative management, they are not free from adverse effects. Multimodal analgesia with its benefit of superior pain relief is now the cornerstone of postoperative pain management. Adding an antineuropathic analgesic improves postoperative pain by preventing the development of central sensitization. The mechanism of action of gabapentin and its successor, pregabalin is likely mediated by binding to the 21 subunits of the presynaptic voltage-gated calcium channels, which are upregulated in the dorsal root ganglia and spinal cord after surgical trauma. Gabapentin may produce antinociception by inhibiting calcium influx via these channels, and subsequently inhibiting the release of excitatory neurotransmitters (e.g., substance P, calcitonin gene-related peptide) from the primary afferent nerve fibers in the pain pathway.2 Pregabalin has a more favorable pharmacokinetic profile, including dose-independent absorption.3,4 Gabapentin and pregabalin have antiallodynic and antihyperalgesic properties useful for treating neuropathic pain.5 These properties may also be beneficial in acute postoperative pain.2 The primary aim was to compare the improvement in pain score preoperatively to 72 hours postoperatively in www.spinejournal.com
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RANDOMIZED TRIAL patients who were given gabapentin, pregabalin, or placebo. Secondary objectives included a comparison of predefined measures of pain and pain-related function up to 3 months postoperatively.
MATERIALS AND METHODS The study was performed in accordance with the ethical standards of the same institute. Informed consent was obtained from each subject at recruitment. This prospective, randomized, double-blind study was conducted in the department of anesthesiology in conjunction with the department of neurosurgery on 90 patients of either sex belonging to the 25 to 72 age group. Inclusion criteria were patients with chronic low back pain persisting up to 6 months in spite of alternative therapies and on radiological intervention diagnosed with intervertebral disc prolapse without ligament hypertrophy posted for lumbar discectomy; minimum visual analogue scale score (VAS) at recruitment, 40 mm; and American Society of Anesthesiologists physical status I, II. Patients excluded from the study were patients with history of previous back surgery, history of gastric ulcers or intestinal bleeding, known allergy to the drugs under study, patients with serious medical problems within the last 6 months including myocardial infarction (heart attack), congestive heart failure, stroke, deep vein thrombosis, pulmonary embolism, kidney disease as evidenced by the need for dialysis or kidney transplant, history of seizure or other neurological disorders, patients intending to become pregnant or who are pregnant or nursing during the projected course of treatment, and those who were taking gabapentin or pregabalin for other medical purposes. According to computer-generated random allocation in this double-blind study, group A received 300 mg of gabapentin, group B received 75 mg of pregabalin, whereas group C received placebo; 60 minutes preoperatively and 8 hourly for 7 days postoperatively. The medication was prescribed according to instructions in a sealed, opaque envelope by an anesthesiologist with no further involvement in the study. Preoperatively, on the evening before surgery (time 0), all patients completed 3 questionnaires in the presence of one of the investigators. These were as follows: • VAS pain at rest and on movement • Oswestry Disability Index (ODI)6 • Modified Prolo economic and functional score.7 With standard hemodynamic monitors in place (electrocardiogram, heart rate, pulse oximeter oxygen saturation, and noninvasive blood pressure, capnography, and temperature monitoring), anesthesia was induced with 2 μg/kg of fentanyl and 2 to 4 mg/kg of propofol, followed by 0.1 mg/kg of vecuronium, to facilitate tracheal intubation and ventilation. Anesthesia was maintained using isoflurane to maintain end tidal concentration 1 to 1.5 minimum alveolar concentration and vecuronium and fentanyl as clinically indicated. At the time of skin closure 75 mg of diclofenac sodium was administered intravenously. Neuromuscular E364
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Gabapentinoids: Postop Pain and Outcome • Khurana et al
block was reversed with 0.5 μg/kg of neostigmine and glycopyrrolate and patient was shifted to postanesthesia care unit. Postoperatively pain score, hemodynamics, oxygen saturation respiratory rate, sedation and side effects like nausea, vomiting, dizziness, dry mouth, general fatigue, somnolence, itching, headache, and urinary retention and requirement of analgesic postoperatively was observed. VAS score at rest was assessed at 0, 3, 6, 12, 24, 36, 48, and 72 hours postoperatively, whereas VAS score at movement was assessed after 6 hours of strict bed rest when the patient was able to perform a 90° logroll while in bed. At any given time, if the VAS score was more than 30 mm, the patient was given 1 to 2 mg/kg of tramadol intravenously. Sedation score was measured using a numerical score (1: completely drowsy, 2: awake but drowsy, 3: asleep but responsive to verbal command, 4: asleep but responsive to tactile stimulus, 5: asleep but not responsive to any stimulus). Then, the 3 questionnaires were filled at 7 days, 21 days, and 3 months by the same recorder who was not involved further in the study. Modified Prolo score was interpreted as: 2 to 4, poor; 5 to 6, fair; 7 to 8, good; and 9 to 10, excellent. ODI score was first calculated as total score/50 × 100 = % disability and was interpreted as: 0% to 20%, minimal; 21% to 40%, moderate; 41% to 60%, severe; 61% to 80%, crippled; and 81% to 100% bedridden.
Statistical Analysis In a pilot study conducted in the department, we observed the number of tramadol doses required to be 8.4 ± 0.48. We anticipated a decrease in the number of analgesic doses required after adding the pharmacological modality to be 18%. On the basis of these values and accepting α = 0.05 and β = 0.8 and using a 1-tail the sample size was 24 so to be conservative we enrolled 30 patients in each group. Data were analyzed for the difference between the groups using the nonparametric Kruskal-Wallis test. The association of the variables among the 3 groups was analyzed by the χ2 test of association. The difference among the same group for the postoperative period was analyzed using the Friedman test for repeated measure.
RESULTS Demographic Data and Operative Period There was no significant difference in the demographic, preoperative scores and operative details among all the groups (Table 1). Most of the patients experienced radicular pain radiating to the unilateral limb. The intraoperative hemodynamic parameters mean arterial pressure, heart rate, and saturated arterial oxygen pressure were similar in all the 3 groups at all measured intervals.
Acute Postoperative Period No patient was withdrawn from the study because of severe pain requiring additional analgesic beyond the recommended March 2014
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TABLE 1. Demographic Profile, Operative Details, and Analgesic Requirement in Postoperative
Period of the 3 Groups
Group A
Group B
Group C
49 ± 10.4
46.9 ± 10.1
47.1 ± 10.7
22:8
24:6
22:8
Height (cm)
161.8 ± 9.19
160.2 ± 5.18
160.1 ± 6.18
Weight (kg)
72.7 ± 9.16
71.6 ± 11.38
70.16 ± 11.01
23:7
22:8
24:6
5 (16.6%)
3 (10%)
3 (10%)
3 (10%)
2 (6.67%)
2 (6.67%)
2 (6.67%)
0
1 (3.33%)
3 (10%)
1 (3.33%)
1 (3.33%)
Smoker
5 (16.6%)
5 (16.67%)
4 (13.3%)
Previous surgery
4 (13.3%)
4 (13.3%)
3 (10%)
3 (10%)
1 (3.33%)
(10%)
28:2
27:3
27:3
2.8 ± 1.7
2.8 ± 1.6
2.8 ± 1.8
4:20:6
3:17:10
3:20:7
104.3 ± 34.4
94.66 ± 25.01
107.7 ± 34.9
Rescue drug given after (hr)
10.7 ± 4.9
11.8 ± 3.7
5.6 ± 2.3*
No. of doses given
6.3 ± 1.4
5.6 ± 1.2
8±1.1*
Age (yr) Sex (male:female)
ASA grade (I:II) Comorbid conditions Diabetes mellitus Hypertension Diabetes + hypertension Alcoholic
Others Site of pain, back + leg:leg Duration of pain (mo) Site of surgery, L3–L4:L4–L5:L5–S1 Operating time (min)
*Significant difference P < 0.05. ASA indicates American Society of Anesthesiologists.
protocol. There was no significant difference in intensity of pain preoperatively among all the 3 groups. Throughout the postoperative period the static and dynamic pain showed consistently reduced pain intensity. Postoperative pain static and dynamic was significantly less in groups A and B as than in group C. Overall, more patients in groups A and B had lower pain scores than in group C (Figures 1, 2). The total postoperative analgesic duration (time from end of surgery to the requirement of first dose of rescue drug) was 11.8 ± 3.7 hours in group B, whereas it was 10.7 ± 4.9 hour in group A, which was insignificant (P = 0.16), but in comparison with group C (5.6 ± 2.3 hr), there was significant difference (P = 0.0001). There was significant difference (P < 0.0001) in the number of doses of rescue analgesia administered between placebo and groups A and B (Table 1).
Functional Outcome VAS score, modified Prolo score, and ODI score was less at 3 months postoperatively compared with preoperative scores in all patients. At 3 months postoperatively, a larger proportion of patients who received pregabalin (43.3%) than those who received placebo (6.6%) had an excellent outcome, Spine
defined as Prolo score 9 or more (Table 2). Preoperatively, most patients in groups A, B, and C had scored 3, 4 points on ODI scale but at the end of 3 months the patients had improved functional scores with majority patients scoring 0, 1 points in groups A, B, whereas the majority of patients in the placebo group had scored 1, 2. Although 90% of subjects in group B had improved ODI score 20% or less, only 53.3% had the best scores in placebo groups (Table 3). Preoperatively, most of the subjects 64 (71.1%) were wary of traveling. However, after 3 months, 14 (46.6%) subjects in placebo group avoided traveling as compared with 7 (20.3%) in group B. Pregabalin had more pronounced clinical effect as compared with gabapentin but was statistically nonsignificant until 21 days, but a statistically significant difference was observed at 3 months (P < 0.01). We observed a statistically significant difference between pregabalin and placebo on all the days of observation (P < 0.01; P < 0.00; P < 0.00).
Complications The overall incidence of complications was 28.8% (26), but the nature was mild to moderate. Most of the complications occurred in the immediate postoperative period, within www.spinejournal.com
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DISCUSSION
Dynamic pain at different me intervals 80
Mean VAS Score
70 60 50
Group A
40
Group B
30
Group C
20
*
*
10 0 0
6 hr
12 hr
24 hr
Figure 1. Mean VAS score for static pain at different time intervals of the 3 groups. *Statistically significant difference (P < 0.05) on comparing group C with group A and group B. †Statistically significant difference (P < 0.05) on comparing group A and group B. VAS indicates visual analogue scale.
24 hours from surgery. All the complications were transient and were managed conservatively. Sedation and nausea were the common side effects in groups A and B, but there was no significant difference between the 2 groups. No other side effects such as ataxia, urinary retention, visual disturbances, and headache were noted in either group. Respiratory depression was not noted in any patient (Table 4).
Follow-up From the immediate postoperative period till the patient was discharged, patient’s compliance was excellent as documented by the nursing charts and the patient pro forma that was duly filled by the unbiased anesthetist who was not included in evaluation of the data. Thereafter, the same anesthesiologist conducted telephonic interviews at regular intervals. It was observed that subjects belonging to groups A and B did not require any additional analgesia than prescribed, whereas subjects in group C required supplement analgesia in the form of nonsteroidal anti-inflammatory drugs.
Static pain at different time interval
60
Mean VAS Score
50 40
Group A Group B
30
Group C 20
* *
10
*
*
*
* †
†
0 0
3 hr
6 hr
12 hr 24 hr 36 hr 48 hr 72 hr
7d
21 d 3 mo
Figure 2. Mean VAS score for static pain at different time intervals of the 3 groups. *Statistically significant difference (P < 0.05) on comparing group C with group A and group B. †Statistically significant difference on comparing group A and group B. VAS indicates visual analogue scale.
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Acute pain management is challenging in patients after spinal surgery. As compared with other surgical procedures postoperative pain in spinal surgery may have different pathophysiology due to pre- and perioperative nerve damage. Postoperative pain in this situation is best managed using a multimodal approach. Gabapentinoids may be especially valuable when used as an adjunct in a multimodal analgesic approach by not only decreasing the opioids consumption but also decreasing the incidence of transition to chronic pain.8 Several studies have elaborated the antiallodynic and antihyperalgesic properties useful for neuropathic pain and suggested that these drugs may be considered for acute perioperative period.2,9–12 This male preponderance can be attributed to the fact that larger population in our state is living mainly in hilly areas. Males of this region are devoted to the farming activities and are laborers lifting heavy weights, hence many workmen in this area engage in activity that involves strain or trauma of lumbar spine. Although the primary concern of the study was to compare gabapentin and pregabalin, we included placebo to compare the individual drugs effectively with the control. In this study, we have administered 75 mg of pregabalin and 300 mg of gabapentin considering that pregabalin is 2½ times more potent than gabapentin.13,14 Most of the studies14,15 have given a single dose, whereas 1 study has included them for 48 hours.16 However, in our study we have given the gabapentinoids for 7 days including the preoperative dose to avoid decreased effect over time. Our results showed that a combination of gabapentinoids with diclofenac sodium showed improved analgesia and functional outcome compared with diclofenac sodium alone after spinal surgery. The acute postoperative analgesic effects of gabapentin and pregabalin in spinal surgery revealed that these drugs (1) decreased postoperative pain scores in the early postoperative period, (2) decreased postoperative tramadol consumption throughout the study period, and (3) both gabapentin and pregabalin reduced movement-evoked pain as compared with placebo, and this speeds the functional postoperative recovery. It has been documented that many patients continue to experience pain 3 months after lumbar discectomy surgery.17 The development of chronic postsurgical pain has attracted increased attention and with central sensitization as a prerequisite, gabapentinoids with its ability to attenuate secondary hyperalgesia in pain models, is an interesting alternative.18 Burke and Shorten,17 in their study, have emphasized that central neuroplasticity is induced by perioperative, intraoperative, and postoperative nociceptive inputs. Neuroplasticity can manifest as inhibitory or excitatory effects and can vary with time.17–19 A study evaluating neuroplasticity in patients undergoing back surgery concluded that, without analgesia, neuroplastic changes after surgery are predominantly inhibitory for the first 24 hours and excitatory at 5 days after surgery.20 Pregabalin, a membrane stabilizer, may decrease perioperative central sensitization and subsequent persistent pain.17 There have been contrasting observations in the literature available regarding long-term benefits of gabapentinoids. March 2014
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Gabapentinoids: Postop Pain and Outcome • Khurana et al
TABLE 2. Comparison of Prolo Scores at Different Time Intervals Between the 3 Groups Prolo Score Presurgery
7d
21 d
3 mo
Group A
Group B
Group C
Group A
Group B
Group C
Group A
Group B
Group C
Group A
Group B
Group C
2–4
29
29
30
6
6
10
4
1
8
0
0
0
5–6
1
1
0
16
13
18
13
15
19
3
3
13
7–8
0
0
0
8
11
2
13
9
3
24
14
8
9–10
0
0
0
0
0
0
0
5
0
3
13
9
Prolo score: 2 to 4, poor; 5 to 6, fair; 7 to 8, good; 9 to 10, excellent.
TABLE 3. Comparison of Oswestry Disability Index Scores at Different Time Intervals Between the
3 Groups
Oswestry Disability Index Scores Group A
Group B
Group C
Preop
7d
21 d
3 mo
Preop
7d
21st Day
3 mo
Preop
7d
21 d
3 mo
0%–20%, minimal
0
0
5
17
0
0
11
27
0
0
1
16
21%–40%, moderate
0
1
25
13
0
0
17
3
0
0
28
14
41%–60%, severe
15
27
0
0
15
29
2
0
15
29
1
0
61%–80%, crippled
15
2
0
0
15
1
0
0
15
1
0
0
81%–100%, bedridden
0
0
0
0
0
0
0
0
0
0
0
0
Preop indicates preoperative.
Burke and Shorten17 have reported that preoperative administration of pregabalin improves long-term functional outcome, but in striking contrast, Gianesello et al15 have demonstrated that there is no difference in the outcome but the perception of subjects’ overall health status was better in pregabalin group as compared with placebo. They hypothesized that patients who received pregabalin in the preoperative period had less pain, good memory, and less perioperative stress that may have led to the greater confidence in the subjects, which continued over the time. In our study, we observed that patient receiving gabapentinoids had better economical and functional status after 7 and 21 days. There
TABLE 4. Comparison of the Incidence of
Complications Between the 3 Groups Group A
Group B
Sedation
4
3
Vertigo
2
2
Nausea
2
4
1
Numbness
2
0
3
Vomiting
1
0
2
Spine
Group C
was no statistically significant difference among groups A and B at 7 and 21 days but had significant difference at 3 months indicating that the economic and functional status had improved significantly in pregabalin group. Both the gabapentinoids have a demonstrated great efficacy in terms of quality of life after spine surgery with pregabalin having an edge over gabapentin. Similar to a previous study, we too observed that pregabalin resulted in an increase in pain tolerance threshold at 24 hours in both lower limbs with the magnitude of this increase being greater in the asymptomatic lower limb. This difference in pain perception threshold between groups may represent an antihyperalgesic effect of pregabalin.17 The strength of this study was that the analgesic efficacy of gabapentinoids has been assessed for 72 hours postoperatively. Because of its linear pharmacokinetics, pregabalin in repeated doses has shown to improve analgesia much more than gabapentin and placebo. The other positive feature in the study is all the surgical procedures were conducted at a single center, collection of the questionnaire was by a single blinded investigator. The limitations of the study was lack of information about the use of analgesic drugs 3 months after surgery and no usage of patient-controlled analgesia because it was not available at that time. www.spinejournal.com
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RANDOMIZED TRIAL CONCLUSION Preoperative pregabalin administration is associated with less pain intensity and improved functional outcomes 3 months after lumbar discectomy followed by gabapentin and then placebo.
➢ Key Points Perioperative administration of gabapentinoids reduces early static and dynamic pain.Findings of the study suggest that in postoperative pain management, gabapentin, and pregabalin are the preferred alternatives in multimodal analgesia. Gabapentinoids effectively reduce the opioid consumption and opioid-related adverse effects after surgery. At the time of the interviews, perceived current health status of all patients was better than before surgery. However, at 3 months, pregabalin has more pronounced effect on economic and functional improvement as compared with gabapentin.
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