Bupivacaine Field Block With Clonidine for Postoperative Pain Control in Posterior Spine Approaches: A Randomized Double-Blind Trial

Bupivacaine Field Block With Clonidine for Postoperative Pain Control in Posterior Spine... Abstract BACKGROUND The synergistic effect of clonidine with bupivacaine, well established in peripheral nerve blocks, remains controversial in local field block for postoperative analgesia. OBJECTIVE To investigate the potential analgesic benefit of adding clonidine to bupivacaine during preincisional field block in posterior approaches for spine surgeries. METHODS Two hundred twenty-five patients were enrolled in this study and underwent lumbar spinal fusion (n = 80), lumbar laminectomy (n = 25), lumbar microdiscectomy (n = 94), or cervical laminectomy (n = 26). In each surgical subgroup, patients were randomly assigned in a double-blinded fashion to receive either 20 mL of 0.25% bupivacaine alone (control group, n = 109) or with 150 μg clonidine (clonidine group, n = 116) in the form of a preincisional field block. Outcome parameters included area under the curve of pain from postoperative day D0 to D8 and rescue morphine consumption from D0 to D3. RESULTS The area under the curve was reduced in the clonidine group, particularly in the microdiscectomy subgroup, and without reaching statistical significance in the cervical laminectomy subgroup. Total rescue morphine consumption was reduced in the clonidine group, particularly at D1-D2, a benefit that was exclusive to the lumbar stenosis and lumbar fusion subgroups. Field block with clonidine, surgical subgroup, and the presence of preoperative spinal pain were factors independently influencing postoperative wound pain in multivariate analysis. CONCLUSION The addition of clonidine to local preincisional field block with bupivacaine resulted in better and prolonged postoperative analgesia in posterior lumbar spine surgeries, an effect that was more pronounced in patients with no preoperative spinal pain. Clonidine, Bupivacaine, Posterior spine surgery, Laminectomy, Microdiscectomy, Postoperative pain control, Wound infiltration ABBREVIATIONS ABBREVIATIONS ASA American Society of Anesthesiologists AUC area under the curve NRS numeric rating scale Control of postoperative pain is essential to reducing postoperative morbidity, as it allows early mobilization and hospital discharge.1 In posterior approach spine surgery, musculoskeletal postoperative pain arises from iatrogenic mechanical damage, intraoperative retraction, and partial devascularization and denervation to structures such as bone, ligaments, muscles, intervertebral disks, and zygapophysial joints.2,3 Multimodal analgesia is a useful postoperative pain management strategy that combines different analgesics that act through different mechanisms at different sites in the nervous system. This strategy results in additive or synergistic analgesia that can be achieved with lower doses of major analgesics, and thus, fewer adverse effects compared to the sole administration of individual analgesics.4,5 Field block (also called wound infiltration) with a local anesthetic agent, especially with bupivacaine, is an important element of multimodal analgesia and is well established as a reliable technique.6-8 In patients undergoing lumbar discectomy in particular, preincisional field block has proven to be more effective than preclosure field block.7,9 Clonidine, an α2-adrenergic agonist, extends the duration of sensory blocks with both ester and amide local anesthetics10,11 when administered in the epidural space or in the vicinity of peripheral nerves. This analgesic synergy has been tested in patients for local field block and was found to be ineffective in inguinal hernia surgery during the first 24 h postsurgery,12 but effective in cholecystectomy patients during the same period.13 When tested in mastectomy, this analgesic synergy is clearly evident, especially with higher clonidine dosage.14 In addition, an experimental study in rats found that clonidine significantly prolongs and improves the local anesthetic and analgesic effect of a field block with bupivacaine, as documented by noxious cutaneous pinprick.15 In this randomized double-blind study, we aimed to evaluate the early and late analgesic value of clonidine administered with bupivacaine in preincisional field block for posterior approach spine surgery. METHODS Patients Two hundred twenty-five patients were enrolled in this randomized double-blind clinical trial between January 2012 and December 2015 and underwent spinal surgery (under the care of senior author JM) at Hôtel-Dieu de France Hospital Beirut-Lebanon, after verification of inclusion and exclusion criteria (see below). Table 1 gives detailed clinical and demographic information on the patients, and Figure 1 represents the CONSORT flow diagram. FIGURE 1. View largeDownload slide Eligibility, randomization, and follow-up. LL+F = lumbar laminectomy with fusion subgroup; LL = lumbar laminectomy subgroup; MD = lumbar microdiscectomy subgroup; CL = cervical laminectomy subgroup. FIGURE 1. View largeDownload slide Eligibility, randomization, and follow-up. LL+F = lumbar laminectomy with fusion subgroup; LL = lumbar laminectomy subgroup; MD = lumbar microdiscectomy subgroup; CL = cervical laminectomy subgroup. TABLE 1. Clinical and Demographical Patient Data Control group Clonidine group P value Patients 109 116  Males 57 (52%) 49 (42%) .13  Females 52 (48%) 67 (58%) Age (mean ± sd) 55.43 ± 15.71 53.93 ± 14.24 .45 ASA class  Class I 79 (72%) 95 (82%) .09  Class II 30 (28%) 21 (18%) Preoperative spinal pain (NRS)  Present 73 (67%) 86 (74.1%) .24  Intensity (mean ± sd) 1.71 ± 1.6 2.01 ± 1.6 .14 Duration of preoperative pain evolution  In months (mean ± sd) 6.6 ± 10.1 6 ± 8.8 .64  Absent 36 (33%) 33 (28.5%)  ≤12 mo 54 (49.6%) 68 (58.6%) χ2 = .37  >12 mo 19 (17.4%) 15 (12.9%) Preoperative neurological deficit  Motor 37 (34%) 52 (44.9%) .09  Sensory 7 (6.5%) 12 (10.4%) .28 Control group Clonidine group P value Patients 109 116  Males 57 (52%) 49 (42%) .13  Females 52 (48%) 67 (58%) Age (mean ± sd) 55.43 ± 15.71 53.93 ± 14.24 .45 ASA class  Class I 79 (72%) 95 (82%) .09  Class II 30 (28%) 21 (18%) Preoperative spinal pain (NRS)  Present 73 (67%) 86 (74.1%) .24  Intensity (mean ± sd) 1.71 ± 1.6 2.01 ± 1.6 .14 Duration of preoperative pain evolution  In months (mean ± sd) 6.6 ± 10.1 6 ± 8.8 .64  Absent 36 (33%) 33 (28.5%)  ≤12 mo 54 (49.6%) 68 (58.6%) χ2 = .37  >12 mo 19 (17.4%) 15 (12.9%) Preoperative neurological deficit  Motor 37 (34%) 52 (44.9%) .09  Sensory 7 (6.5%) 12 (10.4%) .28 ASA = American Society of Anaesthesiologists (note that ASA class III and IV were excluded from the study), NRS = numerical rating scale. View Large TABLE 1. Clinical and Demographical Patient Data Control group Clonidine group P value Patients 109 116  Males 57 (52%) 49 (42%) .13  Females 52 (48%) 67 (58%) Age (mean ± sd) 55.43 ± 15.71 53.93 ± 14.24 .45 ASA class  Class I 79 (72%) 95 (82%) .09  Class II 30 (28%) 21 (18%) Preoperative spinal pain (NRS)  Present 73 (67%) 86 (74.1%) .24  Intensity (mean ± sd) 1.71 ± 1.6 2.01 ± 1.6 .14 Duration of preoperative pain evolution  In months (mean ± sd) 6.6 ± 10.1 6 ± 8.8 .64  Absent 36 (33%) 33 (28.5%)  ≤12 mo 54 (49.6%) 68 (58.6%) χ2 = .37  >12 mo 19 (17.4%) 15 (12.9%) Preoperative neurological deficit  Motor 37 (34%) 52 (44.9%) .09  Sensory 7 (6.5%) 12 (10.4%) .28 Control group Clonidine group P value Patients 109 116  Males 57 (52%) 49 (42%) .13  Females 52 (48%) 67 (58%) Age (mean ± sd) 55.43 ± 15.71 53.93 ± 14.24 .45 ASA class  Class I 79 (72%) 95 (82%) .09  Class II 30 (28%) 21 (18%) Preoperative spinal pain (NRS)  Present 73 (67%) 86 (74.1%) .24  Intensity (mean ± sd) 1.71 ± 1.6 2.01 ± 1.6 .14 Duration of preoperative pain evolution  In months (mean ± sd) 6.6 ± 10.1 6 ± 8.8 .64  Absent 36 (33%) 33 (28.5%)  ≤12 mo 54 (49.6%) 68 (58.6%) χ2 = .37  >12 mo 19 (17.4%) 15 (12.9%) Preoperative neurological deficit  Motor 37 (34%) 52 (44.9%) .09  Sensory 7 (6.5%) 12 (10.4%) .28 ASA = American Society of Anaesthesiologists (note that ASA class III and IV were excluded from the study), NRS = numerical rating scale. View Large Inclusion criteria wereas follows: age above 18, American Society of Anesthesiologists (ASA) class I or II, and patients undergoing their first spinal surgery. Exclusion criteria wereas follows: patients having any known allergy to local anesthetics or clonidine, Raynaud's syndrome, thromboangiitis obliterans, ongoing pregnancy, current treatment with corticosteroids, contraindication for nonsteroidal anti-inflammatory drugs, opiate use, history of substance abuse, and current psychiatric disorder. Patients who were unable to communicate clearly and to sign informed consent were also excluded. All patients included in the study gave written informed consent. Protocols were approved by the local Ethics Committee of the Saint Joseph University (CEHDF384). The study was funded by the research council of the Saint Joseph University, conducted according to the declaration of Helsinki16 and of the World Medical Association (http://www.wma.net), and registered at http://www.clinicaltrials.gov (Identifier NCT01902108). CONSORT reporting guidelines were implemented in this study. Study Design, Intervention, Randomization, and Blinding The protocol was explained to the patients participating in the study. Patients received a protocol information document with a consent form, clearly stating that they would receive either bupivacaine alone (control group) or bupivacaine with clonidine (clonidine group) in the form of local infiltration just before incision. After initial clinical assessment, enrolled patients were assigned to 1 of 4 surgical subgroups, depending on their pathology (ie, lumbar laminectomy with fusion, lumbar laminectomy without fusion, microsurgical lumbar discectomy through interlaminar approach, and cervical laminectomy without fusion), and were randomly allocated (block randomization method, computer generated via http://www.randomization.com) to either control or clonidine group (Table 2). The control group received a preincisional field block consisting of 20 mL of 0.25% bupivacaine alone (Bupivacaine Aguettant, AGUETTANT® laboratory, Lyon, France), whereas the clonidine group received 19 mL of 0.25% bupivacaine with 1 mL (150 μg) of clonidine hydrochloride (Catapres®, Boehringer Ingelheim, Bracknell, Berkshire, United Kingdom). TABLE 2. Operative Patients Data Control group Clonidine group P value Type of surgery  Lumbar spinal fusion 42 (38.5%) 38 (32.8%) χ2 = .77  Lumbar laminectomy 11 (10.1%) 14 (12.1%)  Cervical laminectomy 11 (10.1%) 15 (12.9%)  Lumbar microdiscectomy 45 (41.3%) 49 (42.2%)  Number of operated levels 1 57 (52.8%) 62 (53%) χ2 = .52 2 23 (21.3%) 20 (17.2%) 3 21 (19.4%) 28 (24.1%) 4 5 (4.6%) 6 (5.2%) 6 2 (1.9%) 0 (0%) Intraoperative data (mean ± sd)  Duration of surgery in hours 1.81 ± .94 1.61 ± .88 .10  Blood loss in milliliter 123.28 ± 121.23 103.61 ± 90.67 .17 Control group Clonidine group P value Type of surgery  Lumbar spinal fusion 42 (38.5%) 38 (32.8%) χ2 = .77  Lumbar laminectomy 11 (10.1%) 14 (12.1%)  Cervical laminectomy 11 (10.1%) 15 (12.9%)  Lumbar microdiscectomy 45 (41.3%) 49 (42.2%)  Number of operated levels 1 57 (52.8%) 62 (53%) χ2 = .52 2 23 (21.3%) 20 (17.2%) 3 21 (19.4%) 28 (24.1%) 4 5 (4.6%) 6 (5.2%) 6 2 (1.9%) 0 (0%) Intraoperative data (mean ± sd)  Duration of surgery in hours 1.81 ± .94 1.61 ± .88 .10  Blood loss in milliliter 123.28 ± 121.23 103.61 ± 90.67 .17 View Large TABLE 2. Operative Patients Data Control group Clonidine group P value Type of surgery  Lumbar spinal fusion 42 (38.5%) 38 (32.8%) χ2 = .77  Lumbar laminectomy 11 (10.1%) 14 (12.1%)  Cervical laminectomy 11 (10.1%) 15 (12.9%)  Lumbar microdiscectomy 45 (41.3%) 49 (42.2%)  Number of operated levels 1 57 (52.8%) 62 (53%) χ2 = .52 2 23 (21.3%) 20 (17.2%) 3 21 (19.4%) 28 (24.1%) 4 5 (4.6%) 6 (5.2%) 6 2 (1.9%) 0 (0%) Intraoperative data (mean ± sd)  Duration of surgery in hours 1.81 ± .94 1.61 ± .88 .10  Blood loss in milliliter 123.28 ± 121.23 103.61 ± 90.67 .17 Control group Clonidine group P value Type of surgery  Lumbar spinal fusion 42 (38.5%) 38 (32.8%) χ2 = .77  Lumbar laminectomy 11 (10.1%) 14 (12.1%)  Cervical laminectomy 11 (10.1%) 15 (12.9%)  Lumbar microdiscectomy 45 (41.3%) 49 (42.2%)  Number of operated levels 1 57 (52.8%) 62 (53%) χ2 = .52 2 23 (21.3%) 20 (17.2%) 3 21 (19.4%) 28 (24.1%) 4 5 (4.6%) 6 (5.2%) 6 2 (1.9%) 0 (0%) Intraoperative data (mean ± sd)  Duration of surgery in hours 1.81 ± .94 1.61 ± .88 .10  Blood loss in milliliter 123.28 ± 121.23 103.61 ± 90.67 .17 View Large Anesthetic and Surgical Protocol A standard protocol of general anesthesia was used for all patients. At induction, 3 mg/kg propofol, a bolus of 10 μg sufentanil, and 0.6 mg/kg rocuronium were delivered intravenously. Maintenance of anesthesia was conducted with sevoflurane at 1.2 of the minimal alveolar concentration in a mixture of 60% nitrous oxide and 40% oxygen with boluses of 5 μg sufentanil, according to heart rate and mean arterial pressure. Rocuronium was titrated with 5-mg injections, according to the train of 4. Approximately 40 min before the end of surgery, all patients received 15 mg/kg paracetamol and 1 mg/kg ketoprofen. Crystalloid solution perfusion and continuous noninvasive intraoperative monitoring of pulse, blood pressure, oxygen saturation, and electrocardiography were performed on every patient. During the preparation of the surgical site by the surgeon, the staff nurse of anesthesiology prepared the field block solution according to randomization. Field block was then performed by the surgeon, who was unaware of the type of administered solution, using a 23-gauge needle, in the subcutaneous space and in the paravertebral muscles on both sides of the spinous processes of the presumed surgical approach. Duration of surgery in hours, blood loss in mL (Table 2), and potential neurological or circulatory (especially hypotension) intraoperative complications were noted. Patients were in prone position for all types of surgery, except for microsurgical discectomy (genu pectoral position). Postoperative Hospital Stay Postoperative complications were noted, including those related to opioids or substances used in the field block, especially hypotension. In the postoperative period, all patients received a standardized analgesic protocol from the day of operation (D0) to the third postoperative day (D3), which consisted of intravenous (IV) injection of 1 g paracetamol with 50 mg ketoprofen every 6 h with gastric protection. Rescue analgesic medication consisted of 5 mg morphine subcutaneously administered upon patient request, with a minimum interval of 6 h between 2 rescue morphine doses. After D3, patients received oral paracetamol (1 g every 6 h) and ketoprofen (50 mg every 8 h) with gastric protection. Patients were discharged on D4. Patients in the microdiscectomy group received the IV protocol at D0 and D1 only and were discharged at D2. Clinical Assessment Patients’ postoperative pain was assessed from D0 to D8 through a pain diary. Patients were asked to evaluate pain intensity every 2 h during the day from D0 to D2 and 3 times daily from D3 to D8, and to record a mean pain average during the night. During hospital stay, staff nurses managed the pain diary and explained to the patient and accompanying person(s) how to complete the diary till D8. Pain intensity was measured through a simple numeric rating scale (NRS) from 0 (no pain) to 10 (worst imaginable pain). Rescue morphine consumption between D0 and D3 was also noted. Statistical Analysis Total area under the curve (AUC) of pain was considered the primary outcome measure and was calculated to be the sum of the values obtained by multiplying the different pain intensity values assessed through a pain diary by the period (in hours) of the corresponding assessments. It is expressed in pain unit multiplied by hour. Mean AUC was also calculated at intervals D0to D2, D3to D5, and D6to D8. Daily rescue morphine consumption from D0 to D3, expressed as milligram of morphine, was considered the secondary outcome measure. Sample size (n = 212) was calculated on http://www.sealedenvelope.com/power/binary-superiority (Pocock SJ. Clinical Trials: A Practical Approach. Wiley; 1983), in order to have a 90% chance of detecting, at a 5% level of significance, an increase in pain score improvement from 20% in control group to 40% in clonidine group. Statistical analysis was done using Stata (12th version, StataCorp, College Station, Texas). Basic categorical, clinical, demographic, preoperative, and postoperative characteristics of the control and clonidine groups were compared using chi-squared test. Parametric quantitative data were compared using t-test, whereas nonparametric quantitative data were compared using the Mann–Whitney U-test. Multiple regression analysis on all patients was performed with total AUC and total morphine rescue consumption each as dependent variables. Independent variables were as follows: sex, age, body mass index, socioeconomic level, level of education, type of work, diabetes, smoking, alcoholism, duration of symptoms, mean intensity of preoperative back pain, preoperative neurological deficit, ASA status, type of field block, type of surgery, duration of operation, and blood loss. Probability values less than .05 were considered statistically significant. RESULTS Characteristics of Control and Clonidine Groups Both groups of patients showed no statistical differences (Tables 1 and 2) in terms of demographic and clinical characteristics and in terms of surgical data (chi-squared test and t-test). Pain Intensity The AUC of pain was significantly reduced in the clonidine group compared with the control group, except in the cervical stenosis patients (P = .24; Figure 2A; Table 3). This reduction was most significant in the microdiscectomy subgroup (P < .001). Post hoc statistical power values were 84.6%, 75.4%, 12.7%, and 99.7%, respectively, for lumbar spinal fusion, lumbar stenosis, cervical stenosis, and microdiscectomy subgroups. AUC reduction was similar all along the follow-up period from D0 to D8, when considering each surgical subgroup and all surgical subgroups together (Figures 2B). Mean daily NRS scores in the clonidine and control groups for each surgical subgroup are represented in Figure, Supplemental Digital Content, where significant differences are marked by asterisks. FIGURE 2. View largeDownload slide Patient AUC. A, AUC of pain in both clonidine and control groups, respectively, in the 4 surgical subgroups and in all patients taken together. B, AUC of pain according to time after surgery (3 intervals: day 0-2; day 3-5; day 6-8) in all surgical subgroups taken together. *P value < .05; **P value < .001. FIGURE 2. View largeDownload slide Patient AUC. A, AUC of pain in both clonidine and control groups, respectively, in the 4 surgical subgroups and in all patients taken together. B, AUC of pain according to time after surgery (3 intervals: day 0-2; day 3-5; day 6-8) in all surgical subgroups taken together. *P value < .05; **P value < .001. TABLE 3. Mean Value (Standard Deviation) of AUC of Pain Expressed in Pain Unit × Hour and of Rescue Morphine Consumption (Given Subcutaneously) in Milligram for Control and Clonidine Groups, for Each Surgical Subgroup and for all Surgical Subgroups Taken Together Type of surgery Spinal fusion Lumbar stenosis Cervical stenosis Microdiscectomy All surgical subgroups Outcome parameter Mean (St Dev) Control group (n = 42) Clonidine group (n = 38) P value Control group (n = 11) Clonidine group (n = 14) P value Control group (n = 11) Clonidine group (n = 15) P value Control group (n = 45) Clonidine group (n = 49) P value Control group (n = 109) Clonidine group (n = 116) P value Total AUC 694 (294) 546 (198) .005 673 (285) 430 (221) .01 631 (200) 584 (276) .24 374 (192) 223 (138) <.001 553 (290) 400 (248) <.001 Total rescue morphine 16.8 (8.6) 7.0 (11.1) <.001 18.6 (11.7) 4.3 (5.7) <.001 11.8 (6.2) 7.7 (9.5) .10 3.5 (11.4) 1.6 (6.3) .17 11.0 (11.9) 4.5 (8.9) <.001 Type of surgery Spinal fusion Lumbar stenosis Cervical stenosis Microdiscectomy All surgical subgroups Outcome parameter Mean (St Dev) Control group (n = 42) Clonidine group (n = 38) P value Control group (n = 11) Clonidine group (n = 14) P value Control group (n = 11) Clonidine group (n = 15) P value Control group (n = 45) Clonidine group (n = 49) P value Control group (n = 109) Clonidine group (n = 116) P value Total AUC 694 (294) 546 (198) .005 673 (285) 430 (221) .01 631 (200) 584 (276) .24 374 (192) 223 (138) <.001 553 (290) 400 (248) <.001 Total rescue morphine 16.8 (8.6) 7.0 (11.1) <.001 18.6 (11.7) 4.3 (5.7) <.001 11.8 (6.2) 7.7 (9.5) .10 3.5 (11.4) 1.6 (6.3) .17 11.0 (11.9) 4.5 (8.9) <.001 View Large TABLE 3. Mean Value (Standard Deviation) of AUC of Pain Expressed in Pain Unit × Hour and of Rescue Morphine Consumption (Given Subcutaneously) in Milligram for Control and Clonidine Groups, for Each Surgical Subgroup and for all Surgical Subgroups Taken Together Type of surgery Spinal fusion Lumbar stenosis Cervical stenosis Microdiscectomy All surgical subgroups Outcome parameter Mean (St Dev) Control group (n = 42) Clonidine group (n = 38) P value Control group (n = 11) Clonidine group (n = 14) P value Control group (n = 11) Clonidine group (n = 15) P value Control group (n = 45) Clonidine group (n = 49) P value Control group (n = 109) Clonidine group (n = 116) P value Total AUC 694 (294) 546 (198) .005 673 (285) 430 (221) .01 631 (200) 584 (276) .24 374 (192) 223 (138) <.001 553 (290) 400 (248) <.001 Total rescue morphine 16.8 (8.6) 7.0 (11.1) <.001 18.6 (11.7) 4.3 (5.7) <.001 11.8 (6.2) 7.7 (9.5) .10 3.5 (11.4) 1.6 (6.3) .17 11.0 (11.9) 4.5 (8.9) <.001 Type of surgery Spinal fusion Lumbar stenosis Cervical stenosis Microdiscectomy All surgical subgroups Outcome parameter Mean (St Dev) Control group (n = 42) Clonidine group (n = 38) P value Control group (n = 11) Clonidine group (n = 14) P value Control group (n = 11) Clonidine group (n = 15) P value Control group (n = 45) Clonidine group (n = 49) P value Control group (n = 109) Clonidine group (n = 116) P value Total AUC 694 (294) 546 (198) .005 673 (285) 430 (221) .01 631 (200) 584 (276) .24 374 (192) 223 (138) <.001 553 (290) 400 (248) <.001 Total rescue morphine 16.8 (8.6) 7.0 (11.1) <.001 18.6 (11.7) 4.3 (5.7) <.001 11.8 (6.2) 7.7 (9.5) .10 3.5 (11.4) 1.6 (6.3) .17 11.0 (11.9) 4.5 (8.9) <.001 View Large Morphine Consumption Morphine rescue consumption was reduced in the clonidine group compared with the control group (Figure 3A; Table 3) in the spinal fusion (P < .001) and lumbar stenosis (P < .001) subgroups. This effect was absent in the microdiscectomy (P = .17) and cervical stenosis (P = .099) subgroups (Figure 3A; Table 3). This morphine rescue consumption was significantly reduced from postoperative D1 to D3 (P < .001 in D1 and D2, and P = .04 on D3), but not on the day of surgery, D0 (P = .26; Figure 3B), when considering all the surgical subgroups together. This trend was significant only in the spinal fusion and spinal stenosis subgroups. FIGURE 3. View largeDownload slide Patient postoperative morphine consumption. A, Morphine consumption (in mg) from the day of surgery till postoperative day 3 in both clonidine and control groups, in the 4 surgical subgroups, and in all patients taken together. B, Morphine consumption according to time after surgery (day of surgery; day 1; day 2 and day 3) in all surgical subgroups taken together. *P value < .05; **P value < .001. FIGURE 3. View largeDownload slide Patient postoperative morphine consumption. A, Morphine consumption (in mg) from the day of surgery till postoperative day 3 in both clonidine and control groups, in the 4 surgical subgroups, and in all patients taken together. B, Morphine consumption according to time after surgery (day of surgery; day 1; day 2 and day 3) in all surgical subgroups taken together. *P value < .05; **P value < .001. Correlations and Factors Influencing the Response to Clonidine Multiple linear regression analyses were performed for all surgical subgroups together (considered as independent variable) and showed that factors influencing the primary (AUC) and the secondary (morphine consumption) outcome measures were clonidine, surgical subgroup, and presence of preoperative back pain. Among patients receiving clonidine, those who had preoperative spinal pain presented with higher AUC (P = .02) compared with patients with no such pain. Side Effects None of the patients in either group experienced side effects related to the field block. Notably, no hemodynamic instability or cardiac arrhythmias occurred in any patient. No neurological complications following surgery were reported in either group. Six cases of atelectasis were reported in the clonidine group and 5 in the control group (P = .84; NS—chi-squared test). Four cases of superficial wound infection were reported in the clonidine group and 3 in the control group (P = .76; NS—chi-squared test). One case of deep infection with Klebsiella pneumoniae was reported in the control group and was treated with IV antibiotics without the need for surgical re-exploration. One patient in the clonidine group presented with deep venous thrombosis, documented by lower limb ultrasound. DISCUSSION In this study, we found that the addition of 150 μg of clonidine to bupivacaine in preincisional field block for posterior approach spine surgery was associated with better postoperative pain control and morphine consumption sparing in patients who were followed for 8 d postoperatively. Among surgical subgroups, the microdiscectomy subgroup benefited the most from this combination and the cervical stenosis subgroup had some benefit that did not reach statistical significance. Patients with low back pain prior to surgery benefited less from this combination. Differential Action of Clonidine According to Surgical Subgroups In this study, all lumbar surgery subgroups in the clonidine group, unlike the cervical stenosis subgroup, showed significantly reduced AUC of pain postoperatively at the end of follow-up. Moreover, rescue morphine consumption was also reduced by clonidine addition in the lumbar fusion and lumbar stenosis subgroups, but not in the microdiscectomy subgroup, which may be due to the less invasive nature of microdiscectomy. In fact, patients in the microdiscectomy subgroup had shorter operating time, less wound extension, and thus, less muscle retraction and devascularization compared with other subgroups that underwent lumbar surgery. The cervical stenosis subgroup showed lower AUC and morphine consumption with the addition of clonidine, without reaching statistical significance. Preoperative spinal pain was neither more prevalent nor more intense in the cervical stenosis subgroup compared with the lumbar surgery subgroups, and thus, cannot explain this divergence in clonidine efficacy. From a statistical perspective, this observed difference could be explained by the low statistical power (12.7%) of the analysis for the cervical subgroup. One possible physiological explanation could be the fact that the cervical spine has denser nociceptive innervation, with participation of the trigeminal nucleus,17 than the lumbar spine, which makes the addition of clonidine less potent in the cervical subgroup. The added analgesic value of clonidine in field block with anesthetics has been previously reported in the literature with controversial results. Bollag et al18 found that adding clonidine to local postoperative bupivacaine in transversus abdominis plane block is ineffective in preventing pain in women, either 48 h or 12 mo following a cesarean section. However, the authors considered that the dosage of clonidine (75 μg/site) used in the study might have been insufficient to show an analgesic effect.18 Elliott et al12 found that the analgesia obtained by local bupivacaine in the first 24 h following elective inguinal hernia repair is not improved by addition of clonidine. Their follow-up period was short, and a difference might have been evident if they followed the patients for several days after surgery, as in our study. Bharti et al,13 on the other hand, found enhanced postoperative analgesia when clonidine was administered, either locally or systemically, with a bupivacaine infiltration in cholecystectomy patients. Such discrepancies in results among these studies may be explained mainly by low statistical power, which we encountered in this study's cervical stenosis group, stemming from the small number of patients evaluated. Another study by Mohamed et al14 used 0.5% bupivacaine in combination with 2 different dosages of clonidine (150 μg and 250 μg) in field block following mastectomy and found that the clonidine-bupivacaine combination is associated with significantly less neuropathic pain than placebo or bupivacaine alone. These results cannot be directly compared to ours because our study tested the analgesic effect of clonidine on postoperative nociceptive pain, whereas Mohamed et al's14 mastectomy study tested the effect of clonidine on long-term neuropathic pain. Possible Mechanisms of the Late Effect of Clonidine on Postoperative Pain Addition of clonidine to bupivacaine in a unique preincisional field block remarkably produced prolonged local pain control lasting from D0 to D8, a period far beyond the half-life of clonidine (estimated between 8 and 25 h)19,20 and far beyond the ability of clonidine to prolong the anesthetic action of bupivacaine (around 2 h) as in nerve blockade.21 This, therefore, excludes a direct synergy of clonidine with bupivacaine locally. To the best of our knowledge, this clinical study is the first to have prolonged follow-up and to show prolonged analgesic effect of local clonidine. Although the analgesic value of clonidine is better established for the first 24 h after surgery, it seems less clear for prolonged periods, mainly due to lack of studies with follow-ups over 24 h.22 Goyagi et al23 showed that adding systemic clonidine to epidural morphine remarkably improves analgesia between 24 and 48 h postoperatively in hysterectomy patients. Thus, these results raise the possibility of an intrinsic action of clonidine that promotes the durability of the analgesic effect Clonidine has the ability to activate α2 adrenoceptors with subsequent local vasoconstriction,23,24 hyperpolarization of A-δ and C fibers,25,26 and immunomodulation as activated macrophages and lymphocytes present α2 adrenoceptors on their surface.27 Local vasoconstriction and hyperpolarization of A-δ and C fibers are transient and last only during the period of the half-life of clonidine, and thus, cannot explain the prolonged effect of clonidine.25,26 Ischemia and partial denervation of paraspinal muscles during surgery are responsible for local secretion of inflammatory cytokines, leading to recruitment of circulating macrophages and additional secretion of cytokines.28 The adrenergic system participates in local immunomodulation, as activated macrophages and lymphocytes present α2 adrenoceptors on their surface.27 Because clonidine acts by activating these receptors, it can lead to a local anti-inflammatory action, which most probably mediates the observed prolonged analgesic effect, most likely similar to the anti-inflammatory kinetics of local steroid.29 In fact, experimental studies in rats have shown that local infiltration with clonidine decreases tumor necrosis factor α and interleukin-1β and increases transforming growth factor β1 after sciatic nerve ligation, resulting in prolonged analgesic effect for 28 d after 3 local infiltrations with clonidine.30 Preoperative Spinal Pain and the Role of Spinal Sensitization Spinal sensitization is a common feature of chronic pain syndromes, especially chronic back pain.31,32 Because local infiltration with clonidine has been found to exert an anti-inflammatory action, not only locally but also in the dorsal root ganglion after sciatic nerve ligation in rats,30 clonidine may thereby reduce new-onset spinal sensitization.33 In our study, clonidine exhibited an enhanced analgesic action in patients without preoperative back pain compared with those suffering from it. This suggests that clonidine acts more to prevent rather than alleviate spinal sensitization. Limitations Selection bias was limited by randomization of patients among groups, and observer bias was limited by the double-blind method. Potential confounding factors were recorded and included in the multiple regression analysis. Sample size was calculated for the whole series and not for subgroups. Thus, a bigger sample size may have been necessary in the cervical and lumbar stenosis subgroups in order to yield more robust and valid results, especially for the cervical stenosis subgroup. A third group using intravenous clonidine with local bupivacaine infiltration could have been added to better assess whether the effect of clonidine was local or systemic, as Bharti et al13 have shown equivalent postoperative analgesic action in cholecystectomy patients. However, the postoperative analgesic effect of systemic clonidine was inconsistent across different studies,34-36 with higher incidence of side effects.13 This suggests that local clonidine is at least as effective as systemic clonidine, but with fewer side effects. Another limitation of the study was the pain assessment on the day and first night of surgery, when the patient was still postoperatively under the effect of anesthetic drugs. During this period, pain assessment was prompted and under close supervision of a resident who followed up on the patient, making sure that the pain diary was filled correctly. CONCLUSION We have shown that adding 150 μg of clonidine to a preincisional field block with bupivacaine resulted in better and prolonged postoperative analgesia in posterior lumbar spine surgeries, an effect that was more pronounced in patients with no preoperative spinal pain. Disclosures The research council of the Saint Joseph University of Beirut (FM 217) funded this study. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Notes This research has been previously presented as follows: Title: Randomized double-blind study of the added analgesic value of clonidine in local pre-surgical infiltration of the wound with bupivacaine in posterior spine surgery. Meeting: World association of Lebanese Neurosurgeon Congress. Date: June 19 to 22, 2013. Location: Beirut, Lebanon. Presentation type: plenary Title: Randomized double-blind study of bupivacaine wound pre-surgical infiltration with versus without clonidine in posterior spine surgery. Meeting: 8th congress of the European federation of IASP chapters. Date: October 9 to 12, 2013. Location: Florence, Italy. Presentation type: poster Title: (French) “Efficacité antalgique d’une infiltration locale pré-incisionnelle de bupivacaïne sans et avec clonidine dans la chirurgie rachidienne postérieure. Essai prospectif randomisé en double insu.” Meeting: Annual meeting of the French society of neurosurgery. Date: November 24 to 27, 2013. Location: Paris, France. Presentation type: plenary Title: Randomized double-blind trial comparing the post-operative analgesic added value of local wound infiltration with clonidine in posterior spine surgery. Meeting: 21st annual meeting of the Lebanese Association for the advance of science. Date: April 15 to 17, 2015. Location: Beirut, Lebanon. Presentation type: poster REFERENCES 1. Kehlet H , Dahl JB . Anaesthesia, surgery, and challenges in postoperative recovery . Lancet . 2003 ; 362 ( 9399 ): 1921 - 1928 . Google Scholar CrossRef Search ADS PubMed 2. Sharma S , Balireddy RK , Vorenkamp KE , Durieux ME . Beyond opioid patient-controlled analgesia: a systematic review of analgesia after major spine surgery . Reg Anesth Pain Med . 2012 ; 37 ( 1 ): 79 - 98 . Google Scholar CrossRef Search ADS PubMed 3. Datta G , Gnanalingham KK , Peterson D et al. Back pain and disability after lumbar laminectomy: is there a relationship to muscle retraction? Neurosurgery . 2004 ; 54 ( 6 ): 1413 - 1420 . Google Scholar CrossRef Search ADS PubMed 4. Buvanendran A , Kroin JS . Multimodal analgesia for controlling acute postoperative pain . Curr Opin Anaesthesiol . 2009 ; 22 ( 5 ): 588 - 593 . Google Scholar CrossRef Search ADS PubMed 5. Devin CJ , McGirt MJ . Best evidence in multimodal pain management in spine surgery and means of assessing postoperative pain and functional outcomes . J Clin Neurosci . 2015 ; 22 ( 6 ): 930 - 938 . Google Scholar CrossRef Search ADS PubMed 6. Mullen JB , Cook WA . Reduction of postoperative lumbar hemilaminectomy pain with Marcaine. Technical note . 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Anesthesiology . 1990 ; 73 ( 5 ): 853 - 859 . Google Scholar CrossRef Search ADS PubMed 11. Singelyn FJ , Dangoisse M , Bartholomée S , Gouverneur JM . Adding clonidine to mepivacaine prolongs the duration of anesthesia and analgesia after axillary brachial plexus block . Reg Anesth . 1992 ; 17 ( 3 ): 148 - 150 . Google Scholar PubMed 12. Elliott S , Eckersall S , Fligelstone L , Jothilingam S . Does the addition of clonidine affect duration of analgesia of bupivacaine wound infiltration in inguinal hernia surgery? Br J Anaesth . 1997 ; 79 ( 4 ): 446 - 449 . Google Scholar CrossRef Search ADS PubMed 13. Bharti N , Dontukurthy S , Bala I , Singh G . Postoperative analgesic effect of intravenous (i.v.) clonidine compared with clonidine administration in wound infiltration for open cholecystectomy . Br J Anaesth . 2013 ; 111 ( 4 ): 656 - 661 . Google Scholar CrossRef Search ADS PubMed 14. Mohamed SA-B , Abdel-Ghaffar HS . Effect of the addition of clonidine to locally administered bupivacaine on acute and chronic postmastectomy pain . J Clin Anesth . 2013 ; 25 ( 1 ): 20 - 27 . Google Scholar CrossRef Search ADS PubMed 15. Chen Y-W , Chu C-C , Chen Y-C , Hung C-H , Hsueh M-I , Wang J-J . Clonidine as adjuvant for oxybuprocaine, bupivacaine or dextrorphan has a significant peripheral action in intensifying and prolonging analgesia in response to local dorsal cutaneous noxious pinprick in rats . Neurosci Lett . 2011 ; 496 ( 3 ): 186 - 190 . Google Scholar CrossRef Search ADS PubMed 16. Rickham PP . Human experimentation. code of ethics of the world medical association. declaration of helsinki . Br Med J . 1964 ; 2 ( 5402 ): 177 . Google Scholar CrossRef Search ADS PubMed 17. Taren JA , Kahn EA . Anatomic pathways related to pain in face and neck . J Neurosurg . 1962 ; 19 ( 2 ): 116 - 121 . Google Scholar CrossRef Search ADS PubMed 18. Bollag L , Richebe P , Siaulys M , Ortner CM , Gofeld M , Landau R . Effect of transversus abdominis plane block with and without clonidine on post-cesarean delivery wound hyperalgesia and pain . Reg Anesth Pain Med . 2012 ; 37 ( 5 ): 508 - 514 . Google Scholar CrossRef Search ADS PubMed 19. Anavekar SN , Jarrott B , Toscano M , Louis WJ . Pharmacokinetic and pharmacodynamic studies of oral clonidine in normotensive subjects . Eur J Clin Pharmacol . 1982 ; 23 ( 1 ): 1 - 5 . Google Scholar CrossRef Search ADS PubMed 20. Conway EL , Anavekar SN , Howes LG , Louis WJ . Pharmacokinetic comparison of a slow-release clonidine with a conventional formulation after acute and chronic administration in hypertensives . J Clin Pharmacol . 1992 ; 32 ( 5 ): 427 - 433 . Google Scholar CrossRef Search ADS PubMed 21. Pöpping DM , Elia N , Marret E , Wenk M , Tramèr MR . Clonidine as an adjuvant to local anesthetics for peripheral nerve and plexus blocks: a meta-analysis of randomized trials . Anesthesiology . 2009 ; 111 ( 2 ): 406 - 415 . 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Clonidine enhances the effects of lidocaine on C-fiber action potential . Anesth Analg . 1992 ; 74 ( 5 ): 719 - 725 . Google Scholar CrossRef Search ADS PubMed 26. Butterworth JF , Strichartz GR . The alpha 2-adrenergic agonists clonidine and guanfacine produce tonic and phasic block of conduction in rat sciatic nerve fibers . Anesth Analg . 1993 ; 76 ( 2 ): 295 - 301 . Google Scholar PubMed 27. Maes M , Lin A , Kenis G , Egyed B , Bosmans E . The effects of noradrenaline and alpha-2 adrenoceptor agents on the production of monocytic products . Psychiatry Res . 2000 ; 96 ( 3 ): 245 - 253 . Google Scholar CrossRef Search ADS PubMed 28. Shamash S , Reichert F , Rotshenker S . The cytokine network of Wallerian degeneration: tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-1beta . J Neurosci . 2002 ; 22 ( 8 ): 3052 - 3060 . Google Scholar CrossRef Search ADS PubMed 29. Glasser RS , Knego RS , Delashaw JB , Fessler RG . The perioperative use of corticosteroids and bupivacaine in the management of lumbar disc disease . J Neurosurg . 1993 ; 78 ( 3 ): 383 - 387 . Google Scholar CrossRef Search ADS PubMed 30. Lavand’homme PM , Eisenach JC . Perioperative administration of the alpha2-adrenoceptor agonist clonidine at the site of nerve injury reduces the development of mechanical hypersensitivity and modulates local cytokine expression . Pain . 2003 ; 105 ( 1 ): 247 - 254 . Google Scholar CrossRef Search ADS PubMed 31. Van Oosterwijck J , Nijs J , Meeus M , Paul L . Evidence for central sensitization in chronic whiplash: a systematic literature review . Eur J Pain . 2013 ; 17 ( 3 ): 299 - 312 . Google Scholar CrossRef Search ADS PubMed 32. Bid DD , Soni NC , Rathod PV . Central sensitization in chronic low back pain: a narrative review . Natl J Integr Res Med . 2016 ; 7 ( 3 ): 114 - 123 . 33. Romero-Sandoval A , Eisenach JC . Clonidine reduces hypersensitivity and alters the balance of pro- and anti-inflammatory leukocytes after local injection at the site of inflammatory neuritis . Brain Behav Immun . 2007 ; 21 ( 5 ): 569 - 580 . Google Scholar CrossRef Search ADS PubMed 34. Goyagi T , Tanaka M , Nishikawa T . Oral clonidine premedication enhances postoperative analgesia by epidural morphine . Anesth Analg . 1999 ; 89 ( 6 ): 1487 - 1491 . Google Scholar PubMed 35. Oofuvong M , Chanvej L , Thongsuksai P . Single dose oral clonidine premedication does not enhance postoperative, single low dose epidural morphine analgesia in hysterectomy patients . J Med Assoc Thai . 2005 ; 88 ( 3 ): 358 - 363 . Google Scholar PubMed 36. Simoni RF , Cangiani LM , Pereira AM , Abreu MP , Cangiani LH , Zemi G . Efficacy of intraoperative methadone and clonidine in pain control in the immediate postoperative period after the use of remifentanil . Rev Bras Anestesiol . 2009 ; 59 ( 4 ): 421 - 430 . Google Scholar CrossRef Search ADS PubMed Supplemental digital content is available for this article at www.neurosurgery-online.com. Copyright © 2017 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Bupivacaine Field Block With Clonidine for Postoperative Pain Control in Posterior Spine Approaches: A Randomized Double-Blind Trial

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Oxford University Press
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Copyright © 2017 by the Congress of Neurological Surgeons
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0148-396X
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1524-4040
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10.1093/neuros/nyx313
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Abstract

Abstract BACKGROUND The synergistic effect of clonidine with bupivacaine, well established in peripheral nerve blocks, remains controversial in local field block for postoperative analgesia. OBJECTIVE To investigate the potential analgesic benefit of adding clonidine to bupivacaine during preincisional field block in posterior approaches for spine surgeries. METHODS Two hundred twenty-five patients were enrolled in this study and underwent lumbar spinal fusion (n = 80), lumbar laminectomy (n = 25), lumbar microdiscectomy (n = 94), or cervical laminectomy (n = 26). In each surgical subgroup, patients were randomly assigned in a double-blinded fashion to receive either 20 mL of 0.25% bupivacaine alone (control group, n = 109) or with 150 μg clonidine (clonidine group, n = 116) in the form of a preincisional field block. Outcome parameters included area under the curve of pain from postoperative day D0 to D8 and rescue morphine consumption from D0 to D3. RESULTS The area under the curve was reduced in the clonidine group, particularly in the microdiscectomy subgroup, and without reaching statistical significance in the cervical laminectomy subgroup. Total rescue morphine consumption was reduced in the clonidine group, particularly at D1-D2, a benefit that was exclusive to the lumbar stenosis and lumbar fusion subgroups. Field block with clonidine, surgical subgroup, and the presence of preoperative spinal pain were factors independently influencing postoperative wound pain in multivariate analysis. CONCLUSION The addition of clonidine to local preincisional field block with bupivacaine resulted in better and prolonged postoperative analgesia in posterior lumbar spine surgeries, an effect that was more pronounced in patients with no preoperative spinal pain. Clonidine, Bupivacaine, Posterior spine surgery, Laminectomy, Microdiscectomy, Postoperative pain control, Wound infiltration ABBREVIATIONS ABBREVIATIONS ASA American Society of Anesthesiologists AUC area under the curve NRS numeric rating scale Control of postoperative pain is essential to reducing postoperative morbidity, as it allows early mobilization and hospital discharge.1 In posterior approach spine surgery, musculoskeletal postoperative pain arises from iatrogenic mechanical damage, intraoperative retraction, and partial devascularization and denervation to structures such as bone, ligaments, muscles, intervertebral disks, and zygapophysial joints.2,3 Multimodal analgesia is a useful postoperative pain management strategy that combines different analgesics that act through different mechanisms at different sites in the nervous system. This strategy results in additive or synergistic analgesia that can be achieved with lower doses of major analgesics, and thus, fewer adverse effects compared to the sole administration of individual analgesics.4,5 Field block (also called wound infiltration) with a local anesthetic agent, especially with bupivacaine, is an important element of multimodal analgesia and is well established as a reliable technique.6-8 In patients undergoing lumbar discectomy in particular, preincisional field block has proven to be more effective than preclosure field block.7,9 Clonidine, an α2-adrenergic agonist, extends the duration of sensory blocks with both ester and amide local anesthetics10,11 when administered in the epidural space or in the vicinity of peripheral nerves. This analgesic synergy has been tested in patients for local field block and was found to be ineffective in inguinal hernia surgery during the first 24 h postsurgery,12 but effective in cholecystectomy patients during the same period.13 When tested in mastectomy, this analgesic synergy is clearly evident, especially with higher clonidine dosage.14 In addition, an experimental study in rats found that clonidine significantly prolongs and improves the local anesthetic and analgesic effect of a field block with bupivacaine, as documented by noxious cutaneous pinprick.15 In this randomized double-blind study, we aimed to evaluate the early and late analgesic value of clonidine administered with bupivacaine in preincisional field block for posterior approach spine surgery. METHODS Patients Two hundred twenty-five patients were enrolled in this randomized double-blind clinical trial between January 2012 and December 2015 and underwent spinal surgery (under the care of senior author JM) at Hôtel-Dieu de France Hospital Beirut-Lebanon, after verification of inclusion and exclusion criteria (see below). Table 1 gives detailed clinical and demographic information on the patients, and Figure 1 represents the CONSORT flow diagram. FIGURE 1. View largeDownload slide Eligibility, randomization, and follow-up. LL+F = lumbar laminectomy with fusion subgroup; LL = lumbar laminectomy subgroup; MD = lumbar microdiscectomy subgroup; CL = cervical laminectomy subgroup. FIGURE 1. View largeDownload slide Eligibility, randomization, and follow-up. LL+F = lumbar laminectomy with fusion subgroup; LL = lumbar laminectomy subgroup; MD = lumbar microdiscectomy subgroup; CL = cervical laminectomy subgroup. TABLE 1. Clinical and Demographical Patient Data Control group Clonidine group P value Patients 109 116  Males 57 (52%) 49 (42%) .13  Females 52 (48%) 67 (58%) Age (mean ± sd) 55.43 ± 15.71 53.93 ± 14.24 .45 ASA class  Class I 79 (72%) 95 (82%) .09  Class II 30 (28%) 21 (18%) Preoperative spinal pain (NRS)  Present 73 (67%) 86 (74.1%) .24  Intensity (mean ± sd) 1.71 ± 1.6 2.01 ± 1.6 .14 Duration of preoperative pain evolution  In months (mean ± sd) 6.6 ± 10.1 6 ± 8.8 .64  Absent 36 (33%) 33 (28.5%)  ≤12 mo 54 (49.6%) 68 (58.6%) χ2 = .37  >12 mo 19 (17.4%) 15 (12.9%) Preoperative neurological deficit  Motor 37 (34%) 52 (44.9%) .09  Sensory 7 (6.5%) 12 (10.4%) .28 Control group Clonidine group P value Patients 109 116  Males 57 (52%) 49 (42%) .13  Females 52 (48%) 67 (58%) Age (mean ± sd) 55.43 ± 15.71 53.93 ± 14.24 .45 ASA class  Class I 79 (72%) 95 (82%) .09  Class II 30 (28%) 21 (18%) Preoperative spinal pain (NRS)  Present 73 (67%) 86 (74.1%) .24  Intensity (mean ± sd) 1.71 ± 1.6 2.01 ± 1.6 .14 Duration of preoperative pain evolution  In months (mean ± sd) 6.6 ± 10.1 6 ± 8.8 .64  Absent 36 (33%) 33 (28.5%)  ≤12 mo 54 (49.6%) 68 (58.6%) χ2 = .37  >12 mo 19 (17.4%) 15 (12.9%) Preoperative neurological deficit  Motor 37 (34%) 52 (44.9%) .09  Sensory 7 (6.5%) 12 (10.4%) .28 ASA = American Society of Anaesthesiologists (note that ASA class III and IV were excluded from the study), NRS = numerical rating scale. View Large TABLE 1. Clinical and Demographical Patient Data Control group Clonidine group P value Patients 109 116  Males 57 (52%) 49 (42%) .13  Females 52 (48%) 67 (58%) Age (mean ± sd) 55.43 ± 15.71 53.93 ± 14.24 .45 ASA class  Class I 79 (72%) 95 (82%) .09  Class II 30 (28%) 21 (18%) Preoperative spinal pain (NRS)  Present 73 (67%) 86 (74.1%) .24  Intensity (mean ± sd) 1.71 ± 1.6 2.01 ± 1.6 .14 Duration of preoperative pain evolution  In months (mean ± sd) 6.6 ± 10.1 6 ± 8.8 .64  Absent 36 (33%) 33 (28.5%)  ≤12 mo 54 (49.6%) 68 (58.6%) χ2 = .37  >12 mo 19 (17.4%) 15 (12.9%) Preoperative neurological deficit  Motor 37 (34%) 52 (44.9%) .09  Sensory 7 (6.5%) 12 (10.4%) .28 Control group Clonidine group P value Patients 109 116  Males 57 (52%) 49 (42%) .13  Females 52 (48%) 67 (58%) Age (mean ± sd) 55.43 ± 15.71 53.93 ± 14.24 .45 ASA class  Class I 79 (72%) 95 (82%) .09  Class II 30 (28%) 21 (18%) Preoperative spinal pain (NRS)  Present 73 (67%) 86 (74.1%) .24  Intensity (mean ± sd) 1.71 ± 1.6 2.01 ± 1.6 .14 Duration of preoperative pain evolution  In months (mean ± sd) 6.6 ± 10.1 6 ± 8.8 .64  Absent 36 (33%) 33 (28.5%)  ≤12 mo 54 (49.6%) 68 (58.6%) χ2 = .37  >12 mo 19 (17.4%) 15 (12.9%) Preoperative neurological deficit  Motor 37 (34%) 52 (44.9%) .09  Sensory 7 (6.5%) 12 (10.4%) .28 ASA = American Society of Anaesthesiologists (note that ASA class III and IV were excluded from the study), NRS = numerical rating scale. View Large Inclusion criteria wereas follows: age above 18, American Society of Anesthesiologists (ASA) class I or II, and patients undergoing their first spinal surgery. Exclusion criteria wereas follows: patients having any known allergy to local anesthetics or clonidine, Raynaud's syndrome, thromboangiitis obliterans, ongoing pregnancy, current treatment with corticosteroids, contraindication for nonsteroidal anti-inflammatory drugs, opiate use, history of substance abuse, and current psychiatric disorder. Patients who were unable to communicate clearly and to sign informed consent were also excluded. All patients included in the study gave written informed consent. Protocols were approved by the local Ethics Committee of the Saint Joseph University (CEHDF384). The study was funded by the research council of the Saint Joseph University, conducted according to the declaration of Helsinki16 and of the World Medical Association (http://www.wma.net), and registered at http://www.clinicaltrials.gov (Identifier NCT01902108). CONSORT reporting guidelines were implemented in this study. Study Design, Intervention, Randomization, and Blinding The protocol was explained to the patients participating in the study. Patients received a protocol information document with a consent form, clearly stating that they would receive either bupivacaine alone (control group) or bupivacaine with clonidine (clonidine group) in the form of local infiltration just before incision. After initial clinical assessment, enrolled patients were assigned to 1 of 4 surgical subgroups, depending on their pathology (ie, lumbar laminectomy with fusion, lumbar laminectomy without fusion, microsurgical lumbar discectomy through interlaminar approach, and cervical laminectomy without fusion), and were randomly allocated (block randomization method, computer generated via http://www.randomization.com) to either control or clonidine group (Table 2). The control group received a preincisional field block consisting of 20 mL of 0.25% bupivacaine alone (Bupivacaine Aguettant, AGUETTANT® laboratory, Lyon, France), whereas the clonidine group received 19 mL of 0.25% bupivacaine with 1 mL (150 μg) of clonidine hydrochloride (Catapres®, Boehringer Ingelheim, Bracknell, Berkshire, United Kingdom). TABLE 2. Operative Patients Data Control group Clonidine group P value Type of surgery  Lumbar spinal fusion 42 (38.5%) 38 (32.8%) χ2 = .77  Lumbar laminectomy 11 (10.1%) 14 (12.1%)  Cervical laminectomy 11 (10.1%) 15 (12.9%)  Lumbar microdiscectomy 45 (41.3%) 49 (42.2%)  Number of operated levels 1 57 (52.8%) 62 (53%) χ2 = .52 2 23 (21.3%) 20 (17.2%) 3 21 (19.4%) 28 (24.1%) 4 5 (4.6%) 6 (5.2%) 6 2 (1.9%) 0 (0%) Intraoperative data (mean ± sd)  Duration of surgery in hours 1.81 ± .94 1.61 ± .88 .10  Blood loss in milliliter 123.28 ± 121.23 103.61 ± 90.67 .17 Control group Clonidine group P value Type of surgery  Lumbar spinal fusion 42 (38.5%) 38 (32.8%) χ2 = .77  Lumbar laminectomy 11 (10.1%) 14 (12.1%)  Cervical laminectomy 11 (10.1%) 15 (12.9%)  Lumbar microdiscectomy 45 (41.3%) 49 (42.2%)  Number of operated levels 1 57 (52.8%) 62 (53%) χ2 = .52 2 23 (21.3%) 20 (17.2%) 3 21 (19.4%) 28 (24.1%) 4 5 (4.6%) 6 (5.2%) 6 2 (1.9%) 0 (0%) Intraoperative data (mean ± sd)  Duration of surgery in hours 1.81 ± .94 1.61 ± .88 .10  Blood loss in milliliter 123.28 ± 121.23 103.61 ± 90.67 .17 View Large TABLE 2. Operative Patients Data Control group Clonidine group P value Type of surgery  Lumbar spinal fusion 42 (38.5%) 38 (32.8%) χ2 = .77  Lumbar laminectomy 11 (10.1%) 14 (12.1%)  Cervical laminectomy 11 (10.1%) 15 (12.9%)  Lumbar microdiscectomy 45 (41.3%) 49 (42.2%)  Number of operated levels 1 57 (52.8%) 62 (53%) χ2 = .52 2 23 (21.3%) 20 (17.2%) 3 21 (19.4%) 28 (24.1%) 4 5 (4.6%) 6 (5.2%) 6 2 (1.9%) 0 (0%) Intraoperative data (mean ± sd)  Duration of surgery in hours 1.81 ± .94 1.61 ± .88 .10  Blood loss in milliliter 123.28 ± 121.23 103.61 ± 90.67 .17 Control group Clonidine group P value Type of surgery  Lumbar spinal fusion 42 (38.5%) 38 (32.8%) χ2 = .77  Lumbar laminectomy 11 (10.1%) 14 (12.1%)  Cervical laminectomy 11 (10.1%) 15 (12.9%)  Lumbar microdiscectomy 45 (41.3%) 49 (42.2%)  Number of operated levels 1 57 (52.8%) 62 (53%) χ2 = .52 2 23 (21.3%) 20 (17.2%) 3 21 (19.4%) 28 (24.1%) 4 5 (4.6%) 6 (5.2%) 6 2 (1.9%) 0 (0%) Intraoperative data (mean ± sd)  Duration of surgery in hours 1.81 ± .94 1.61 ± .88 .10  Blood loss in milliliter 123.28 ± 121.23 103.61 ± 90.67 .17 View Large Anesthetic and Surgical Protocol A standard protocol of general anesthesia was used for all patients. At induction, 3 mg/kg propofol, a bolus of 10 μg sufentanil, and 0.6 mg/kg rocuronium were delivered intravenously. Maintenance of anesthesia was conducted with sevoflurane at 1.2 of the minimal alveolar concentration in a mixture of 60% nitrous oxide and 40% oxygen with boluses of 5 μg sufentanil, according to heart rate and mean arterial pressure. Rocuronium was titrated with 5-mg injections, according to the train of 4. Approximately 40 min before the end of surgery, all patients received 15 mg/kg paracetamol and 1 mg/kg ketoprofen. Crystalloid solution perfusion and continuous noninvasive intraoperative monitoring of pulse, blood pressure, oxygen saturation, and electrocardiography were performed on every patient. During the preparation of the surgical site by the surgeon, the staff nurse of anesthesiology prepared the field block solution according to randomization. Field block was then performed by the surgeon, who was unaware of the type of administered solution, using a 23-gauge needle, in the subcutaneous space and in the paravertebral muscles on both sides of the spinous processes of the presumed surgical approach. Duration of surgery in hours, blood loss in mL (Table 2), and potential neurological or circulatory (especially hypotension) intraoperative complications were noted. Patients were in prone position for all types of surgery, except for microsurgical discectomy (genu pectoral position). Postoperative Hospital Stay Postoperative complications were noted, including those related to opioids or substances used in the field block, especially hypotension. In the postoperative period, all patients received a standardized analgesic protocol from the day of operation (D0) to the third postoperative day (D3), which consisted of intravenous (IV) injection of 1 g paracetamol with 50 mg ketoprofen every 6 h with gastric protection. Rescue analgesic medication consisted of 5 mg morphine subcutaneously administered upon patient request, with a minimum interval of 6 h between 2 rescue morphine doses. After D3, patients received oral paracetamol (1 g every 6 h) and ketoprofen (50 mg every 8 h) with gastric protection. Patients were discharged on D4. Patients in the microdiscectomy group received the IV protocol at D0 and D1 only and were discharged at D2. Clinical Assessment Patients’ postoperative pain was assessed from D0 to D8 through a pain diary. Patients were asked to evaluate pain intensity every 2 h during the day from D0 to D2 and 3 times daily from D3 to D8, and to record a mean pain average during the night. During hospital stay, staff nurses managed the pain diary and explained to the patient and accompanying person(s) how to complete the diary till D8. Pain intensity was measured through a simple numeric rating scale (NRS) from 0 (no pain) to 10 (worst imaginable pain). Rescue morphine consumption between D0 and D3 was also noted. Statistical Analysis Total area under the curve (AUC) of pain was considered the primary outcome measure and was calculated to be the sum of the values obtained by multiplying the different pain intensity values assessed through a pain diary by the period (in hours) of the corresponding assessments. It is expressed in pain unit multiplied by hour. Mean AUC was also calculated at intervals D0to D2, D3to D5, and D6to D8. Daily rescue morphine consumption from D0 to D3, expressed as milligram of morphine, was considered the secondary outcome measure. Sample size (n = 212) was calculated on http://www.sealedenvelope.com/power/binary-superiority (Pocock SJ. Clinical Trials: A Practical Approach. Wiley; 1983), in order to have a 90% chance of detecting, at a 5% level of significance, an increase in pain score improvement from 20% in control group to 40% in clonidine group. Statistical analysis was done using Stata (12th version, StataCorp, College Station, Texas). Basic categorical, clinical, demographic, preoperative, and postoperative characteristics of the control and clonidine groups were compared using chi-squared test. Parametric quantitative data were compared using t-test, whereas nonparametric quantitative data were compared using the Mann–Whitney U-test. Multiple regression analysis on all patients was performed with total AUC and total morphine rescue consumption each as dependent variables. Independent variables were as follows: sex, age, body mass index, socioeconomic level, level of education, type of work, diabetes, smoking, alcoholism, duration of symptoms, mean intensity of preoperative back pain, preoperative neurological deficit, ASA status, type of field block, type of surgery, duration of operation, and blood loss. Probability values less than .05 were considered statistically significant. RESULTS Characteristics of Control and Clonidine Groups Both groups of patients showed no statistical differences (Tables 1 and 2) in terms of demographic and clinical characteristics and in terms of surgical data (chi-squared test and t-test). Pain Intensity The AUC of pain was significantly reduced in the clonidine group compared with the control group, except in the cervical stenosis patients (P = .24; Figure 2A; Table 3). This reduction was most significant in the microdiscectomy subgroup (P < .001). Post hoc statistical power values were 84.6%, 75.4%, 12.7%, and 99.7%, respectively, for lumbar spinal fusion, lumbar stenosis, cervical stenosis, and microdiscectomy subgroups. AUC reduction was similar all along the follow-up period from D0 to D8, when considering each surgical subgroup and all surgical subgroups together (Figures 2B). Mean daily NRS scores in the clonidine and control groups for each surgical subgroup are represented in Figure, Supplemental Digital Content, where significant differences are marked by asterisks. FIGURE 2. View largeDownload slide Patient AUC. A, AUC of pain in both clonidine and control groups, respectively, in the 4 surgical subgroups and in all patients taken together. B, AUC of pain according to time after surgery (3 intervals: day 0-2; day 3-5; day 6-8) in all surgical subgroups taken together. *P value < .05; **P value < .001. FIGURE 2. View largeDownload slide Patient AUC. A, AUC of pain in both clonidine and control groups, respectively, in the 4 surgical subgroups and in all patients taken together. B, AUC of pain according to time after surgery (3 intervals: day 0-2; day 3-5; day 6-8) in all surgical subgroups taken together. *P value < .05; **P value < .001. TABLE 3. Mean Value (Standard Deviation) of AUC of Pain Expressed in Pain Unit × Hour and of Rescue Morphine Consumption (Given Subcutaneously) in Milligram for Control and Clonidine Groups, for Each Surgical Subgroup and for all Surgical Subgroups Taken Together Type of surgery Spinal fusion Lumbar stenosis Cervical stenosis Microdiscectomy All surgical subgroups Outcome parameter Mean (St Dev) Control group (n = 42) Clonidine group (n = 38) P value Control group (n = 11) Clonidine group (n = 14) P value Control group (n = 11) Clonidine group (n = 15) P value Control group (n = 45) Clonidine group (n = 49) P value Control group (n = 109) Clonidine group (n = 116) P value Total AUC 694 (294) 546 (198) .005 673 (285) 430 (221) .01 631 (200) 584 (276) .24 374 (192) 223 (138) <.001 553 (290) 400 (248) <.001 Total rescue morphine 16.8 (8.6) 7.0 (11.1) <.001 18.6 (11.7) 4.3 (5.7) <.001 11.8 (6.2) 7.7 (9.5) .10 3.5 (11.4) 1.6 (6.3) .17 11.0 (11.9) 4.5 (8.9) <.001 Type of surgery Spinal fusion Lumbar stenosis Cervical stenosis Microdiscectomy All surgical subgroups Outcome parameter Mean (St Dev) Control group (n = 42) Clonidine group (n = 38) P value Control group (n = 11) Clonidine group (n = 14) P value Control group (n = 11) Clonidine group (n = 15) P value Control group (n = 45) Clonidine group (n = 49) P value Control group (n = 109) Clonidine group (n = 116) P value Total AUC 694 (294) 546 (198) .005 673 (285) 430 (221) .01 631 (200) 584 (276) .24 374 (192) 223 (138) <.001 553 (290) 400 (248) <.001 Total rescue morphine 16.8 (8.6) 7.0 (11.1) <.001 18.6 (11.7) 4.3 (5.7) <.001 11.8 (6.2) 7.7 (9.5) .10 3.5 (11.4) 1.6 (6.3) .17 11.0 (11.9) 4.5 (8.9) <.001 View Large TABLE 3. Mean Value (Standard Deviation) of AUC of Pain Expressed in Pain Unit × Hour and of Rescue Morphine Consumption (Given Subcutaneously) in Milligram for Control and Clonidine Groups, for Each Surgical Subgroup and for all Surgical Subgroups Taken Together Type of surgery Spinal fusion Lumbar stenosis Cervical stenosis Microdiscectomy All surgical subgroups Outcome parameter Mean (St Dev) Control group (n = 42) Clonidine group (n = 38) P value Control group (n = 11) Clonidine group (n = 14) P value Control group (n = 11) Clonidine group (n = 15) P value Control group (n = 45) Clonidine group (n = 49) P value Control group (n = 109) Clonidine group (n = 116) P value Total AUC 694 (294) 546 (198) .005 673 (285) 430 (221) .01 631 (200) 584 (276) .24 374 (192) 223 (138) <.001 553 (290) 400 (248) <.001 Total rescue morphine 16.8 (8.6) 7.0 (11.1) <.001 18.6 (11.7) 4.3 (5.7) <.001 11.8 (6.2) 7.7 (9.5) .10 3.5 (11.4) 1.6 (6.3) .17 11.0 (11.9) 4.5 (8.9) <.001 Type of surgery Spinal fusion Lumbar stenosis Cervical stenosis Microdiscectomy All surgical subgroups Outcome parameter Mean (St Dev) Control group (n = 42) Clonidine group (n = 38) P value Control group (n = 11) Clonidine group (n = 14) P value Control group (n = 11) Clonidine group (n = 15) P value Control group (n = 45) Clonidine group (n = 49) P value Control group (n = 109) Clonidine group (n = 116) P value Total AUC 694 (294) 546 (198) .005 673 (285) 430 (221) .01 631 (200) 584 (276) .24 374 (192) 223 (138) <.001 553 (290) 400 (248) <.001 Total rescue morphine 16.8 (8.6) 7.0 (11.1) <.001 18.6 (11.7) 4.3 (5.7) <.001 11.8 (6.2) 7.7 (9.5) .10 3.5 (11.4) 1.6 (6.3) .17 11.0 (11.9) 4.5 (8.9) <.001 View Large Morphine Consumption Morphine rescue consumption was reduced in the clonidine group compared with the control group (Figure 3A; Table 3) in the spinal fusion (P < .001) and lumbar stenosis (P < .001) subgroups. This effect was absent in the microdiscectomy (P = .17) and cervical stenosis (P = .099) subgroups (Figure 3A; Table 3). This morphine rescue consumption was significantly reduced from postoperative D1 to D3 (P < .001 in D1 and D2, and P = .04 on D3), but not on the day of surgery, D0 (P = .26; Figure 3B), when considering all the surgical subgroups together. This trend was significant only in the spinal fusion and spinal stenosis subgroups. FIGURE 3. View largeDownload slide Patient postoperative morphine consumption. A, Morphine consumption (in mg) from the day of surgery till postoperative day 3 in both clonidine and control groups, in the 4 surgical subgroups, and in all patients taken together. B, Morphine consumption according to time after surgery (day of surgery; day 1; day 2 and day 3) in all surgical subgroups taken together. *P value < .05; **P value < .001. FIGURE 3. View largeDownload slide Patient postoperative morphine consumption. A, Morphine consumption (in mg) from the day of surgery till postoperative day 3 in both clonidine and control groups, in the 4 surgical subgroups, and in all patients taken together. B, Morphine consumption according to time after surgery (day of surgery; day 1; day 2 and day 3) in all surgical subgroups taken together. *P value < .05; **P value < .001. Correlations and Factors Influencing the Response to Clonidine Multiple linear regression analyses were performed for all surgical subgroups together (considered as independent variable) and showed that factors influencing the primary (AUC) and the secondary (morphine consumption) outcome measures were clonidine, surgical subgroup, and presence of preoperative back pain. Among patients receiving clonidine, those who had preoperative spinal pain presented with higher AUC (P = .02) compared with patients with no such pain. Side Effects None of the patients in either group experienced side effects related to the field block. Notably, no hemodynamic instability or cardiac arrhythmias occurred in any patient. No neurological complications following surgery were reported in either group. Six cases of atelectasis were reported in the clonidine group and 5 in the control group (P = .84; NS—chi-squared test). Four cases of superficial wound infection were reported in the clonidine group and 3 in the control group (P = .76; NS—chi-squared test). One case of deep infection with Klebsiella pneumoniae was reported in the control group and was treated with IV antibiotics without the need for surgical re-exploration. One patient in the clonidine group presented with deep venous thrombosis, documented by lower limb ultrasound. DISCUSSION In this study, we found that the addition of 150 μg of clonidine to bupivacaine in preincisional field block for posterior approach spine surgery was associated with better postoperative pain control and morphine consumption sparing in patients who were followed for 8 d postoperatively. Among surgical subgroups, the microdiscectomy subgroup benefited the most from this combination and the cervical stenosis subgroup had some benefit that did not reach statistical significance. Patients with low back pain prior to surgery benefited less from this combination. Differential Action of Clonidine According to Surgical Subgroups In this study, all lumbar surgery subgroups in the clonidine group, unlike the cervical stenosis subgroup, showed significantly reduced AUC of pain postoperatively at the end of follow-up. Moreover, rescue morphine consumption was also reduced by clonidine addition in the lumbar fusion and lumbar stenosis subgroups, but not in the microdiscectomy subgroup, which may be due to the less invasive nature of microdiscectomy. In fact, patients in the microdiscectomy subgroup had shorter operating time, less wound extension, and thus, less muscle retraction and devascularization compared with other subgroups that underwent lumbar surgery. The cervical stenosis subgroup showed lower AUC and morphine consumption with the addition of clonidine, without reaching statistical significance. Preoperative spinal pain was neither more prevalent nor more intense in the cervical stenosis subgroup compared with the lumbar surgery subgroups, and thus, cannot explain this divergence in clonidine efficacy. From a statistical perspective, this observed difference could be explained by the low statistical power (12.7%) of the analysis for the cervical subgroup. One possible physiological explanation could be the fact that the cervical spine has denser nociceptive innervation, with participation of the trigeminal nucleus,17 than the lumbar spine, which makes the addition of clonidine less potent in the cervical subgroup. The added analgesic value of clonidine in field block with anesthetics has been previously reported in the literature with controversial results. Bollag et al18 found that adding clonidine to local postoperative bupivacaine in transversus abdominis plane block is ineffective in preventing pain in women, either 48 h or 12 mo following a cesarean section. However, the authors considered that the dosage of clonidine (75 μg/site) used in the study might have been insufficient to show an analgesic effect.18 Elliott et al12 found that the analgesia obtained by local bupivacaine in the first 24 h following elective inguinal hernia repair is not improved by addition of clonidine. Their follow-up period was short, and a difference might have been evident if they followed the patients for several days after surgery, as in our study. Bharti et al,13 on the other hand, found enhanced postoperative analgesia when clonidine was administered, either locally or systemically, with a bupivacaine infiltration in cholecystectomy patients. Such discrepancies in results among these studies may be explained mainly by low statistical power, which we encountered in this study's cervical stenosis group, stemming from the small number of patients evaluated. Another study by Mohamed et al14 used 0.5% bupivacaine in combination with 2 different dosages of clonidine (150 μg and 250 μg) in field block following mastectomy and found that the clonidine-bupivacaine combination is associated with significantly less neuropathic pain than placebo or bupivacaine alone. These results cannot be directly compared to ours because our study tested the analgesic effect of clonidine on postoperative nociceptive pain, whereas Mohamed et al's14 mastectomy study tested the effect of clonidine on long-term neuropathic pain. Possible Mechanisms of the Late Effect of Clonidine on Postoperative Pain Addition of clonidine to bupivacaine in a unique preincisional field block remarkably produced prolonged local pain control lasting from D0 to D8, a period far beyond the half-life of clonidine (estimated between 8 and 25 h)19,20 and far beyond the ability of clonidine to prolong the anesthetic action of bupivacaine (around 2 h) as in nerve blockade.21 This, therefore, excludes a direct synergy of clonidine with bupivacaine locally. To the best of our knowledge, this clinical study is the first to have prolonged follow-up and to show prolonged analgesic effect of local clonidine. Although the analgesic value of clonidine is better established for the first 24 h after surgery, it seems less clear for prolonged periods, mainly due to lack of studies with follow-ups over 24 h.22 Goyagi et al23 showed that adding systemic clonidine to epidural morphine remarkably improves analgesia between 24 and 48 h postoperatively in hysterectomy patients. Thus, these results raise the possibility of an intrinsic action of clonidine that promotes the durability of the analgesic effect Clonidine has the ability to activate α2 adrenoceptors with subsequent local vasoconstriction,23,24 hyperpolarization of A-δ and C fibers,25,26 and immunomodulation as activated macrophages and lymphocytes present α2 adrenoceptors on their surface.27 Local vasoconstriction and hyperpolarization of A-δ and C fibers are transient and last only during the period of the half-life of clonidine, and thus, cannot explain the prolonged effect of clonidine.25,26 Ischemia and partial denervation of paraspinal muscles during surgery are responsible for local secretion of inflammatory cytokines, leading to recruitment of circulating macrophages and additional secretion of cytokines.28 The adrenergic system participates in local immunomodulation, as activated macrophages and lymphocytes present α2 adrenoceptors on their surface.27 Because clonidine acts by activating these receptors, it can lead to a local anti-inflammatory action, which most probably mediates the observed prolonged analgesic effect, most likely similar to the anti-inflammatory kinetics of local steroid.29 In fact, experimental studies in rats have shown that local infiltration with clonidine decreases tumor necrosis factor α and interleukin-1β and increases transforming growth factor β1 after sciatic nerve ligation, resulting in prolonged analgesic effect for 28 d after 3 local infiltrations with clonidine.30 Preoperative Spinal Pain and the Role of Spinal Sensitization Spinal sensitization is a common feature of chronic pain syndromes, especially chronic back pain.31,32 Because local infiltration with clonidine has been found to exert an anti-inflammatory action, not only locally but also in the dorsal root ganglion after sciatic nerve ligation in rats,30 clonidine may thereby reduce new-onset spinal sensitization.33 In our study, clonidine exhibited an enhanced analgesic action in patients without preoperative back pain compared with those suffering from it. This suggests that clonidine acts more to prevent rather than alleviate spinal sensitization. Limitations Selection bias was limited by randomization of patients among groups, and observer bias was limited by the double-blind method. Potential confounding factors were recorded and included in the multiple regression analysis. Sample size was calculated for the whole series and not for subgroups. Thus, a bigger sample size may have been necessary in the cervical and lumbar stenosis subgroups in order to yield more robust and valid results, especially for the cervical stenosis subgroup. A third group using intravenous clonidine with local bupivacaine infiltration could have been added to better assess whether the effect of clonidine was local or systemic, as Bharti et al13 have shown equivalent postoperative analgesic action in cholecystectomy patients. However, the postoperative analgesic effect of systemic clonidine was inconsistent across different studies,34-36 with higher incidence of side effects.13 This suggests that local clonidine is at least as effective as systemic clonidine, but with fewer side effects. Another limitation of the study was the pain assessment on the day and first night of surgery, when the patient was still postoperatively under the effect of anesthetic drugs. During this period, pain assessment was prompted and under close supervision of a resident who followed up on the patient, making sure that the pain diary was filled correctly. CONCLUSION We have shown that adding 150 μg of clonidine to a preincisional field block with bupivacaine resulted in better and prolonged postoperative analgesia in posterior lumbar spine surgeries, an effect that was more pronounced in patients with no preoperative spinal pain. Disclosures The research council of the Saint Joseph University of Beirut (FM 217) funded this study. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Notes This research has been previously presented as follows: Title: Randomized double-blind study of the added analgesic value of clonidine in local pre-surgical infiltration of the wound with bupivacaine in posterior spine surgery. Meeting: World association of Lebanese Neurosurgeon Congress. Date: June 19 to 22, 2013. Location: Beirut, Lebanon. Presentation type: plenary Title: Randomized double-blind study of bupivacaine wound pre-surgical infiltration with versus without clonidine in posterior spine surgery. Meeting: 8th congress of the European federation of IASP chapters. Date: October 9 to 12, 2013. Location: Florence, Italy. Presentation type: poster Title: (French) “Efficacité antalgique d’une infiltration locale pré-incisionnelle de bupivacaïne sans et avec clonidine dans la chirurgie rachidienne postérieure. Essai prospectif randomisé en double insu.” Meeting: Annual meeting of the French society of neurosurgery. Date: November 24 to 27, 2013. Location: Paris, France. Presentation type: plenary Title: Randomized double-blind trial comparing the post-operative analgesic added value of local wound infiltration with clonidine in posterior spine surgery. Meeting: 21st annual meeting of the Lebanese Association for the advance of science. Date: April 15 to 17, 2015. Location: Beirut, Lebanon. Presentation type: poster REFERENCES 1. Kehlet H , Dahl JB . Anaesthesia, surgery, and challenges in postoperative recovery . Lancet . 2003 ; 362 ( 9399 ): 1921 - 1928 . Google Scholar CrossRef Search ADS PubMed 2. Sharma S , Balireddy RK , Vorenkamp KE , Durieux ME . 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Google Scholar CrossRef Search ADS PubMed Supplemental digital content is available for this article at www.neurosurgery-online.com. Copyright © 2017 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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NeurosurgeryOxford University Press

Published: Jul 21, 2017

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