Perioperative Oral Melatonin, Pregabalin and their Combination for Management of Lower Limb Phantom Pain after Spinal Anesthesia

Transcription

1 Med. J. Cairo Univ., Vol. 82, No. 1, December: , Perioerative Oral Melatonin, Pregabalin and their Combination for Management of Lower Limb Phantom Pain after Sinal Anesthesia HOSAM M. ATEF, M.D. The Deartment of Anesthesia & ICU, Suez Canal University, Ismailia, Egyt Abstract Background: Persistent ain after amutation is an imortant Clinical roblem with no reliably effective treatment. The aim of our study is to imrove management of hantom limb ain in atients having lower limb amutations by comaring the effect of eri-oeratively oral regabalin, melatonin or their combination versus a control grou regarding the incidence and severity of hantom limb ain. Methods: This study was a randomized double-blind controlled Clinical trial on 84 ASA Physical status I, II, and III atients undergone above or below knee amutation under sinal anesthesia were done at the Suez Canal University Hosital in the emergency oerative theatres, inward and the outatient ain clinic. Patients were randomly assigned into one of four equal grous: Grou C: Received an oral lacebo; Grou P: Received oral regabalin casules (15mg every 12 hours); Grou M: Received oral melatonin tablets 9mg every 12 hours); Grou PM: Received both oral regabalin casules (75mg every 12 hours) lus oral melatonin tablets (6mg every 12 hours). All medications were given at 5, 38, 26, 14 and 2 hours reoeratively and 1, 22, 34 and 46 hours ostoeratively. All atients were interviewed using several questionnaires at six endoints. These questionnaires were Short-Form McGill Pain Questionnaire; Neuroathic Pain Diagnostic Questionnaire; Daily Slee Interference Scale; and Patients Global Imression of Change. Incidence, intensity (mild, moderate, severe) and frequency (daily, weekly, monthly) of PLP was recorded during the 3-month follow-u eriod. Postoerative morhine consumtion was also recorded. Endoint 1: Before starting medication (48-hour reoeratively). Endoint 2: Before induction of Anesthesia (Sinal anesthesia). Endoint 3: After the last dose of ostoerative medication (48-hr ostoeratively). Endoint 4: At 4-week endoint (4 weeks ostoeratively). Endoint 5: At 8-week endoint (8 weeks ostoeratively). Endoint 6: At 12-week endoint (12 weeks ostoeratively). Corresondence to: Dr. Hosam M. Atef hosamatef375@yahoo.com Results: Melatonin, regabalin or their combination versus a lacebo drug, showed that combination grou followed by melatonin treatment achieved the best control of ain and neuroathy as well as least slee interference with no incidence of hantom limb ain. This was evident reoeratively by lower VAS values just rior to Surgery, and ost-oeratively by lower morhine consumtion; however, atients had the highest incidence of medication-related adverse effects. The melatonin grou showed lower incidence of slee interference with better control of neuroathic symtoms following amutations comared to the control and regabalin grous in reoerative eriods. Conclusion: Perioerative oral melatonin or regabalin or their combination could be a roer additive to erioerative theray for hantom limb after sinal Anesthesia. A larger multicenter study is required. Key Words: Perioerative oral melatonin Pregabalin Lower limb Phantom ain Sinal anesthesia. Introduction PREVALENCE of hantom ain generally varies between 5 and 8%, with severe ain being reorted in aroximately 5% of atients [1]. Both PLP (hantom limb ain) and (residual limb ain) RLP are common sequelae of limb amutation and usually have a considerable imact on atients quality of life [2]. Persistent ain after amutation is an imortant Clinical roblem with no reliably effective treatment [3]. Treatment of hantom ain has been attemted at all levels of ain transmission and ercetion: Periheral, sinal, and central. Several Theraeutic interventions have been evaluated for PLP revention and/or treatment, [4] including anticonvulsants, tricyclic antideressant, [5] and N-methyl-d-asartate-antagonistic drugs, [6] calcitonin, [7] intravenous [8] or eidural [9] ketamine administration, ostoerative erineural buivacaine/clonidine infusion, [1] and oral gabaentin, [11] but their effectiveness remains unclear. However, secific treatment guidelines are yet to evolve and most successful measures emloy multidiscilinary aroaches in the management of 781

2 782 Perioerative Oral Melatonin, Pregabalin & their Combination ain and in rehabilitation [12]. Preemtive use of analgesics and anesthetics during the reoerative eriod is believed to revent the noxious stimulus from the amutated site from triggering hyerlastic changes and central neural sensitization which may revent the amlification of future imulses from the amutation site [13]. However, the results of the studies in this area have not been definitive [14]. Several changes that occur in the nocicetion athway ost amutation. With this knowledge, novel theraies were found that could decrease Phantom Limb Pain. One such drug is regabalin which affects unique stes in the nocicetion athway [15]. Melatonin ossesses sedative, hynotic, analgesic, antiinflammatory, antioxidative, and chronobiotic roerties that distinguish it as an attractive alternative remedicant [16]. Melatonin has been tried during Surgical oerating conditions and has been shown to enhance both reoerative and ostoerative analgesia [17,18]. Exogenous melatonin has been used effectively in the management of ain in Medical conditions such as fibromyalgia, irritable bowel syndrome and migraine and cluster headache [19-23]. based on Internet research no randomized control Clinical trial using melatonin involving the reemtive technique was used in the management of hantom limb ain. Primary objectives: Comare the effect of regabalin, melatonin and their combination versus a control grou regarding the incidence and severity of hantom limb ain (PLP) following lower limb amutations. Secondary objectives: To comare grous regarding Present Pain intensity (PPI) and Visual Analogue Scale (VAS) using Short-Form McGill Pain Questionnaire (SF-MPQ) [24] scores; resence of neuroathy using DN4 Neuroathic Pain Diagnostic Questionnaire scores; [25] slee interference using Daily Slee Interference Scale (DSIS) [26] ; and change in the atient s overall status using Patients Global Imression of Change (PGIC) [27] [Baseline, before induction of anesthesia, and on day 2 and at 4, 8 and 12-week endoints]. Patients and Methods After obtaining aroval by the Ethics Committee of the Suez Canal University Hosital, from and written informed atient consent from 84 ASA Physical status I, II, and III atients undergone above or below knee amutation under sinal anesthesia were included. Samle size was calculated at the significance level of.5 and ower of 8%. The roortion of resonder rate (5% reduction in mean ain score from baseline to end oint), which was 72.6% with melatonin [16]. The roortion of resonder rate (5% reduction in mean ain score from baseline to end oint), which was 28% with the regabalin (3mg/day) [28]. Exected dro out of 1% was added. 21 atients for each grou were randomly assigned into one of four equal grous. Grou C: (21 atients) received oral control 5, 38, 26, 14 and 2 hours reoeratively and 1, 22, 34 and 46 hours ostoeratively. Grou P: (21 atients) received oral regabalin casules (15mg every 12 hours) 5, 38, 26, 14 and 2 hours reoeratively and 1, 22, 34 and 46 hours ostoeratively. Grou M: (21 atients) received oral melatonin tablets (9mg every 12 hours) 5, 38, 26, 14 and 2 hours reoeratively and 1, 22, 34 and 46 hours ostoeratively. Grou PM: (21 atients) received both oral regabalin casules (75mg every 12 hours) and oral melatonin tablets (6mg every 12 hours) 5, 38, 26, 14 and 2 hours reoeratively and 1, 22, 34 and 46 hours ostoeratively. This study was a randomized double-blind controlled Clinical trial had been done at Suez Canal University Hosital in the emergency oerative theatres, inward and outatient ain Clinic, Adults more than 21 years of age of both genders, ASA. I, II and ASA III and Body Mass Index (BMI) >_2 and <_3kg/m 2. Patients with any of the following criteria were excluded from the study: Patients under general anesthesia due to failure of sinal block, Schizohrenia or other sychotic disorder (a revious diagnosis of any sychiatric disorder listed in Diagnostic and Statistical Manual of Mental Disorders IV[), history of untreated nonsychotic emotional disorders or cognitive imairment which can imair or interfere with erioerative and follow-u rocedures, History of drug deendency or substance addiction, A known sensitivity to morhine, regabalin, Earlier amutation of the same limb excet toes or atients who underwent further amutations during the followu eriod and History of drugs abuse. Drugs were reared by a harmacist in a way that allows for administration of identical drug forms (casule + tablet) for each of the four study grous. All study medications were identical in aearance. Each atient, assigned to articiate in the study, had a numbered sealed enveloe containing a randomization code. Allocation of codes to either grou was develoed using comuter

3 Hosam M. Atef 783 generated seudo-random numbers. The enveloes were concealed until after consent is obtained. During the study, the investigator, involved in drug administration and assessments, was blinded to atient allocation until all subjects comlete their 3-months assessment. Patient-reorted outcome measures: All atients were interviewed using three questionnaires; before starting medication (Time 1), immediately before induction of anesthesia (Time 2), at 48-hours ostoeratively (Time 3), and during the follow-u visits or via hone contact at 4- weeks (Time 4), 8-weeks (Time 5) and 12-weeks (Time 6) endoints. This was Short-Form McGill Pain Questionnaire (SF-MPQ); [24] and DN4 Neuroathic Pain Diagnostic Questionnaire [25] ; and change in the atient s overall status using Patients Global Imression of Change (PGIC) [27]. Assessment of ain severity was done by measuring ain intensity (mean visual analogue scale (VAS) during the ast eriod since the last interview, PPI, DSIS and resence of neuroathy) and hantom ain frequency (constant, hourly, daily, weekly, or monthly). Preoerative VAS and hantom limb ain VAS (PLP-VAS) was categorized into mild (1-3), moderate (4-6) and severe (7-1) ain [29]. The Daily Slee Interference Scale (DSIS) was used to quantify slee interference due to ain. The DSIS is a single-item measure that is comleted by atients once a day (uon awakening) to accurately cature variability in slee interference due to ain daily, thus minimizing recall bias. As no cut-oints were ublished for the slee interference score, grous similar to those used for the ain score were defined: No or mild slee interference was through 3.; moderate slee interference was 3.1 through 6.; and the severe slee categories was defined as those with a score of 6.1 through 1.. Safety assessment included incidence of adverse events e.g. Nausea, vomiting, ruritus, dizziness and somnolence. Rescue anti-emetics (1mg metocloromide) were offered to atients who comlain of nausea or vomiting. Incidence, intensity (mild, moderate, severe) and frequency (daily, weekly, monthly) of PLP was recorded during the 3-month follow-u eriod. Patients who develoed residual (stum) limb ain during the follow-u eriod continued articiation in the study for the remaining follow-u eriod. Table (1): Endoints for assessment of outcome measures. Time 1 Time 2 Before starting the study medication (48-hour reoeratively). Before induction of Anesthesia (Sinal anesthesia). Time 3 After the last dose of ostoerative medication (48- hr ostoeratively). Time 4 Time 5 Time 6 At 4-week endoint (4 weeks ostoeratively). At 8-week endoint (8 weeks ostoeratively). At 12-week endoint (12 weeks ostoeratively). Clinician-reorted outcome measures: Intravenous Patient-Controlled morhine Analgesia (iv-pca) was commenced on admission to the PACU in all grous. The PCA solution contained morhine.5mg/ml and the um device was rogrammed to deliver 1mg of morhine as a demand dose (bolus) with a 1min lockout time, a maximum dose of 5mg/h and no basal rate infusion. Rescue analgesic (1mg of iv-morhine) was offered to atients who comlain of ain desite a revious regimen. Total ostoerative morhine consumtion was recorded. The statistical analysis erformed using a Statistical Package for the Social Sciences SPSS version 15 (SPSS Inc., Chicago, IL, USA) for Windows 8 oerating systems. Descritive data were exressed as mean and SD for continuous variables, and count/total and ercentages (%) for categorical and dichotomous variables. One-way analysis of variance (ANOVA) was used to analyze the arametric data between grous (i.e., Age, length of surgery, ain score and daily slee interference score (DSIS) before randomization and total morhine consumtion), whereas a Kruskal- Wallis test was used to assess differences between grous for non-normally distributed (non arametric) variables (ain scores and DSIS). Statistically significant differences between the studied grous were further assessed using Fisher s least significant difference (LSD) ost hoc analysis. The level of statistical significance will be considered to be <.5. Results Twenty one subjects were allocated into one of four grous; One atient died within the 1 st followu month (Grou P) and was excluded from further analysis while five subjects subsequently had a below knee amutation revised to an above knee (after comletion of the 3 rd follow-u month). In the resent study, there were no significant differences between grous with resect to age, weight,

4 784 Perioerative Oral Melatonin, Pregabalin & their Combination height, gender distribution, BMI, ASA classes and tye of surgery (AKA/BKA ratio) (Table 2). The causes leading to amutation varied between infected diabetic foot, ischemia and trauma with no significant differences between grous. The incidence of hantom limb ain was statistically significantly different between the four studied grous only during the first month (-value.29), with the highest incidence in the control grou, and the lowest rate was among the combination grou. In addition, both regabalin and melatonin grous demonstrated a nearly similar incidence of hantom limb ain (Table 3). Table (4) showed non-significant differences demonstrated between the four grous regarding hantom limb ain intensity. On the other hand, hantom limb ain frequency showed a statistically significant difference between the four studied grous only during the first month, with the most frequent hantom limb ain in the control grou (-value.3). The incidence of residual limb ain was not statistically significant differences between all grous. Total 48-hours morhine consumtion was significantly different between the four studied grous with the lowest value in the combination grou (less than 1mg) and the highest value in the control grou comared to other grous (Table 6). Post hoc analysis showed that total morhine consumtion was significantly lower in the melatonin grou comared to the regabalin grou (.5). VAS of all grous became significantly lower at the end of the study eriod, comared to their baseline level. In addition, this table demonstrated that there were statistically significant differences between the four studied grous in the VAS in the reoerative eriod and at one month after amutation with the least ain values in the melatonin grou in both time endoints. Post hoc analysis showed a significantly higher VAS in the control grou comared to other grous in these endoints. However, the VAS was significantly lower during the reoerative eriod in the melatonin grou comared to the Pregabalin grou. In addition, VAS at one month after the amutation was significantly lower in the combination grou comared to the Pregabalin grou. Otherwise, the differences did not reach significant levels (Table 7). Although matched at baseline readings (insignificant difference); PPI was significantly different between the four studied grous reoeratively; 48-hours ostoeratively; at one and two months after amutation. However, there was no significant difference after three months. Melatonin grou showed the highest incidence of No Pain reoeratively and 48-hours ostoeratively (76.2% and 9.5%, resectively) comared to control grou which showed the highest incidence of Distressing & Horrible Pain (38.1% & 19% resectively) reoeratively (Table 8). Combination grou showed the highest incidence of No Pain after one and two months interval (61.9% and 85.7% resectively) comared to control grou which showed the highest incidence of Distressing & Horrible Pain. Neuroathy between the four grous reoeratively and 48-hour ostoeratively were statistically significant differences (.5), with the highest incidence of neuroathy among atients in the control grou comared to other grous and the lowest among regabalin grou comared to the melatonin grou. In addition, neuroathy was less frequent in the combination grou comared to other grous at those time intervals. Neuroathic ain had decreased from the baseline till after three months after amutation in all grous, but reached significant levels only in the regabalin and melatonin grous. There is an insignificant difference in follow-u of neuroathy among atients in the control grou (Table 9). The DSIS decreased significantly along the different time endoints within each grou comared with the baseline (Table 1). This table also showed that although being matched with the baseline data, there were highly statistically significant differences in daily slee interference scale between the four grou s at all follow-u endoints with lower values in the three intervention grous (lowest values in melatonin grou) comared to control grou. However, differences within the intervention grous themselves were insignificant at all follow-u endoints as shown by Post-hoc analysis. The atients global imression of change between the four grous reoeratively was high statistically significant different, 48-hr ostoeratively, and at one month after amutation. More atients reorted global imrovement at one month endoint in the melatonin and combination grous comared to control and regabalin grous. However, more regabalin-treated atients than control and other intervention grous, reorted that they were better or a great deal better immediately

5 Hosam M. Atef 785 reoeratively and 48-hr ostoeratively. All atients in the control and combination grou reorted No change or little better immediately reoeratively and 48-hr ostoeratively (Table 11). Increasing ain severity is associated with high incidence of hantom ain highly statistically significant at the first and second months (Table 12). Table (2): Characteristics of atients. Control Grou Pregabalin Grou Melatonin Grou Grou value Gender (M/F) Age (years) a 13/8 5.48± ± / ± ±2.77 7/ ± ± / ± ±2.76 BMIa ASA (I/II/III) 2/13/6 /14/7 /16/5 /16/5.327 Cause for surgery (DM/PVD/trauma) 14/5/2 12/9/ 12/9/ 16/5/.168 Tye of surgery (AKA/BKA) 7/14 9/12 9/12 6/15.71 Duration of surgery (minutes) a 211.9± ± ± ± Grou C : (control grou). a : Data are resented as mean ±SD. Grou : (regabalin grou). AKA : Above knee amutation. Grou M : (Melatonin grou). BKA : Below knee amutation. Grou PM : (regabalin & Melatonin grou) Table (3): Incidence of hantom limb ain (PLP). Control Grou Pregabalin Grou Melatonin Grou Grou value Incidence At 1 month At 2 months At 3 months 7/21 (33.3%) 3/21 (14.3%) 3/21 (14.3%) 1/2 (5%) 3/21 (14.3%).29* * : Statistically significant difference (-value<.5). Table (4): Severity of hantom limb ain (PLP-VAS). Control Grou Pregabalin Grou Melatonin Grou Grou value Intensity (VAS) At 1 month: At 2 months: Mild Moderate Severe Mild Moderate Severe.415 1/2 (4.8%).687 At 3 months: Mild Moderate Severe.293 Frequency At 1 month: At 2 months: Daily Weekly Monthly Daily Weekly Monthly.3* 3/21 (14.3%).257 1/2 (4.8%) At 3 months: Monthly.293 * : Statistically significant difference (-value <.5).

6 786 Perioerative Oral Melatonin, Pregabalin & their Combination Table (5): Incidence of residual limb ain (RLP). Control Grou Pregabalin Grou Melatonin Grou Grou value Incidence At 1 month 8/21 (38.1%) 6/21 (28.6%) 6/21 (28.6%) 3/21(14.3%).383 At 2 months 2/2 (1%) 2/21(9.5%).729 At 3 months 1/2 (5%) 1. Table (6): Total 48 hours ostoerative morhine consumtion. Control Grou Pregabalin Grou Melatonin Grou Grou Total morhine consumtion (mg) a 23.29± ± ± ±.97.** 1.** 2.5 * 3.** a * ** : Data are resented as mean ±SD. : Statistically significant difference (-value <.5). : High statistically significant difference ( -value <.5). : -value for F test (ANOVA) for comaring between the four studied grous. : -value for ANOVA on Ranks with LSD ost-hoc analysis for comaring between the Control (C) and each of other grous. : -value for ANOVA on Ranks with LSD ost-hoc analysis for comaring between the Pregabalin (P) and Melatonin (T) grous. : -value for ANOVA on Ranks with LSD ost-hoc analysis of the Combination (PM) grou comared to either Pregabalin (P) or Melatonin grous. Table (7): Mean visual analogue scale (VAS) at different time endoints. Control Grou Pregabalin Grou Melatonin Grou Grou VAS baseline a VAS reoerativelya VAS 48-hr ostoeratively a VAS at 1 month a VAS at 2 months a VAS at 3 months a 4.81 ± ± ± ± ± ± ± ± ± ± ±.79.56±.6 5.± ± ± ± ±1.8.67± ± ± ± ± ± ± **.79.** **.**.**.** Preoeratively: 1 4.** ** 3.59 At 1 month: 1 4.** * VAS a * ** : Visual Analogue Scale. : Data are resented as mean ±SD. : Statistically significant difference ( -value <.5). : High statistically significant difference (-value <.5). : -value for F test (ANOVA) for comaring between the four studied grous. : -value for F test (ANOVA) for the time course within each grou comared to the baseline values. : -value for ANOVA on Ranks with LSD ost-hoc analysis for comaring between the Control (C) and each of other grous. : -value for ANOVA on Ranks with LSD ost-hoc analysis for comaring between the Pregabalin (P) and Melatonin (M) grous. : -value for ANOVA on Ranks with LSD ost-hoc analysis for comaring between the Pregabalin (P) and Combination (PM) grous. : -value for ANOVA on Ranks with LSD ost-hoc analysis for comaring between the Melatonin (M) and Combination (PM) grous.

7 Hosam M. Atef 787 Table (8): Present ain intensity (PPI) at different time endoints. Control Grou Pregabalin Grou Melatonin Grou Grou PPI baseline PPI re-oeratively PPI 48-hr ostoerative PPI at 1 month PPI at 2 months No ain /21 / Mild ain 3/21 (14.3%) 5/21 (23.8%) Discomforting 6/21 (28.6%) 6/21 (28.6%) 6/21 (28.6%) 6/21 (28.6%) Distressing 9/21 (42.9%) 6/21 (28.6%) 6/21 (28.6%) 6/21 (28.6%) Horrible 3/21 (14.3%) No ain /21 3/21 (14.3%) 16/21 (76.2%) 6/21 (28.6%).** Mild ain 3/21 (14.3%) 9/21 (42.9%) 12/21 (57.1%) Discomforting 6/21 (28.6%) 5/21 (23.8%) 3/21 (14.3%) Distressing 8/21 (38.1%) 3/21 (14.3%) Horrible No ain 7/21 (33.3%) 14/21 (66.7%) 19/21 (9.5%) 14/21 (66.7%).5 * Mild ain 1/21 (47.6%) 5/21 (23.8%) 2/21(9.5%) 7/21 (33.3%) Discomforting No ain 7/21 (33.3%) 9/21 (42.9%) 13/21 (61.9%).** Mild ain 9/21 (42.9%) 14/21(66.7%) 7/21 (33.3%) Discomforting 3/21 (14.3%) 6/21(28.6%) Distressing 6/21 (28.6%) Horrible No ain 11/21 (51.4%) 13/2 (65%) 7/21 (33.3%) 18/21 (85.7%).2** Mild ain 5/21 (23.8%) 7/2 (35%) 12/21 (57.1%) Discomforting 3/21 (14.3%) Distressing 3/21 (14.3%) PPI at 3 months No ain 11/21 (52.4%) 19/2 (95%) 16/21 (76.2%) 18/21 (85.7%).55 Mild ain 5/21 (23.8%) 1/2 (5%) 3/21 (14.3%) Discomforting Distressing ** : Highly statistically significant difference (-value <.5). * : Statistically significant difference (-value <.5). PPI : Present ain intensity. Table (9): Incidence of neuroathy at different time endoints among grous. Control Grou Pregabalin Grou Melatonin Grou Grou Neuroathy baseline 9/21 (42.9%) 11/21 (52.4%) 7/21 (33.3%) 7/21 (33.3%).537 Neuroathy reoeratively 9/21 (42.9%) 7/21 (33.3%).7* Neuroathy 48-hr ostoeratively 7/21 (33.3%).4** Neuroathy at 1 month 7/21 (46.7%) 3/21 (14.3%) 3/21 (14.3%).188 Neuroathy at 2 month 3/21 (14.3%) 3/2 (14.3%).915 Neuroathy at 3 month 1/2 (4.8%) 1/2 (4.8%).881 * ** **.4*.75 1.** 2.5** 3.** : Statistically significant difference ( -value <.5). : High statistically significant difference (-value <.5). : -value for F test (ANOVA) for comaring between the four studied grous. : -value for F test (ANOVA) for the time course within each grou comared to the baseline values. : -value for ANOVA on Ranks with LSD ost-hoc analysis for comaring between the Control (C) and each of other grous. : -value for ANOVA on Ranks with LSD ost-hoc analysis for comaring between the Pregabalin (P) and Melatonin (M) grous. : -value for ANOVA on Ranks with LSD ost-hoc analysis for comaring between the Pregabalin (P) and Combination (PM) grous comared to either Pregabalin (P) or Melatonin grous.

8 788 Perioerative Oral Melatonin, Pregabalin & their Combination Table (1): Daily slee interference scale (DSIS) at different time endoints. Control Grou Pregabalin Grou Melatonin Grou Grou DSIS baseline a DSIS reoeratively a DSIS 48-hr ostoeratively a DSIS at 1 month a DSIS at 2 months a DSIS at 3 months a 3.33 ± ± ± ± ± ± ± ± ±.8.29±.78.1±.31.±. 2.57± ±.73.14±.36.38±.97.1±.3.14± ±3.1.95± ±.4.24±.77.29±.9.14± **.**.**.**.**.**.**.**.** Preoeratively: 1.** hr ostoeratively: 1.** At 1 month: 1.1 ** At 2 months: 1.** At 3 months: 1.** DSIS : Daily slee interference scale. a : Data are resented as mean ±SD. * : Statistically significant difference (-value <.5). ** : High statistically significant difference ( -value <.5). : -value for F test (ANOVA) for comaring between the four studied grous. : -value for F test (ANOVA) for the time course within each grou comared to the baseline values. : -value for ANOVA on Ranks with LSD ost-hoc analysis for comaring between the Control (C) and each of other grous. 1 : -value for ANOVA on Ranks with LSD ost-hoc analysis for comaring between the Pregabalin (P) and Melatonin (M) grous. 2 : -value for ANOVA on Ranks with LSD ost-hoc analysis for comaring between the Pregabalin (P) and Combination (PM) grous 3 comared to either Pregabalin (P) or Melatonin grous. Table (11): Patients global imression of change (PGIC) at different time endoints. Control Grou Pregabalin Grou Melatonin Grou Grou -value PGIC scale reoeratively No change Almost same Little better Somewhat better Moderately better Better A great deal better 7/21 (33.3%) 11/21 (52.4%) 3/21 (14.3%) 5/21 (23.8%) 5/21 (23.8%) 3/21 (14.3%) 7/21 (33.3%) 5/21 (23.8%) 13/21 (61.9%) 3/21 (14.3%).** PGIC scale 48-hr ostoeratively No change Almost same Little better Somewhat better Moderately better Better A great deal better 14/21 (66.7%) 3/21 (14.3%) 7/21 (33.3%) 7/21 (33.3%) 3/21 (14.3%) 11/21 (52.4%) 3/21 (14.3%) 6/21 (28.6%) 3/21 (14.3%) 6/21 (28.6%) 6/21 (28.6%).** PGIC scale at 1 month No change Almost same Little better Somewhat better Moderately better Better 9/21 (42.9%) 11/21 (52.4%) 7/21 (33.3%) 8/21 (38.1%) 6/21 (28.6%) 6/21 (28.6%) 7/21 (33.3%) 1/21 (47.6%) 3/21 (14.3%) 3/21 (14.3%) 3/21 (14.3%).** ** : Highly statistically significant difference (-value <.5). PGIC : Patients global imression of change.

9 Hosam M. Atef 789 Table (12): Incidence of adverse effects. Control Grou Pregabalin Grou Melatonin Grou Pregabalin & Melatonin Grou -value Somnolence 16/21(76.2%) 5/21 (23.8%) 14/21 (66.7%).** Dizziness 12/21 (57.1%) 5/21 (23.8%) 18/21 (85.7%).** Dry mouth 13/21 (61.9%) 14/21 (66.7%).** Hand/ feet edema 3/21 (14.3%) 3/21 (14.3%).91 Blurring of vision 3/21 (14.3%).98 Nausea 7/21 (33.3%) 6/21 (28.6%) 2/21 (9.6%) 5/21 (23.8%).299 Vomiting 3/21 (14.8%) 3/21 (14.8%) 1/21 (4.9%) 2/21 (9.6%).713 Constiation 2/21 (9.6%) 4/21 (19.2%) 5/21 (23.8%).14 Headache 2/21 (9.6%) 3/21 (14.3%).125 * : Statistically significant difference (-value <.5). ** : Highly statistically significant difference (-value <.5). Table (13): Relation between reoerative VAS and incidence of hantom limb ain. Preoerative VAS No ain Mild ain Moderate ain Severe ain -value Incidence of PLP: At 1 month /12 1/46 (2.2%) 8/2 (4%) 4/6 (66.7%).** At 2 months /12 /45 5/2 (25%) 1/6 (16.7%).2** At 3 months /12 /45 2/2 (1%) 1/6 (16.7%).6 ** : Highly statistically significant difference (-value <.5). Discussion Not all amutees exerience ersistent ain, and the reasons for this are unclear. One of the risk factors that seems to be associated with a higher revalence of ersistent ain is severe and oorly controlled ain before surgery [3]. The Guideline Develoment Grou (GDG) acknowledged that there were few studies involving comarative trials and combination theray trials, and that most of the resulting evidence was of low or very low quality [31]. The resent study included 84 atients underwent lower limb amutation over the 18-month eriod. In this study, the incidence of hantom limb ain was found to be statistically significantly different between the studied grous only during the first month, with the highest incidence in the control grou, and the lowest rate was among the combination grou. In addition, both regabalin and melatonin grous demonstrated a nearly similar incidence of hantom limb ain while the PLP frequency was significantly lower only during the first month after amutation in the intervention grous comared to the control grou. Since there are no revious studies comaring either melatonin, regabalin or their combination in these grous, efforts were tried to include relatively comarable trials. Karanikolas et al., [32] showed similar results with lower PLP VAS, PLP frequency and revalence in the intervention grous, including otimized eidural analgesia or intravenous PCA, starting 48h reoeratively and continuing for 48h ostoeratively, then the control grou at six months follow-u being the lowest in those who received erioerative eidural analgesia and eidural anesthesia. Prolonged ostoerative erineural or intraneural infusion of roivacaine.5% after lower extremity amutation, effectively reduced PLP incidence and PLP VAS (only 3% with severe tointolerable PLP) at the end of the 12-month evaluation eriod [33,34]. Jahangiri et al., [34] and Bach et al., [36] also showed that erioerative eidural infusion of diamorhine, clonidine and buivacaine (started one to three days reoeratively and continued at least three days ostoeratively) reduced incidence of hantom ain after amutation at 7-day, 6-month and 1-year follow-u. On the contrary, PLP rates and intensity didn t differ at any of the assessments through a whole year between eidural buivacaine/ketamine grou and buivacaine/saline grou [9]. This can be exlained by the fact that both grous started the

10 79 Perioerative Oral Melatonin, Pregabalin & their Combination eidural infusion just before Surgery and continued for 48 to 72 hours ostoeratively and no remedication was given. One should be cautious in data interretation Since even without treatment, the natural course of PLP may result in a decrease in intensity and frequency as short as six months ost amutation [37]. Reuben et al., [38] also showed that there were no differences in the incidence of hantom limb ain in the erineural clonidine infiltration (injected 5 minutes before nerve transaction) grou comared to the control (erineural saline infiltration) grou. Another study also showed that erioerative eidural block (buivacaine and morhine) had no effect on incidence or intensity of hantom ain, mechanical and thermal sensibility or rate of allodynia and wind-u-like ain at any of the ostoerative assessments (one week and 6 and 12 months) in comarison to the control grou (intramuscular or oral morhine) [39,4]. All of these reorts can also be exlained by the lack of roer reoerative analgesia. In consistence with the resent study that showed that incidence of residual (stum) limb ain didn t differ among the studied grous at any ostoerative assessment, several studies also demonstrated that it did not differ after any or various interventions from the control grou [9,32,35]. A main finding in the resent study was the suerior efficacy of the two-drug combinations in reduction of ostoerative morhine consumtion. The 48-hours ostoerative morhine consumtion was significantly different between the four studied grous with the lowest values in the combination grou (less than 1mg) and the highest value in the control grou comared to other grous. Moreover, the total morhine consumtion was significantly lower in the melatonin grou comared to the Pregabalin grou. Melatonin reoeratively resented a greater reduction in ain and required lower morhine consumtion in the ostoerative eriod. The benefits of these interventions were statistically and clinically significant. Melatonin roduced ostoerative anxiolysis, which led to lower ostoerative ain, as well as lower morhine consumtion throughout the first 24-hours after Surgery. Antinocicetive actions of melatonin have been well demonstrated in various studies. Melatonin interacts with multile recetor sites including oioidergic, benzodiazeinergic, muscarinic, nicotinic, serotonergic, α 1 -adrenergic, a2-adrenergic, and most imortantly MT 1 /MT2 melatonergic recetors resent in the dorsal horn of the sinal cord as well in the central nervous system [16,4]. Misanalysis done by yousaf et al., nine of the 1 studies showed statistically significant reduction of reoerative anxiety with melatonin remedication comared with lacebo. An oioid-saring effect or reduced ain scores were evident in five studies whereas three studies were contradictory [16]. The overall effect of melatonin on neuroathic ain, the tye of melatonin recetor involved, and the otential role of the oioid system and GABAA recetors were studied; Melatonin influences the mechanical allodynia but not thermal hyeralgesia via activation of oioid system and benzodiazeine- GABAergic athway [42]. Treatment of fibromyalgia atients with melatonin had been carried out in four studies. Treatment with melatonin alone caused significant imrovements in ain, fatigue, slee/rest activity, deression and morning stiffness. Melatonin was administered in doses of 3-5mg orally for four weeks 3 minutes before bed time [2]. Another Clinical condition in which melatonin has been found useful is irritable bowel syndrome (IBS). There are two randomized lacebo-controlled Clinical trials administering 3mg/day of oral melatonin for six to eight weeks a reduction in ain symtoms with imrovements in the IBS was noted in all atients [21]. The effects of melatonin on ain (rimary aim) and slee (secondary aim) as comared with lacebo in a double-blind, randomized arallel-grou trial. This study rovided additional evidence suorting the analgesic effects of melatonin on ain scores and analgesic consumtion in atients with mild-to-moderate chronic myofascial TMD ain. Furthermore, melatonin imroves slee quality but its effect on ain aears to be indeendent of changes in slee quality [42]. In agreement with the strategy of resent study, Grant and Wood [34], Fisher and Meller [43] showed that ostoerative intra-neural local anesthetic infusion following major lower limb amutations reduced ostoerative oioid analgesic requirement in a retrosective study [34]. On the contrary, the number of analgesics rescribed ostoeratively was insignificantly different between eidural buivacaine/ketamine grou and buivacaine/saline grou [9]. Consistently, oioid analgesic requirements showed no significant difference in continuous regional analgesia by intraneural block from the control grou [44].

11 Hosam M. Atef 791 In our study, there was significant differences between-grou in the reoerative VAS with excellent analgesic management in the combination grou which subsequently led to significant reduction between-grou differences in the VAS at one month assessment after amutation. Postoerative VAS did not differ between the 4 grous as all atients were on iv-pca morhine for ostoerative analgesia. Therefore, efficacy of ostoerative analgesia was reflected via ostoerative 48-hs morhine consumtion (mg). On the other hand, there was a significant reduction from baseline values in all four grous at all time oints ostoeratively. Wilson et al., [9] showed that total McGill ain questionnaire (MPQ) scores were highest before surgery, and then fell down at 12-months. Scores in both grous were significantly less than reoerative values by six weeks (<.1), although contrary to our study, both grous did not differ from each other at any time oint. In our study, records of PPI showed significant differences between the four grous at all ostoerative assessments (excet at 3 months) with being the lowest values in the combination grou. Karanikolas et al., [32] showed that MPQ variables (ain rating index PRIR, resent ain intensity PPI and number of words chosen NWC) were only significantly lower in the grou who received erioerative eidural analgesia and eidural anesthesia at one and six months for PRIR and NWC although they showed no significant between-grou differences at any time oint for PPI. The resent study showed that there were statistically significant differences in the resence of neuroathy between the four grous reoeratively and 48-hr ostoeratively, with lower incidence of neuroathy among atients in the intervention grous comared to control grou and the lowest among regabalin grou comared to the melatonin grou. In addition, neuroathy showed the lowest frequency in the combination grou comared to other grous at those time intervals. Neuroathic ain had decreased from the baseline till after three months after amutation in all grous, but reached significant levels only in the regabalin and melatonin grous. There is insignificant difference in neuroathy between different follow-u endoints among atients in the control grou. Better control of neuroathic ain was observed with regabalin and melatonin treated atients. Pregabalin is structurally related to GABA but is thought not to elicit its effects through the GABA recetor comlex [45]. While its antinocicetive mechanism of action is unknown, it has been roosed to demonstrate these effects by binding to the alha-2-delta subunit of the N-tye voltagedeendent calcium channels in the axon terminus, where it suresses hyerexcitabilty by blocking calcium influx and thus limiting the neuron s ability to secrete glutamate and substance P into the synase [46]. In the case of PLP, regabalin may also hel to decrease the sontaneous nerve stimulation that develos in the damaged nerve fibers and those adjacent fibers in the stum in PLP atients [47]. Pregabalin, have been reorted to be efficacious in the treatment of ainful diabetic eriheral neuroathy (DPN) and ostheretic neuralgia (PHN). In a revious study results suggest that relative to lacebo, regabalin in daily doses of 15 to 6mg/d was effective and well tolerated in Chinese atients diagnosed with moderate-tosevere DPN or PHN, indicated through imroved ain scores and PGIC scores [48]. In randomized controlled trials Pregabalin had demonstrated efficacy in ost heretic neuralgia [49,51], ainful diabetic olyneuroathy [28,52,53] ; their combination [54] ; and in neuroathic ain associated with sinal cord injury [55]. Karanikolas et al., [32] showed that neuroathic ain scale (NPS) scores started high and droed with time over the 12 months. There was a significant reduction from re-oerative values in both grous at all time oints ost-oeratively, but with no difference between grous [32]. In our study, although being matched at baseline values, daily slee interference scale values were highly significantly different among the four study grous at all follow-u endoints with lower values in the intervention grous comared to the control grou (lowest values in the regabalin grou). However, differences within the intervention grous themselves were insignificant at all follow-u endoints. Higher slee interference was associated with oor ain control and lower slee interference was noted in the regabalin grou due to its sedating actions. Descritive analyses by McCracken and Iverson [56] showed that 88.9% of atients reorted as least one roblem with disturbed slee. Correlation analyses showed that greater slee disturbance was associated with greater ain, disability, deression and Physical symtoms, and less daily utime [56]. Sabatowski et al., [5] showed that by one week and for the study s duration, 15 and 3mg/day

12 792 Perioerative Oral Melatonin, Pregabalin & their Combination regabalin significantly reduced weekly mean slee interference scores when treating neuroathic ain in atients with ost-heretic neuralgia (PHN) [5]. Similar studies, evaluating the efficacy and safety of regabalin for relief of central neuroathic ain associated with sinal cord injury [55] and relief of neuroathic ain associated with ost-heretic neuralgia (PHN) [51] and with diabetic eriheral neuroathy (DPN) [28], showed that slee interference in all regabalin grous was also significantly imroved at endoint, comared with lacebo [28,51,55]. In our study, more atients reorted global imrovement at one month endoint in the melatonin and combination grous comared to control and regabalin grous. However, more regabalintreated atients than control and other intervention grous, reorted that they were better or a great deal better immediately reoeratively and 48-hr ostoeratively. All atients in the control and combination grou reorted No change or little better immediately reoeratively and 48-hr ostoeratively. This could be exlained by the fact that increased associated drug-induced adverse effects reduce the atient ercetion of global imrovement. Sabatowski et al., [5] showed that by one week duration of using 15 and 3mg/day regabalin for treating neuroathic ain in atients with ostheretic neuralgia, more regabalin-treated atients than lacebo-treated atients reorted that they were much imroved or very much imroved [5]. Similar results were shown by Rosenstock et al., [28] in a randomized, double-blind, lacebocontrolled, arallel-grou, multicenter; 8-week trial evaluating the effectiveness of regabalin in alleviating ain associated with diabetic eriheral neuroathy (DPN) [28]. Siddall et al., [55] and van Seventer et al., [51] showed also similar results. Our study showed significantly higher incidence of adverse effects in the combination and regabalin grou comared the other grous. Medicationrelated adverse events included higher incidence of somnolence, dizziness and dry mouth in the combination and Pregabalin grou. Constiation, blurring of vision, headache, nausea and vomiting was statistically non significant. Gilron et al., [57] also showed that combined gabaentin and morhine administration achieved better analgesia than either as a single agent, with constiation, sedation and dry mouth as the most frequent adverse effects. In a regabalin trial, an 83% incidence of minor adverse events was reorted in the treatment grou, but the incidence of withdrawal was highest in the lacebo grou [5]. Pregabalin roduces dose-deendent side effects. It has also demonstrated anxiolytic effects in randomized controlled trials, which may rovide additional benefit in atients with chronic ain. Because it is a new medication, long-term safety of regabalin is not as well established as it is for gabaentin [58,59]. Our study showed that reoerative ain (VAS) was significantly associated with higher incidence of hantom limb ain after 1 and 2 month ostoeratively. Similarly, several studies showed severe ain rior to Surgical amutation is associated with a higher revalence of ost-amutation ain, suggesting that aggressive efforts to control ain before Surgery may have the otential of decreasing the revalence of chronic ain [32,4,6]. Conclusion: Perioerative adequate analgesic ain control regimen for an aroriate duration after major lower limb amutations is essential to revent hantom limb ain and either erioerative oral melatonin or regabalin or their combination could be a roer additive to eri-oerative Theray of hantom limb after sinal anesthesia. A larger multicenter study is required. References 1- RICHARDSON C., GLENN S., NURMIKKO T. and HORGAN M.: Incidence of hantom henomena including hantom limb ain 6 months after major lower limb amutation in atients with eriheral vascular disease. Clin. J. Pain, 22: , BADURA-BRZOZA K., MATYSIAKIEWICZ J., PIEG- ZA M., RYCERSKI W., NIEDZIELA U. and HESE R.T.: Sociodemograhic factors and their influence on anxiety and deression in atients after limb amutation. Psychiatr. Pol., 4: , HALBERT J., CROTTY M., and CAMERON I.D.: Evidence for the otimal management of acute and chronic hantom ain: A systematic review. Clin. J. Pain, 18: 84-92, GEHLING M. and TRYBA M.: Prohylaxis of hantom ain: Is regional analgesia ineffective?. Schmerz, 17: 11-19, FINNERUP N.B., OTTO M., McQUAY H.J., JENSEN T.S. and SINDRUP S.H.: Algorithm for neuroathic ain treatment: An evidence based roosal. Pain, 118: , MAIER C., DERTWINKEL R., MANSOURIAN N., HOSBACH I., SCHWENKREIS P., SENNE I., SKIPKA

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