Effect of melatonin and gabapentin on anxiety and pain associated with retrobulbar eye block for cataract surgery: A randomized double-blind study

Abstract

Objectives:

To compare the effect of melatonin and gabapentin on anxiety, pain, sedation scores, and satisfaction of surgeon in patients of cataract surgery.

Materials and Methods:

One hundred thirty patients aged between 35 and 85 years scheduled for cataract surgery were randomly allocated to three study groups to receive melatonin (6 mg), gabapentin (600 mg) or placebo 90 min before arrival in the operating room. Pain, anxiety, and sedation scores during block and surgery as well as the surgeon's satisfaction with the surgery were assessed.

Results:

Anxiety scores decreased significantly in melatonin and gabapentin groups compared to the placebo group after premedication and extended to early postoperative period. The level of anxiety showed no statistically significant difference between melatonin and gabapentin groups at any time of measurement. There were significant differences between the pain scores during retrobulbar placement in gabapentin versus placebo (95% CI 3 to 4; P = 0.001) and melatonin (95% CI 3 to 4; P = 0.040) groups. Also, there were significant differences between the sedation scores during retrobulbar placement in gabapentin and placebo groups (95% CI 2 to 2.5; P = 0.046). The difference in sedation scores during retrobulbar placement in melatonin versus gabapentin and placebo groups was not significant. Neither the intraoperative pain scores nor the postoperative pain scores were different between the three groups. The surgeon reported similar quality of operation conditions during surgery for the three study groups.

Conclusion:

The level of anxiety was significantly lower with both anxiolytic drugs compared to placebo. Furthermore, gabapentin decreased the pain and improved the sedation scores only during retrobulbar placement compared to the placebo.

Introduction

The principle goal of sedation for eye surgery is to prepare the patients to stay calm during retrobulbar injection and surgery. Both insufficient sedation and deep sedation may lead to sudden movements by patients, which may potentially result in harmful complications during open eye surgery. Cognitive impairment has been demonstrated in patients undergoing cataract surgery under local anesthesia with sedation leading to major problems at time of discharge of the patient. Several drugs such as propofol, benzodiazepines, opioids, and dexmedetomidine have been used for sedation during this procedure.[1] However, each of these drugs has its own limitations, leading to impairment of patient's cooperation during surgery and making these agents less than ideal for the intraoperative management of sedation. Therefore, the potential clinical advantages of newly-marketed therapeutic drugs should be thoroughly evaluated. Gabapentin and melatonin are two well-tolerated drugs that are associated with anxiolytic and antinociceptive properties.[2,3] Several studies have reported that melatonin given as preoperative premedication is associated with sedation and preoperative anxiolysis without cognitive dysfunction including the memory recall and driving performances or the quality of recovery.[4,5] Also, it is reported that melatonin has been associated with the relief of pain in patients with major tissue injuries.[6,7] Ismail et al. reported that the administration of oral melatonin as preoperative premedication in patients undergoing cataract surgery under topical anesthesia produces anxiolytic and analgesic effects while reducing the intraocular pressure, leading to desirable operating conditions.[6] On the contrary, it is reported that gabapentin has anxiolytic[8] and antinociceptive effects.[9,10] In another study, it is claimed that this drug does not depress respiration with no effect on gastric mucosa, platelets, and renal function.[10] Moreover, gabapentin seems to be an anxiolytic without amnesic effects[11] which is an important advantage for elderly patients. Leung and colleagues[11] reported that delirium is significantly less in patients receiving gabapentin before spine surgery. Several studies have shown that gabapentin might be a useful adjuvant to postoperative analgesia in patients with regional analgesia.[9,10]

In our literature review, we could not find any study evaluating the effect of gabapentin and melatonin on anxiety, pain, sedation scores, satisfaction of surgeon, and hemodynamic parameters in cataract surgery under retrobulbar anesthesia. We hypothesized that gabapentin and melatonin might be valuable premedications for cataract surgery under retrobulbar anesthesia. To test our hypothesis, we designed this randomized double-blind, placebo-controlled study to evaluate the effect of melatonin and gabapentin on anxiety, pain, and sedation scores as well as the satisfaction of surgeon during cataract surgery.

Materials and Methods

This clinical trial was registered with the United States National Institutes of Health (www.clinicaltrials.gov), under the number NCT01200641. After obtaining the approval of the Institutional Ethics Committee, and written informed consent, 130 patients scheduled for cataract surgery by phacoemulsification were recruited in a prospective, double-blinded randomized trial. The consolidated standards of reporting trials (CONSORT) recommendations for reporting randomized controlled clinical trials[12] were followed [Figure 1]. This study was performed in Booali Hospital, Qazvin (Iran) during September 2010 to January 2011. Patients with ASA (American Society of Anesthesiologists) status IV, history of hepatic or renal disease, confusion, dementia, or communication difficulty resulting from deafness or language barrier, chronic use of narcotics, barbiturates or psychotropic medications, allergy or contraindications to any of the study drugs, visual impairment of nonoperative eye, and weight less than 40 kg or more than100 kg were excluded. Patients were randomly allocated to one of three groups each with 40 patients to receive melatonin 6 mg (group M), gabapentin 600 mg (group G), or placebo (group P) orally 90 min before arrival in the operating room. Randomization was based on computer-generated codes. Allocation was managed by a resident external to the project and the study drugs given by a nurse noninvolved in the study. The anesthetist was blinded to the patient's group assignment, and the study data were recorded by a blinded observer. The study drugs were administered by a nurse who was noninvolved in this project. No premedication was given except for the drugs predetermined by the study protocol. The primary outcomes of this randomized, double blind and placebo-controlled clinical trial were to evaluate anxiety and pain scores in each patient before premedication (T1), 90 min after premedication, on arrival in the operating room (T2), during retrobulbar block (RBB) placement (T3), during operation period (T4), and postoperatively prior to dischargefromthe recovery room (T5). At the preoperative visit, the verbal pain score (VPS) ranging from 0 to10 (0 = no pain and 10 = worst pain imaginable) and the verbal anxiety score (VAS) ranging from 0 to 10 (0 = completely calm, 10 = the worst possible anxiety) were fully explained to patients. At the end of surgery, the patients were asked about the average level of their anxiety and pain during operation period according to the VAS and VPS explained before premedication. A 20-gauge cannula was inserted into one of the two hands. Patients were monitored with electrocardiogram, noninvasive measurement of blood pressure, and pulse oximetry (SPO₂). Retrobulbar nerve block was performed by an ophthalmologist who was unaware of patient assignment, with 1.5 ml of solution prepared by a nurse (2 ml of lidocaine 2% and 0.5 ml of bupivacaine 0.5%) via percutaneous route with a 25 G, 38 mm Atkinson needle (John Weiss and Son Limited, Milton Keynes, England), at inferotemporal site. No patient received any supplementary facial nerve block. The secondary outcomes included the assessment of the sedation level of patients during the performance of block, the mean arterial blood pressure (MAP), and the heart rate (HR) before premedication (T1), 90 min after premedication, on arrival in the operating room (T2), during retrobulbar block placement (T3) during operation period (5 min after beginning of surgery) (T4), and postoperatively before discharging the patient from the recovery room (T5). The sedation level of patients during the performance of block was assessed using a 4-point scale with 0 = movements of the head, arms, and trunk, 1 = slight movement of arms, 2 = slight change in face, and 3 = complete calmness. If sedation showed to be inadequate, fentanyl was given at a dose of 0.5 μg/kg. At the end of surgery, the surgeon was also asked to verbally rate the level of satisfaction according to a 3-point scale as ‘very bad, moderate, and good’. The mean arterial blood pressure (MAP) and the heart rate (HR) were recorded by a noninvasive automatic blood pressure measuring device and electrocardiogram monitoring before premedication (T1), 90 min after premedication, on arrival in the operating room (T2), 1 min after retrobulbar block placement (T3) during operation period (5 min after the beginning of surgery) (T4), and postoperatively before discharge from the recovery room (T5). Based upon previously published data,[6,7,10] the authors hypothesized that the placebo would have an effect over reducing the anxiety scores in 5% of patients whereas melatonin and gabapentin are reported to produce a reducing effect in at least 40% of patients and to provide an 80% power with an error equal to 0.05, a sample size of 30 patients per group was determined to be sufficient. To compensate for dropout cases and shifting from normality in data distribution, 40 cases were studied in each group. Parametric data were expressed as the mean±SD. Normality of the data was tested by one sample Kolmogorov–Smirnov test. The t-test analysis was used for continuous parametric variables such as, weight, height, age, and the duration of surgery. The difference between the highest mean arterial pressure and heart rate and the values obtained for lowest mean in each patient was compared between the groups using one-factor ANOVA test. Within each groups, this comparison was made using the Student's paired t-test with Tukey correction. Nonparametric data were expressed as median (interquartile range). Mann-Whitney rank-sum test was used to compare the values obtained for VAS and VPS between the two groups. The Wilcoxon's test was used for comparison of the variables at different times. The Chi square test and Fisher's exact test were performed used to compare the conditions in surgery field between the groups. The Kruskal Wallis test was used to compare the values obtained for VAS and VPS and sedation scores among the three groups. P value of <0.05 was considered statistically significant. The statistical analysis was carried out using SPSS version 16 for Windows software program (SPSS, Chicago, IL).

Figure 1.

Consort Flow of Diagram of study of gabapentin and melatonin during retrobulbar eye block for cataract surgery

Results

One hundred thirty patients were recruited of whom ten were excluded from the study groups, due to logistical reasons or other factors violating the study protocol [Figure 1]. There were no significant differences between the three groups with respect to the demographic properties (age, gender, body weight, height, and duration of surgery) [Table 1]. The baseline characteristics such as HR and mean arterial pressure were similar in the three study groups [Table 2]. Figure 2 shows that the anxiety scores decreased significantly in melatonin and gabapentin groups compared to the placebo group after premedication. There were significant differences between gabapentin and placebo groups in anxiety scores after premedication (95% CI 2.5 to 3; P = 0.005), during retrobulbar block placement (95% CI 3 to 3.5; P = 0.000), intraoperatively (95% CI 1 to 1.5; P = 0.002), and postoperatively before discharge from the recovery room (95% CI 0.00 to 1; P = 0.002). Also, there were significant differences between melatonin and placebo groups in anxiety scores after premedication (95% CI 2.5 to 3; P = 0.000), during retrobulbar block placement (95% CI 3 to 4; P = 0.000), intraoperatively (95% CI 1 to 1.5; P = 0.001), and postoperatively before discharge from the recovery room (95% CI 0.00 to 1; P = 0.006). The level of anxiety showed no statistically significant difference between melatonin and gabapentin groups after premedication (P = 0.423), during retrobulbar the block placement (P = 0.539), intraoperatively (P = 0.938), and postoperatively prior to discharge from recovery room (P = 0.559). There were significant differences between the pain scores during the RBB placement in gabapentin versus placebo (95% CI 3 to 4; P = 0.001) and melatonin (95% CI 3 to 4; P = 0.040) groups [Figure 3]. The difference in pain scores during the RBB placement between melatonin and placebo (P = 0.207) groups was not significant. Also, the difference in intraoperative pain scores in melatonin versus the placebo (P = 0.059) and gabapentin (P = 0.785) groups was insignificant. Neither the intraoperative pain scores (P = 0.73), nor the postoperative pain scores (P = 0.333) were different between gabapentin and placebo groups [Figure 3]. Significant differences were observed between the sedation scores during the RBB placement in gabapentin and placebo groups (95% CI 2 to 2.5; P = 0.046) [Figure 4]. The difference in sedation scores during the RBB placement in melatonin versus gabapentin (P = 0.280) and placebo (P = 0.270) groups was insignificant.

Table 1.

An evaluation of effect of melatonin and gabapentin on anxiety and pain in cataract surgery: characteristics of the enrolled patients (n = 120)

Table 2.

Comparison of intraoperative fentanyl consumption and operating condition scores in the three study groups

Figure 2.

Verbal anxiety scores (VAS) in the three study groups VAS scores were expressed as median and error bars representing minimum and maximum values. P values are from Kruskal Wallis test

Figure 3.

Verbal pain scores (VPS) in the three study groups VPS scores were expressed as median (interquartile range). P values are from Kruskal Wallis test

Figure 4.

Comparison of the sedation scores in patients during retrobulbar block placement in the three study groups. The sedation scores was defined as 0 = movements of the head, arms, and trunk, 1= slight movement of arms, 2 = slight change in face, 3 = complete calmness. P value is from Kruskal Wallis test

All patients within the three groups were able to recall the needle insertion. Twelve patients in the placebo group needed fentanyl boluses whereas it was six in the melatonin and gabapentin groups; there was no significant difference (P = 0.434) between the three groups [Table 2]. Comparison of hemodynamic consequences of RBB and surgery failed to reveal any statistically significant differences between the groups [Table 3]. The difference between the highest mean arterial pressure and heart rate and the lowest mean arterial pressure and heart rate in each patient was compared between the study groups. The mean fluctuation of MAP in group G was 20.74 ± 10.86, group M 21.25 ± 17.55, and group P 18.96 ± 9.94. The difference between group M versus G (P = 0.877) and P (P = 0.477) groups was not significant. Similarly, the difference between group G and P (P = 0.448) was also insignificant. The mean fluctuation of HR in group G was 14.57 ± 7.34, group M 15.82 ± 10.42, and in group P it was 13.92 ± 7.06. The difference between group M versus G (P = 0.537) and P (P = 0.343) was not significant. Likewise, the difference between group G and P (P = 0.688) was also insignificant. The surgeon reported similar quality of operation conditions during surgery in all groups. The quality of operation conditions during the surgery in gabapentin versus placebo (P = 0.546) and melatonin (P = 0.546) groups was insignificant. No patient developed hypoxia, hypotension, bradycardia, excessive drowsiness (or sleepiness), nausea, and vomiting during the surgery. One patient in the melatonin group complained of mild headache and one in gabapentin group of severe dizziness while staying at the ward.

Table 3.

Hemodynamic variables measured in the three study groups receiving melatonin, gabapentin or placebo during retrobulbar eye block for cataract surgery

Discussion

The results of this study revealed that both anxiolytic drugs (melatonin and gabapentin) decreased the anxiety scores in the same manner. Further, a single oral dose of gabapentin, given as preoperative medication, decreased the pain and this was associated with more sedation scores compared to placebo only during the retrobulbar block placement although the intraoperative and early postoperative pain scores were similar in the three study groups. Our finding associated with the anxiolytic effect of melatonin and gabapentin is consistent with previous studies.[6,7,13,14,15,16,17] The anxiolytic effects of melatonin may be related to the activation of GABAergic system.[17] Melatonin produces considerable dose-dependent increases in GABA concentrations in the central nervous system.[5] Another important finding of our study was the ability of gabapentin in producing a statistically significant and clinically important improvement in the preoperative anxiety scores, a finding in agreement with previous studies.[8,15,16] In several studies it was reported that gabapentin was effective in treating the anxiety associated with panic disorders.[16,18] Although several studies published previously[6,7,13] have reported that the pain scores in the melatonin group were significantly lower than those in the control group, the present study did not demonstrate such a decrease in the pain scores by melatonin. The results of our study are consistent with two studies carried out by Naguib et al. in which it was reported that there was no significant difference in the intraoperative use of opioid or total doses of analgesics consumption in the melatonin, midazolam, or placebo groups over 90 min after the end of anesthesia at postanesthesia care unit.[14] Yousaf et al.,[2] in a systematic analysis of qualified clinical trials suggested that the analgesic effects of melatonin during the perioperative period were limited and that the results remained controversial. Also, Caumo et al.[7] reported that the administration of combined melatonin–clonidine as preoperative premedication decreased the postoperative morphine use by more than 30% in patients undergoing abdominal hysterectomy with moderate and severe anxiety whereas in mildly anxious patients, it was not associated with analgesic effect. This is again in agreement with our findings.[7] The level of anxiety score in most of our patients was mild and therefore, it seems that melatonin had no effect on pain. In this study, a single oral dose of gabapentin given as preoperative medication reduced the pain and this was associated with more sedation scores only during the retrobulbar block placement compared to the placebo. These results are also in concurrence with several studies in which it was demonstrated that gabapentin is effective in reducing the pain scores and morphine consumption in the early postoperative period.[19] Mao et al. showed that pretreatment with gabapentin prevents the occurrence of hyperalgesia, suggesting a preventive effect of gabapentin[20] which is compatible with our results in which the pain scores of patients during the retrobulbar placement in group G was lower compared to the placebo. Gabapentin may produce analgesia by reducing the release of neurotransmitters from sensory neurons, via a calcium-dependent process.[21] In this study, gabapentin was found to have higher analgesic effects than melatonin during the retrobulbar block placement. This difference, in addition to anxiolytic properties of gabapentin, may be mainly related to the direct analgesic effects of this drug.[15,16] In our study, the pain scores of patients during intraoperative and early postoperative pain were similar in all three groups. The possible explanations for the difference found between our results and the previous studies[19,20] may be related to either the low pain scores obtained for our patients due to performance of retrobulbar block in the three study groups or the difference in populations used in different studies. Elderly are known to under-report their pain due to cognitive dysfunction and depression.[22] We did not investigate the postoperative pain in these patients, which may be considered as a limitation of our study. Kong et al.[3] in a comprehensive analysis of the eligible clinical trials declared that the incidence of sedation in patients who received gabapentin as preoperative medication was significantly high which is in accordance with our results. We chose to administer 6 mg of melatonin orally 90 min before the surgery in our study as the onset of melatonin-induced sedation is reported to appear approximately 30 min after the administration of this drug and that the melatonin concentration remains stable for approximately 1.5 h at its peak level.[14,23] In addition, it seems that the doses of melatonin between 0.3–10 mg have similar hypnotic effectiveness.[24] Moreover, the reason for using a single dose of 600 mg gabapentin was based on the reports in which this concentration of the drug was the most commonly used dose of gabapentin in both acute and chronic pain studies.[3,5,6,7] Kong et al. in their systematic analysis claimed that gabapentin, as a potential multimodal perioperative drug, could be given 1–2 h before surgery.[3] Also, in a recent dose-response study, gabapentin at a dose of 600 mg was the optimal preemptive dose for reducing the postoperative pain,[25] and that increasing the dose over 600 mg not only failed to enhance analgesia but also increased the risk of adverse effects.[25] We thus empirically chose to use this single dose (600 mg) of gabapentin as a reasonable compromise between the efficacy and toxicity.

In our study, the comparison of hemodynamic variables changes during the RBB placement and surgery did not reveal any statistically significant difference between the three groups. However, in a study by Fassoulaki et al. the gabapentin-treated (1600 mg) patients had significantly lower systolic and diastolic arterial pressure during the first 10 min after endotracheal intubation compared to placebo with no obvious effect on heart rate changes.[26] Also, in another study by Memis et al.[27] the administration of 800 mg of gabapentin to patients as premedication caused a significant reduction in mean arterial pressure and heart rate during the first 10 min after endotracheal intubation compared to 400 mg gabapentin or placebo. However Kong et al.[3] in a systematic analysis of qualified clinical trials suggested that these effects may be dose-dependent and the changes in heart rate are conflicting.[3] In our study, we used gabapentin at a dose of 600 mg, which was lower than the dose used in those studies. Regarding the hemodynamic effect of melatonin, Ismail et al.[6] found that MAP was considerably reduced after melatonin premedication although it was described this difference at some points was insignificant between the groups. However, a large dose of melatonin may produce apparent results.

Conclusion

It is concluded that pretreatment with either melatonin or gabapentin decreases the anxiety scores in a similar way. Further, a single oral dose of gabapentin administered as preoperative medication decreases the pain and this is associated with more sedation scores compared with the placebo during the retrobulbar block. Further studies are required to determine the analgesic efficacy of combined melatonin–gabapentin as premedication during cataract surgery.