Phacoemulsification cataract surgery is commonly performed under topical anesthesia. Topical anesthesia is a noninvasive and simple modality that is free from vision interruption, ecchymosis, and other injection complications.1 Painless cataract surgery under topical anesthesia without systemic analgesia and/or sedation is possible and desirable. However, some patients may express pain and discomfort during iris manipulation, irrigation aspiration, and lens implantation.1 Differences in pain sensitivity among individuals or increased intraocular manipulations can also cause pain. Surgical pain causes patient anxiety and agitation with undesirable effects.2 In such cases, systemic analgesia and/or sedation might be required to relieve patient discomfort and increase a patient’s tolerance to surgery. The commonly used analgesic and sedative drugs have drawbacks and limitations, such as respiratory depression, disorientation, excessive sedation, or excitation. A premedicant that reduces analgesic requirements would be of value.
Melatonin is a hormone secreted by the pineal gland. Several studies reported that melatonin has analgesic potential in addition to anxiolytic and sedative effects without disturbances of the cognitive and psychomotor skills, and thus improves the quality of recovery.3–6 In addition, it has been shown in previous experimental and human studies that melatonin reduces intraocular pressure (IOP).7,8 These beneficial effects may be valuable when melatonin is used as a premedicant for cataract surgery. Our primary hypothesis was that melatonin premedication would decrease pain and anxiety scores and reduce the need for analgesic medication during cataract surgery under topical analgesia. Secondary objectives include evaluation of its effect on IOP and hemodynamics. The aim of this study was to evaluate the effects of melatonin premedication in patients undergoing elective phacoemulsification cataract surgery during topical anesthesia along with the incidence of adverse effects.
After approval of the local Ethics Committee and an informed written consent from each patient, 40 ASA physical status I–III adult patients older than 60 yr, scheduled for cataract surgery with intraocular lens implantation using phacoemulsification under topical anesthesia, were included in the study. Patients with an autoimmune disease, diabetes, depressive disorder, epilepsy, leukemia, insufficient pupillary dilation, nystagmus, deafness, allergy to the study drugs, those receiving analgesic or sedative drugs regularly, and those who could not tolerate Shioetz tonometer during IOP measurement in the ophthalmology clinic were excluded from the study. Patients were randomly allocated using an online research randomizer (http://www.randomizer.org) into two groups (20 patients each) to receive either melatonin 10 mg tablet (Melatonin®, NATROL, Chatsworth, CA) (melatonin group) or a placebo tablet (control group) orally 90 min before surgery. No other sedative or analgesic premedications were used. At the preoperative visit, the verbal pain score (VPS) of 10 (0 = no pain and 10 = worst pain imaginable) and the level of anxiety using a verbal anxiety score (VAS) ranging from 0 to 10 (0 = completely calm, 10 = the worst possible anxiety)9 were explained to each patient. A baseline anxiety score was recorded in each patient before premedication.
On arrival in the operating room (OR), 90 min after premedication, patients were asked to express their anxiety level using the same VAS. Patients were monitored with an electrocardiogram, noninvasive arterial blood pressure, and plethysmographic pulse oximetry using an anesthesia machine (Datex-Ohmeda S/5, ADU, Finland).
An ophthalmologist who was blinded to the group allocation applied the topical anesthesia by instillation of one drop of oxybuprocaine 0.4% (benoxinate 0.4%) in the lower fornix four times at 3-min intervals before surgery.10 A sponge soaked with lidocaine 2% was inserted into the upper fornix and removed before draping. An additional two drops of oxybuprocaine were instilled in the eye after application of the speculum. All patients were administered oxygen using a nasal cannula at a rate of 3 L/min. Surgery started after a routine preparation and draping. Surgery was performed early in the morning to avoid diurnal variations in the melatonin level and IOP.
Mean arterial blood pressures (MAP), heart rate (HR), and peripheral oxygen saturation values were recorded before premedication (T1), on arrival to the OR 90 min after premedication (T2), at 10, 20, 30 min after the start of surgery (T3, T4, T5, respectively), at the end of surgery (T6) and postoperatively before discharging the patient from the recovery room (T7). An ophthalmologist, who was unaware of patient assignment, measured IOP using a Shioetz tonometer under topical analgesia in the nonoperated eye. IOP was recorded before premedication and on arrival to the OR and at the end of surgery. Pain was assessed, using the same VPS, at 10-min intervals during surgery and if the patient complained of pain. The maximal pain score during the interval was recorded at 10, 20, 30 min after the start of surgery, at the end of surgery, and postoperatively before discharge from the recovery room. Supplemental 0.5 μg/kg IV fentanyl was given if VPS ≥4 and was repeated after 5 min if necessary. The total intraoperative fentanyl consumption was recorded. At the end of surgery, the patient was asked to give an average level of their anxiety during the operation using the same VAS. Postoperatively, the operating surgeon, who was blinded to patient allocation, was asked to assess the adequacy of intraoperative conditions according to the following scale: excellent, good, and poor. The incidence of adverse effects, including excessive dizziness, insomnia, unresponsiveness, agitation, airway obstruction, respiratory depression, or nausea and vomiting was recorded. The attending anesthesiologist who was unaware of patient group assignment managed the patients and recorded all data.
Power analysis was based on a pilot study, which showed an average fentanyl consumption of 50 ± 25 μg. A reduction of 50% in fentanyl requirement between the two groups in this age group was thought to be clinically significant. A sample size of 17 patients in each group was calculated to detect this difference with Type I error of 0.05 and Type II error of 0.20. To compensate for dropout cases and shifting from normality in data distribution, 20 cases were studied in each group. Parametric data were expressed as the mean ± sd and mean ± 95% confidence intervals in the graphs. Nonparametric data were expressed as median and interquartile range. Data were tested for normal distribution using the Kolmogorov-Smirnov test. Two-way repeated measure analysis of variance was used for continuous parametric variables as HR, MAP, and IOP, and the differences were then calculated by post hoc testing (Newman–Keuls test). Friedman repeated measures analysis of variance followed by Newman–Keuls test were used for within-group comparison of nonparametric variables, such as anxiety and pain scores and Mann–Whitney rank-sum test for the comparison of values between the groups. A P value <0.05 was considered significant. Analysis was performed using Statistica software version 7.0 for Windows (Statsoft).
There were no significant differences between the two groups with regard to age, weight, height, gender, and duration of surgery (Table 1). There were also no significant differences in the baseline HR, MAP, IOP, and anxiety scores.
As shown in Figure 1, anxiety scores decreased significantly after premedication in the melatonin group (P < 0.05). There were significant differences between the two groups in anxiety scores after premedication (P = 0.04) and intraoperatively (P = 0.005). Pain scores were significantly lower in the melatonin group than in the control group (Fig. 2). Fifteen patients in the control group and seven patients in the melatonin group needed fentanyl boluses (P = 0.025) resulting in a lower fentanyl requirement (median, interquartile range) during surgery in the melatonin group compared with the control group, 0, 0–32.5 vs 47.5, 30–65 μg, respectively, P = 0.007. Surgeons reported better quality of operative conditions with excellent and good scores of 16/20 and 4/20 vs 8/20 and 12/20 patients in the melatonin and control groups, respectively (P = 0.02).
Figure 3 shows the changes of HR, MAP, and IOP over time. No significant differences in HR between the two groups were recorded at any time. Contrary to the control group, MAP decreased significantly after melatonin premedication. No incidence of hypotension or bradycardia requiring intervention was reported in groups. There was no significant difference in the baseline IOP between both groups. However, after premedication IOP decreased significantly in the melatonin group and this reduction was maintained to end of surgery (P < 0.001).
No patient developed hypoxia and there were no reported intraoperative complications interfering with the course of surgery or interrupting the surgeons. One patient in the melatonin group complained of dizziness, and another patient in the control group suffered nausea. No patient requested further analgesia in the recovery room.
The main findings in our study were that melatonin premedication provided anxiolytic effects, improved perioperative analgesia, decreased IOP with better operating conditions, and stabilized the hemodynamic variables during cataract surgery under topical anesthesia.
The levels of anxiety scores in patients receiving melatonin were lower than those receiving placebo. The anxiolytic effect of melatonin premedication is supported with previous clinical trials in adults.3–5 On the other hand, Capuzzo et al.11 reported that melatonin premedication did not reduce anxiety more than placebo in elderly patients undergoing surgery. However, in their study the level of anxiety scores decreased 33% after melatonin premedication. The anxiolytic effects of melatonin may be mediated via GABAergic system activation.12 One concern that may be raised about the assessment of anxiety in the present study is the use of VAS rather than more sophisticated scores. However, we found that the VAS was easier to use by our study population as some of them found difficulty following the more complicated multiple response scores, such as State-Trait Anxiety Inventory score. Additionally, previous studies showed that VAS correlated well with the State-Trait Anxiety Inventory score in measuring fear of anesthesia and it was concluded that the simple VAS is a valid measure of preoperative anxiety.9
The melatonin analgesic effect in the current study was clinically evident by lower pain scores and the fewer subjects who needed fentanyl with a reduction in the intraoperative fentanyl consumption. In a previous study, fentanyl provided an increase inpatient comfort and decreased VPS during cataract surgery with topical anesthesia.13 However, during cataract surgery, the combined effects of premedication, opioid analgesics, the surgical draping, intraoperative sedatives, and concomitant cardiovascular and/or respiratory diseases may predispose elderly patients to potential morbidity.14 Therefore, a reduction in intraoperative fentanyl supplementation, even by a dose of around 30 μg as in our study, may be beneficial in this age group.
Several animal studies have shown that systemic melatonin provided dose-dependent antinociception and enhanced morphine analgesia.15 Moreover, in a recent clinical study of female patients undergoing abdominal hysterectomy under epidural anesthesia, Caumo et al.6 proved that melatonin premedication enhanced postoperative analgesia. In addition, it was demonstrated that melatonin improved tourniquet tolerance and enhanced postoperative analgesia in patients receiving IV regional anesthesia.16 The precise mechanism and site of action of melatonin antinociception are not completely obvious. However, several studies on experimental animals tried to clarify these mechanisms. Melatonin may enhance the levels of β-endorphin and the antinociception induced by δ opioid receptor agonists.14 In addition, it could activate MT2 melatonin receptors in the dorsal horn of the spinal cord.17 Other mechanisms might be mediated via an interaction with the adrenergic (α2 adrenoceptors), dopaminergic (D2-receptors), serotonergic (5-HT2a receptors), and opioid systems in addition to the l-arginine-nitric oxide pathway.18 All these sites could be reached considering the high lipid-solubility of melatonin.
An important finding in the present study was that melatonin reduced IOP. The ocular hypotensive effect of melatonin has been demonstrated in previous experimental and human studies.7,8 The mechanism of the ocular hypotensive effect of melatonin is not clear. Melatonin may have a complex, albeit, undefined role in aqueous humor formation since melatonin receptors (M2 and M3) were recognized in the ciliary body tissues in animals.7,19 In addition, IOP exhibits diurnal variations with the lowest pressure occurring in the early morning at the time of high melatonin levels.8 Intraocular surgery under topical anesthesia necessitates a calm and cooperative patient as well as a quiet eye. Moreover, prevention of increases in IOP could improve operating conditions and circumvent the theoretical risk of vitreous loss. These prerequisites are fulfilled with melatonin premedication.
In our study, MAP decreased after melatonin premedication and extended to the early postoperative period. Although it increased at some points in the control group, no significant differences were detected between groups. Elderly patients undergoing cataract surgery may suffer hypertension and cardiac ischemia. Therefore, this mild hypotensive effect of melatonin may be beneficial in elderly patients, particularly those at cardiovascular risk. Previous studies showed that melatonin could decrease MAP in healthy women20 and men.21 The mechanism of action of melatonin on circulation is complex and unclear. Melatonin may bind to specific melatonin receptors in the blood vessels, interfering with the vascular response to catecholamine.22 Furthermore, melatonin may interfere with the peripheral and central autonomic system, causing a reduction in adrenergic outflow and catecholamines levels.23 In addition, it may induce relaxation of the smooth muscle of the arterial walls via increasing nitric oxide availability.24
The selected dose of oral melatonin (10 mg) was based on a previous study in elderly patients.11 Different dose regimens have been used in clinical studies for melatonin premedication. Premedication with sublingual melatonin 5 mg3 or 0.05 mg/kg4 was associated with preoperative anxiolysis and sedation. In addition, Naguib et al.5 proved that oral melatonin premedication in a dose of 0.2 mg/kg significantly decreased the doses of both propofol and thiopental required to induce anesthesia. Moreover, oral melatonin premedication, in a dose of either 3 or 5 mg, reduced the required dose of propofol to achieve a Bispectral Index score of 45.25 However, the melatonin dose with analgesic potentials is undefined. Although oral melatonin has low bioavailability,26 1–5 mg doses increase serum melatonin concentrations 10–100 times higher than the nighttime peak level within 60 min after oral intake.27
Although melatonin had anxiolytic and analgesic effects, its administration in patients receiving painful regional anesthetic techniques, such as injection of ocular blocks remains unknown. One limitation of our study is that we did not measure melatonin plasma levels after melatonin premedication. Further studies are required to determine plasma levels of melatonin. Additionally, the optimum dose and route of administration of melatonin as premedication during cataract surgery needs to be determined.
In conclusion, premedication with oral melatonin provided anxiolysis, enhanced perioperative analgesia, decreased the IOP, and improved the operating conditions during cataract surgery under topical anesthesia.
1. Yaylali V, Yildirim C, Tatlipinar S, Demirlenk I, Arik S, Ozden S. Subjective visual experience and pain level during phacoemulsification and intraocular lens implantation under topical anesthesia. Ophthalmologica 2003;217:413–6
2. Kallio H, Uusitalo RJ, Maunuksela EL. Topical anesthesia with or without propofol sedation versus retrobulbar/peribulbar anesthesia for cataract extraction. Prospective randomized trial. J Cataract Refract Surg 2001;27:1372–9
3. Naguib M, Samarkandi AH. Premedication with melatonin: a double-blind, placebo controlled comparison with midazolam. Br J Anaesth 1999;82:875–80
4. Naguib M, Samarkandi AH. The comparative dose-response effect of melatonin and midazolam for premedication of adult’s patients: a double-blinded placebo-controlled study. Anesth Analg 2000;91:473–9
5. Naguib M, Samarkandi AH, Moniem MA, Mansour Eel-D, Alshaer AA, Al-Ayyaf HA, Fadin A, Alharby SW. The effects of melatonin premedication on propofol and thiopental induction dose-response curves: a prospective, randomized, double-blind study. Anesth Analg 2006;103:1448–52
6. Caumo W, Torres F, Moreira NL Jr, Auzani JA, Monteiro CA, Londero G, Ribeiro DF, Hidalgo MP. The clinical impact of preoperative melatonin on postoperative outcomes in patients undergoing abdominal hysterectomy. Anesth Analg 2007;105:1263–71
7. Pintor J, Peláez J, Hoyle CH, Peral A. Ocular hypotensive effects of melatonin receptor agonists in the rabbit: further evidence for an MT3
receptor. Br J Pharmacol 2003;138:381–6
8. Samples JR, Krause G, Lewy AJ. Effect of melatonin on intraocular pressure. Curr Eye Res 1988;7:649–53
9. Kindler CH, Harms C, Amsler F, Ihde-Scholl T, Scheidegger D. The Visual Analog Scale allows effective measurement of preoperative anxiety and detection of patients’ anesthetic concerns. Anesth Analg 2000;90:706–12
10. Patel BC, Burns TA, Crandall A, Shomaker ST, Pace NL, van Eerd A, Clinch T. A comparison of topical and retrobulbar anesthesia for cataract surgery. Ophthalmology 1996;103:1196–203
11. Capuzzo M, Zanardi B, Schiffino E, Buccoliero C, Gragnaniello D, Bianchi S, Alvisi R. Melatonin does not reduce anxiety more than placebo in the elderly undergoing surgery. Anesth Analg 2006;103:121–3
12. Wan Q, Man HY, Liu F, Braunton J, Niznik HB, Pang SF, Brown GM, Wang YT. Differential modulation of GABAA receptor function by Mel 1a and Mel 1b receptors. Nat Neurosci 1999; 2:401–3
13. Aydin ON, Kir E, Ozkan SB, Gursoy F. Patient-controlled analgesia and sedation with fentanyl in phacoemulsification under topical anesthesia. J Cataract Refract Surg 2002;28:1968–72
14. Aydin ON, Ugur B, Kir E, Ozkan SB. Effect of single-dose fentanyl on the cardiorespiratory system in elderly patients undergoing cataract surgery. J Clin Anesth 2004;16:98–103
15. Yu CX, Zhu B, Xu SF, Cao XD, Wu GC. The analgesic effects of peripheral and central administration of melatonin in rats. Eur J Pharmacol 2000;403:49–53
16. Mowafi HA, Ismail SA. Melatonin improves tourniquet tolerance and enhances postoperative analgesia in patients receiving intravenous regional anesthesia. Anesth Analg 2008;107:1422–6
17. Yu CX, Zhu CB, Xu SF, Cao XD, Wu GC. Selective MT2
melatonin receptor antagonist blocks melatonin-induced antinociception in rats. Neurosci Lett 2000;282:161–4
18. Mantovani M, Kaster MP, Pertile R, Calixto JB, Rodrigues AL, Santos AR. Mechanisms involved in the antinociception caused by melatonin in mice. J Pineal Res 2006;41:382–9
19. Serle JB, Wang RF, Peterson WM, Plourde R, Yerxa BR. Effect of 5-MCA-NAT, a putative melatonin MT3
receptor agonist, on intraocular pressure in glaucomatous monkeys eyes. J Glaucoma 2004;13:385–8
20. Cagnacci A, Arangino S, Angiolucci M, Maschio E, Melis GB. Influences of melatonin administration on the circulation of women. Am J Physiol 1998;274:R335–R338
21. Arangino S, Cagnacci A, Angiolucci M, Vacca AM, Longu G, Volpe A, Melis GB. Effects of melatonin on vascular reactivity, catecholamine levels, and blood pressure in healthy men. Am J Cardiol 1999;83:1417–9
22. Sewerynek E. Melatonin and the cardiovascular system. Neuro Endocrinol Lett 2002;23(suppl 1):79–83
23. Buijs RM, La Fleur SE, Wortel J, Van Heyningen C, Zuiddam L, Mettenleiter TC, Kalsbeek A, Nagai K, Niijima A. The suprachiasmatic nucleus balances sympathetic and parasympathetic output to peripheral organs through separate preautonomic neurons. J Comp Neurol 2003;464:36–48
24. Anwar MM, Meki AR, Rahma HH. Inhibitory effects of melatonin on vascular reactivity: possible role of vasoactive mediators. Comp Biochem Physiol C Toxicol Pharmacol 2001;130:357–67
25. Turkistani A, Abdullah KM, Al-Shaer AA, Mazen KF, Alkatheri K. Melatonin premedication and the induction dose of propofol. Eur J Anaesthesiol 2007;24:399–402
26. DeMuro RL, Nafziger AN, Blask DE, Menhinick AM, Bertino JS Jr. The absolute bioavailability of oral melatonin. J Clin Pharmacol 2000;40:781–4
27. Brzezinski A. Melatonin in humans. N Engl J Med 1997;336: 186–95