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  Table of Contents 
Year : 2020  |  Volume : 21  |  Issue : 1  |  Page : 50-55

The preventive effects of oral caffeine and melatonin on headache after spinal anesthesia for lower limb surgery: A double-blinded, randomized clinical trial

1 Department of Anesthesiology and Critical Care, Arak University of Medical Sciences, Arak, Iran
2 Department of Anesthesiology, Students Research Committee, Arak University of Medical Sciences, Arak, Iran
3 Department of Epidemiology and Biostatistics, Neuroscience Research Center, Faculty of Health, Qom University of Medical Sciences, Qom, Iran

Date of Submission13-Nov-2019
Date of Decision09-Jan-2020
Date of Acceptance10-Jan-2020
Date of Web Publication13-Feb-2020

Correspondence Address:
Dr. Esmail Moshiri
Department of Anesthesiology and Critical Care, Arak University of Medical Sciences, Arak
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/TheIAForum.TheIAForum_85_19

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Background: Postdural puncture headache (PDPH) is a common complication after spinal anesthesia, mainly due to the loss of cerebrospinal fluid. This study was aimed to compare the preventive effect of oral caffeine (CAF) and melatonin (MEL) on headache after the spinal anesthesia for lower limb surgery (LLS).
Methods: A double-blinded, randomized clinical trial enrolled on 150 patients undergoing LLS were randomly divided into three groups (n = 50 in each). CAF, MEL, and placebo (PBO) (control group) receiving a capsule containing 300 mg CAF, MEL 3 mg tablet, and a placebo 1 h before the spinal anesthesia. While recording the variables (SaO2, heart rate, mean blood pressure, and the dose of analgesic drug consumption), the pain score was measured using the visual analog scale at 12 and 24 h, as well as 2, 3, 5, and 7 days after surgery, afterward followed by SPSS-based data analysis.
Results: Significant differences were found in headache pain score among the three groups (P < 0.001). The lowest pain score was seen with the CAF until 3 days after the surgery and in the MEL on day 5 and 7 days after the surgery. The incidence of PDPH in CAF, MEL, and PBO groups was 18%, 22%, and 36%, respectively (P = 0.006).
Conclusion: CAF and MEL reduced the incidence of PDPH after spinal anesthesia for LLS with no hemodynamic changes. Based on the study results, the preventive effects of CAF on PDPH have been confirmed, and MEL can be suggested to be used for its prevention. However, further studies, with larger sample sizes, will be needed to completely prove these findings.

Keywords: Caffeine, headache, lower limb surgery, oral melatonin, spinal anesthesia

How to cite this article:
Modir H, Moshiri E, Modir A, Modir A, Mohammadbeigi A. The preventive effects of oral caffeine and melatonin on headache after spinal anesthesia for lower limb surgery: A double-blinded, randomized clinical trial. Indian Anaesth Forum 2020;21:50-5

How to cite this URL:
Modir H, Moshiri E, Modir A, Modir A, Mohammadbeigi A. The preventive effects of oral caffeine and melatonin on headache after spinal anesthesia for lower limb surgery: A double-blinded, randomized clinical trial. Indian Anaesth Forum [serial online] 2020 [cited 2020 Dec 3];21:50-5. Available from: http://www.theiaforum.org/text.asp?2020/21/1/50/278192

  Introduction Top

The spinal anesthesia technique has many advantages over general anesthesia, including patient convenience, outweighing the risks of tracheal intubation and aspiration, shortened hospital stays, and postoperative pain management.[1],[2] However, this technique may also be associated with some complications among which headache is a common problem after spinal anesthesia that is defined as postdural puncture headache (PDPH).[3],[4] The incidence of PDPH varied from 11% to 66%, of which 66% and 90% of cases occur 2 and 3 days after spinal anesthesia, respectively.[5],[6] The symptoms of disease onset generally occur in the first 7 days postdural puncture and continue until 7 days later.[7] The headache becomes classically steady on the postoperative 2nd or 3rd day.[4]

The PDPH is characterized by the pain caused in the forehead and occipital areas, exacerbated by sitting and standing and somewhat and partly or completely relieved by lying down. It is usually described as vague or throbbing.[4] Although the problems are usually transient, they can lead to serious complications because brain displacement is capable of causing the vein puncture and progression of subdural hematoma.[8] The symptoms of PDPH are caused by the loss and leakage of cerebrospinal fluid (CSF) from the intrathecal space and cranial vasodilatation, whereas this type of headache is mainly caused by the contraction of the dura mater and stretching of the meninges surrounding arterial and venous vessels.[4],[6],[7]

The treatment of PDPH involves the use of nonnarcotic analgesics, reduction of preoperative fasting time, reduction of auditory and visual stimuli, use of 300 mg caffeine (CAF) orally, or 500 mg CAF intravenous in 1 L of saline in 2 h.[6],[9] In recent years, numerous drug treatments have been recommended by epidural saline injection and intrathecal catheter insertion to reduce headaches.[10],[11],[12],[13] For nonresponsive patients, epidural blood patches are used, in which 15–20 mL of patient blood taken with the aseptic technique is injected into the epidural space.[8] As the current approaches are not able to completely eliminate the headache and lead to patient dissatisfaction, prolonged hospitalization, and increased treatment costs, prevention is far more important than the treatment. However, the results of the studies are contradictory. CAF and melatonin (MEL) administration are two methods for decreasing the severity of PDPH after spinal anesthesia and before the onset of headache.[14],[15],[16]

CAF administration is a way to prevent and treat headache after spinal anesthesia. It is effective in relieving pain, relieving migraine headaches, stimulating brain and respiratory center, and treating cough and[17] belongs to the methylxanthine group of drugs that prevents drowsiness by reversibly blocking adenosine from its receptors and stimulates certain portions of the autonomic nervous system.[18] It also acts as a cerebral vasoconstrictor and thereby reducing headache. Existing literature supports CAF to prevent and treat headache after spinal anesthesia, but conflicting results are found in clinical studies.[19] MEL (5-methoxy N-acetyltryptamine) is the primary secretory product of the pineal gland and effective in releasing and regulating opioid peptides and changes in hormone levels in pain sensation.[20] Research on receptors has shown that MEL receptors are present at different sites of the central nervous system and other human body tissues.[21] It is an epiphysis hormone (from the pineal gland) that is effective in treating sleep disorders, anxiety, and pain.[15],[22] MEL interacts with many receptors, including opioidergic, benzodiazepinergic, muscarinic, nicotinic, serotonergic, α1-/α2-adrenergic, and melatonergic receptors present in the central nervous system.[15],[21] Many studies have shown MEL's effect on sleep onset and maintenance[23] as a natural sleep aid that effects on MEL MT1 and MT2 receptors.[24]

The researchers hypothesized that CAF may produce contraction of CSF when prescribing before spinal anesthesia to prevent vasodilation in spinal anesthesia and it can prevent a headache from it, whereas MEL administration before spinal anesthesia may be effective in preventing headache after spinal anesthesia due to its pain-relief effects. This study aimed to explore the effect of CAF and MEL on the prevention of headache after spinal anesthesia for lower limb surgery (LLS).

  Methods Top

This study was a double-blinded, randomized clinical trial for determining the effects of CAF and MEL on the prevention of headache after spinal anesthesia in patients undergoing LLS under spinal anesthesia. The sample size was determined by considering power 80%, type one error 5%, and a mean difference score of pain according to the recent studies. After obtaining the code (IR.ARAKMU.REC.1397.115) of ethics from the Medical University's Ethics Committee, written informed consent was obtained from all patients. The eligible patients belonged to the American Society of Anesthesiologists I–II classes and were randomly split into three groups [n = 50 in each based on CONSORT chart in [Figure 1], including CAF, MEL, and placebo (PBO) control by the block randomization method. Moreover, this study registered in the Iranian Registry Clinical Trial center by IRCT20141209020258N94.
Figure 1: CONSORT diagram showing the flow of participants through each stage of a randomized trial

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The inclusion criteria were patients >18 years of age, willingness to participate in the study, lack of sensitivity to CAF and MEL, absence of background diseases such as chronic migraine headache, high BP, diabetes, coagulation disorders, pregnancy poisoning, seizure, and lack of consumption of tobacco and drugs. Therefore, the exclusion criteria were more than once spinal anesthesia attempts, failure of the spinal anesthetic and the use of other anesthesia methods, having complete bed rest more than 8 h after surgery, a history of CAF-containing medications, headache before and during the first 8 h after surgery, patient's uncontrolled asthma, reluctance to continue cooperation, and surgery duration >120 min.


The CAF received a capsule containing 300 mg CAF (Supernatural company, Canada), whereas the MEL, a MEL 3 mg tablet (Natrol, Canada) 1 h before the spinal anesthesia given by an anesthesiologist resident. Each MEL pill was powdered and spilled into empty capsules similar to CAF capsules and given to the patients, for matching and blinding intravenous drugs. Moreover, flour was spilled into empty capsules and similarly given to the PBO group. Before spinal anesthesia, all patients received 10 cc/kg body weight of Ringer's lactate solution for 30 min before surgery. The anesthesia was once performed with a 25G Quincke needle through the midline approach, whereas the L3–L4 interspace was chosen. 15 mg bupivacaine 0.5% was injected to induce spinal anesthesia. Each group of patients received the same fluid volume equivalent to 5–7 mL/kg body weight of Ringer's solution during surgery, SaO2, heart rate (HR), and mean blood pressure were measured and recorded every 5 min until 30 min and then every 10 min until surgery end.

Spinal anesthesia and administration of 15 mg bupivacaine were used for the surgery in all three groups intrathecally. No intraoperative analgesics were used for patients in all three groups. Diclofenac suppository was used if the visual analog scale (VAS) >6 for any causes of pain (except headache) and if pain persisted 12 h later, the next dose of suppository was administered. All spinal anesthesia procedures were performed by one person while the study was double-blinded so that no patients knew the medicine they received, and the person collecting the data was unaware of patient grouping. The usual care was the same in the groups. Three groups received diclofenac sodium suppository 75 mg for pain management, in the case of pain in sites other than the head (VAS >7), and the dose of the used drug was recorded.


Demographic information, including age, gender, education level and length of surgery, and medication administration, was recorded for three groups 1 h before spinal anesthesia by an unaware anesthesiologist.

The headache intensity was measured and recorded using a valid and standard VAS tool. The VAS score higher than 2 was defined as PDPH in patients, and the incidence of PDPH was noted in each patient. All patients were interviewed for the pain using VAS, and we provided each patient a ruler with characteristics instructed to answer. The patients were interviewed on headache and the severity, based on the VAS 12 and 24 h after the surgery and at a specified hour on the 2nd, 3rd, 5th, and 7th days, but those who were discharged sooner were interviewed by the telephone. The interviewer did not know the patient grouping. The headache was considered as a PDPH, which is worsened by sitting or standing and eased by lying down. Pain due to other causes was different from PDPH, and the severity of this pain was recorded.

Statistical analysis

Data were analyzed using the SPSS software version 20 (SPSS Inc., Chicago, IL, USA). The analysis of variance was used to compare the mean of pain at different times among the three groups. Tukey post hoc test was used for comparing the pain and hemodynamic parameters group by group. The Chi-square test was used to compare the groups regarding sex distribution and satisfaction level. The analysis of variance for repeated measurements was used to compare the change in pain during 7 days after the operation. A statistically significant level was considered as 0.05.

  Results Top

This study was a double-blinded, randomized clinical trial to determine the effects of CAF and MEL on the prevention of headache after spinal anesthesia for LLS in which participants (n = 150) were randomly split into three groups (minimum and maximum age of 19 and 51 years, respectively; the mean age of 34.39 ± 7.38 years; and 75 [50%] males and 75 [50%] females). [Table 1] showed the details of age and gender comparison among the three study groups. Based on the results, no statistically significant difference was found in age (P = 0.854), body mass index (P = 0.756), and gender (P = 0.564), among the three groups. Moreover, the patients in three groups were not differ significantly in BP, HR, and SaO2 at the time of the study (P < 0.05).
Table 1: Comparison of mean of age, body mass index, and gender distribution in three groups

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Based on the results in [Table 2], a statistically significant difference was seen in headache pain score among the three groups (P < 0.001). The lowest pain score was observed in the CAF until 3 days after the surgery. Moreover, the MEL group had a lower headache compared to the PBO group. In addition, the pain score of headache was lower in both MEL and CAF groups than PBO group on day 5 and 7 days. The MEL and CAF groups were similar regarding to the pain score during the 7 days follow-up. [Figure 2] showed the change in headache pain during 7 days follow-up in three groups. The repeated measurement showed a statistically significant difference among the three groups. The post-hoc Tukey test showed that MEL and CAF groups were significantly different with PBO group (P < 0.05).
Table 2: Comparison of mean and standard deviation of headache pain in three groups during 7 days after operation

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Figure 2: Comparison of change in headache pain in three groups during 7 days after surgery

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Based on the results [Table 3], no significant difference was found in pain due to other causes among the three groups (P = 0.58). Moreover, no statistically significant difference was observed in the duration of surgery among the three groups (P = 0.323). However, based on the results in [Table 4], the incidence of PDPH was significantly different among groups and the lower incidence observed in CAF (18%) and MEL (22%) groups than PBO group (36%) (P = 0.016). Nevertheless, no statistically significant difference was found in the analgesic drug consumption among the three groups (P = 0.701). A dose of 75 mg diclofenac suppository was given every 12 h if the analgesic drug was used.
Table 3: Comparison of mean and standard deviation of pain due to other causes and duration of surgery in three groups

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Table 4: Comparison of the frequency and percentage of the analgesic drug consumption in three groups

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  Discussion Top

Our results showed a significant difference in headache severity among the three groups, including CAF, MEL, and PBO, and the pain score was significantly lower in the CAF in the first 3 days after surgery. Moreover, the pain score was lower in both MEL and CAF than the PBO at 5 and 7 days. However, the three groups were similar in other variables, including duration of surgery, BP, HR, SaO2, the dose of analgesic drugs consumption, age, and gender. In fact, CAF and MEL reduced the headache after spinal anesthesia for LLS, so that the headache was lower in the CAF during the first 3 days. Other studies showed similar results in some aspects.

Ragab and Facharzt compared the effect of 500 mg CAF sodium benzoate intravenously with normal saline in preventing PDPH in young adult patients and found that the VAS decreased significantly in the CAF group. Moreover, the incidence of severe and moderate headaches was higher in the control group, and the patients' request for analgesia was lower in the CAF group.[14] Our results are consistent with their study. However, comparing the placebo, 500 mg paracetamol plus 75 mg CAF and 500 mg paracetamol plus 125 mg CAF orally every 6 h for 3 days, Esmaoglu et al.[25] showed the incidence of PDPH was 15.7% in placebo, 14.28% in second, and 14.28% in third group and was nonsignificant among groups. In addition, the complications of spinal anesthesia were similar in them.[26] The results of their study were not consistent with our study, probably because of the difference in dose of CAF used in the two studies. Nevertheless, another Iranian study by Eshghizadeh et al. showed that coffee consumption in patients undergoing cesarean section with spinal anesthesia can prevent PDPH and reduce the severity of the headache.[27]

Based on our results, MEL had inferior results to CAF in preventing the PDPH after spinal anesthesia. A review study by Danilov and Kurganova assessed the effect of MEL on chronic pain syndrome and showed that consumption of 10 mg MEL for 14 days before bedtime reduced the severity and frequency of pain attacks for cluster headaches, and consumption of 25 mg/day of agomelatine for 3 months reduced the number and duration of migraine headaches.[28] Their results can be labeled as consistent to our study that MEL reduced the headache after spinal anesthesia for until 7 days. Moreover, Gonçalves et al. conducted a clinical trial to compare oral 3 mg MEL, oral 25 mg amitriptyline, and placebo for migraine prevention and concluded that 3 mg MEL was better than placebo in preventing migraines, also better tolerable than amitriptyline, and that its preventive effects were equal to those in amitriptyline.[26]

Two theories have been proposed to explain how PDPH is produced. The first and most conventional is the frequency of spinal anesthesia and the reduced CSF volume due to dural puncture and the reduced CSF volume caused by the stimulation of intracranial structures, especially when a patient placed in the supine position experiences a headache.[4],[9] The second is related to the reduced CSF volume and intracerebral vasodilation.[29]

The clinician dissatisfaction rate and need for more analgesic drug consumption were lower in MEL and CAF groups in our study. However, it is due to preventing of PDPH as well as other following symptoms of spinal anesthesia. Nausea and vomiting, anorexia, malaise, neck pain, dizziness, tinnitus, hearing impairment, vision problems, including diplopia, blurred vision, photophobia or black spots in vision, and cranial nerve palsy, and eventually seizures are other symptoms of PDPH that may occur.[4] Age is one of the most important factors affecting headache and occurs less frequently in children while increasing with puberty and decreasing with age after puberty. Moreover, female gender, needle size, needle type, pregnancy, repeated attempts to numbness, history of previous headaches, and dehydration are other risk factors.[8]

  Conclusion Top

CAF and MEL reduced the headache caused by spinal anesthesia for LLS, with no hemodynamic changes. Our findings showed that the headache incidence was lower in the CAF during the first 3 days after the operation. Hence, CAF and MEL are recommended to be used for preventing headache after spinal anesthesia due to their pain-preventive effects due to the low incidence of consequences and declining the pain score 5 days after the operation. Moreover, further studies with larger sample sizes will be needed to confirm these findings.


This article is a result of a research project approved on July 2, 2018, with the code of ethics IR.ARAKMU.REC.1397.115, and the clinical practice code IRCT20141209020258N94. Hence, we would like to thank the Clinical Research Council at Valiasr Hospital for its guidance and the research deputy of Arak University of Medical Sciences for his assistance and support.

Financial support and sponsorship

This study was financially supported by the Arak University of Medical Sciences, Arak, Iran.

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4]


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