Marseglia L, Manti S, D'Angelo G, et al. Potential use of melatonin in procedural anxiety and pain in children undergoing blood withdrawal. J Biol Regul Homeost Agents. 2015;29(2):509-514.
Double-blind, placebo-controlled, randomized, clinical trial for the purpose of assessing the effect of supplemental melatonin on anxiety and pain levels of children subjected to medical procedures.
Sixty children, ages 1 to 14 years, who required blood testing, randomized into 2 equal groups. Patients with sleep disorder, neurodevelopmental delay, ongoing treatment with hypnotics or psychotropic drugs within a week before admission, daily analgesic treatment, or corticosteroid treatment were excluded.
Study Medication and Dosage
Either melatonin orally (0.5 mg/kg body weight, to a max of 5 mg) or placebo 30 minutes before a blood draw
Preprocedural anxiety was assessed using the scale from the Children’s Anxiety and Pain Scales, while procedural pain used the Face, Legs, Activity, Cry and Consolability assessment tool for children under the age of 3 years, Faces Pain Scale-Revised for children ages 3 to 8 years, and Numeric Rating Scale for children over the age of 8 years.
Oral administration of melatonin before the blood withdrawal procedure significantly reduced both anxiety (P<0.0005) and pain levels compared to placebo (P<0.0002 for children under 3 years and P<0.0039 for children over 3 years).
The results of this study are surprising. Though natural health practitioners have employed melatonin at various doses for many years to treat a wide range of conditions from jet lag to cancer, few of us have thought to use melatonin for the purposes described here.
The data from this study should encourage us to expand our use of this hormone both for the specific situation tested—pediatric blood draws—and also for a range of procedures that cause anxiety and pain in this population. We might also consider employing melatonin in adults to reduce anxiety or pain induced in certain situations.
Medical procedures involving needles frighten most children, and for some the fear persists into their adult years.
A number of other strategies have been tested for relieving discomfort during pediatric blood draws. These fall into 2 main categories: techniques of distraction and use of local anesthetics. Distraction techniques include having children look through kaleidoscopes,1,2 and using distraction cards.3,4 Various techniques to numb the site of the blood draw include the use of topical vapo-coolants,5 needle-free powdered lidocaine,6 amethocaine, and liposomal lidocaine.7,8 Even having patients perform a Valsalva maneuver has been tested in children.9
Most practitioners, and most of the public as well, are familiar with melatonin’s use in treating jet lag and insomnia. Many of us consider using melatonin for its oncostatic properties and also for its vulnerary effects on the digestive tract. The anxiolytic and nociception effects are less well known.
In modern medicine, pain control is considered a fundamental right, particularly for children and even more so for neonates who are apparently more sensitive to pain than older infants or adults.10,11 Experimental data tell us that melatonin has an analgesic effect, though the actual mechanisms of action remains unclear. A variety of mechanisms are proposed, but none proven.12
Pain and anxiety tend to go hand in hand in hospitals, and anxiety can increase perceived pain intensity.
Melatonin appears to reduce pain due to inflammation by inhibiting nitric oxide (NO) production and reducing activation of nuclear factor kappa-B (NF-kappaB), expression of cyclooxygenase and prostaglandins and the recruitment of polymorphonuclear cells to the site of inflammation.13 We have been vaguely familiar with using melatonin in treating a number of conditions that produce chronic pain, including fibromyalgia,14 irritable bowel syndrome,15 and migraine.16
Pain and anxiety tend to go hand in hand in hospitals, and anxiety can increase perceived pain intensity.17 It comes as no surprise to read that melatonin levels drop after surgery and remain depressed during a patient’s hospital stay,18 or that giving melatonin to these patients improves their sleep19 and may reduce anxiety.20
The authors of this current study have been investigating the use of melatonin in a pediatric hospital setting for a number of years and have authored several interesting publications. In a 2013 paper, these researchers reviewed the protective role melatonin can offer in neonatal diseases. Many of the complications seen in premature infants are described as the “oxygen radical diseases of neonatology,” and the authors suggest that melatonin may help counteract these injuries—in particular “chronic lung disease, perinatal brain injury, necrotizing enterocolitis, and retinopathy of prematurity.”21
In 2012, Gitto and colleagues evaluated melatonin’s ability to decrease pain caused by endotracheal intubation in newborns. Neonatal Infant Pain Scale (NIPS) and Premature Infant Pain Profile (PIPP) scores were used as primary measures of effect. Blood levels of various cytokines implicated in pain were also assessed, providing an objective marker. A total of 60 preterm infants were divided into 2 groups of 30, 1 group treated with standard sedatives and analgesics and the second group receiving these drugs plus melatonin. During early-phase evaluations, the pain scores were similar between groups. At later phases, however, the melatonin group fared better, reaching statistical significance at 12, 24, 48, and 72 hours of intubation and mechanical ventilation. Inflammatory and pain-related cytokines were lower in the melatonin group at 24, 48, and 72 hours and also at 7 days. This suggests melatonin has a value even in neonates.22
Earlier rat studies in 2010 had predicted this pain-relief benefit.23 So had a 2009 study on adult patients undergoing cataract surgery. In this trial 40 patients undergoing cataract surgery under topical anesthesia were randomly divided into 2 groups of 20 and received either 10 mg of melatonin or placebo 90 minutes before surgery. Melatonin significantly reduced anxiety scores. Perioperative pain was also significantly reduced.24
Numerous long-term studies in both children and adults have failed to identify any substantive side effects after orally administered melatonin.25 This matches the clinical experiences of many of us who have used high-dose melatonin (20 mg/night) in patients with cancer since the mid 1990s.
This study offers us a reasonable way to reduce pain and anxiety from medical procedures, specifically in children. The melatonin is administered orally about a half-hour prior. Earlier published information suggests that we might consider a similar strategy in adults who are anxious before a medical procedure that will cause pain.
- Karakaya A, Gözen D. The effect of distraction on pain level felt by school-age children during venipuncture procedure—randomized controlled trial. Pain Manag Nurs. 2015 Oct 9. pii: S1524-9042(15)00156-3. doi: 10.1016/j.pmn.2015.08.005. Epub ahead of print.
- Tüfekci FG, Celebioglu A, Küçükoglu S. Turkish children loved distraction: using kaleidoscope to reduce perceived pain during venipuncture. J Clin Nurs. 2009;18(15):2180-2186.
- Canbulat N, Inal S, Sönmezer H. Efficacy of distraction methods on procedural pain and anxiety by applying distraction cards and kaleidoscope in children. Asian Nurs Res (Korean Soc Nurs Sci). 2014;8(1):23-28.
- Sahiner NC, Bal MD. The effects of three different distraction methods on pain and anxiety in children. J Child Health Care. 2015 Jun 2. pii: 1367493515587062. Epub ahead of print.
- Hogan ME, Smart S, Shah V, Taddio A. A systematic review of vapocoolants for reducing pain from venipuncture and venous cannulation in children and adults. J Emerg Med. 2014;47(6):736-749.
- Zempsky WT, Bean-Lijewski J, Kauffman RE, et al. Needle-free powder lidocaine delivery system provides rapid effective analgesia for venipuncture or cannulation pain in children: randomized, double-blind Comparison of Venipuncture and Venous Cannulation Pain After Fast-Onset Needle-Free Powder Lidocaine or Placebo Treatment trial. Pediatrics. 2008;121(5):979-987.
- Poonai N, Alawi K, Rieder M, Lynch T, Lim R. A comparison of amethocaine and liposomal lidocaine cream as a pain reliever before venipuncture in children: a randomized control trial. Pediatr Emerg Care. 2012;28(2):104-108.
- Brenner SM, Rupp V, Boucher J, Weaver K, Dusza SW, Bokovoy J. A randomized, controlled trial to evaluate topical anesthetic for 15 minutes before venipuncture in pediatrics. Am J Emerg Med. 2013;31(1):20-25.
- Akdas O, Basaranoglu G, Ozdemir H, Comlekci M, Erkalp K, Saidoglu L. The effects of Valsalva maneuver on venipuncture pain in children: comparison to EMLA(®) (lidocaine-prilocaine cream). Ir J Med Sci. 2014;183(4):517-520.
- Anand KJ. Clinical importance of pain and stress in preterm neonates. Biol Neonate. 1998;73:1-9.
- Fitzgerald M, Millard C, MacIntosh N. Hyperalgesia in premature infants. Lancet. 1988;1:292.
- Marseglia L, D'Angelo G, Manti S, et al. Analgesic, anxiolytic and anaesthetic effects of melatonin: new potential uses in pediatrics. Int J Mol Sci. 2015;16(1):1209-1220.
- Esposito E, Paterniti I, Mazzon E, Bramanti P, Cuzzocrea S. Melatonin reduces hyperalgesia associated with inflammation. J Pineal Res. 2010;49:321-331.
- Citera G, Arias MA, Maldonado-Cocco JA, et al. The effect of melatonin in patients with fibromyalgia: a pilot study. Clin Rheumatol. 2000;19:9-13.
- Mozaffari S, Rahimi R, Abdollahi M. Implications of melatonin therapy in irritable bowel syndrome: A systematic review. Curr Pharm Des. 2010;16:3646-3655.
- Peres MF, Zukerman E, Cunha Tanuri F, Moreira FR, Cipolla-Neto J. Melatonin 3 mg is effective for migraine prevention. Neurology. 2004;63:757.
- Ploghaus A, Narain C, Beckmann CF, et al. Exacerbation of pain by anxiety is associated with activity in a hippocampal network. J Neurosci. 2001;21:9896-9903.
- Basket JJ, Cockrem JF, Todd MA. Melatonin levels in hospitalized elderly patients: A comparison with community based volunteers. Age Ageing. 1991;20:430-434.
- Tzischinsky O, Laive P. Melatonin possesses time-dependent hypnotic effects. Sleep. 1994;17:638-645.
- Weaver DR, Stehle JH, Stopa EG, Reppert SM. Melatonin receptors in human hypothalamus and pituitary: Implications for circadian and reproductive responses to melatonin. J Clin Endocrinol Metab. 1993;76:295-301.
- Gitto E, Marseglia L, Manti S, et al. Protective role of melatonin in neonatal diseases. Oxid Med Cell Longev. 2013;2013:980374.
- Gitto E, Aversa S, Salpietro CD, et al. Pain in neonatal intensive care: role of melatonin as an analgesic antioxidant. J Pineal Res. 2012;52(3):291-295.
- Esposito E, Paterniti I, Mazzon E, Bramanti P, Cuzzocrea S. Melatonin reduces hyperalgesia associated with inflammation. J Pineal Res. 2010;49(4):321-331.
- Ismail S, Mowafi HA. Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia. Anesth Analg. 2009;108(4):1146-1151.
- Gordon N. The therapeutics of melatonin: a paediatric perspective. Brain Dev. 2000;22:213-217.