Analgesic and anti-hyperalgesic effects of melatonin in a human inflammatory pain model: a randomized, double-blind, placebo-controlled, three-arm crossover study (original) (raw)
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Melatonin administration reduces inflammatory pain in rats
Journal of Pain Research, 2012
In view of the broad range of effects attributed to melatonin, this study evaluated its analgesic effect on inflammatory pain induced by complete Freund's adjuvant (CFA) in Wistar rats. Inflammation was induced by intradermal CFA injection in the hind paw of all animals, which were then divided into two groups that received either 60 mg/kg of melatonin or vehicle (1% alcohol in saline), intraperitoneally, for three days. The analgesic effect of melatonin was assessed by the hot-plate test, immediately and thereafter at 30, 60, 90, and 120 minutes after the first administration and 24 hours after once-daily administration for 2 more days. After CFA injection, melatonin administration increased withdrawal latency at 60 minutes after the first dose. After the end of treatment, melatonin showed a significant analgesic effect on inflammatory pain. This study paves the way for exploration of how brief courses of treatment could improve this analgesic effect in the late phases of inflammatory pain.
PLOS ONE, 2013
Background: Previous studies have suggested that melatonin may produce antinociception through peripheral and central mechanisms. Based on the preliminary encouraging results of studies of the effects of melatonin on pain modulation, the important question has been raised of whether there is a dose relationship in humans of melatonin on pain modulation. Objective: The objective was to evaluate the analgesic dose response of the effects of melatonin on pressure and heat pain threshold and tolerance and the sedative effects. Methods: Sixty-one healthy subjects aged 19 to 47 y were randomized into one of four groups: placebo, 0.05 mg/kg sublingual melatonin, 0.15 mg/kg sublingual melatonin or 0.25 mg/kg sublingual melatonin. We determine the pressure pain threshold (PPT) and the pressure pain tolerance (PPTo). Quantitative sensory testing (QST) was used to measure the heat pain threshold (HPT) and the heat pain tolerance (HPTo). Sedation was assessed with a visual analogue scale and bispectral analysis. Results: Serum plasma melatonin levels were directly proportional to the melatonin doses given to each subject. We observed a significant effect associated with dose group. Post hoc analysis indicated significant differences between the placebo vs. the intermediate (0.15 mg/kg) and the highest (0.25 mg/kg) melatonin doses for all pain threshold and sedation level tests. A linear regression model indicated a significant association between the serum melatonin concentrations and changes in pain threshold and pain tolerance (R 2 = 0.492 for HPT, R 2 = 0.538 for PPT, R 2 = 0.558 for HPTo and R 2 = 0.584 for PPTo). Conclusions: The present data indicate that sublingual melatonin exerts well-defined dose-dependent antinociceptive activity. There is a correlation between the plasma melatonin drug concentration and acute changes in the pain threshold. These results provide additional support for the investigation of melatonin as an analgesic agent.
Studies on the Anti-Inflammatory and Anti-Nociceptive Effects of Melatonin in the Rat
Pharmacological Research, 2002
The present study aimed to evaluate the anti-inflammatory and anti-nociceptive effects of melatonin in the rat. Acute inflammation was induced by sub-plantar injection of carrageenan (1%) in the rat hind paw. The rats received vehicle or drug 30 min before carrageenan administration and were evaluated for paw oedema at 1, 2, 3, and 4 h post-carrageenan. The induced inflammation and the formation of oedema were determined by measurement of the paw thickness. Nociception was tested by determining vocalization following electrical stimulation of the tail. Given intraperitoneally (i.p.) 30 min before carrageenan, melatonin caused significant and a dose-dependent reduction of hind paw swelling induced by carrageenan. At doses of 0.5 and 1 mg kg −1 , melatonin inhibited the carrageenan-induced oedema by 20.5 and 29.6% versus control values at 4 h post-carrageenan, respectively. Melatonin (0.5 and 1 mg kg −1 , i.p.) 30 min beforehand displayed anti-nociceptive effect in the electric stimulation of the rat tail test, increasing nociceptive thresholds to electrically-induced pain at 4 h post-treatment by 29.6 and 39.5%, respectively. Melatonin given simultaneously with the non-selective COX-1 and COX-2 inhibitor indomethacin (5 mg kg −1 , i.p.) 30 min prior to carrageenan, enhanced the anti-inflammatory effect of the latter in the carrageenan-induced paw oedema model by 23%. Melatonin (0.5 mg kg −1 , i.p.) increased the anti-nociceptive effect of indomethacin (5 mg kg −1 , i.p.). Meanwhile, the anti-inflammatory and anti-nociceptive effect of the highly selective COX-2 inhibitor rofecoxib (2.25 mg kg −1 , i.p.) was only slightly increased by melatonin administration at 0.5 mg kg −1 . Melatonin enhanced the anti-inflammatory effect of cysteamine (300 mg kg −1 , s.c.) in the carrageenan-induced paw oedema. Melatonin (20 and 40 µg per paw) given prior to carrageenan into the rat hind paw was devoid of anti-inflammatory effect. These results indicate that melatonin possesses anti-inflammatory and anti-nociceptive properties in the rat and enhance those of indomethacin. This effect is likely to be centrally mediated.
Melatonin in Antinociception: Its Therapeutic Applications
Current Neuropharmacology, 2012
The intensity of pain sensation exhibits marked day and night variations. Since the intensity of pain perception is low during dark hours of the night when melatonin levels are high, this hormone has been implicated as one of the prime antinociceptive substances. A number of studies have examined the antinociceptive role of melatonin in acute, inflammatory and neuropathic pain animal models. It has been demonstrated that melatonin exerts antinociceptive actions by acting at both spinal cord and supraspinal levels. The mechanism of antinociceptive actions of melatonin involves opioid, benzodiazepine, α 1 -and α 2 -adrenergic, serotonergic and cholinergic receptors. Most importantly however, the involvement of MT 1 /MT 2 melatonergic receptors in the spinal cord has been well documented as an antinociceptive mechanism in a number of animal models of pain perception. Exogenous melatonin has been used effectively in the management of pain in medical conditions such as fibromyalgia, irritable bowel syndrome and migraine and cluster headache. Melatonin has been tried during surgical operating conditions and has been shown to enhance both preoperative and post-operative analgesia. The present review discusses the available evidence indicating that melatonin, acting through MT 1 /MT 2 melatonin receptors, plays an important role in the pathophysiological mechanism of pain.
The effects of melatonin on burn-induced inflammatory responses and coagulation disorders in rats
Methods and Findings in Experimental and Clinical Pharmacology, 2010
The experimental procedure was approved by the Home Office for Care and Use of Laboratory Animals and performed with a strong consideration for ethics in animal experimentation. Age-matched male rats weighing 220-250 g and fasting for 12 h were allowed free access to water before injury. Animals were housed in a 20 °C tem
Journal of Mind and Medical Sciences
Introduction. Thermal injury activates an inflammatory response. Melatonin possesses antioxidant and anti-inflammatory properties. The objective of the present work was to study melatonin effects on the inflammatory response under conditions of oxidative stress during the early stage of thermal injury. Materials and methods. We used 24 white male rats of Wistar breed, randomly divided into three experimental groups. Group one was the control, group two was inflicted with burn trauma, and group three was inflicted with burn trauma, with melatonin application following the thermal injury. Melatonin was applied twice in doses of 10 g/kg b.m. immediately after the burn trauma and again at 12 hours. Plasma levels of tumor necrosis-factor-α (TNF-α), a pro-inflammatory mediator, and of interleukin-10 (Il-10), an anti-inflammatory mediator, were examined and their ratio was calculated. The levels of malondialdehyde (MDA), an oxidative stress marker, were also estimated. Results. Thermal trauma significantly increased plasma TNF-α levels (ð<0.01) and TNF-α /IL-10 ratio but did not change IL-10 ones. Plasma MDA concentrations were significantly elevated as well (ð<0.0001). Melatonin application significantly reduced TNF-α (ð<0.05), increased IL-10 (ð<0.05), down-regulated TNF-α/IL-10 ratio and changed MDA concentrations (ð<0.01). In conclusion, our results show that local alteration induces oxidative stress and inflammatory response with TNF-α /IL-10 disbalance. Melatonin modulates this response and attenuates oxidative stress in experimental burn injury.
Salivary melatonin response to acute pain stimuli
Journal of Pineal Research, 2001
Evidence for a relationship between melatonin, nociception, and analgesia in humans is based on data that are only linked by association and simultaneous occurrence. Studies have reported inverse correlation of the circadian melatonin rhythm with nociception latency and enhancement of opioid analgesia by simultaneous administration of melatonin in animals. This study examines the response of salivary melatonin to acute pain stimuli in 18 healthy subjects ranging in age from 19 to 50 years. A biphasic melatonin response following an acute pain stimulus of 36 V was observed, F(8, 8)=17.839, P<0.001. Within 5 min of the stimulus, melatonin decreased and reached a plateau of 36 pg/mL below baseline by 20 min. This decrease was followed by an increase of 5 pg/mL. Melatonin levels subsequently decreased until they had reached levels similar to those anticipated for the time of day and did not vary thereafter. The magnitude of the melatonin response was not related to age or gender. The...
The effect of thermal injury and melatonin on incisional wound healing.
Background: Oxygen -free radicals are generated during inflammatory reactions and cause tissue damage when overproduced. The wounds, especially burn injuries which comprise several events, result in generation of reactive oxygen species and impairment of cellular functions as in wound healing process. This experimental study was done in order to investigate whether 20% body surface area, third degree burn injury creates systemic impairment in wound healing. Additionally, our aim was to evaluate the effects of melatonin on incisional cutaneous wound healing. Methods: Fifty adult Wistar-Albino rats were included in the study. A group of animals were subjected to dorsal burn injury followed by full-thickness midline skin incision, 2 cm in length on the abdominal region which was primarily sutured. Melatonin was administered on incisional wounds and breaking strength, hydroxyproline, thiobarbituric acid reactive substance values and antioxidant enzyme activities in the wounded tissue were determined at day 7; to examine firstly the influence of thermal injury on systemic wound healing and secondly, whether melatonin possesses improving effects. Results: No detrimental effect of 20% burn injury on unburned cutaneous incisional wound healing was determined. There was not any difference in breaking strength, hydroxyproline, thiobarbituric acid reactive substance and glutathione peroxidase values, except for significantly elevated catalase and superoxide dismutase activities in melatonin-treated animals comparing to the control group. Conclusion: This preliminary study disclosed that exogenous melatonin, at a dose of 10mg/kg for two days, exerted few variation in antioxidant status during wound repair. Nevertheless, half-life of melatonin is short and further studies are required, to investigate longer duration or higher dosage of administration which may be beneficial for cutaneous wound healing.
Saving the zone of stasis in burns with melatonin: An experimental study in rats
Turkish Journal of Trauma and Emergency Surgery, 2015
BACKGROUND: Studies aimed at recovering the zone of stasis are one of the major issues of experimental burn studies. Many drugs including antithrombotics, anticoagulants, anti-inflammatories have been investigated experimentally for saving the zone of stasis. In this study, the effect of the systemic melatonin on the zone of stasis was evaluated. METHODS: Twenty Wistar Albino rats were used in the study. Rats were assigned to two groups (n=10). The metal comb 1x2 cm in size was immersed in boiling water and held for 20 seconds on the back of the rats to create burn wounds.No treatment was given to the control group. Melatonin was given at a dose of 10 mg/kg/d by intraperitoneal injection in the treatment group for 7 days. Daily digital photographs of both groups were obtained. Total necrotic burn areas and the zone of stasis were assessed with Auto CAD and Visual Analyzing computer programs. At the end of one week, rats were sacrificed and skin biopsies were taken for histological examination. Edema, congestion, inflammatory infiltration, vascular proliferation and fibrosis were the parameters evaluated. Data were evaluated statistically by Chi-square test and Student-t test. RESULTS: When histopatologic data and the measured values for total necrotic areas and zone of stasis of the experimental group werecompared to control group, the results were statistically significant (p<0.05). CONCLUSION: According to the results of this study, melatonin is efficient in saving the zone of stasis in burns.