The analgesic effects of exogenous melatonin in humans.

The hormone, melatonin is produced with circadian rhythm by the pineal gland in humans. The melatonin rhythm provides an endogenous synchronizer, modulating e.g. blood pressure, body temperature, cortisol rhythm, sleep-awake-cycle, immune function and anti-oxidative defence. Interestingly, a number of experimental animal studies demonstrate significant dose-dependent anti-nociceptive effects of exogenous melatonin. Similarly, recent experimental- and clinical studies in humans indicate significant analgesic effects. In study I, we systematically reviewed all randomized studies investigating clinical effects of perioperative melatonin. Meta-analyses demonstrated significant analgesic and anxiolytic effects of melatonin in surgical patients, equating reductions of 20 mm and 19 mm, respectively on a VAS, compared with placebo. Profound heterogeneity between the included studies was, however, present. In study II, we aimed to investigate the analgesic, anti-hyperalgesic and anti-inflammatory effects of exogenous melatonin in a validated human inflammatory pain model, the human burn model. The study was performed as a randomized, double blind placebo-controlled crossover study. Primary outcomes were pain during the burn injury and areas of secondary hyperalgesia. No significant effects of exogenous melatonin were observed with respect to primary or secondary outcomes, compared to placebo. Study III and IV estimated the pharmacokinetic variables of exogenous melatonin. Oral melatonin demonstrated a tmax value of 41 minutes. Bioavailability of oral melatonin was only 3%. Elimination t1/2 were approximately 45 minutes following both oral and intravenous administration, respectively. High-dose intravenous melatonin was not associated with increased sedation, in terms of simple reaction times, compared to placebo. Similarly, no other adverse effects were reported. In Study V, we aimed to re-analyse data obtained from a randomized analgesic drug trial by a selection of standard statistical test. Furthermore, we presented an integrated assessment method of longitudinally measured pain intensity and opioid consumption. Our analyses documented that the employed statistical method impacted the statistical significance of post-operative analgesic outcomes. Furthermore, the novel integrated assessment method combines two interdependent outcomes, lowers the risk of type 2 errors, increases the statistical power, and provides a more accurate description of post-operative analgesic efficacy. Exogenous melatonin may offer an effective and safe analgesic drug. At this moment, however, the results of human studies have been contradictory. High-quality randomized experimental- and clinical studies are still needed to establish a "genuine" analgesic effect of the drug in humans. Other perioperative effects of exogenous melatonin should also be investigated, before melatonin can be introduced for clinical routine use in surgical patients. Despite promising experimental and clinical findings, several unanswered questions also relate to optimal dosage, timing of administration and administration route of exogenous melatonin.

Pharmacokinetics of Melatonin: The Missing Link in Clinical Efficacy?

Despite widespread clinical application of melatonin, several unanswered questions remain regarding the pharmacokinetics of this drug. This lack of knowledge may contribute to the inconsistency of results in previous clinical studies. Currently, a t max value of 30-45 min and a t ½elimination of 45 min are well established. Several questions relate to what constitutes a clinically effective plasma concentration, the choice of ideal administration route, and the optimal method of analysis. Furthermore, investigations of melatonin metabolites in humans are urgently needed in order to characterize their biological functions and the metabolic fates of these derivatives. Finally, pharmacokinetics in patients should be investigated further in order to reduce the risk of potential adverse effects, such as daytime sleepiness or unintended sedation.

The Safety of Melatonin in Humans.

Exogenous melatonin has been investigated as treatment for a number of medical and surgical diseases, demonstrating encouraging results. The aim of this review was to present and evaluate the literature concerning the possible adverse effects and safety of exogenous melatonin in humans. Furthermore, we provide recommendations concerning the possible risks of melatonin use in specific patient groups. In general, animal and human studies documented that short-term use of melatonin is safe, even in extreme doses. Only mild adverse effects, such as dizziness, headache, nausea and sleepiness have been reported. No studies have indicated that exogenous melatonin should induce any serious adverse effects. Similarly, randomized clinical studies indicate that long-term melatonin treatment causes only mild adverse effects comparable to placebo. Long-term safety of melatonin in children and adolescents, however, requires further investigation. Due to a lack of human studies, pregnant and breast-feeding women should not take exogenous melatonin at this moment.

Clinical pharmacokinetics of melatonin: a systematic review.

PURPOSE: The aim of the review was to provide an overview of studies investigating the pharmacokinetics of exogenous melatonin in humans and if possible, to provide recommendations for clinical use. METHODS: The review was conducted in accordance to PRISMA guidelines. A systematic literature search was performed in PubMed and Embase databases. The pharmacokinetic variables included maximal plasma/serum concentration (Cmax), time to maximal plasma/serum concentration (Tmax), elimination half-life (T1/2), area-under-the-curve plasma/serum concentrations (AUC), clearance (Cl), volume of distribution (VD), and bioavailability. RESULTS: The literature search identified 392 records. Twenty-two studies were included in the review. Melatonin dosages varied between 0.3 and 100 mg and were administered either orally or intravenously. Cmax ranged from 72.1 (10 ml/h; 0.02 mg, IV) to 101,163 pg/ml (100 mg, oral). Tmax ranged between 15 (2 mg) and 210 min (10 mg). T1/2 ranged from 28 (0.005 mg, IV) to 126 min (4 mg, oral), whereas AUC ranged between 5400 (0.005 mg, IV) and 6.56 × 10(10) pg/ml × min (1 mg, oral). Cl ranged from 0.97 (0.005 mg, IV) to 132.50 L/min (6 mg, oral), whereas VD ranged between 35 (0.005 mg, IV) and 1602 L (4 mg, oral). Bioavailability of oral melatonin ranged from 9 to 33%. Pharmacokinetics was affected by age, caffeine, smoking, oral contraceptives, feeding status, and fluvoxamine. Critically ill patients displayed accelerated absorption and compromised elimination. CONCLUSIONS: Despite methodological differences between the included studies, Tmax was approximately 50 min following oral immediate-release formulations of melatonin. T1/2 was 45 min in both administration routes. Cmax, AUC, Cl, and VD varied extensively between studies. Bioavailability of oral melatonin was approximately 15%.

Absence of analgesic effect of intravenous melatonin administration during daytime after laparoscopic cholecystectomy: a randomized trial.

STUDY OBJECTIVE: To investigate whether melatonin administered intraoperatively reduced pain following laparoscopic cholecystectomy. DESIGN: Randomized, placebo-controlled, double-blinded study. SETTING: Two surgical departments in Copenhagen. PATIENTS: 44 women between 18 and 70 years of age, who were surgical candidates for laparoscopic cholecystectomy. INTERVENTIONS: Patients were anesthetized by a standard protocol and received a standard multimodal postoperative analgesic regimen. Patients undergoing surgery were admitted on the day of surgery and were discharged the day after surgery. Ten mg of intravenous (IV) melatonin or placebo were administered at the time of surgical incision. MEASUREMENTS: Pain was assessed by a set of questionnaires documenting "pain at rest" using a visual analog scale (VAS). The use of rescue medication was recorded. Sleep quality and general well-being were measured on separate VAS scales. Sleepiness was assessed by the Karolinska Sleepiness Scale. MAIN RESULTS: Forty-four patients were included and randomized to the study. Three patients did not complete the study. No differences in VAS pain scores, sleep quality, general well-being, or sleepiness were found between the two groups in the postoperative period. The use of postoperative rescue medication did not differ between the groups. CONCLUSIONS: The use of 10mg of IV melatonin administered during laparoscopic cholecystectomy did not affect postoperative pain or use of analgesic medication.

Emergence delirium.

Emergence delirium (ED) is a well-known phenomenon in the postoperative period. However, the literature concerning this clinical problem is limited. This review evaluates the literature with respect to epidemiology and risk factors. Treatment strategies are discussed. The review concludes that there is a need for guidelines concerning diagnosis and treatment of ED. Risk factors should be investigated further in the clinical setting in the future.

Psychological and physical stress among experienced and inexperienced surgeons during laparoscopic cholecystectomy.

PURPOSE: Surgical procedures are mentally and physically demanding, and stress during surgery may compromise patient safety. We investigated the impact of surgical experience on surgeons' stress levels and how perioperative sleep quality may influence surgical performance. METHODS: Eight experienced and 8 inexperienced surgeons each performed 1 laparoscopic cholecystectomy. Questionnaires measuring perioperative mental and physical strain using validated visual analog scale and Borg scales were completed. Preoperative and postoperative sleep quality of the surgeon was registered and correlated to perioperative strain parameters. RESULTS: Preoperative to postoperative frustration among experienced surgeons was significantly reduced and this was not found in the inexperienced surgeons (visual analog scale: preoperative 13 (2-65) mm, postoperative 4 (0-51) mm vs. preoperative 5(0-10) mm, postoperative 5(1-46) mm; P=0.04). Physical strain was significantly induced in both groups in the upper extremities. Preoperative and postoperative sleep quality was significantly correlated to postoperative mental strain parameters. CONCLUSIONS: Perioperative frustration levels were different among inexperienced and experienced surgeons. Perioperative sleep quality may influence postoperative mental strain and should be considered in studies examining surgeons' stress.

Psychological and physical stress in surgeons operating in a standard or modern operating room.

PURPOSE: There have been no studies examining the effect of optimized ergonomic and technical environment on the psychological and physiological stress of the surgeon. The aim of this study was to examine whether optimized ergonomics and technical aids within a modern operating room (OR) affect psychological and physiological stress in experienced laparoscopic surgeons. METHODS: This was a prospective case-controlled study including 10 experienced surgeons. Surgery was performed in 2 different ORs: a standard room and a modern room (OR1-suite, Karl Storz). The surgeons filled out questionnaires concerning physical and psychological wellbeing before and after surgery and had their heart rate variability registered during surgery. RESULTS: Preoperative to postoperative physical strain and pain measurements revealed a systematical difference with 14 of 15 parameters favoring the modern OR. Two of these parameters reached statistical significance. We did not find any significant differences in the subjective parameters of surgeon satisfaction or the measured heart rate variability parameters. CONCLUSIONS: Physical strain on the surgeon was reduced when performing laparoscopic cholecystectomy in a modern OR compared with a standard room.

Long-term recurrence and complication rates after incisional hernia repair with the open onlay technique.

BACKGROUND: Incisional hernia after abdominal surgery is a well-known complication. Controversy still exists with respect to the choice of hernia repair technique. The objective of this study was to evaluate the long-term recurrence rate as well as surgical complications in a consecutive group of patients undergoing open repair using an onlay mesh technique. METHODS: Consecutive patients undergoing open incisional hernia repair with onlay-technique between 01/05/1995 and 01/09/2007 at a single institution were included in the study. For follow-up patients were contacted by telephone, and answered a questionnaire containing questions related to the primary operation, the hernia and general risk factors. Patients were examined by a consultant surgeon in the outpatient clinic or in the patient's home if there was suspicion of an incisional hernia recurrence. RESULTS: The study included 56 patients with 100% follow-up. The median follow-up was 35 months (range 4-151). Recurrent incisional hernia was found in 8 of 56 patients (15%, 95% CI: 6-24). The overall complication rate was 13% (95% CI, 4-22). All complications were minor and needed no hospital admission. CONCLUSION: This study with a long follow-up showed low recurrence and complication rates in patients undergoing incisional hernia repair with the open onlay technique.

Increased risk of anastomotic leakage with diclofenac treatment after laparoscopic colorectal surgery.

BACKGROUND: Over a period our department experienced an unexpected high frequency of anastomotic leakages. After diclofenac was removed from the postoperative analgesic regimen, the frequency dropped. This study aimed to evaluate the influence of diclofenac on the risk of developing anastomotic leakage after laparoscopic colorectal surgery. METHODS: This was a retrospective case-control study based on 75 consecutive patients undergoing laparoscopic colorectal resection with primary anastomosis. In period 1, patients received diclofenac 150 mg/day. In period 2, diclofenac was withdrawn and the patients received an opioid analgesic instead. The primary outcome parameter was clinically significant anastomotical leakage verified at reoperation. RESULTS: 1/42 patients in the no-diclofenac group compared with 7/33 in the diclofenac group had an anastomotic leakage after operation (p = 0.018). In a multivariate regressional analysis, none of the recorded factors were significantly associated with the frequency of anastomotical leakages when diclofenac treatment was omitted from the model. CONCLUSIONS: We found an increased number of clinically significant anastomotic leakages in patients receiving oral diclofenac for postoperative analgesia. There is an urgent need to test our hypothesis in prospective randomized clinical trials and to examine whether our findings can be extended to open surgery and to other NSAIDs.

[Problems concerning analysis of learning curves in surgery]. / Indlaeringskurver--vildledning eller vejledning?

The introduction of laparoscopic surgery has put focus on the assessment of the technical abilities of the surgeon. Studies on learning curves have often focused on operative time, conversion rate, complication rate and length of hospital stay as effect parameters. Learning is a complex process, and the interpretation of learning curves is not straight-forward. This paper addresses the problems concerning the analysis of learning curves in surgery.

Incisional hernia after open versus laparoscopic sigmoid resection.

BACKGROUND: Incisional hernia after open surgery is a well-known complication with an incidence of up to 20% after a 10-year period. Data regarding the long-term hernia risk after laparoscopic colonic surgery are lacking in the literature. In the present study we compared the long-term hernia incidence after laparoscopic versus open sigmoid resection. METHODS: The study included patients undergoing laparoscopic sigmoid resection in the period January 1995 to December 2004 in the eastern part of Denmark. This group was matched with a consecutive group of patients undergoing open surgery in our department in the same period. Patients were contacted by telephone, and a questionnaire was completed for each patient. If the patient was believed to have a hernia or if there was any suspicion of a hernia, a consultant surgeon examined the patient and completed the questionnaire. Factors related to the primary operation, the hernia and general risk factors were registered for all patients. RESULTS: A total of 201 patients answered the questionnaire (95.3%). The laparoscopy group was comprised of 58 patients and 143 patients were included in the laparotomy group. The patients had a median follow-up of 4.6 years (range 2.4-11.7 years) and 4.9 years (range 2.4-8.5 years) after laparoscopic and open surgery, respectively (P = 0.326). Incisional hernia was found in two of 58 patients (3.4%, 95% CI -1.4-7.4) in the laparoscopic surgery group compared with 21 of 143 patients (14.7%, 95% CI 8.9-20.5) in the open surgery group (P = 0.026). There were no significant differences in demographic data or the occurrence of risk factors between the two groups. CONCLUSION: Laparoscopic sigmoid resection leads to a significantly lower incidence of incisional hernia compared with the open surgical technique.