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Clinical Uses of Melatonin: Evaluation of Human Trials
Abstract and Figures
During the last 20 years, numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. The objective of this article is to review, in depth, the science regarding clinical trials performed to date. The efficacy of melatonin has been assessed as a treatment of ocular diseases, blood diseases, gastrointestinal tract diseases, cardiovascular diseases, diabetes, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome, infectious diseases, neurological diseases, sleep disturbances, aging and depression. Melatonin has been also used as a complementary treatment in anaesthesia, hemodialysis, in vitro fertilization and neonatal care. The conclusion of the current review is that the use of melatonin as an adjuvant therapy seems to be well funded for macular degeneration, glaucoma, protection of the gastric mucosa, irritable bowel syndrome, arterial hypertension, diabetes, side effects of chemotherapy and radiation in cancer patients or hemodialysis in patients with renal insufficiency and, especially, for sleep disorders of circadian etiology (jet lag, delayed sleep phase syndrome, sleep deterioration associated with aging, etc.) as well as in those related with neurological degenerative diseases (Alzheimer, etc.,) or Smith-Magenis syndrome. The utility of melatonin in anesthetic procedures has been also confirmed. More clinical studies are required to clarify whether, as the preliminary data suggest, melatonin is useful for treatment of fibromyalgia, chronic fatigue syndrome, infectious diseases, neoplasias or neonatal care. Preliminary data regarding the utility of melatonin in the treatment of ulcerative colitis, Crohn's disease, rheumatoid arthritis are either ambiguous or negative. Although in a few cases melatonin seems to aggravate some conditions, the vast majority of studies document the very low toxicity of melatonin over a wide range of doses.
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... Growing evidence supports the other beneficial multi-organ effects of melatonin, as extensively reviewed previously 4,115 . The therapeutic potential of melatonin includes metabolic disorders 116 , various cancers 117 , neurodegenerative diseases 118 , reproductive diseases 119 , bone diseases (osteopenia, osteoporosis, and periodontal disease) 120 , eye (macular degeneration, glaucoma) 121 and skin diseases 122 . ...
... Previous studies reported the effective melatonin dosage to reduce oxidative stress, related to a surgical procedure, to be as high as 10 mg/kg [124][125][126] . On average the melatonin dose used in the clinical studies are however significantly lower than those used in the experimental models 115 . Dwaich et al furthermore demonstrated the importance of melatonin dosing by reporting on the dose dependant decrease in troponin and inflammatory markers following cardiac surgery 109 . ...
... The majority of clinical trials, as reviewed by two review articles, have shown very low melatonin toxicity 55,115,127 . In a phase I dose escalation study to assess the tolerability and pharmacokinetics in healthy volunteers, no adverse effects were noticed following the oral doses of 20, 30, 50, and 100 mg of melatonin 21,128 . ...
Australasian Anaesthesia (the Blue Book) is produced every two years, and contains a diverse range of topics of interest to anaesthetists, intensive care physicians and pain medicine specialists.
... Likewise, melatonin interacts with toxic reagents, generating other metabolites that are in turn direct free radical scavengers. The combined actions of melatonin and its derivatives greatly enhance the efficacy of melatonin in protecting against free radical damage and reducing the likelihood of human disease [130]. ...
Beer is a world-famous beverage, second only to tea and coffee, where the yeasts traditionally used are Saccharomyces cerevisiae and Saccharomyces pastorianus for the production of ale and lager beer, respectively. Their production, especially craft beer production, has grown in recent years, as has the development of new products. For this reason, research has focused on the selection of yeasts with good fermentation kinetics, as well as beers with outstanding aromatic profiles. The final flavor and aroma of beer is a combination of hundreds of active aroma compounds produced mostly during fermentation as a result of yeast metabolism (higher alcohols, esters, aldehydes, and vicinal diketones). Likewise, several studies have demonstrated the potential of wild yeasts of the genus Saccharomyces, both in aromatic production and in the production of healthy compounds of interest such as melatonin. This chapter therefore focuses on non-conventional Saccharomyces yeasts as they have the capacity to produce outstanding aroma compounds, as well as compounds that can provide health benefits, under moderate consumption.
... Several studies have shown that melatonin exhibits very low toxicity when administered at various doses [44]. In particular, for every 1 mg of exogenous melatonin consumed by the mother, an increase from 0.4 to 1 mcg/L of its concentrations in breast milk is observed. ...
We present a pediatric case of the antiplatelet effect of melatonin taken through breast milk in an 18-month-old child. The child was referred to our hematology outpatient clinic because of bleeding episodes that she presented since birth. Blood tests excluded the presence of blood coagulation diseases. The family history was negative for bleeding disorders. The child did not consume any drugs, food supplements, herbal teas or infusions. We performed an aggregation platelet test, which showed a reduced platelet aggregation. Shortly before, the baby had been breastfed. We speculated that breast milk could interfere with the result of the test; therefore, we decided to repeat the test in a fasting state. This time the test showed a normal platelet aggregation time. We learned that the child’s mother was taking a mixture of valerian and melatonin. Thus, we decided to suspend maternal intake of melatonin and perform a new platelet aggregation test after three months. The test results were negative. After the suspension of melatonin, the patient did not present further bleeding events. In this case, melatonin, through the inhibition of platelet aggregation, had an important role on the hemostatic system of the child. Melatonin is considered as a dietary supplement and is mostly available as an alternative medicine without formal prescription and dosage regulation. It is important, especially during breastfeeding, to investigate personal and medication history, including also homeopathic remedies or dietary supplements.
... It has a suitable solubility in water and lipid and can be absorbed within minutes after oral administration or injection [14]. To date, a large number of experimental and clinical studies have been conducted to investigate the beneficial effects of melatonin in different diseases such as neurological degenerative diseases (like Alzheimer's and depression), cancer, sleep disorders, fatigue syndrome, fibromyalgia, cystic fibrosis, and some others [15][16][17]. ...
Resistance to therapy and the toxicity of normal tissue are the major problems for efficacy associated with chemotherapy and radiotherapy. Drug resistance is responsible for most cases of mortality associated with cancer. Furthermore, their side effects can decrease the quality of life for surviving patients. An enhancement in the tumor response to therapy and alleviation of toxic effects remain unsolved challenges. One of the interesting topics is the administration of agents with low toxicity to protect normal tissues and/or sensitize cancers to chemo/radiotherapy. Melatonin is a natural body hormone that is known as a multitasking molecule. Although it has antioxidant properties, a large number of experiments have uncovered interesting effects of melatonin that can increase the therapeutic efficacy of chemo/radiation therapy. Melatonin can enhance anticancer therapy efficacy through various mechanisms, cells such as the immune system, and modulation of cell cycle and death pathways, tumor suppressor genes, and also through suppression of some drug resistance mediators. However, melatonin may protect normal tissues through the suppression of inflammation, fibrosis, and massive oxidative stress in normal cells and tissues. In this review, we will discuss the distinct effects of melatonin on both tumors and normal tissues. We review how melatonin may enhance radio/chemosensitivity of tumors while protecting normal tissues such as the lung, heart, gastrointestinal system, reproductive system, brain, liver, and kidney.
... mprove fatigue in patients with MS, no significant improvements in the levels of fatigue were observed in stroke patients . Another study by Sanchez-Barcelo et. al. investigated the efficacy of Melatonin, a natural hormone which regulates wake and sleep cycles. This also proved largely unsuccessful in improving levels of fatigue in stroke patients (Sanchez-Barcelo et. al., 2010). With the failure of conventional treatments in directly targeting fatigue in stroke victims, there is currently insufficient evidence to guide physicians towards an effective treatment for fatigue in their stroke patients. ...
Project Supervisor: Professor Trudie Chalders
Assistant Project Supervisor: Dr. Alicia Hughes
... 26 The dosage range used varies from 0.1 to 300 mg per day for long-term administration and up to 2000 mg for short-term administration. 28,51,55 In addition, even though exogenous melatonin toxicology and safety have been studied in a limited manner, the general conclusion is that melatonin lacks toxic adverse effects and is a safe drug for clinical treatments. 15 Compelling evidence has demonstrated the association of melatonin with a depressive effect on the central nervous system, 10,41 reduced alertness, 4,21,32,52 and decreased body temperature. ...
Context:
Melatonin is an ancient molecule with a wide range of functions in mammals, such as antioxidant, anti-inflammatory, and hypothermic effects among others. However, the influence of acute melatonin administration on human physical performance is debatable.
Objective:
To summarize available data from controlled trials about the effects of acute melatonin administration on human physical performance, especially with respect to strength, power, speed, and short- and long-term continuous exercise.
Data sources:
A systematic search of the PubMed, Web of Science, Scopus, Embase, and Cochrane databases up to December 10, 2021, was conducted using specified keywords and Boolean operators ("melatonin" AND "exercise OR circuit-based exercise OR plyometric exercise OR exercise tolerance OR exercise test").
Study selection:
Only controlled studies in the English language and with humans were accepted.
Study design:
Systematic review.
Level of evidence:
Level 1.
Data extraction:
Participants' characteristics (sex, age, body mass, height and fat percentage), melatonin dose and administration time, and outcomes from the performance trial were extracted.
Results:
A total of 10 studies were identified after the screening process. Overall, melatonin did not change speed or short-term continuous exercise performances. However, in relation to strength and power, the results are debatable since 5 articles showed no difference, while another 2 pointed to a decrease in performance. In terms of performance improvement, only 1 study reported an increase in balance and another in long-term continuous exercise performance in nonathletes, with no advantage found for athletes.
Conclusion:
Melatonin did not cause any significant change in strength, speed, power, and short-term continuous exercise performances. In fact, it led to reduced strength and power performances in specific tests. On the other hand, melatonin seems to have improved balance and long-term continuous exercise performance, at least in nonathletes. More investigations are required to corroborate these findings.
... The use of melatonin for the management of gastrointestinal cancer has received great attention as a potential alternative therapy; this relates to its high safety profile, its anti-cancer actions, and finally its very low toxicity (79). Melatonin co-administration with other therapeutic agents enhances their efficacy (80). ...
Several factors impact the mortality rate of patients with gastrointestinal cancers including late diagnosis, metastases to distance sites, and lack of efficacy of the conventional therapies. To reduce mortality rate, the novel effective remedies should be explored. Melatonin is an anti-inflammatory, antioxidant and oncostatic molecule and has been showed potential in controlling various malignancies. In the gastrointestinal tract, melatonin plays an important role via its membrane receptors of MT1 and MT2. It can diminish esophageal lesions resulting from acid–pepsin–bile contact and also inhibits expression of myosin light chain kinase as well as reduces its activity by regulating extracellular signal-transduction of protein kinase. The aim of the present study was to review the critical functions of melatonin in the prevention and treatment of esophageal squamous cell carcinoma including its influence on gastrointestinal pathology, oncostatic role and potential mechanisms. Particularly, the inhibitory function of melatonin on esophageal squamous cell carcinoma and its therapeutic effects are summarized. We suggest that melatonin co-treatment will enhance the efficacy of conventional treatments and survival times in patients with esophageal squamous cell carcinoma.
A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or “good stress” and is characterized by low to mild levels of oxidants involved in the regulation of various biochemical transformations such as carboxylation, hydroxylation, peroxidation, or modulation of signal transduction pathways such as Nuclear factor-κB (NF-κB), Mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase, nuclear factor erythroid 2–related factor 2 (Nrf2) and other processes. Increased levels of ROS/RNS, generated from both endogenous (mitochondria, NADPH oxidases) and/or exogenous sources (radiation, certain drugs, foods, cigarette smoking, pollution) result in a harmful condition termed oxidative stress (“bad stress”). Although it is widely accepted, that many chronic diseases are multifactorial in origin, they share oxidative stress as a common denominator. Here we review the importance of oxidative stress and the mechanisms through which oxidative stress contributes to the pathological states of an organism. Attention is focused on the chemistry of ROS and RNS (e.g. superoxide radical, hydrogen peroxide, hydroxyl radicals, peroxyl radicals, nitric oxide, peroxynitrite), and their role in oxidative damage of DNA, proteins, and membrane lipids. Quantitative and qualitative assessment of oxidative stress biomarkers is also discussed. Oxidative stress contributes to the pathology of cancer, cardiovascular diseases, diabetes, neurological disorders (Alzheimer’s and Parkinson’s diseases, Down syndrome), psychiatric diseases (depression, schizophrenia, bipolar disorder), renal disease, lung disease (chronic pulmonary obstruction, lung cancer), and aging. The concerted action of antioxidants to ameliorate the harmful effect of oxidative stress is achieved by antioxidant enzymes (Superoxide dismutases-SODs, catalase, glutathione peroxidase-GPx), and small molecular weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine, and others). Perhaps one of the most effective low molecular weight antioxidants is vitamin E, the first line of defense against the peroxidation of lipids. A promising approach appears to be the use of certain antioxidants (e.g. flavonoids), showing weak prooxidant properties that may boost cellular antioxidant systems and thus act as preventive anticancer agents. Redox metal-based enzyme mimetic compounds as potential pharmaceutical interventions and sirtuins as promising therapeutic targets for age-related diseases and anti-aging strategies are discussed.
Background:
The present study aims to evaluate and compare the effects of 1% melatonin gel plus platelet rich fibrin (PRF) and PRF alone in treatment of furcation defects, clinically and radiographically using cone-beam computed tomography (CBCT).
Methods:
This split-mouth clinical trial included 23 patients with 46 bilateral Grade II furcation defects in 1st or 2nd maxillary or mandibular molars. Control group was treated with PRF alone while Test group with 1% melatonin gel and PRF. Clinical attachment level (CAL) and Horizontal probing depth (HPD) were primary outcome parameters while secondary outcome parameters were probing depth (PD) and defect volume (DV) assessed at 3 and 6 months postoperatively.
Results:
Significantly greater mean reduction of PD, HPD and CAL gain was observed in Test group (2.23 ± 0.41 mm, 2.36 ± 0.68 mm and 2.97 ± 0.62 mm respectively) in comparison with Control group (2.83 ± 0.78mm, 2.85 ± 0.67 mm and 3.21 ± 0.86 mm respectively) at 6 months. A significant reduction in the mean DV was exhibited radiographically in Test group (1.06 ± 0.5 mm3 ) as compared with Control group (3.94 ± 1.32 mm3 ) at the end of 6 months. Both the groups showed improvements in assessed parameters.
Conclusions:
In Grade II furcation defects the combination therapy of 1% melatonin + PRF shows a statistically significant degree of bone fill within the periodontal tissues and also better results in terms of decrease in PD, HPD and a greater CAL gain. This article is protected by copyright. All rights reserved.
Oral cancer (OC) has emerged as a major medical and social issue in many industrialized nations due to the high death rate. It is becoming increasingly common in people under the age of 45, although the underlying causes and mechanisms of this increase remain unclear. Melatonin, as a pleiotropic hormone, plays a pivotal role in a wide variety of cellular and physiological functions. Mounting evidence supports melatonin's ability to modify/influence oral carcinogenesis, help in the reduction of the incidence of OC, and increase chemo- and radiosensitivity. Despite its potential anti-carcinogenic effects, the precise function of melatonin in the management of OC is not well understood. This review summarizes the current knowledge regarding melatonin function in anti-carcinogenesis mechanisms for OC. In addition, clinical assessment and the potential therapeutic utility of melatonin in OC are discussed. This review will provide a basis for researchers to create new melatonin-based personalized medicines for treating and preventing OC.
to determine whether melatonin will improve quality of sleep in healthy older people with age-related sleep maintenance problems.
a double blind randomised placebo controlled crossover trial in healthy older volunteers.
a largely urban population, Auckland, New Zealand.
participants were part of the larger Possible Role of Melatonin in Sleep of Elders study. People 65 years or more of age were recruited through widespread advertising. We screened 414 potential participants by mail using the Pittsburgh Sleep Quality Index, and selected 194 for clinic interview. Exclusions included depression, cognitive impairment, hypnosedative medications, sleep phase abnormalities, medical and/or environmental problems that might impair sleep. Twenty normal and 20 problem sleepers were randomly allocated for this study from a larger sample of 60 normal and 60 problem sleepers. Measurements and results: 24-hour urine 6-sulphatoxymelatonin was measured to estimate melatonin secretion in each participant. Five milligrams of melatonin, or matching placebo were each taken at bedtime for 4 weeks, separated by a 4-week washout period. Sleep quality was measured using sleep diaries, the Leeds Sleep Evaluation Questionnaire, and actigraphy. There was a significant difference between the groups in self-reported sleep quality indicators at entry, but no difference in melatonin secretion. Melatonin did not significantly improve any sleep parameter measured in either group.
5 mg of fast release melatonin taken at bedtime does not improve the quality of sleep in older people with age-related sleep maintenance problems.
Objective: This the first of two articles reviewing the scientific literature on the evaluation and treatment of circadian rhythm sleep disorders (CRSDs), employing the methodology of evidence-based medicine. In this first part of this paper, the general principles of circadian biology that underlie clinical evaluation and treatment are reviewed. We then report on the accumulated evidence regarding the evaluation and treatment of shift work disorder (SWD) and jet lag disorder (JLD). Methods: A set of specific questions relevant to clinical practice were formulated, a systematic literature search was performed, and relevant articles were abstracted and graded. Results: A substantial body of literature has accumulated that provides a rational basis the evaluation and treatment of SWD and JLD. Physiological assessment has involved determination of circadian phase using core body temperature and the timing of melatonin secretion. Behavioral assessment has involved sleep logs, actigraphy and the Morningness-Eveningness Questionnaire (MEQ). Treatment interventions fall into three broad categories: 1) prescribed sleep scheduling, 2) circadian phase shifting ("resetting the clock"), and 3) symptomatic treatment using hypnotic and stimulant medications. Conclusion: Circadian rhythm science has also pointed the way to rational interventions for the SWD and JLD, and these treatments have been introduced into the practice of sleep medicine with varying degrees of success. More translational research is needed, using subjects who meet current diagnostic criteria.
We designed this prospective, randomized, double-blinded, placebo-controlled study to compare the perioperative effects of different doses of melatonin and midazolam. Doses of 0.05, 0.1, or 0.2 mg/kg sublingual midazolam or melatonin or placebo were given to 84 women, approximately 100 min before a standard anesthetic. Sedation, anxiety, and orientation were quantified before, 10, 30, 60, and 90 min after premedication, and 15, 30, 60, and 90 min after admission to the recovery room. Psychomotor performance of the patient was evaluated at these times also, by using the digit-symbol substitution test and Trieger dot test. Patients who received premedication with either midazolam or melatonin had a significant decrease in anxiety levels and increase in levels of sedation preoperatively compared with control subjects. Patients in the three midazolam groups experienced significant psychomotor impairment in the preoperative period compared with melatonin or placebo. After operation, patients who received 0.2 mg/kg midazolam premedication had increased levels of sedation at 90 min compared with 0.05 and 0.1 mg/kg melatonin groups. In addition, patients in the three midazolam groups had impairment of performance on the digit-symbol substitution test at all times compared with the 0.05 mg/kg melatonin group. Premedication with 0.05 mg/kg melatonin was associated with preoperative anxiolysis and sedation without impairment of cognitive and psychomotor skills or affecting the quality of recovery.
Implications: Premedication with 0.05 mg/kg melatonin was associated with preoperative anxiolysis and sedation without impairment of cognitive and psychomotor skills or affecting the quality of recovery.
Study of 2 randomized groups of patients with coronary heart disease, stable exertional angina combined with arterial hypertension, receiving traditional treatment and combined therapy with inclusion of melatonin, was performed. All patients (43 persons at the age from 44 to 69 years) before and after treatment underwent daily monitoring of arterial pressure (AP) by system "BR-102 Schiller", Switzerland. As a result of study, in the group of traditional treatment positive dynamics such as significant decrease in average daily values of systolic arterial pressure (SAP) from 159.7 +/- 3.4 to 146.1 +/- 4.6 (p = 0.02), diastolic arterial pressure (DAP) from 92.7 +/- 1.2 to 88.6 +/- 1.3 (p = 0.03), average daytime AP indices, average nighttime SAP indices, was noticed. SAP and DAP variability was significantly decreased only at daytime from 23.1 +/- 1.7 to 18.8 +/- 1.4 (p = 0.05) and from 18.1 +/- 0.5 to 16.5 +/- 0.4 respectively. Insufficient decrease in SAP and DAP at nighttime was detected. Inclusion of melatonin in traditional therapy leaded to more expressed decrease in average daily, daytime and nighttime AP indices and significant decrease in load by pressure value (SAP and DAP time indices were significantly reduced both at daytime and at nighttime). Degree of SAP and DAP nighttime decrease initially was upon the average 8.1 +/- 1.1% and 7.0 +/- 1.0% respectively (non-dippers), and after combined treatment was 13.4 +/- 0.9% (p = 0.003) and 11.0 +/- 1.1% (dippers), which proved recovery of normal daily AP profile. Significant decrease in SAP variability at daytime from 22.3 +/- 1.8 to 15.1 +/- 1.2 (p = 0.003), at nighttime from 16.1 +/- 1.4 to 12.7 +/- 1.0 (p = 0.05) in DAP variability at daytime from 17.5 +/- 0.4 to 14.5 +/- 0.4 (p < 0.001), at nighttime from 13.1 +/- 0.7 to 11.1 +/- 0.7 (p = 0.05).
Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal disorder affecting up to 3–15% of the general population in Western countries. It is characterised by unexplained abdominal pain, discomfort and bloating in association with altered bowel habits. The pathophysiology of IBS is considered to be multifactorial, involving disturbances of the brain-gut-axis: IBS has been associated with abnormal gastrointestinal motor functions, visceral hypersensitivity, psychosocial factors, autonomic dysfunction and mucosal inflammation. Traditional IBS therapy is mainly symptom oriented and often unsatisfactory. Hence, there is a need for new treatment strategies. Increasing knowledge of brain-gut physiology, mechanisms, and neurotransmitters and receptors involved in gastrointestinal motor and sensory function have led to the development of several new therapeutic approaches. This article provides a systematic overview of recently approved or novel medications that show promise for the treatment of IBS; classification is based on the physiological systems targeted by the medication. The article includes agents acting on the serotonin receptor or serotonin transporter system, novel selective anticholinergics, α-adrenergic agonists, opioid agents, cholecystokinin antagonists, neurokinin antagonists, somatostatin receptor agonists, neurotrophin-3, corticotropin releasing factor antagonists, chloride channel activators, guanylate cyclase-c agonists, melatonin and atypical benzodiazepines. Finally, the role of probiotics and antibacterials in the treatment of IBS is summarised.
A physiological dose of orally administered melatonin shifts circadian rhythms in humans according to a phase-response curve (PRC) that is nearly opposite in phase with the PRCs for light exposure: melatonin delays circadian rhythms when administered in the morning and advances them when administered in the afternoon or early evening. The human melatonin PRC provides critical information for using melatonin to treat circadian phase sleep and mood disorders, as well as maladaptation to shift work and transmeridional air travel. The human melatonin PRC also provides the strongest evidence to date for a function of endogenous melatonin and its suppression by light in augmenting entrainment of circadian rhythms by the light-dark cycle.
IL–2 immunotherapy has been proven to be effective in the treatment of metastatic renal cell cancer (RCC). However, several drugs commonly used in the palliative therapy of cancer may potentially influence IL–2 efficacy, since the anticancer immunity has appeared to depend on complex interactions between immune system and psychoneuroimmunomodulation. In particular, experimental studies and preliminary clinical investigations have shown that the opioid substances, namely morphine, may suppress the anticancer immunity and the efficacy of IL–2 itself. In contrast, other neuroactive substances, in particular the pineal hormone melatonin (MLT), have been proven to stimulate the immune response, including the anticancer immunity, and to abrogate opioid–induced immunosuppression. On this basis, a study was planned to evaluate the effect of a concomitant MLT administration on the efficacy of IL–2 immunotherapy in advanced cancer patients chronically treated with morphine for cancer–related pain. The study was carried out in 30 metastatic RCC patients under chronic therapy with morphine at oral doses ranging from 60 to 120 mg/day. Patients were randomized to receive morphine alone or morphine plus MLT (20 mg/day orally in the evening). The immunotherapeutic cycle consisted of IL–2 subcutaneous administration at a dose of 6 million IU/day for 6 days/week for 4 consecutive weeks. In nonprogressing patients, a second cycle was planned after a 21–day rest period. The percent of partial responses achieved in patients treated with morphine alone was significantly lower than that observed in patients concomitantly treated with MLT (1/16 vs. 4/14, p