<p>Metadon je sintetski agonist opijatnih receptora koji se primenjuje u sklopu supstitucione terapije opijatnih zavisnika metadonom (STM) i u terapiji hroničnog bola. Dugoročna primena STM je praćena blagim, uglavnom prolaznim, neželjenim delovanjima. Međutim, metadon pripada grupi lekova koji mogu da prouzrokuju prolongaciju korigovanog QT intervala (QTc) u elektrokardiogramu (EKG-u) i povećaju rizik za nastanak potencijalno fatalnih aritmija tipa torsades de pointes. Opijatni zavisnici metadon najčešće koriste u kombinaciji sa benzodiazepinima, i ova kombinacija lekova predstavlja faktor rizika za nastanak smrtnog ishoda. Iako je najveći broj lekara upoznat sa rizikom za razvoj respiratorne depresije prilikom primene opijata u kombinacji sa benzodiazepinima, velika studija otkriva da su ventrikularne aritmije i srčani zastoj najčešće prijavljivana neželjena delovanja metadona, primenjenog u kombinaciji sa benzodiazepinima. Ciljevi ovoga radu su da se analizom smrtnih slučajeva povezanih sa upotrebom metadona (MRDs) tokom desetogodišnjeg perioda na teritoriji Vojvodine i sprovođenjem kliničkog ispitivanja kod opijatnih zavisnika na STM proceni kardiološka bezbednost primene metadona, posebno u kombinaciji sa benzodiazepinima. Sprovedena je retrospektivna studija za određivanje karakteristika MRDs na teritoriji Vojvodine, kao i kliničko ispitivanje u kome su učestvovali opijatni zavisnici koji počinju sa STM. Snimanje EKG-a (za izračunavanje QTc intervala) i uzorkovanje krvi (za određivanje koncentracije metadona i diazepama i vrednosti troponina) je sprovedeno kod svih učesnika istraživanja u 5 vremenskih tačaka (pre početka primene STM, 8. i 15. dana i nakon 1. i 6. meseca primene STM). Koncentracije metadona i diazepama u serumu su određivane metodom tečne hromatografije sa masenom spektrometrijom (LC-MS). U Vojvodini je zapažena rastuća tendencija MRDs, ali ni jedan od umrlih nije bio na STM, i najverovatnije su samoinicijativno koristili metadon i benzodiazepine. Patohistološki nalaz na srcu može govoriti u prilog kardiotoksičnosti metadona i njegove kombinacije sa benzodiazepinima, pogotovo kod slučajeva sa pronađenim akutnim miokardijalnim oštećenjem. Što se tiče hroničnih promena na srcu, ne postoji mogućnosti da se potvrdi niti opovrgne uloga psihostimulanasa. Detektovane koncentracije metadona i diazepama kod MRDs su bile u opsegu terapijskih (<1 μg/ml). Poredeći socio-demografske karakteristike opijatnih zavisnika koji su počeli sa STM u ovom istraživanju sa podacima iz sličnih studija sprovedenih širom sveta, zapažena je sličnost u pogledu velikog broja karakteristika. Srednje doze metadona 8., 15. dana i nakon 1. i 6. meseca primene STM su bile 40,23±17,11 mg, 47,11±16,79 mg, 50,00±17,55 mg i 78,63±18,14 mg, dok su srednje doze diazepama u istim vremenskim tačkama bile 35,92±10,47 mg, 33,89±9,23 mg, 28,33±11,55 mg i 28,12±11,67 mg. Srednje koncentracije metadona su u posmatranim tačkama ispitivanja iznosile 153,44±111,51 ng/ml, 157,43±112,39 ng/ml, 176,77±118,56 ng/ml i 342,86±181,54 ng/ml, dok su srednje koncentracije diazepama bile 923,00±537,89 ng/ml, 923,76±739,96 ng/ml, 560,74±436,72 ng/ml i 1045,32±932,72 ng/ml. Dužina QTc intervala pre primene STM je bila 411,87±27,22 ms, tj. 414,64±29,38 ms 8. dana STM, 416,97±26,39 15. dana, i 425,20±17,71 ms nakon 1. meseca tj. 423,50±14,72 ms nakon 6. meseca primene STM. Pokazan je statistički značajan porast dužine QTc intervala nakon 1. i nakon 6. meseca primene STM u odnosu na vrednost pre primene STM, kako u grupi svih ispitanika, tako i u podgrupi muškog pola. Pokazano je postojanje statistički značajne korelacije između koncentracije metadona i dužine QTc intervala nakon 15. dana, 1. i 6. meseca primene STM, kako kod svih ispitanika, tako i u podgrupi muškog pola. Ova korelacija ostaje statistički značajna i ukoliko se uključe i drugi faktori – koncentracija diazepama i dužina perioda upotrebe heroina, kod svih ispitanika i u podgrupi muškog pola nakon 15 dana i mesec dana primene STM, kao i u podgrupi muškog pola nakon 6. meseca STM. Iako nijedan pacijent nije prijavio neko neželjeno delovanje metadona na nivou kardiovaskularnog sistema, najveći broj pacijenata oba pola se nakon prvog meseca primene STM žalio na pojačano znojenje i opstipaciju. Koncentracije metadona i diazepama u uzorcima krvi kod MRDs se nalaze u rasponu koncentracija ovih lekova u krvi ispitanika koji su učestvovali u prospektivnoj studiji. Trećina umrlih je imala samo znake akutnog oštećenja srca, dok do porasta troponina i vrednosti QTc intervala preko 500 ms nije došlo ni kod jednog ispitanika iz prospektivne studije. Potrebno je sprovesti dalja istraživanja sa ciljem razjašnjenja moguće uloge benzodiazepina u povećanju kardiotoksičnosti metadona kod opijatnih zavisnika na STM.</p> / <p>Methadone is a synthetic agonist of opioid receptors which is used in methadone maintenance tratment (MMT) of opiate addicts as well as in the treatment of chronic pain. A long-term use of MMT is followed by mild, mostly transient, adverse effects. However, methadone belongs to a group of medicines which can provoke a prolongation of QTc (corrected QT) interval in electrocardiogram (ECG) and thus increase the risk from the development of potentially fatal arrhythmias – torsades de pointes. Moreover, methadone is widely associated with benzodiazepines use in heroin addicts, and this combination is considered as a risk factor for lethal outcome. Despite the fact that most of health care professionals are aware of possible respiratory depressant effect of methadone and benzodiazepines co-administration, recently published data reveal that ventricular arrhythmia and cardiac arrest are currently the most frequent adverse event attributed to methadone and benzodiazepine co-medication. The aim of this study is to assess cardiac safety of methadone use, especially in combination with benzodiazepines, by analyzing characteristics of methadone-related deaths (MRDs) during 10-year period as well as by conducting a clinical trial among opiate addicts in MMT. A retrospective study to determine the characteristics of MRDs in Vojvodina, as well as a clinical trial in which participated opiate addicts at the start of MMT were performed. ECG (to calculate QTc interval) and blood sampling (to determine methadone and diazepam concentrations and troponin values) were performed in all study participants at five time points (before the introduction of MMT, on 8th, on 15th day, after 1 and 6 months of MMT). Methadone and diazepam concentrations in serum were determined by using liquid chromatography-mass spectrometry (LC-MS). An increasing tendency of MRDs was observed in the region of Vojvodina, but none of the victims were under healthcare professionals’ control, and, most commonly, they used methadone and benzodiazepines, on their own initiative. Pathohistological findings in the heart in MRDs might support cardiac adverse effects of methadone and its combination with benzodiazepines, especially in cases with acute myocardial damage. As for the chronic heart changes, we can neither confirm nor exclude the role of psychostimulants. Detected concentrations of methadone and diazepam were in therapeutic range (<1 μg/ml). Comparing socio-demographic characteristics of opiate addicts who started with MMT in this study with data from similar studies conducted worldwide, the similarity in terms of large number of features was observed. The mean methadone dose on the 8th, 15th days, and after 1 and 6 months of MMT was 40.23±17.11 mg, 47.11±16.79 mg, 50.00±17.55 mg and 78.63±18.14 mg, respectively, while the mean diazepam dose at the same time points was 35.92±10.47 mg, 33.89±9.23 mg, 28.33±11.55 mg and 28.12±11.67 mg, respectively. The mean methadone concentration at observed time points was 153.44±111.51 ng/ml, 157.43±112.39 ng/ml, 176.77±118.56 ng/ml and 342.86±181.54 ng/ml, respectively, while the mean diazepam concentration was 923.00±537.89 ng/ml, 923.76±739.96 ng/ml, 560.74±436.72 ng/ml and 1045.32±932.72 ng/ml, respectively. The length of QTc interval before the introduction of MMT was 411.87±27.22 ms, 414.64±29.38 ms on the 8th day of MMT, 416.97±26.39 on the 15th day of MMT, after 1 month of MMT 425.20±17.71 ms and after 6 months of MMT 423.50±14.72 ms. There was a statistically significant increase in the length of QTc interval after 1 and 6 months of MMT in comparison to the value before the application of MMT, within the whole group of patients and in the subgroup of men. A statistically significant correlation between the concentration of methadone and QTc interval length after 15 days, 1 and 6 months of MMT, both in the whole group and in the subroup of men was observed. The correlation remained statistically significant if the other factors, such as concentration of diazepam and the length of heroin use, were included, in all patients and in the subgroup of men after 15 days and one month of MMT as well as in the subgroup of men after 6 months of MMT. Although none of the patients reported any cardiac adverse effect of methadone, the majority of them complained of sweating and constipation after the first month of MMT. Concentrations of methadone and diazepam in blood samples in MRDs were within the range of concentrations of these drugs in blood of patients who participated in the prospective study. In one third of MRDs only signs of acute myocardial damage were detected, while an increase in troponin values and the length of QTc interval over 500 ms did not occur in any patient in the prospective study. Further studies could clarify the possible role of benzodiazepines in the increasing cardiotoxicity of methadone in opiate addicts in MMT.</p>
| Identifer | oai:union.ndltd.org:uns.ac.rs/oai:CRISUNS:(BISIS)87273 |
| Date | 22 October 2014 |
| Creators | Mijatović Vesna |
| Contributors | Samojlik Isidora, Petković Stojan, Sabo Ana, Srdanović Ilija, Savić Slobodan, Dickov Aleksandra, Vasović Velibor |
| Publisher | Univerzitet u Novom Sadu, Medicinski fakultet u Novom Sadu, University of Novi Sad, Faculty of Medicine at Novi Sad |
| Source Sets | University of Novi Sad |
| Language | Serbian |
| Detected Language | Unknown |
| Type | PhD thesis |
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