BACKGROUND AND PURPOSE: Opioids and benzodiazepines are frequently combined in medical as well as in non-medical contexts. At high doses, such combinations often result in serious health complications attributed to pharmacodynamics interactions. Here, we investigate the contribution of the metabolic interactions between oxycodone, diazepam and diclazepam (a designer benzodiazepine) in abuse/overdose conditions through ex vivo, in vivo and in silico approaches. EXPERIMENTAL APPROACH: A preparation of pooled human liver microsomes was used to study oxycodone metabolism in the presence or absence of diazepam or diclazepam. In mice, diazepam or diclazepam was concomitantly administered with oxycodone to mimic acute intoxication. Diclazepam was introduced on Day 10 in mice continuously infused with oxycodone for 15 days to mimic chronic intoxication. In silico modelling was used to study the molecular interactions of the three drugs with CYP3A4 and 2D6. KEY RESULTS: In mice, in acute conditions, both diazepam and diclazepam inhibited the metabolism of oxycodone. In chronic conditions and at pharmacologically equivalent doses, diclazepam drastically enhanced the production of oxymorphone. In silico, the affinity of benzodiazepines was higher than oxycodone for CYP3A4, inhibiting oxycodone metabolism through CYP3A4. Oxycodone metabolism is likely to be diverted towards CYP2D6. CONCLUSION AND IMPLICATIONS: Acute doses of diazepam or diclazepam result in the accumulation of oxycodone, whereas chronic administration induces the accumulation of oxymorphone, the toxic metabolite. This suggests that overdoses of opioids in the presence of benzodiazepines are partly due to metabolic interactions, which in turn explain the patterns of toxicity dependent on usage. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.
- MeSH
- Benzodiazepines toxicity MeSH
- Cytochrome P-450 CYP3A MeSH
- Diazepam pharmacology MeSH
- Humans MeSH
- Models, Animal MeSH
- Mice MeSH
- Analgesics, Opioid toxicity MeSH
- Oxycodone * MeSH
- Oxymorphone MeSH
- Drug Overdose * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Benzodiazepiny (BZDs) a Z-hypnotika jsou silně návykové látky, které působí na identické GABA receptory. Detoxifikace by měla být dlouhodobá a postupná, obvykle s využitím dlouhodobě působícího BZD (diazepamu). Zatím však neexistuje žádný vhodný komerčně dostupný produkt s potřebným nízkým obsahem diazepamu. Tento přehledový článek popisuje specifické farmakologické aspekty a srovnání jednotlivých BZDs ve vztahu k jejich účinkům a návykovosti. Úspěch léčby souvisí s komfortem pacienta během procesu vysazování léku. Pacienti se obvykle obávají přechodu na vhodnější dlouhodobě působící BZD (diazepam) a během vysazování mají obavy z abstinenčních příznaků. Tyto překážky by bylo možné překonat individualizovanou detoxifikací podle již publikovaných léčebných režimů. K dispozici je třeba mít lékovou formu s velmi přesnými dávkami diazepamu, což by umožnilo dlouhodobé postupné snižování dávky s možnou přísadou adjuvantních léčiv. Snížení dávky přitom nemění vnější vzhled lékové formy a pacient by mohl být léčen až do fáze podávání placeba. Individuálně připravená léková forma s odlišným a přesným obsahem diazepamu může být použita pro pohodlnou detoxifikaci a může také eliminovat psychogenní stres při přechodu z původního léčiva na diazepam a při snižování dávky v průběhu vysazování.
Benzodiazepines (BZDs) and Z-drugs are strongly addictive substances, acting on identical GABA receptors. Detoxification should be long-term and gradual, usually by tapering a long-acting BZD (diazepam) but no suitable commercial pharmaceutic product exists with the necessary low drug content. This review describes the specific pharmacological aspects and comparisons of individual BZDs in relation to their effects and addictiveness. The success of the treatment relates to the patient’s comfort during this process. Patients are typically afraid of switching to a more suitable longacting BZD (diazepam), and become stressed during the tapering and anxious from withdrawal symptoms. These obstacles could be overcome through individualized detoxification according to already published withdrawal schedules based on the administration of very precise diazepam doses in a long-term gradual tapering with possible addition of adjuvant drugs. Dose reduction does not change external appearance of the dosage form, and the patient could be treated until the placebo phase. Individually prepared pharmaceutics with different and precise diazepam contents can be used for comfortable detoxification and also may eliminate psychogenic stress during switching, tapering, and the withdrawal period.
- Keywords
- Z-hypnotika, snižování dávky, detoxifikace,
- MeSH
- GABA-A Receptor Agonists adverse effects therapeutic use MeSH
- Benzodiazepines * adverse effects toxicity MeSH
- Hypnotics and Sedatives * adverse effects toxicity MeSH
- Humans MeSH
- Withholding Treatment MeSH
- Substance-Related Disorders therapy MeSH
- Drug Administration Schedule MeSH
- Drug Tapering MeSH
- Zolpidem adverse effects therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
- Keywords
- Myolastan, Diane 35, Chloe, Minerva, Vrea,
- MeSH
- Benzodiazepines pharmacology adverse effects toxicity MeSH
- Diclofenac MeSH
- Adult MeSH
- Risk Assessment MeSH
- Cardiovascular Diseases etiology MeSH
- Drug and Narcotic Control * methods MeSH
- Skin Diseases etiology MeSH
- Pharmaceutical Preparations standards MeSH
- Drug-Related Side Effects and Adverse Reactions * MeSH
- Safety-Based Drug Withdrawals * MeSH
- Adverse Drug Reaction Reporting Systems MeSH
- Thromboembolism etiology MeSH
- Check Tag
- Adult MeSH
- Female MeSH
- MeSH
- Benzodiazepines administration & dosage adverse effects toxicity MeSH
- Hypnotics and Sedatives administration & dosage adverse effects toxicity MeSH
- Middle Aged MeSH
- Humans MeSH
- Substance-Related Disorders diagnosis therapy MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
Dvacetiletá žena byla nalezena mrtvá ve svém pokoji. Byla medikamentózně léčena pro depresivní a panické poruchy, a opakovaně se pokoušela o suicidium. V blízkosti těla bylo nalezeno mnoho balení předepsaných léčiv, včetně paroxetinu. Při pitvě byly plíce edematózní. Orgány vykazovaly známky mírné kongesce a změny způsobené rozkladem. Autolýzou způsobená ruptura, označená jako gastromalacie, byla popsána na přední části stěny žaludku v oblasti kardie. Toxikologické vyšetření stanovilo 0,78, 3,20 a 17,63 µg/ml paroxetinu v kardiální, respektive femorální krvi a v moči. Acetaminophen a phenobarbital byly také stanoveny, a to v terapeutické či subletální koncentraci. Autoři vyhodnotili údaje získané post mortem, při čemž vzali v úvahu posmrtnou difuzi léků a došli k závěru, že smrt byla způsobena toxicitou paroxetinu spolu se serotoninovým syndromem.
A female in her twenties was found dead in her room. She had received medications for depression and panic disorder, and had attempted suicide several times. Many packets of prescribed drugs, including paroxetine, were found near the corpse. At autopsy, the lungs were edematous. The organs were slightly congested with putrefactive change. Autolytic rupture, considered as gastromalasia, was observed in the anterior cardiac portion of stomach wall. Toxicological examination revealed 0.78, 3.20 and 17.63 µg/ml of paroxetine in the heart blood, femoral blood and urine, respectively. Acetaminophen and phenobarbital were also identified within therapeutic or sub-lethal levels. Taking into consideration postmortem diffusion of drugs, we evaluated postmortem data and concluded that the death was mainly due to toxicity of paroxetine with serotonin syndrome.
- MeSH
- Benzodiazepines isolation & purification toxicity MeSH
- Humans MeSH
- Young Adult MeSH
- Drug-Related Side Effects and Adverse Reactions MeSH
- Poisoning diagnosis etiology pathology MeSH
- Acetaminophen isolation & purification toxicity MeSH
- Paroxetine isolation & purification toxicity MeSH
- Autopsy methods MeSH
- Postmortem Changes MeSH
- Selective Serotonin Reuptake Inhibitors isolation & purification toxicity MeSH
- Serotonin Syndrome diagnosis MeSH
- Forensic Pathology MeSH
- Check Tag
- Humans MeSH
- Young Adult MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Benzodiazepines * poisoning adverse effects toxicity supply & distribution MeSH
- Chemically-Induced Disorders * MeSH
- Incidence MeSH
- Data Interpretation, Statistical MeSH
- Drug Interactions MeSH
- Humans MeSH
- Prescription Drug Diversion MeSH
- Drug-Related Side Effects and Adverse Reactions MeSH
- Mass Screening MeSH
- Substance-Related Disorders MeSH
- Drug Overdose MeSH
- Check Tag
- Humans MeSH
- Geographicals
- Czech Republic MeSH
- MeSH
- Antidotes therapeutic use MeSH
- Benzodiazepines toxicity MeSH
- Child MeSH
- Ibuprofen toxicity MeSH
- Carbamazepine toxicity MeSH
- Humans MeSH
- Poisoning diagnosis prevention & control therapy MeSH
- Acetaminophen toxicity MeSH
- Poison Control Centers organization & administration utilization MeSH
- Check Tag
- Child MeSH
- Humans MeSH
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Nestr. : il. ; 32 cm
Zajišťování změn účinnosti a toxicity farmak (opioidů,benzodiazepinů a antibiotik) při modelové infekci AIDS a oportunních infekcí (Toxoplasma Gondii).Vliv chronického působení benzodiazepinů na průběh uvedených infekcí.
- MeSH
- Benzodiazepines pharmacology toxicity MeSH
- Infections MeSH
- Disease Models, Animal MeSH
- Narcotics pharmacology toxicity MeSH
- Pain Threshold MeSH
- Toxoplasma pathogenicity MeSH
- Friend murine leukemia virus pathogenicity MeSH
- Conspectus
- Farmacie. Farmakologie
- NML Fields
- toxikologie
- psychofarmakologie
- behaviorální vědy
- NML Publication type
- závěrečné zprávy o řešení grantu IGA MZ ČR
- MeSH
- Atrophy chemically induced MeSH
- Benzodiazepines toxicity MeSH
- Brain Damage, Chronic chemically induced MeSH
- Humans MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
