Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Respiratory depression, the most serious side-effect of opioid treatment, is well documented for morphine, the most commonly used opioid in neonatal care. Less is known about methadone, a clinically relevant opioid analgesic, especially during neonatal development. This study was undertaken to determine the neonatal respiratory effects of methadone. We hypothesize that methadone is equipotent to morphine, compared to our previous morphine results in the same animal model, but has a much longer duration of action, due to its longer elimination half-life. Neonatal guinea pigs (3-14 days old) randomly received a single subcutaneous dose of methadone or saline. Using a non-invasive plethysmographic method, we measured ventilatory and metabolic parameters before injection and at intervals for 32 hr after injection while pups breathed "room air" or 5% CO(2) gas mixtures. Methadone-induced depression of ventilation was most evident during 5% CO(2) challenge. The onset of drug effects was within 15 min for all ages and doses, but the duration of action decreased with age. While the depth of methadone-induced respiratory depression did not depend on pup age, the control of breathing was different in 3-day-old pups, where inspiratory time increased fourfold; twice that of older pups. We conclude that methadone induces a naloxone reversible respiratory depression in guinea pig neonates and, in the very young, causes an abnormal breathing pattern due to changes in respiratory timing. Methadone is more potent than morphine with respect to neonatal respiratory depression, but surprisingly, the duration of methadone action was not longer than morphine.
 ...
PMID:Methadone-induced respiratory depression in the neonatal guinea pig. 1796 93

Methadone is commonly used by patients presenting to the Emergency Department (ED). The common, acute side effects of central nervous system depression and respiratory depression are easily recognizable by treating physicians as attributable to methadone; however, the cardiac toxicity of chronic methadone use recently has only been recognized. Both chronic use of large doses and a recent increase in the daily dose of methadone have been associated with QT prolongation and subsequent development of torsades de pointes. We describe the case of a 40-year-old woman whose methadone dose recently had been increased to 135 mg per day. She then presented to the ED with symptomatic torsades de pointes. She was stabilized in the ED by cardioversion and infusions of magnesium sulfate and lidocaine. The markedly prolonged corrected QT interval significantly shortened after discontinuing methadone. Inpatient cardiology evaluation found no other cause for the dysrhythmia. She was definitively treated with reduction of the daily methadone dose and an implanted cardioverter-defibrillator.
 ...
PMID:Chronic methadone therapy complicated by torsades de pointes: a case report. 1802 86

Methadone is an interesting analgesic for multiple reasons. The unique properties of the agent, low cost and widespread availability have led to increases in methadone prescribing. Despite advantages, methadone is challenging to work with, particularly in patients with high opioid requirements. Recent concerns regarding cardiac arrhythmias and respiratory depression have led to changes in the labeling of methadone. This editorial highlights some of these concerns and provides some recommendations for the appropriate use of methadone in the setting of pain.
 ...
PMID:The safety of methadone hydrochloride. 1817 10

Methadone is increasingly prescribed for chronic pain, yet the associated mortality appears to be rising disproportionately relative to other opioid analgesics. We review the available evidence on methadone-associated mortality, and explore potential pharmacokinetic and pharmacodynamic explanations for its greater apparent lethality. While methadone shares properties of central nervous system and respiratory depression with other opioids, methadone is unique as a potent blocker of the delayed rectifier potassium ion channel (IKr). This results in QT-prolongation and torsade de pointes (TdP) in susceptible individuals. In some individuals with low serum protein binding of methadone, the extent of blockade is roughly comparable to that of sotalol, a potent QT-prolonging drug. Predicting an individual's propensity for methadone-induced TdP is difficult at present given the inherent limitations of the QT interval as a risk-stratifier combined with the multifactorial nature of the arrhythmia. Consensus recommendations have recently been published to mitigate the risk of TdP until further studies better define the arrhythmia risk factors for methadone. Studies are needed to provide insights into the clinical covariates most likely to result in methadone-associated arrhythmia and to assess the feasibility of current risk mitigation strategies.
 ...
PMID:Methadone-induced mortality in the treatment of chronic pain: role of QT prolongation. 1943 94

Smoking is highly prevalent (85%-98%) in methadone maintenance treatment (MMT) patients. Methadone has been shown to increase cigarette smoking in a dose-dependent manner, whereas smoking/nicotine has been shown to increase methadone self-administration and reinforcing properties. The objective of this study was to evaluate methadone-nicotine interactions in MMT patients during trough and peak methadone effect conditions. Subjective effects of nicotine (administered by cigarette smoking, 4 mg of nicotine gum and placebo gum) and methadone and their combination were assessed in 40 regularly smoking, stabilized MMT patients using a randomized, placebo-controlled, within-subject study design. Subjects responded to a battery of subjective assessments before and after nicotine administration both before methadone administration (cycles 1 and 2) and 3 hours after methadone administration (cycles 3 and 4). There was a main effect of methadone on the decrease of opioid withdrawal scores (P < 0.001), and cigarette smoking enhanced this effect (day x methadone interaction, P = 0.031). Both nicotine and methadone had main effects on the decrease of nicotine withdrawal scores (P < 0.001 and P = 0.001, respectively); this was associated with the cigarette day (day x nicotine interaction, P = 0.003, and day x methadone interaction, P = 0.004). Nicotine plasma levels were highest on the cigarette smoking day (P < 0.001). Methadone and nicotine shared main effects on the increase of ratings of euphoria and drug liking and on the decrease of restlessness, irritability, and depression. The overall results may help to explain high smoking rates in the MMT population and may account for reports of increased positive effects of methadone when the drugs are taken together.
 ...
PMID:Methadone-nicotine interactions in methadone maintenance treatment patients. 1944 76

The purpose of the study was to present recommendations, relevant to the management of neonates and infants aged 0-1 years, treated in intensive care settings. They include general principles and recommendations for pain and sedation assessment, sedation and pain management and advice on the use of pharmacological strategies. The bolus (on demand) administration of sedative agents should be avoided because of increased risk of cardiovascular depression and/or neurological complications. Midazolam administration time should be limited to 72 hours because of tachyphylaxis, and the possibility of development of a withdrawal syndrome and neurological complications (grade A, LOE 1b). The level of sedation and pain should be regularly assessed and documented, using presented scales; the COMFORT scale is preferred. Opioids, given in continuous infusion, are the drugs of choice for neonatal sedation. To avoid withdrawal syndrome, the total doses and time of administration of sedative agents should be limited. Methadone is a drug of choice in the treatment of a withdrawal (Grade B, LOE 2). Intravenous ketamine is recommended, when short-term sedation/anaesthesia is required (Grade C, LOE 3) for painful and/or stressful intensive care procedures. (Grade C, LOE 2). Muscle relaxants should be used for endotracheal intubation and in the situations when mechanical ventilation is not possible due to maximal respiratory effort of the patient.
 ...
PMID:[Recommendations for analgesia and sedation in neonatal intensive care]. 1947 Oct 72

Methadone is administered as a racemic mixture, although its analgesic and respiratory effects are attributed to R-isomer activity at the mu opioid receptor (MOP). Recently, we observed a four-fold increase in inspiratory time in 3-day-old guinea pigs following an injection of racemic methadone. We hypothesized that this effect was due to augmentation of R-methadone induced respiratory depression by the S-methadone isomer. In the current longitudinal study, we injected 3-, 7-, and 14-day-old neonatal guinea pigs with saline, R-methadone, S-methadone, or R- plus S-methadone in order to characterize the roles of the individual isomers, as well as the synergistic effects of co-administration. Using plethysmography, we measured respiratory parameters while breathing room air and during a 5% CO(2) challenge. S-Methadone alone had no respiratory effects. However, the R- plus S-methadone group showed greater respiratory depression and increased inspiratory time than the R-methadone group in the youngest animals, suggesting that the respiratory effects of R-methadone are augmented by S-methadone in early development.
 ...
PMID:S-Methadone augments R-methadone induced respiratory depression in the neonatal guinea pig. 1974 79

Opioids are known to induce respiratory depression. We aimed to characterize in rats the effects of four opioids on arterial blood gases and plethysmography after intraperitoneal administration at 80% of their LD(50) in order to identify opioid molecule-specific patterns and classify response severity. Opioid-receptor (OR) antagonists, including intravenous 10 mg kg(-1)-naloxonazine at 5 min [mu-OR antagonist], subcutaneous 30 mg kg(-1)-naloxonazine at 24 h [mu1-OR antagonist], subcutaneous 3 mg kg(-1)-naltrindole at 45 min [delta-OR antagonist], and subcutaneous 5 mg kg(-1)-Nor-binaltorphimine at 6 h [kappa-OR antagonist] were pre-administered to test the role of each OR. Methadone, morphine, and fentanyl significantly decreased PaO(2) (P<0.001) and increased PaCO(2) (P<0.05), while buprenorphine only decreased PaO(2) (P<0.05). While all opioids significantly increased inspiratory time (T(I), P<0.001), methadone and fentanyl also increased expiratory time (T(E), P<0.05). Intravenous 10 mg kg(-1)-naloxonazine at 5 min completely reversed opioid-related effects on PaO(2) (P<0.05), PaCO(2) (P<0.001), T(I) (P<0.05), and T(E) (P<0.01) except in buprenorphine. Subcutaneous 30 mg kg(-1)-naloxonazine at 24 h completely reversed effects on PaCO(2) (P<0.01) and T(E) (P<0.001), partially reversed effects on T(I) (P<0.001), and did not reverse effects on PaO(2). Naltrindole reversed methadone-induced T(E) increases (P<0.01) but worsened fentanyl's effect on PaCO(2) (P<0.05) and T(I) (P<0.05). Nor-binaltorphimine reversed morphine- and buprenorphine-induced T(I) increases (P<0.001) but worsened methadone's effect on PaO(2) (P<0.05) and morphine (P<0.001) and buprenorphine's (P<0.01) effects on pH. In conclusion, opioid-related respiratory patterns are not uniform. Opioid-induced hypoxemia as well as increases in T(I) and T(E) are caused by mu-OR, while delta and kappa-OR roles appear limited, depending on the specific opioid. Regarding severity of opioid-induced respiratory effects at 80% of their LD(50), all drugs increased T(I). Methadone and fentanyl induced hypoxemia, hypercapnia, and T(E) increases, morphine caused both hypoxemia and hypercapnia while buprenorphine caused only hypoxemia.
 ...
PMID:Characteristics and comparative severity of respiratory response to toxic doses of fentanyl, methadone, morphine, and buprenorphine in rats. 1981 13

Methadone may cause respiratory depression. We aimed to understand methadone-related effects on ventilation as well as each opioid-receptor (OR) role. We studied the respiratory effects of intraperitoneal methadone at 1.5, 5, and 15 mg/kg (corresponding to 80% of the lethal dose-50%) in rats using arterial blood gases and plethysmography. OR antagonists, including intravenous 10 mg/kg-naloxonazine at 5 minutes (mu-OR antagonist), subcutaneous 30 mg/kg-naloxonazine at 24 hours (micro1-OR antagonist), 3 mg/kg-naltrindole at 45 minutes (delta-OR antagonist) and 5 mg/kg-Nor-binaltorphimine at 6 hours (kappa-OR antagonist) were pre-administered. Plasma concentrations of methadone enantiomers were measured using high-performance liquid chromatography coupled to mass-spectrometry. Methadone dose-dependent inspiratory time (T(I)) increase tended to be linear. Respiratory depression was observed only at 15 mg/kg and characterized by an increase in expiratory time (T(E)) resulting in hypoxemia and respiratory acidosis. Intravenous naloxonazine completely reversed all methadone-related effects on ventilation, while subcutaneous naloxonazine reduced its effects on pH (P < 0.05), PaCO(2) (P < 0.01) and T(E) (P < 0.001) but only partially on T(I) (P < 0.001). Naltrindole reduced methadone-related effects on T(E) (P < 0.001). Nor-binaltorphimine increased methadone-related effects on pH and PaO(2) (P < 0.05) Respiratory effects as a function of plasma R-methadone concentrations showed a decrease in PaO(2) (EC(50): 1.14 microg/ml) at lower concentrations than those necessary for PaCO(2) increase (EC(50): 3.35 microg/ml). Similarly, increased T(I) (EC(50): 0.501 microg/ml) was obtained at lower concentrations than those for T(E) (EC(50): 4.83 microg/ml). Methadone-induced hypoxemia is caused by mu-ORs and modulated by kappa-ORs. Additionally, methadone-induced increase in T(E) is caused by mu1- and delta-opioid receptors while increase in T(I) is caused by mu-ORs.
 ...
PMID:Mechanisms of respiratory insufficiency induced by methadone overdose in rats. 2000 23

Methadone-maintained pregnant patients with mood disorders have compromised treatment outcomes ( [1] ). This study examined the relationship between the presence of mood disorders and delivery and neonatal outcomes. Participants were categorized into two groups: no current mood disorder (n = 30) or primary mood disorder (n = 38). The mood disorder group reported more serious lifetime and current depression than did the no current mood disorder group. Neonates from mothers with mood disorders had a longer length of stay in the neonatal intensive care unit than the no current mood disorder group. Findings emphasize the need to treat mood disorders in methadone-maintained pregnant patients.
 ...
PMID:The impact of mood disorders on the delivery and neonatal outcomes of methadone-maintained pregnant patients. 2018 Jun 64


<< Previous 1 2 3 4 5 6 Next >>