Plasma metabolites changes in male heroin addicts during acute and protracted withdrawal.

BACKGROUND: Heroin addiction and withdrawal have been associated with an increased risk for infectious diseases and psychological complications. However, the changes of metabolites in heroin addicts during withdrawal remain largely unknown. METHODS: A total of 50 participants including 20 heroin addicts with acute abstinence stage, 15 with protracted abstinence stage and 15 healthy controls, were recruited. We performed metabolic profiling of plasma samples based on ultraperformance liquid chromatography coupled to tandem mass spectrometry to explore the potential biomarkers and mechanisms of heroin withdrawal. RESULTS: Among the metabolites analyzed, omega-6 polyunsaturated fatty acids (linoleic acid, dihomo-gamma-linolenic acid, arachidonic acid, n-6 docosapentaenoic acid), omega-3 polyunsaturated fatty acids (docosahexaenoic acid, docosapentaenoic acid), aromatic amino acids (phenylalanine, tyrosine, tryptophan), and intermediates of the tricarboxylic acid cycle (oxoglutaric acid, isocitric acid) were significantly reduced during acute heroin withdrawal. Although majority of the metabolite changes could recover after months of withdrawal, the levels of alpha-aminobutyric acid, alloisoleucine, ketoleucine, and oxalic acid do not recover. CONCLUSIONS: In conclusion, the plasma metabolites undergo tremendous changes during heroin withdrawal. Through metabolomic analysis, we have identified links between a framework of metabolic perturbations and withdrawal stages in heroin addicts.

Is Phosphorus the "Key" of cancer?

Bobko et al. reported a very interesting article concerning the impact of interstitial inorganic phosphate (Pi) on tumor progression. Previous studies have shown that blood levels of Pi might be related with either the presence or growth of cancer in the human body. Heroin-addicted persons have normal values of Pi, while the incidence of cancer in these individuals seems to be very low. The question rises: Is Pi the key of cancer? Further studies are definitely needed, focusing on the correlation between inorganic Pi and cancer.

The Amount of Phosphorus in the Blood of Heroin Abusers Compared to that of Healthy Subjects.

BACKGROUND: The aim of the current retrospective study was to assess any difference in terms of serum phosphate (P) between heroin addicts and healthy subjects. METHODS: Between 2011 and 2012, under the authority of the Greek Organization Against Drugs (OKANA), 30 regular heroin addicts, 22 males and 8 females (Group A) participated at the study. Between 2010 and 2011, 30 healthy individuals, 22 males and 8 females (Group B), presented on an outpatient basis for either fatigue or common flu symptoms without fever at the 424 Military Hospital of Thessaloniki. RESULTS: No significant difference between group A and B, in terms of either age (p = 0.454, Mann-Whitney test) or male/female ratio (p = 0.573, Chi2 test), suggesting a homogeneity for the population of individuals participating in the study. The mean values of serum-P in group A and B were 3.47 ± 0.65 and 3.35 ± 0.58, respectively (p = 0.45, Mann Whitney test). CONCLUSIONS: The absence of statistical difference of serum-P between heroin addicts and healthy subjects as shown in our results should be confirmed in further studies.

Abnormal functional integration of thalamic low frequency oscillation in the BOLD signal after acute heroin treatment.

Heroin addiction is a severe relapsing brain disorder associated with impaired cognitive control, including deficits in attention allocation. The thalamus has a high density of opiate receptors and is critically involved in orchestrating cortical activity during cognitive control. However, there have been no studies on how acute heroin treatment modulates thalamic activity. In a cross-over, double-blind, vehicle-controlled study, 29 heroin-maintained outpatients were studied after heroin and placebo administration, while 20 healthy controls were included for the placebo condition only. Resting-state functional magnetic resonance imaging was used to analyze functional integration of the thalamus by three different resting state analysis techniques. Thalamocortical functional connectivity (FC) was analyzed by seed-based correlation, while intrinsic thalamic oscillation was assessed by analysis of regional homogeneity (ReHo) and the fractional amplitude of low frequency fluctuations (fALFF). Relative to the placebo treatment and healthy controls, acute heroin administration reduced thalamocortical FC to cortical regions, including the frontal cortex, while the reductions in FC to the mediofrontal cortex, orbitofrontal cortex, and frontal pole were positively correlated with the plasma level of morphine, the main psychoactive metabolite of heroin. Furthermore, heroin treatment was associated with increased thalamic ReHo and fALFF values, whereas fALFF following heroin exposure correlated negatively with scores of attentional control. The heroin-associated increase in fALFF was mainly dominated by slow-4 (0.027-0.073 Hz) oscillations. Our findings show that there are acute effects of heroin within the thalamocortical system and may shed new light on the role of the thalamus in cognitive control in heroin addiction. Future research is needed to determine the underlying physiological mechanisms and their role in heroin addiction.

Relationship between plasma concentrations of the l-enantiomer of methadone and response to methadone maintenance treatment.

This study evaluated the relationship between the plasma concentration of l-methadone and response to methadone in real-world patients, in order to identify a minimum plasma concentration above which methadone treatment is effective. Ninety-four patients with opioid dependence under maintenance methadone treatment were consecutively recruited. Response was defined as negative urine analyses in the three weeks prior to the blood sampling. The percentage of participants with a plasma l-methadone concentration between 100 and 250 ng/ml was 54.2% among those with a methadone dosage ≥60 mg/day. Plasma l-methadone concentrations were significantly higher in patients with negative urine analyses compared with those with positive urine analyses (median 93 vs. 77 ng/ml, Mann-Whitney test, P<0.05). Above plasma l-methadone concentrations of 200 ng/ml no heroin use was reported and urine analyses were negative. Moreover, above concentrations of 250 ng/ml craving was absent. Examination of demographic correlates of treatment outcome indicated that older age, a stable job and being married were protective against the use of heroin. Mean plasma l-methadone concentration was significantly lower in patients who used cannabis compared with those who did not use cannabis, after adjusting for methadone dosage. In conclusion our results identify specific cut-offs for plasma l-methadone concentrations about which therapeutic response is observed and provide new evidence that therapeutic response is associated with patient׳s demographic characteristics. This underscores the need to monitor plasma methadone concentrations as part of Drug Addiction Services routine practice, in order to provide an objective framework for changing the methadone dosage.

Effects of Jitai tablet, a traditional Chinese medicine, on plasma adrenocorticotropic hormone and cortisol levels in heroin addicts during abstinence.

OBJECTIVES: To investigate the changes in adrenocorticotropic hormone (ACTH) and cortisol in heroin addicts given Jitai tablet treatment during abstinence. DESIGN: Double-blind, randomized, placebo-controlled clinical trial. SETTINGS/LOCATION: Drug Rehabilitation Bureau of Shanghai Police, China. PARTICIPANTS: 99 volunteers, including 69 heroin addicts and 30 healthy volunteers. INTERVENTIONS: 69 heroin addicts randomly divided into two groups: the Jitai tablet group, which comprised 34 heroin addicts given Jitai tablet treatment during abstinence, and the placebo group, which comprised 35 heroin addicts given placebo. A control group consisted of 30 sex- and age-matched healthy volunteers. OUTCOME MEASURES: ACTH and cortisol in plasma were measured in all groups at baseline and in the Jitai tablet and placebo groups on the third, seventh, and 14th days of abstinence. RESULTS: Levels of both ACTH (p<.01) and cortisol (p<.001) were significantly higher in heroin addicts at baseline than in the healthy volunteers. Jitai tablet treatment restored plasma cortisol levels to normal more rapidly than did placebo treatment (p<.05), but not ACTH levels. A positive correlation between ACTH and cortisol values at baseline (p<.01) was also found with withdrawal symptom scores and daily dosages of heroin. CONCLUSIONS: Heroin addicts could respond to Jitai tablets through changes in the hypothalamus-pituitary-adrenal axis.

[Effect of electroacupuncture at Jiaji (EX-B 2) on drug craving of heroin addicts and beta-EP and Dyn-A in plasma].

OBJECTIVE: To explore the clinical effect and mechanism of electroacupuncture at Jiaji (EX-B 2) on drug craving of heroin addicts. METHODS: One hundred and twenty cases of heroin addicts were randomly divided into 4 groups, 30 cases in each. In acupuncture group 1, the Jiaji (EX-B 2) points of T5-T7 and Shenshu (BL 23) were selected with electroacupuncture; in acupuncture group 2, Neiguan (PC 6), Shenmen (HT 7) and Zusanli (ST 36) etc. were selected with electroacupuncture; in simulation group, Zusanli (ST 36) and Sanyinjiao (SP 6) were selected with analog electrical stimulation, and in blank group no any therapy was applied. The changes of drug craving were evaluated by Visual Analogue Scale (VAS) and the changes of beta-EP and Dyn-A in plasma before and after treatment were tested by radioimmunoassay. RESULTS: The relapse rate of 77.3% (17/22) in acupuncture group 1 was lower than those of 88.5% (23/26) in acupuncture group 2, 90.5% (19/21) in simulation group and 95.7% (22/23) in blank group (all P < 0.05). At the 8th and 10th week of treatment, the VAS scores in acupuncture group 1 and 2 were much lower than those in blank group and simulation group (all P < 0.01); in which, it was lower in acupuncture group 1 than that in acupuncture group 2 (P < 0.05), and lower in simulation group than that in blank group. After 10 weeks of treatment, compared with the status before treatment, beta-EP and Dyn-A in plasma were increased in acupuncture group 1 and 2 (P < 0.05, P < 0.01), Dyn-A was decreased in both simulation and blank groups (both P < 0. 01) which was less obvious than those in both acupuncture groups (both P < 0.01) and superior in acupuncture group 1 than that in group 2 (P < 0.05). CONCLUSION: Electroacupuncture at Jiaji (EX-B 2) can suppress the drug craving and reduce the relapse rate, and the mechanism may be related with the content of beta-EP, especially the increase of Dyn-A in plasma.

Determination of morphine in the plasma of addicts in using Zeolite Y extraction following high-performance liquid chromatography.

BACKGROUND: The measurement of morphine in biological samples has become a routine in many clinical and forensic toxicology laboratories. A high-performance liquid chromatography (HPLC) method was developed for the determination of morphine in plasma. METHODS: Samples were extracted using Zeolite Y column followed by reversed phase HPLC with fluorescence detection. This method was based on an ex-calibration procedure and was linear between 20 and 200 ng/ml of morphine. Blood from 10 male opiate addicts were obtained from Rosbeh Hospital. All of the male smoked opiate (heroin, opium) and cigarettes. RESULTS: The mean total level 5 h after the last abuse was 152.4 ng/ml and 37.6 ng/ml at 10-15 h. The method was reliable for morphine determination in blood even after 5 half-lives after the last abuse. CONCLUSIONS: This method is simple and rapid and may be useful for routine monitoring of plasma morphine concentration.

Niveles plasmáticos de metadona. Resultados después de 15 meses de seguimiento en el Programa Municipal de Drogas de Majadahonda / Plasma methadone concentration by enzymoimmunoassay tecnique (EIA) after 15 months in patients of Drugs Program of Mahadahonda (Spain)

Analizamos los niveles de 71 pacientes en programa de metadona mediante técnicas inmunoenzimáticas (EIA) durante 15 meses, evaluando si eran útiles para valorar la dosis adecuada en función de la situación clínica individual a lo largo del tiempo y se relacionaban con la aparición de SAO, consumo de opiáceos, enfermedades asociadas (VIH y/o Hepatitis) e interacciones con fármacos. Hubo correlación en pacientes previamente estabilizados entre SAO y la disminución progresiva de los niveles p<0,01, con recaída en el consumo de heroína (33,5 por ciento). Los pacientes con benzodiacepinas precisaron mayores dosis (124mg.vs 86 mg). No hubo diferencias en las dosis ni en los niveles en pacientes VIH +, en cambio, los pacientes con VHC necesitaron dosis más altas para conseguir un nivel similar (99 mg vs 73 mg). No se observaron diferencias significativas ni en las dosis ni en los niveles entre pacientes con/sin medicación al inicio del estudio, posteriormente hubo un aumento progresivo de dosis (145ñ58 vs 81,6ñ31,2) p<0,01, con significación estadística, a partir de la tercera extracción, acompañada de una caída de las concentraciones plasmáticas (145ñ58 vs 81,6ñ31,2) p<0.01 coincidiendo con fármacos inductores del metabolismo de la metadona (228ñ33 vs 212,7ñ157,2). Por tanto los "Niveles plasmáticos Adecuados", más que las dosis adecuadas pueden utilizarse como instrumento clínico para valorar la eficacia del tratamiento con metadona y para detectar alteraciones en pacientes estabilizados (AU)

[Effect of 2/100 Hz transcutaneous electrical nerve stimulation on sexual dysfunction and serum sex hormone of heroin addicts].

OBJECTIVE: To evaluate the effect of 2/100 Hz electrical stimulation produced by Han's acupoint nerve stimulator (HANS) in treating heroin induced sex dysfunction. METHODS: Thirty-three heroin addicts were randomly divided into 2 groups to receive either buprenorphine (BPN group, n = 16) or HANS plus small dose of BPN (HANS group, n = 17) for 14 days. The doses of BPN were tailored according to individual requirement that could totally abolish withdrawal syndrome. The frequency of HANS was 2 Hz and 100 Hz shifting automatically, each lasting for 3 seconds. The stimulation was applied to 8 acupoints, the Hegu and Laogong of one upper limb, Neiguan and Waiguan of another limb, Sanyinjiao and Xingjian of both lower limbs, for 30 min. The therapy was carried out 3-4 times per day in the initial two weeks of treatment, and reduced to 1-2 times per day in the following 2 weeks. RESULTS: (1) The urine analysis for morphine in both groups turned to negative 14 days after treatment. (2) After 2 weeks of treatment, the composite score (Visual Analog Scale, VAS) of sexual function in HANS group showed a 102% increase (P < 0.01) compared with before treatment and was 107% of that in the BPN group (P < 0.01). (3) After 4 weeks treatment the serum concentration of luteinizing hormone (LH) and testosterone (T) in the HANS group showed a 137% and 118% increase respectively compared with those before treatment (P < 0.05), and the level of LH was 79.6% of that in the BPN group (P < 0.05). CONCLUSION: The 2/100 Hz transcutaneous electrical stimulation produced by Han's acupoint nerve stimulator could improve the recovery of sexual function and raise the serum concentration of LH and T in heroin addicts.

Heroin dependence effects on some major and trace elements.

In this study, 56 (14 control and 42 addicts) adult human subjects of both sexes of different periods of heroin dependence were subjected to the measurement of whole blood, serum, and red blood cell levels of some trace elements (zinc, manganese, iron copper, and bromine), as well as some major elements (phosphorus, sulfur, calcium, potassium, and chlorine). This was done by the energy-dispersive X-ray fluorescence (EDXRF) technique, in which copper and bromine showed a significant rise in whole blood (male) (22 and 32%, respectively), while zinc, iron, manganese, calcium, sulfur phosphorus, potassium, and chlorine showed a significant drop (49, 8, 25, 34, 21, 51, 61, and 72%, respectively) in proportion to the period of heroin intake (6 yr) and in comparison with the control group. No significant sexual variation has been reported.

Impaired ACTH and beta-endorphin response to sauna-induced hyperthermia in heroin addicts.

To evaluate the responses of circulating beta-endorphin, met-enkephalin and ACTH to sauna-induced hyperthermia, 8 male heroin addicts recently admitted to a therapeutic community and 8 age-matched normal subjects were examined. Compared with control subjects, heroin addicts showed 1. A decrease of the basal levels of beta-endorphin; 2. Absence of the normal increase of beta-endorphin and ACTH after sauna; 3. A lower increase in systolic blood pressure. It is concluded that an impairment of the adaptive response to stress may be present in heroin addicts, even after a relatively short drug-free period (14 days).

Immunoassayable beta-endorphin level in the plasma and CSF of heroin addicted and normal subjects before and after electroacupuncture.

The present study was undertaken to evaluate if plasma or CSF beta-endorphin level can be induced to rise during the treatment of heroin addiction by electroacupuncture. Based on the examination of 30 addicts, we obtained no evidence indicating an increase of beta-endorphin level in either the plasma or the CSF after 30 min of acupuncture. In spite of this, the majority of the addicts experienced a reduction of withdrawal symptoms during treatment. Since electroacupuncture may only induce a highly localized secretion of beta-endorphin in the brain, our results cannot unequivocally exclude the possibility that this peptide is involved in mediating the action of acupuncture.

Changes in adrenocorticotropic hormone (ACTH) and cortisol levels in drug addicts treated by a new and rapid detoxification procedure using acupuncture and naloxone.

Plasma ACTH, cortisol, and cyclic-AMP levels of eleven heroin addicts were dertermined before and after treatment with a fast detoxification procedure using acupuncture and electrical stimulation (AES) together with the administration of limited doses of naloxone. At the end of the treatment period, the average plasma ACTH, cortisol, and cyclic-AMP level rose 130,83, and 24 percent, respectively. In view of the appearance of mild withdrawal signs during this method of treatment, the observed increases in ACTH and cortisol levels probably reflect the inability of AES to suppress withdrawal symptoms induced by naloxone completely. The mechanism underlying this new method of treatment is discussed in relation to AES's ability to stimulate the secretion of endorphins.

Reduction of adrenocorticotropic hormone (ACTH) and cortisol in drug addicts treated by acupuncture and electrical stimulation (AES).

Forty-two heroin addicts and 31 normal persons were examined for the effect of acupuncture and electrical stimulation (AES) on plasma ACTH, cortisol and cyclic-AMP levels. Both ACTH and cortisol levels were reduced significantly in the addicts after treatment whereas no such significant reduction was observed in the normals. Plasma cyclic-AMP level was not affected in either group. Taken together, results from the present study suggest that the mechanism of AES in the treatment of addiction may have a neuroendocrinological basis. This hypothesis is particularly attractive in view of the isolation of opiate-like peptides from the brain.

Pituitary-gonadal function in heroin addicts.

The present study deals with pituitary-gonadal function in male heroin addicts, 6 patients with schizophrenia and 31 with mild personality disorders. We examined the serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone levels at the moment of hospitalization (at the maximum of heroin addiction), and 48 h and 10 days later. FSH levels were definitely reduced in all the patients and did not change during the period of heroin withdrawal. The LH levels were reduced to a lesser extent, but significantly, and did not change after 10 days of abstinence from the drug. Testosterone levels were very low and increased in the schizophrenics during withdrawal, but not in the other addicts. The possible influence of heroin addiction on catecholamine metabolism in the central nervous system and, therefore, on the hypothalamic releasing factor and pituitary gonadotrophins, and the peripheral effect on testicular function are discussed.