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E-mail: maverick mail. Use the link below to share a full-text version of this article with your friends and colleagues. Learn more. Methadone maintenance treatment MMT is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. In mouse model, oestrogen mitigates methadone antinociceptive response, facilitates methadone catabolism and up-regulates methadone-associated metabolizing enzymes.

Oestrogen also ablates chronic methadone administration-induced rewarding response. At last, preclinical study via targeting estrogen al that tamoxifen TMX; selective estrogen receptor modulator, SERM could facilitate the tolerance phase rewarding response of methadone. In conclusion, this study demonstrates altering methadone metabolism through targeting estrogen als might be able to free morphine addictive patients from the addiction of opioid replacement therapy.

Opioid drugs are the most effective therapeutic analgesic for chronic and cancer pain 1. Continual use of opioids, however, in the development of tolerance and dependence 2 , 3. It is also considered as most effective alleviating agent for heroin-addiction withdrawal syndrome 5 - 7. One major purpose of introducing opioid replacement therapy is to provide opportunity for social supporting systems to help patients get rid of opioids agents. Although methadone has been shown to be effective in reducing withdrawal symptoms and impulsive injection of opioids 8 , chronic use of methadone has also exhibited addictive liability and respiratory repression in some patients 9.

Oral taken methadone subjected to first-pass effect and could be detected in the plasma after 30 min. CYP enzymes modulator has been demonstrated to alter plasma concentration of methadone Gender in substances-abuse individuals has been reported in terms of severity, craving, medical conditions and impairment in associated central nervous system CNS functional areas 15 - Except for neuronal activity, it has been reported that sex hormones regulate differential panels of liver CYPs, namely feminine or masculine CYPs 19 - 21 , through which explained the mechanisms of sexual dimorphism on drugs and xenobiotics.

Genome-wide association studies reported that the SNPs related to CYPs, opioid receptors, sex hormone producing enzymes provides possible explanation to the individualized methadone dosing in clinics Methadone metabolism is linked to MMT efficacy and also associated to genders. Different metabolic enzymes are involved in enantiomeric S- and R-methadone metabolism Luk et al.

In addition, the methadone clearance was increased during pregnancy, which may be due to the raising of CYP2B6 activity and mRNA by increased oestrogen levels Moreover, the gender effects were also exhibited in choices of abuse drugs and addictive behaviours. In addition, there is a tendency of abusing opioids shift from prescription analgesics to street methadone for solving the analgesics liability in women This indicates sex hormones als might be involved in regulating the emotion and motivation for opioids preference.

This study intended to decrease MMT dosing and hopefully to reduce the opioid liability, from female hormone perspective. The cohort 1 heroin abusers were recruited from a hospital-based study, the cohort 1 was to develop the hypothesis that whether oestradiol modulates the methadone dosing. The cohort 1 was consisted of heroin abusers age range of 20—70 years recruited from psychiatric outpatients in CMUH from Jan. In addition, each patient receiving methadone therapy for at least 6 months and keeping unchanged dose for at least 4 weeks before recruitment.

At the time of enrolment, two cohorts of all patients were requested to complete the constructed questionnaire, including demographic data and heroin addictive behaviour survey. This study deed a item questionnaires, heroin using and craving HUC to evaluate the behaviours, for heroin abusers received methadone maintenance therapy Each question scores 0—4. The questionnaire is divided into two parts: part I HUC 1—HUC 6 is to assess the urge for heroin and whether one can shift the attention from heroin.

The part I sum score is calculated range from 0 to The part II HUC 7—HUC 14 is to investigate the daily or weekly frequencies of heroin usage, daily life disturbance, anxiety emotion and the ability to overcome heroin use. The part II sum calculated score ranges from 0 to The higher the score, the more severe the cravings for heroin use.

The mouse age 6—12 weeks and weighing 20—30 g was used for the experiments. Animals were handled for 3—4 days before the experiments performed. On the test day, animals were transported to the testing room and to habituate with the environment at least for 1 hr. All the animal experiments were performed in accordance with the ethical guidelines which was approved by CMU Animal Core and Use Committee CMU animal protocol: N and followed throughout the study. The procedure of OVX on female mice follows report In brief, 10—weeks of female mice were anaesthetized and lower flanks open wound 0.

After 2-week recovery, the mice were subjected to experiments. Each mouse was injected subcutaneously s. The tail flick test was carried out on mice using a modified method of Dai et al. The tail flick latency was defined by the time sec. The infrared intensity of the tail-flick machine was set at eight, which produced a baseline tail flick latency of 2—3 sec.

The rat was put in a restrainer for 5 min. To measure the analgesic effect of opioid agonists, animals were subjected to the tail-flick procedure once a day to minimize the learning effects. All experimental animals were randomly ased from different cages to ensure a general effect in the population.

The CPP apparatus used is a two-compartment acrylic plastic box. Patients were randomly placed into the apparatus and given free access to the entire box door open for 15 min. During the conditioning, the connection door was closed. Animals were kept for 1 hr in the corresponding compartment with the connection doors closed. The paired condition was performed one white and one black a day with 6-hr interval.

The days of post-drug place preference examination were shown in Figure 3A. The post-drug place preference was conducted for 15 min. Mice were sacrificed following the treatment and behavioural testing schedule of methadone. Immediately, the liver was dissected and frozen in liquid nitrogen. The assay was performed as ly described 36 , After 2 min.

Electro Chemi Luminescent immunoassay ECLIA was used for the quantitative determination of oestrogen in mouse serum on a Roche Elecsys instrument Roche, Basel, Switzerland according to the manufacturer instructions. The chemiluminescence reaction for the detection of the reaction complex is initiated by applying a voltage to the sample solution resulting in a precisely controlled reaction. Hardy—Weinberg equilibrium was tested by chi-square test for goodness of fit.

Student's t-test was used to assess the difference between luciferase activity and genotypes. In addition, we also employed Student's t-test to compare the different methadone doses, sex hormone in gender during trials. All statistical analyses were carried out using sas version 9. As described, sexes and related hormones could contribute to opioid actions, including MMT dosing in patients.

Patients carried TT genotype Females were ificantly correlated with higher MMT dosing compared to males. This result implicating oestrogen is the confounder in the sexual dimorphic MMT dosing. We therefore would like to test whether oestrogen participates in methadone metabolism Table 3 and MMT efficacy Table 4 in second cohort patients.

Literature reported that R-form methadone exerts opioid function, which related to alleviating withdrawal syndrome On the contrary, S-form is associated with the electropathological cardiac QT-interval prolongation complications of methadone In order to associate methadone metabolism to MMT therapeutic efficacy, we introduced the questionnaire 30 by which measuring the heroin using and craving after receiving MMT.

The questionnaire HUC 1—6 represents the extent of mind using heroin and whether one can shift attention from heroin use, where HUC 7—14 was used to investigate the daily or weekly frequency of heroin usage, life and work disturbed, prong to anxiety emotion, desiring to use heroin and the ability to overcome heroin use We scored and calculated the result in each patient to evaluate the association with methadone metabolism data. In addition, the demonstrated that oestradiol affects both S-form and R-form methadone metabolism.

In other words, the higher the S-form methadone metabolite, the lower is the heroin craving compulsive behaviour. Furthermore, inificance association result of HUC 1—6 scores indicated the heroin obsessive craving, assessing the mind using of heroin is independent to methadone metabolite. Together, Tables provide strong association that oestrogen al might contribute to MMT sex biased dosing, alter methadone pharmacology actions, through which abate methadone efficacy in patients.

We have tested E2 effect on the methadone antinociception in mice by removing endogenous female hormones OVX , or exogenous injection of E2 in male. This implicating oestrogen could influence methadone, in part, go through facilitating methadone metabolism. In order to delineate the relation of oestrogen on methadone metabolism and CYPs expressions, the related liver enzymes mRNA expressions were measured Fig. The conditioned place preference CPP test was also used to test the oestrogen effect on methadone-induced rewarding behaviour.

As shown in Fig. On the other hand, chronic methadone administration could also prolong CPP duration in male mice, while co-administration of E2 could diminish methadone effect Fig. To sum up, the result in Fig. Conceptually, at the beginning of methadone tolerance phase, the dosing goal is to reduce withdrawal syndrome and avoid drug-seeking behaviour.

After tolerance phase, the patient can be stabilized under MMT program and then gradually reduce doses in tapping phase. Our data showed methadone reward response can be observed after seven-day injection in both male Fig. Furthermore, while we gradually reduce methadone dose in same mice and measure CPP duration reduction, we found the reduction velocity is faster in TMX co-administration mice compared to placebo co-administration Fig. Together, the data in Figure 3 indicating that targeting oestrogen al via TMX co-administration not only enhance rewarding response during tolerance phase, but also shorten tapping and abstinence phases of MMT program.

This study illustrated the roles of oestrogen al on methadone metabolism, through which alters MMT efficacy. This report approached hypothesis directly into human with two study cohorts. The E2-CYPs-methadone metabolism axis was delineated by in vivo and in vitro experiments.

The pathway characterization of oestrogen-CYP-ERE-SNP was performed in genomic levels; and oestrogen-methadone chiral-chemical metabolomics was analysed to link with patient drug seeking behaviour. At last, the proof-of-concept preclinical trial creates a translational value for future MMT therapy. Therefore, the impact of this study might be extension of the followings.

Methadone prevents withdrawal and limits cravings 7 but additional methadone may increase cravings for heroin Methadone dosing is interfering by methadone metabolism, plasma level, heroin craving and withdrawal and many other factors. High dropout of MMT and heroin relapse was related to low dose of methadone 45 , and methadone dose was highly variable among countries.

The measurement of E2 or CYP2B6 polymorphism might be useful for dosing adjustment for clinical methadone treatment. The cycle of addiction is constituted with positively reinforcement of drug-induced euphoria and negatively reinforcement of withdrawal or craving dysregulation In other words, in the induction or early phase of addiction, the drug use trigger trended intention for getting euphoria desire. Over time, chronic drug use could disrupt reward circuits and produce dysphoric states; at this time, the drug use trigger trended to avoid suffering.

Our findings also indirectly approve this theory. E2 has been reported to be involved in various neuronal activities, for example pain sensation, mood, seizures susceptibility and stroke or Alzheimer's disease neuroprotection Among those human diseases-related activities, there is an important reciprocal regulatory mechanism exists in E2 and opioid system in the CNS.

In reverse, opioid system also influences the prolactin release through the oestrogen regulation 49 or abolishes oestrogen-induced antinociception and hyperalgesia For example, CNS E2 level might influence the endocrine circuit via opioid system to regulate the plasma E2 level.

Although E2 regulatory role in CNS opioid receptor has been reported, whether this circuit participates in MMT program is not weight yet. This study describes SERM enhances methadone effect and reduces methadone liability through its metabolism in the peripheral. It is of great interests to evaluate whether changing E2 al could also alter neuronal activity upon methadone administration. The reason is due to a ificant population of hepatic function impairment or multiple toxic agents' ingestion, for example alcohol or mix-opiates exists in patients.

There are three phases, tolerance, tapping and abstinence, in MMT program that patient encounters as clinicians intensely monitored. In the past, most MMT receivers fall on two scenarios of therapy outcome Fig. First, patient takes higher methadone doses during the tolerance phase, following with a dose descending in the tapping and abstinence phases. However, liability gradually increases and switches to methadone addictive mode. Our study describes the third scenario Fig.

On the other hand, while methadone doses descending in the tapping and abstinence phases, TMX co-administration also showed faster decline of CPP duration. This implicating the rewarding response is lowered in TMX co-administration mice.

The ificance of the translational study is that the higher dosing or difficult treating MMT patients might use SERM as combination therapy.

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