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Official websites use. Share sensitive information only on official, secure websites. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Methadone maintenance treatment MMT is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. At last, preclinical study via targeting estrogen signal 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 signals might be able to free morphine addictive patients from the addiction of opioid replacement therapy. Keywords: methadone maintenance treatment, opiate addiction, estrogen, tamoxifen. Opioid drugs are the most effective therapeutic analgesic for chronic and cancer pain 1. Continual use of opioids, however, results in the development of tolerance and dependence 2 , 3. 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. CYP enzymes modulator has been demonstrated to alter plasma concentration of methadone Except for neuronal activity, it has been reported that sex hormones regulate differential panels of liver CYPs, namely feminine or masculine CYPs 19 , 20 , 21 , through which explained the mechanisms of sexual dimorphism on drugs and xenobiotics. Methadone metabolism is linked to MMT efficacy and also associated to genders. 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 signals 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 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. 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. The procedure of OVX on female mice follows previous report 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 rat was put in a restrainer for 5 min. All experimental animals were randomly assigned from different cages to ensure a general effect in the population. 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. 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 previously 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. 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 significantly 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. 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. Furthermore, insignificance 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 1 , 2 , 3 , 4 provide strong association that oestrogen signal 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 results implicating oestrogen could influence methadone, in part, go through facilitating methadone metabolism. An injection to restore E2 reversed this effect in OVX mice. CPP was measured at day 0 and day In order to delineate the relation of oestrogen on methadone metabolism and CYPs expressions, the related liver enzymes mRNA expressions were measured Fig. As shown in Fig. To sum up, the result in Fig. B The reference ERE sequence is shown in the upper panel. After tolerance phase, the patient can be stabilized under MMT program and then gradually reduce doses in tapping phase. A Experimental procedures performed during the tolerance, tapering and abstinence phases of MMT blue coloured. After 28 days, mice were injected with PBS for another eight consecutive days in abstinence phase. B and C. D and E TMX shortened preference duration in both the male mice D and female mice E during the tapering and abstinence phases. This study illustrated the roles of oestrogen signal on methadone metabolism, through which alters MMT efficacy. This report approached hypothesis directly into human with two study cohorts. 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. 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 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 signal could also alter neuronal activity upon methadone administration. 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. The hypothetical model illustrates changes in methadone liability and craving during MMT in three different treatment approaches, which links to three outcome scenarios. The significance of the translational study is that the higher dosing or difficult treating MMT patients might use SERM as combination therapy. Other authors stated no interest conflict. We would like to thank Mr. James Steed for his comments on the manuscript and for his help editing the English. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. J Cell Mol Med. Open in a new tab. Click here for additional data file. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

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Methadone maintenance treatment MMT remains the cornerstone for the management of opiate abuse. However, MMT can be associated with complex factors, including complications during the tolerance phase, the inability of some patients to maintain treatment effects during the tapering or abstinence phases, and the development of methadone dependence. Previous studies have revealed a sex disparity in MMT efficacy, showing that women undergoing MMT experiencing an increase in psychological symptoms compared with men and suggesting a link between disparate responses and the effects of estrogen signaling on methadone metabolism. More specifically, estradiol levels are positively associated with MMT dosing, and the expression of a single-nucleotide polymorphism SNP associated with estrogen receptor ER regulation is also associated with MMT dosing. In addition to performing mechanistic dissections of estrogen signaling in the presence of methadone, past studies have also proposed the targeting of estrogen signaling during MMT. The present report provides an overview of the relevant literature regarding sex effects, including differences in sex hormones and their potential impacts on MMT regimens. Preliminary preclinical experiments were also performed to evaluate the potential effects of targeting estrogen signaling with tamoxifen on methadone metabolism. The use of illicit opioids remains an ongoing issue for both individuals and society at large 1. Individuals who develop opioid dependency often experience personal or social problems and often engage in opioid abuse. Opioid abuse patients present with behavioral changes, such as social withdrawal 2 ; increased risk of contracting human immunodeficiency virus HIV ; and greater susceptibility to other opportunistic infections, such as hepatitis C and tuberculosis TB 3. In addition, individuals who abuse opiates exhibit higher rates of other infections 4 ; medical and psychiatric comorbidities 5 ; polysubstance consumption 5 ; and criminal behaviors, and an increase in opioid abuse has resulted in a surge in opioid-related deaths 6. Methadone maintenance treatment MMT consists of the administration of methadone over a prolonged period of time to treat an individual addicted to opioids, such as heroin. MMT is typically used to treat individuals who experience relapse following typical detoxification regimens or admission to a substance abuse treatment facility that requires complete abstinence 7. MMT has been used to treat opioid abuse patients for decades and has long served as the standard treatment for opiate dependence. However, MMT is associated with complications, including differential efficacies, and some patients experience difficulty during the transition from MMT to abstinence 8. Appropriate dosing that aims to prevent the occurrence of withdrawal symptoms is a key component of the MMT strategy and is typically divided into three phases. When a patient first visits a treatment clinic, their craving for opiates is evaluated, and the initial dosage is determined and administered accordingly. The physician can then increase the dosage if the cravings are not mitigated by the initial dose. Once a good balance between dosing and craving is achieved, the physician will gradually reduce the dosage to push the boundary at which the craving reoccurs. During this phase, social and mental support are typically provided to reduce the probability that the patient will seek the acquisition of street drugs. Finally, the physician will discontinue methadone dosing. The evaluation of MMT regimen outcomes is based on the degree to which opiate-addicted patients can be successfully maintained in treatment programs, which contribute to the prevention of potential social impacts from crime and other addiction-related behaviors. However, significant numbers of opiate abusers who undergo MMT discontinue their treatment programs due to insufficient dosage, often in favor of the acquisition of street drugs 9 , Unfortunately, methadone overdose can be fatal 11 , requiring strict constraints on dosing during the tolerance phase. Studies published in recent years have reported sex-associated disparities in the efficacy and complication rates associated with MMT, although the results have varied across different geographic regions. Therefore, in the present report, we aimed to summarize the current knowledge regarding these issues and, through preliminary tests, provide important perspectives regarding potential treatment strategies for addressing them. A sex disparity in the responses to MMT regimens has been reported, with women experiencing more psychological symptoms than men In , Bawor et al. They found that men and women differed significantly in terms of alcohol use, amphetamine use, legal involvement, and employment while receiving MMT treatment. Sex differences were also prominent in terms of polysubstance use. In that study, the women were younger and more likely to be married, divorced, or widowed than the men, and the women also had higher rates of unemployment despite being better educated on average. The men were reported to use sedatives more frequently and presented with higher rates of psychiatric comorbidities such as depression, self-injury attempts, and suicide attempts. High doses of methadone and the use of methadone in combination with psychotherapy improved treatment retention for both men and women. By contrast, a study by Leone et al. Wang et al. When examining sex-specific differences in MMT outcomes, women are reported to have higher odds of discontinuing MMT to seek illicit opioids than men 16 , This discrepancy could be associated with pharmacodynamic differences because the methadone concentration-to-dose ratio CDR has been reported to be significantly lower among women than men One study indicated that the MMT discontinuation rate could partially be attributed to MMT complications associated with prolonged QT intervals 19 the QT interval is the time from the beginning of the QRS complex in an electrocardiograph, representing ventricular depolarization, to the end of the T wave, resulting from ventricular repolarization , although the results of another study did not support this theory However, prolonged QT intervals could be associated with differences in the serum levels of sex hormones Yee et al. Interestingly, altered testosterone levels appear to be unrelated to prolactin levels 21 , which suggests the involvement of steroidogenic cytochrome enzymes in the associated process. Kringen et al. As early as the s, a report described the complication of amenorrhea among women treated with methadone, which was associated with the secretion of gonadotropins from the hypothalamus Therefore, methadone metabolism was suspected to be related to sex hormone production. For example, studies showed that the placental aromatase CYP19 mediated methadone metabolism and that methadone suppressed the aromatization of testosterone to estrogen 24 , The suppression of estrogen production might represent a long-term effect of methadone rather than an acute response In , Lu et al. Sex-related differences in methadone metabolites are prominent in the literature. Chalabianloo et al. Several lines of evidence suggest that CYP2B6, one of the feminizing CYPs, increases the drug clearance of methadone in pregnant women, and pregnancy is characterized by elevated estradiol E2 levels In addition, CYP2B6 can be activated by xenotropic agents, including the synthetic opioids pethidine and methadone, through the activation of the constitutive androstane receptor and pregnane X receptor in the liver In a recent study, Chiang et al. Chiang et al. They replicated the phenotype observed in mice and found that the ablation of estrogen levels by ovariectomy in female mice suppressed methadone metabolism. By contrast, the implantation of E2 in male mice facilitated methadone metabolism. The manipulation of E2 levels also altered the addictive behaviors among mice addicted to methadone. The conditioned place preference CPP test, which measures retention time to evaluate the opioid craving status, was used to demonstrate that increased estrogen levels increased the retention time of methadone in both sexes. The cohort consisted of heroin abusers age range: 20—70 years recruited from January — December from among psychiatric outpatients treated by CMUH in Taichung, Taiwan. In addition, each patient received methadone therapy for at least 6 months and maintained an unchanged methadone dosage for at least 4 weeks prior to recruitment. At the time of enrollment, all subjects were asked to complete a questionnaire that included demographic data and a survey of heroin addictive behavior. All animal experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals of the Ministry of Science and Technology and were conducted with approval from China Medical University approval number N. Shuyuan Yeh and Prof. PCR was used to identify the mouse genotypes from DNA obtained from tail skin treated overnight with cell lysis buffer containing 0. All wild-type vs. All protocols related to animal use and treatment were evaluated and approved by the Animal Care and Use Committee of China Medical University, and all animals were treated in accordance with National Laboratory for Experimental Animals guidelines. Each mouse was injected subcutaneously s. The tail-flick test was performed in mice using a modified version of the method described by Dai et al. The infrared intensity of the tail-flick machine was set at 8, which produced a baseline tail-flick latency of 2—3 seconds, and the cutoff time was set to 10 seconds to prevent tissue damage. The mice were adapted to the restrainer for 5 min prior to performing the tail-flick test. To measure the analgesic effects of opioid agonists, the animals were subjected to the tail-flick procedure once per day to minimize learning effects. All of the experimental animals were randomly assigned from different cages to ensure a general effect in the population. A Chiralcel OD-R column x 4. The chemiluminescence reaction for the detection of the reaction complex was initiated by applying a voltage to the sample solution, resulting in a precisely controlled reaction. All statistical analyses were performed using SAS version 9. To correlate estrogen levels with the outcomes of MMT, we measured the E2 levels of patients undergoing an MMT program in a cohort study. We also measured the E2 levels of the patients in this cohort and found that they were associated with the MAX dose during the tolerance phase, the SS dose at the onset of the tapering phase, and the previous term of MAX dosing pMAX. Figure 1 E2 effects on MMT dosing. Using the well-known ERE Figure 1B , SNP sequence alignments were performed to determine which genes are correlated with the opioid response and opioid metabolism. Each group of data were collected from 6 mice. Two major estrogenic ablation therapies are currently used to treat estrogen-sensitive breast cancer. One consists of inhibiting the ER function using with SERMs, whereas the other consists of reducing estrogen production through the use of aromatase inhibitors AIs to inhibit enzymatic activity. AIs have been demonstrated to influence female reproductive systems. For example, Wu et al. In another study, Tabatabaie et al. The pharmacological action of SERMs involves the suppression of estrogenic signaling through the inhibition of ER function by preventing the estrogen-induced transactivation of ERs. For example, as early as , Mishell et al. SERMs, including clomiphene citrate and TMX, have also been used as the first-line treatment of choice for anovulation Shandley et al. However, the effects of these add-ons in male patients, which constitute the majority of MMT patients, must also be considered. In addition, a recent report indicated that AIs could increase the chances of developing insulin insensitivity 49 , which represents another potential factor that should be considered prior to using AIs in MMT. Some reports have suggested that the use of AIs in male patients could lead to increased sexual activity and increased erectile ability 50 , In addition, the use of AIs could also increase the chances of pregnancy in females, compared with the use of SERMs The results showed excellent tolerance behavior, and the addition of TMX to MMT also enhanced the CPP retention time, indicating that TMX has the potential to relieve stress-induced cravings for opioids during the tolerance phase of MMT programs, which could prevent the chances of a methadone overdose. More strikingly, the addition of TMX to the tapering and abstinence phases rapidly reduced the CPP retention time, which indicates that the addition of TMX to the MMT protocol was able to reduce drug-seeking behavior even as the methadone dose was reduced. Although the study by Chiang et al. The results obtained showed that the serum concentrations of TMX were differentially elevated in response to the various injection doses Figure 3B. By contrast, the S-methadone retention times were prolonged, and the associated Cmax values were dramatically increased Figures 3E, F. The mechanism underlying the superior suppressive effect on S-methadone metabolism may be associated with the TMX-mediated inhibition of CYP2B6 being more effective in experimental rodents compared with the inhibition of human CYP2C19 However, the ability to utilize TMX to suppress ER function and prolong methadone metabolism was confirmed by this study. Figure 3 Pharmacodynamic alterations in methadone metabolism with or without tamoxifen TAM injections. A Experimental design and treatment procedures. The 6-wk-old Wistar rats were randomly assigned to each of the study groups. B The serum TAM levels were measured at 4 h after methadone injection. C The serum R-methadone levels were measured in each group. E The serum S-methadone levels were measured in each group. P: intra-peritoneal injection. In addition, CYP3A4 is a potent methadone-metabolizing enzyme without an indicated preference for either racemate Therefore, raloxifene, ospemifene, and LY could potentially be tested as add-on agents in MMT for opiate abuse patients. Figure 4 The model illustrates changes in methadone liability and cravings during MMT, which is associated with three outcome scenarios. The dark-pink area shows the MMT regimen-related liability to quickly increase over the tolerance phase, decline over the taper phase, but then increase again during the abstinence phase. The light pink area indicates morphine-related liability. It declined to an even lower degree during both the tapering and abstinence phases. The inset shows a schematic illustration of methadone metabolism. Racemate catalyzation is selectively affected by various SERMs. CYP3A4 can catalyze both racemates. Tamoxifen was found to suppress CYP2B6 predominantly through the inhibition of gene expression and the suppression of CYP3A4 through direct interaction. Although the use of TMX led to more robust increases in S-methadone, which is associated with complications, future testing with other SERMs would be of great interest. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Y-CC and J-CY executed the animal experiments, performed statistical analyses, and edited the manuscript. Grants to H-YL and I-KH supported this study, and they participated in associated discussions and edited the manuscript. W-LM initiated the study, interpreted the data, supported the entire project, and edited and approved the final manuscript. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Okie S. N Engl J Med —5. Int J Eat Disord —7. Syst Rev Can J Public Health —3. Arch Gen Psychiatry — Mt Sinai J Med — PubMed Abstract Google Scholar. J Subst Abuse Treat —6. Ruadze E, Todadze K. Harm Reduct J Br J Clin Pharmacol — Addict Behav — Subst Use Misuse — Biol Sex Differ Int J Neuropsychopharmacol —7. Subst Use Misuse 1— Environ Health Prev Med —6. Psychopharmacol Berl J Palliat Med —8. J Addict Med — J Sex Med — Ther Drug Monit —5. Fertil Steril — Methadone Metabolism by Human Placenta. Biochem Pharmacol — Drug Metab Dispos — Dickmann LJ, Isoherranen N. Drug Metab Dispos —4. Acta Pharm Sin B — J Cell Mol Med — J Pathol — Carcinogenesis — Gastroenterology —55, Theranostics — Am J Reprod Immunol — Behav Brain Res —7. Nucleic Acids Res D— Talanta —8. Jantos R, Skopp G. Forensic Sci Int — Aromatase in Human Liver and Its Diseases. Cancer Med — Fertil Steril — e Gynecol Endocrinol — Eur J Gynaecol Oncol —5. Reprod Sci — Contraception —6. What Role of Estrogens in Ovarian Stimulation. Maturitas — Am J Obstet Gynecol e51— J Clin Endocrinol Metab —6. Andrologia e Eur Endocrinol — Anesthesiology — Basic Clin Pharmacol Toxicol — Crit Rev Clin Lab Sci — Clin Pharmacol Ther — Mol Pharmacol — Arch Biochem Biophys —8. Biochemistry —9. Biopharm Drug Dispos — Drug Metabol Drug Interact — Chem Biol Interact — The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Top bar navigation. About us About us. Sections Sections. About journal About journal. Article types Author guidelines Editor guidelines Publishing fees Submission checklist Contact editorial office. Translational and Clinical Endocrinology. Introduction The use of illicit opioids remains an ongoing issue for both individuals and society at large 1. The Impacts of Estrogen Signaling on MMT Efficacy As early as the s, a report described the complication of amenorrhea among women treated with methadone, which was associated with the secretion of gonadotropins from the hypothalamus Tail-Flick Assay The tail-flick test was performed in mice using a modified version of the method described by Dai et al. Reviewed by: Ma.

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