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Mitragynine Attenuates Morphine Withdrawal Effects in Rats—A Comparison with Methadone and Buprenorphine

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Mitragynine Attenuates Morphine Withdrawal Effects in Rats—A Comparison with Methadone and Buprenorphine ORIGINAL RESEARCH published: 07 May 2020 doi: 10.3389/fpsyt.2020.00411 Mitragynine Attenuates Morphine Withdrawal Effects in Rats—A Comparison With Methadone and Buprenorphine Rahimah Hassan 1, Cheah Pike See 2, Sasidharan Sreenivasan 3, Sharif M. Mansor 1, Christian P. Müller 4* and Zurina Hassan 1,5* 1 Centre for Drug Research, Universiti Sains Malaysia, Minden, Malaysia, 2 Department of Human Anatomy, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Malaysia, 3 Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden, Malaysia, 4 Section of Addiction Medicine, Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany, 5 Addiction Behaviour and Neuroplasticity Laboratory, National Neuroscience Institute, Singapore, Singapore Edited by: Simona Zaami, Background: Opiate addiction is a major health problem in many countries. A crucial Sapienza University of Rome, component of the medical treatment is the management of highly aversive opiate Italy Reviewed by: withdrawal signs, which may otherwise lead to resumption of drug taking. In a Fabrizio Schifano, medication-assisted treatment (MAT), methadone and buprenorphine have been University of Hertfordshire, implemented as substitution drugs. Despite MAT effectiveness, there are still limitations United Kingdom Ornella Corazza, and side effects of using methadone and buprenorphine. Thus, other alternative therapies University of Hertfordshire, with less side effects, overdosing, and co-morbidities are desired. One of the potential United Kingdom pharmacotherapies may involve kratom's major indole alkaloid, mitragynine, since kratom *Correspondence: (Mitragyna speciosa Korth.) preparations have been reported to alleviate opiate Christian P. Müller [email protected] withdrawal signs in self-treatment in Malaysian opiate addicts. Zurina Hassan [email protected] Methods: Based on the morphine withdrawal model, rats were morphine treated with increasing doses from 10 to 50 mg/kg twice daily over a period of 6 days. The treatment Specialty section: was discontinued on day 7 in order to induce a spontaneous morphine abstinence. The This article was submitted to withdrawal signs were measured daily after 24 h of the last morphine administration over a Addictive Disorders, a section of the journal period of 28 abstinence days. In rats that developed withdrawal signs, a drug replacement Frontiers in Psychiatry treatment was given using mitragynine, methadone, or buprenorphine and the global Received: 06 December 2019 withdrawal score was evaluated. Accepted: 22 April 2020 Published: 07 May 2020 Results: The morphine withdrawal model induced profound withdrawal signs for 16 days. Citation: Mitragynine (5–30 mg/kg; i.p.) was able to attenuate acute withdrawal signs in morphine Hassan R, Pike See C, Sreenivasan S, dependent rats. On the other hand, smaller doses of methadone (0.5–2 mg/kg; i.p.) and Mansor SM, Müller CP and Hassan Z (2020) Mitragynine Attenuates buprenorphine (0.4–1.6 mg/kg; i.p.) were necessary to mitigate these effects. Morphine Withdrawal Effects in Rats—A Comparison With Conclusions: These data suggest that mitragynine may be a potential drug candidate for Methadone and Buprenorphine. opiate withdrawal treatment. Front. Psychiatry 11:411. doi: 10.3389/fpsyt.2020.00411 Keywords: mitragynine, kratom, morphine, withdrawal, substitution, methadone, buprenorphineI Frontiers in Psychiatry | www.frontiersin.org 1 May 2020 | Volume 11 | Article 411 Hassan et al. Mitragynine for Morphine Withdrawal INTRODUCTION the second week, 25 fatalities were reported with one case of methadone toxicity, 5 cases of other drug toxicity, and 19 cases of Abuse and addiction to opioids including prescription pain other death causes (14). Meanwhile, another study done by Kelty relievers, heroin, and synthetic opioids such as fentanyl caused et al. demonstrated a high rate of mortality in methadone-treated a serious national crisis in the United States (US), that affects patients during the first 28 days of treatment as compared to public health as well as social and economic welfare (1). naltrexone-treated patients (15). Moreover, a study done by Bell According to Centers for Disease Control and Prevention et al. revealed 60 sudden deaths associated with methadone, (CDC), the opioid crisis has occurred in three waves. The first where 19 out of 32 in-treatment cases and 24 out of 28 cases of wave began in the 1990s with the rises of death cases related to out-treatment were linked to overdose (16). The autopsy results overdose of prescription opioids. The second wave emerged in for all 43 methadone overdose positive deaths revealed at least 2010 involving heroin overdoses. The third wave began in 2013 one other drug was involved (16). with the sharp rise of overdose death numbers involving An alternative option to methadone is the buprenorphine synthetic opioids, particularly illicitly manufactured fentanyl replacement therapy. It acts as mu-partial agonist at mu opiate (IMF). Fentanyl is 50–100 times more potent than morphine receptor (MOR) and has “ceiling effect” for respiratory depression. as an analgesic agent. In the US alone, more than 47,000 opioid- Thus, it offers advantages in terms of safety as compared to related overdose deaths occurred during 2017, which are closely methadone. Buprenorphine has been approved in several related to synthetic opioids, especially fentanyl (2). At present, countries as an efficient and safe maintenance therapy for heroin IMF still contributes greatly to overdose fatalities (3) in many addiction which resulted in a salutary effect with a reduction in states of the US and in Canada (4, 5). IMF fatalities are generally heroin overdose-related deaths in countries that implemented due to co-administration of other illicit drugs, such as cocaine, office-based buprenorphine maintenance. In France, however, heroin, and methamphetamine (6, 7), which leads to overdose several cases of asphyxia deaths were reported among addicts and consequently death. treated with buprenorphine concomitant with other drugs like As stated in the World Drug Report 2019, an estimated 271 benzodiazepines. Drug–drug interactions with buprenorphine million people worldwide used drugs and almost 13% are may cause severe respiratory depression (17). Buprenorphine has estimated to suffer from drug use disorder, to a point where been reported to cause seven fatality cases, four cases were they may experience dependence and/or require treatment (8). associated with buprenorphine poisoning, followed by two In Malaysia, opioid remains the main type of illicit substance, suicidal cases and one undetermined case (18). with estimated 187 771 opiate users. Mu-opioid receptor agonists The kratom plant (Mitragyna speciosa Korth.) has been long are the mainstay in drug replacement therapy. Buprenorphine used traditionally for its pharmacological effects and its narcotic and methadone are recommended in pharmacotherapy of opioid action in Southeast Asian nations, especially Thailand and use disorder based on their mechanisms of action in alleviating Malaysia. People use kratom plant preparations for their withdrawal signs (9). However, both have clinical limitations in medicinal value in treating pain,moodswing,coughing, their effectiveness and safety. diarrhea, and intestinal infection (19, 20). Kratom is also used Typically, methadone therapy is considered as safe. It has a as a substitution of heroin and morphine when access to these long half-life and makes outpatient management feasible. drugs is prevented and as treatment for drug withdrawal signs Nevertheless, several risk factors have been recognized, such as; (21, 22). Kratom leaves consist of over 25 alkaloids, where i) drug–drug interaction with other drugs, ii) torsade de pointes, mitragynine is the main indole alkaloid (23). which elevated risk of some individuals, and iii) the inadequate Recent fatality reports by CDC revealed 152 deaths between or erroneous dose increase adjustment, specifically, when July 2016 and December 2017, where multiple drugs were prescribing methadone for pain (10). Moreover, methadone detected in almost every kratom-related death (24). Another efficacy shows high inter-individual variance due to study reported 156 death cases linked to kratom use, where 87% pharmacokinetic and pharmacodynamic factors (11). The cases associated with polydrug use. Another 23% cases was due effective half-life of methadone for analgesia in many patients to kratom itself, with 6 cases found mitragynine in toxicology test does not reflect the half-life for respiratory depression and (25). However, the claim that six fatalities was due to cardiac side effects, making consistent and safe dosing difficult mitragynine alone does not mention the sources, thus, the for methadone (12). This often leads to an overdose which is truth on the claim was unclear. High post-mortem mitragynine associated with serious side effects, including potentially lethal concentration may not always reflect the direct involvement in a respiratory depression. Indeed, unintentional deaths are much fatality (26). Gershman et al. reviewed the Colorado death more common after methadone administration than after any certificates for any mentioning of kratom or mitragynine from other opioid (13). Methadone fatality occurred not only among 1999 through 2017. They found four death cases due to out-treatment patient but also for in-treatment
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