Hypoxic Brain Damage in Methadone Misuse: Insights from MRI Imaging and Comparative Study

doi:10.21203/rs.3.rs-4888396/v1

Download PDF

Research Article

Hypoxic Brain Damage in Methadone Misuse: Insights from MRI Imaging and Comparative Study

https://doi.org/10.21203/rs.3.rs-4888396/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background: This study aimed to investigate the potential presence of brain disorders, particularly hypoxia, via magnetic resonance imaging (MRI) in patients misusing methadone, with a comparison to regular opium users and a control group.

Methods: Conducted as a cross-sectional comparative study at Kamali Hospital in Karaj, Iran, the research included male participants comprising methadone users, opium users, and controls. Inclusion criteria were stringent, focusing on substance use duration and absence of brain structural disorders. MRI scans were performed using a 1.5T MRI scanner. Qualitative MRI assessments and chi-square tests analyzed associations between substance use and hypoxia, while logistic regression examined potential confounding variables.

Results: Significant hypoxia was observed in the methadone group (16.7%, 5/24; p = 0.00057), with no cases in the opium or control groups. Logistic regression analysis showed no significant predictors of hypoxia regarding dose, duration of use, or age. MRI findings in methadone users with hypoxia included varied ADC intensities, high signal intensities on T2-weighted and diffusion-weighted imaging (DWI) sequences, and angiogenesis patterns on TOF sequences. The co-use of methadone and alcohol was noted in three of the five hypoxia cases.

Conclusion: Methadone misuse, particularly with alcohol, poses a significant risk of hypoxia, detectable via MRI. This study underscores the need for routine MRI monitoring, stricter regulation of non-prescribed methadone, and enhanced public health education to mitigate misuse risks. Future research should expand sample sizes and incorporate advanced imaging techniques to further elucidate methadone's neurological impact.

Methadone

Hypoxia

MRI

Substance Use

Brain Disorders

Opioids

Public Health

Methadone, a synthetic opioid introduced in the 1960s, plays a critical role in the management of opioid withdrawal symptoms and chronic pain [1, 2]. As a racemic mixture, the (R)-methadone enantiomer is the active component responsible for its therapeutic effects [3]. Despite its common oral administration, methadone can also be delivered via rectal, sublingual, and intravenous routes, enhancing its versatility in clinical settings [4, 5].

Methadone's analgesic properties arise from its multi-faceted mechanisms of action, which include opioid receptor activation, NMDA receptor antagonism, and inhibition of serotonin and norepinephrine reuptake [6, 7]. These mechanisms not only underpin its efficacy as a potent analgesic but also distinguish methadone from other long-acting opioids through its unique pharmacological attributes, such as fat solubility and high plasma protein binding affinity [8]. Consequently, methadone exhibits a prolonged duration of action, albeit with a variable terminal half-life ranging from 15 to 50 hours, necessitating careful dosage titration and frequent monitoring to prevent drug accumulation and adverse effects [9].

Beyond its primary use in opioid withdrawal management, methadone is integral to Methadone Maintenance Treatment (MMT) programs, significantly reducing injection drug use and transmission rates of HIV and hepatitis C virus [10, 11]. Its effectiveness extends to managing various chronic pain conditions, including cancer and neuropathic pain, as well as acute post-operative pain, due to its combined analgesic and antihyperalgesic effects [12–14].

Methadone's therapeutic benefits are counterbalanced by substantial risks, especially in the context of poly-drug use, which increases the potential for adverse interactions and overdose [15–21]. Methadone overdose significantly contributes to opioid-related mortality, often leading to severe outcomes such as respiratory depression and cardiac arrest [22–24]. Imaging studies have revealed methadone-induced neurotoxicity, showing specific brain abnormalities [25–29]. High doses of methadone can cause severe hypoxia, raising the risk of stroke and delay post-hypoxic encephalopathy. MRI scans of affected patients often display diffuse abnormal T2 signals in the corona radiata, centrum semiovale, and subcortical white matter, indicating extensive brain damage [30]. Proton magnetic resonance spectroscopy (MRS) has shown decreased N-acetyl aspartate (NAA) levels and elevated lactate levels, suggesting mitochondrial dysfunction and hypoxia-related processes [25, 29]. These findings highlight the need for vigilant monitoring and precise dosing to prevent severe hypoxic events in patients on methadone therapy [31]. Additionally, methadone maintenance treatment is associated with significant weight gain and increased cardiovascular risk factors, necessitating further research to identify predictors and develop tailored interventions, including nutritional and lifestyle recommendations [32, 33]. Higher doses of methadone are linked to changes in the QTc interval and the prevalence of U waves, which are associated with cardiac arrhythmias and torsade de pointes, emphasizing the need for careful monitoring, especially in patients at risk of arrhythmia [34, 35].

The complex interplay of methadone's pharmacokinetics and pharmacodynamics, coupled with wide interindividual variability, underscores the importance of a cautious approach to its administration [1, 4, 36–44]. Moreover, while methadone aims to alleviate opioid dependency, it often perpetuates a cycle of dependency, highlighting the need for a critical reassessment of its role in addiction treatment [24]. This necessitates the implementation of more effective strategies that address the underlying causes of addiction while minimizing harm [45, 46].

Despite the recognition of methadone's adverse effects, there is a lack of comprehensive studies with substantial sample sizes addressing brain-related disorders associated with high doses of methadone. Most existing research is limited to case reports, underscoring the need for more extensive investigations to understand the full scope and mechanisms of methadone-induced neurological complications.

Our study aimed to explore the potential presence of brain disorders via magnetic resonance imaging (MRI) in patients who misuse methadone or combine it with other drugs.

This cross-sectional comparative study was conducted at Kamali Hospital in Karaj, Iran, among three distinct groups: individuals using methadone obtained through non-medical sources, regular opium users, and matched controls. The study included only male participants of Middle Eastern descent. The Methadone Group consisted of individuals using methadone not obtained through a methadone maintenance treatment program, while the Opium Group included individuals with regular, self-reported opium use. The control group consisted of participants who did not use any substances. To ensure consistency and reliability of the data, all participants underwent a comprehensive screening process, which included standardized questionnaires such as the Addiction Severity Index (ASI) to assess psychiatric comorbidities and substance use history (Table 1). Trained interviewers conducted these screenings. Participants were recruited over six years through community outreach programs, which included distributing flyers in community centers, posting on social media platforms, and conducting direct outreach through community health workers trained to identify and approach potential participants. Recruitment was challenging due to the strict exclusion criteria and the difficulty in persuading individuals with substance use histories to participate in scientific research and undergo MRI scans. Monetary compensation was provided to participants to incentivize their involvement.

Table 1

ASI (Addiction Severity Index) questionnaire
Domain	Questions
Medical Status	Do you currently have any medical problems not related to substance use? If yes, please describe.
Employment and Support	Are you currently employed or receiving any financial assistance? If yes, please describe.
Drug Use	During the past 30 days, how often have you used [specific drug(s)]? On average, how much do you use each time?
Alcohol Use	During the past 30 days, how often have you consumed alcohol?
Psychiatric Status	Have you ever been diagnosed with a mental health disorder (e.g., depression, anxiety)? If yes, please describe

Inclusion criteria for the study required participants in the experimental groups (Methadone and Opium) to be male with a mean duration of substance use of 1 year and no history of brain structural disorders. The Control Group included male participants with no history of substance use and no brain structural disorders. Exclusion criteria were stringent and included a documented history of neurological or psychiatric disorders, contraindications to MRI, severe claustrophobia, significant medical conditions affecting brain structure or function, current substance withdrawal (including opioids), enrollment in a methadone maintenance program, recreational substance use, or if motion artifacts degraded MRI image quality. All participants underwent a thorough screening process, including interviews and standardized questionnaires, to ensure they met the inclusion and exclusion criteria. This careful selection process and extensive screening were crucial to focus the study on the effects of substance use on brain structure in otherwise healthy individuals.

The study received approval from Shahid Beheshti University of Medical Sciences (Approval Code: IR.sbmu.retech.rec.1396.973). Prior to participation, all individuals provided written informed consent following a comprehensive explanation of the study's procedures, potential risks, and benefits. The study adhered to the ethical principles outlined in the Declaration of Helsinki. Confidentiality and anonymity were strictly upheld throughout the research. Data were anonymized and securely stored in a restricted-access database. Unique identifiers were assigned to participants to ensure anonymity. Informed consent was obtained in a private setting, allowing participants sufficient time to ask questions and address any concerns. All data were securely stored, and personal information was de-identified before analysis.

MRI scans were conducted using a Scimedix 1.5T MRI scanner with a 32-channel head coil. A standard brain MRI protocol was employed, including T1-weighted, T2-weighted, FLAIR, and diffusion-weighted imaging (DWI) sequences, along with an ADC map, and Time-of-Flight (TOF) scans. No contrast media was used. The imaging procedure lasted approximately 15 minutes.

MRI Protocol Details:

T1-weighted Spin-Echo Images (T1WI): TR/TE = 300/12 msec, matrix size = 256 × 256, FOV = 24 × 24 cm², slice thickness = 5 mm, gap = 1 mm.
T2-weighted Fast Spin-Echo (T2 WI): TR/TE = 3750/120 msec, matrix size = 256 × 256, FOV = 24 × 24 cm², slice thickness = 5 mm, gap = 1 mm.
FLAIR: TR/TE = 6400/71 msec, matrix size = 256 × 256, FOV = 24 × 24 cm², slice thickness = 5 mm, gap = 1 mm.
Diffusion-weighted Imaging (DWI): TR/TE = 7600/122 msec, matrix size = 112 × 96, FOV = 24 × 24 cm², slice thickness = 5 mm, gap = 1 mm.
Time-of-Flight (TOF): TR/TE = 250/3.6 msec, matrix size = 256 × 200, FOV = 24 × 24 cm², slice thickness = 1 mm.

A board-certified radiologist with expertise in MRI interpretation conducted a qualitative assessment by visually examining the MRI images for stroke. The radiologist was blinded to the participants' group status to prevent bias. MRI findings, detailed in Table 2, involved assessing hyperintense signals on T2-weighted and FLAIR sequences, evaluating diffusion-weighted imaging (DWI) intensity and ADC values for acute ischemic changes, and utilizing Time-of-Flight (TOF) magnetic resonance angiography (MRA) to identify vascular abnormalities relevant to stroke, and T1-weighted images (T1 WI) for assessing anatomical structure and detecting hemorrhage.

Table 2

MRI Imaging Assessments
MRI Findings	Description	Assessed (Yes/No)	Involvement
T2 and FLAIR Hyperintensity	Assessment of hyperintense signals on T2-weighted and FLAIR sequences
DWI and ADC Intensity	Evaluation of diffusion-weighted imaging (DWI) intensity and ADC values for detecting acute ischemic changes
Brain Angiography with TOF	Utilization of TOF MRA to identify vascular abnormalities relevant to stroke
T1-WI	Evaluation of T1-weighted images for assessing anatomical structures and detecting hemorrhage

Statistical analysis was performed using the chi-square test to examine associations between categorical variables and the presence of neurological disorders identified through MRI imaging. Statistical analysis was performed using the Python programming language, employing libraries such as SciPy for chi-square tests and Pandas for data management. P-values less than 0.05 were considered statistically significant.

Potential confounding variables, such as age, duration of substance use, and dose of substance used by individuals, were controlled for by matching participants across groups and using these variables as covariates in the statistical analysis. Additionally, logistic regression was employed using Python to examine the influence of these independent variables on the outcomes. Libraries such as `statsmodels` and `scikit-learn` were utilized to handle the statistical modeling. This approach helped to ensure that observed differences were more likely attributable to substance use rather than other factors, as the regression model could account for the potential influence of the confounding variables. By controlling for these variables, the analysis provided a clearer understanding of the relationship between substance use and the observed outcomes, reducing the likelihood that the results were skewed by extraneous factors.

This study involved 96 male participants of Middle Eastern descent, categorized into patients and controls. The patient group comprised 38 individuals using Methadone or Opium, while the control group consisted of 58 non-substance users. Methadone users (n = 24) had a mean age of 32.3 years (range: 28–36) and used doses of 2–3 grams for 2–5 years. Opium users (n = 14) had a mean age of 45.7 years (range: 35–50) and used doses of 1–5 grams over 3–15 years. The control group, with a mean age of 33.8 years (range: 24–48), showed an even age distribution (Figs. 1 and 2).

Logistic regression analysis revealed that dose, duration of use, and age did not significantly predict hypoxia (dose: coefficient − 0.09, p = 0.948; duration: coefficient − 0.13, p = 0.824; age: coefficient 0.20, p = 0.450), suggesting no substantial relationship between these variables and the likelihood of hypoxia (Table 3). Additionally, the scatter plot matrix shown in Fig. 3 illustrates the relationships between Age, Dose, Time of Use, and the presence of Hypoxia in methadone patients. Despite thorough regression analysis, no significant correlations were found among these variables (Fig. 3).

Table 3

Logistic regression results show no significant predictors of hypoxia among Dose, Time of use, and Age variables (p > 0.05)
Variable	Coefficient	p-value
Intercept	-7.28	0.389
Dose	-0.09	0.948
Time of use	-0.13	0.824
Age	0.2	0.45

Chi-square analysis indicated significant associations between substance use and hypoxia (χ² = 15.82, p = 0.0012). Methadone users showed a significant association with hypoxia (χ² = 11.87, p = 0.00057), whereas no significant association was found in Opium users (χ² = 0.77, p = 0.38) (Table 4). Specifically, 16.7% (5 out of 24) of Methadone users experienced hypoxia (Table 5), highlighting a notable correlation between Methadone use and increased risk of hypoxia compared to Opium users and non-substance users.

Table 4

Chi-Square Analysis of Substance Use and Hypoxia
Group	Substance	Chi-Square Value (χ²)	p-value
Total	-	15.82	0.0012
Control	-	3.19	0.074
Patient	Methadone	11.87	0.00057
Patient	Opium	0.77	0.38

Table 5

Table presents demographic details and hypoxia incidence rates among study participants categorized into patient groups receiving Methadone or Opium, and a control group.
Group	Subgroup	Number of Participants	Age Range (years)	Mean Age (years)	Hypoxia Incidence (%)
Patient	Methadone	24	28–36	32.3	16.7
	Opium	14	35–50	45.7	-
Control	-	58	24–48	33.8	-

MRI imaging findings in the Methadone group revealed varied ADC intensities, with high intensity in acute cases and low intensity in chronic cases. T2-weighted and DWI sequences consistently showed high signal intensities. FLAIR sequences consistently displayed high signal intensities. TOF sequences indicated angiogenesis patterns, and in chronic cases, reduced vascular flow was observed. Table 6 outlining imaging findings across five hypoxia cases.

Table 6

MRI imaging findings in a group of methadone patients
Patient Number	Age	Dose (gr)	Duration (years)	T2	DWI	ADC	FLAIR	T1	TOF	Involvement
1	32	2	4	High signal	High signal	Low signal	High signal	ISO	Angiogenesis	Parietal lobe
2	35	2	3	High signal	High signal	Low signal	High signal	ISO	Angiogenesis	Parietal lobe
3	33	3	3	High signal	High signal	Low signal	High signal	ISO	Angiogenesis	Parieto-occipital
4	32	2	3	High signal	High signal	High signal	High signal	Low	Reduced flow	Occipital
5	33	2	2	High signal	High signal	High signal	High signal	Low	Reduced flow	Parieto-occipital

Methadone offers significant therapeutic benefits, but it also comes with considerable risks. These risks are particularly heightened when methadone is used alongside other drugs, as this can lead to dangerous interactions and a higher likelihood of overdose. Consequently, careful monitoring and management are essential to ensure patient safety. This balance of benefits and risks must be meticulously maintained to avoid adverse outcomes [15-21].

Our study aimed to explore the potential presence of brain disorders via magnetic resonance imaging (MRI) in patients who misuse methadone or combine it with other drugs. The main finding indicates a significant occurrence of hypoxia in the methadone group, which is absent in both the opium and control groups. This suggests a unique risk profile associated with methadone misuse, particularly in combination with alcohol. Notably, three out of the five hypoxia cases involved methadone and alcohol co-use, highlighting a potential interaction that exacerbates the risk of hypoxia. Furthermore, all five individuals with hypoxia lacked knowledge about the pharmacodynamics of methadone, suggesting that educational deficits may contribute to unsafe usage patterns. Logistic regression analysis did not reveal any significant predictors of hypoxia in terms of dose, duration of use, or age. The coefficients for dose, time of use, and age indicate that these variables do not substantially contribute to the risk of hypoxia in the studied population. This lack of a dose-response relationship suggests that even low doses and shorter durations of methadone use can pose significant risks. Therefore, it emphasizes the need for cautious prescribing and vigilant monitoring practices to mitigate potential adverse effects.

The MRI scans were performed at various times post-hypoxia, which might explain the variability in apparent diffusion coefficient (ADC) signals observed, indicating both chronic and acute hypoxia among the patients [47]. This variability underscores the need for timely and consistent imaging protocols to accurately assess and monitor hypoxia in methadone users. The MRI findings in methadone users revealed distinct patterns associated with hypoxia, including high ADC intensities in acute cases and low in chronic cases [47], consistently high signal intensities on T2-weighted and diffusion-weighted imaging (DWI) sequences, and high signal intensities on fluid-attenuated inversion recovery (FLAIR) sequences [48, 49]. Time-of-flight (TOF) sequences indicated angiogenesis patterns and reduced flow in chronic cases (Figures 4 and 5) [50, 51]. These imaging characteristics can provide valuable insights into the temporal progression of hypoxic brain injury in methadone users and highlight the utility of MRI in detecting and characterizing such injuries [52].

In comparison with previous research, our study is novel in incorporating an opium group alongside a control group, thus providing a more comprehensive analysis. Despite the opium group using higher doses and for longer durations than the methadone group, no hypoxia cases were observed among them. This is consistent with existing literature, which primarily documents encephalopathy in methadone users but does not provide extensive imaging evidence [25-29]. The limited existing studies are mostly case reports [15, 25, 28, 30, 53-59], lacking the breadth of our comparative analysis across different substance use groups. While some prior research suggests methadone-related hypoxia [31, 60-63], They did not employ MRI, a method typically used for diagnosing brain hypoxia, thereby limiting their diagnostic precision.

Our findings have significant implications for clinical practice and public health policy. Routine MRI monitoring should be considered for methadone patients presenting with hypoxia symptoms to ensure early detection and intervention. Additionally, there is an urgent need for stricter regulations to prevent the sale of non-prescribed methadone, as its affordability and accessibility contribute to misuse [64]. Public health initiatives should also focus on educating individuals about the distinct and cumulative effects of methadone [9], particularly its differences from opium, to mitigate misuse risks. An important aspect of our study is the identification of educational deficits among the individuals who experienced hypoxia, pointing to a critical gap in understanding that may contribute to unsafe usage patterns. Providing comprehensive education on the risks associated with methadone misuse, especially in combination with other substances like alcohol, could potentially mitigate some of the adverse outcomes observed in this study.

This study is not without limitations. The small sample size, stemming from the challenges in recruiting such patients, underscores the need for governmental collaboration in future research. Moreover, self-reported data on drug use are inherently unreliable, and motion artifacts in MRI scans often necessitate the exclusion of non-cooperative subjects, reducing the usable sample size further. Financial incentives required for participant cooperation also highlight the need for adequate funding in addiction research. Additionally, the inclusion of overweight individuals may confound the effects of methadone on respiratory depression and cardiac arrest [32].

Future research should address these limitations by expanding the sample size and incorporating blood tests to verify drug use. Excluding overweight participants could provide clearer insights into methadone’s specific effects. Advances in MRI techniques, including spectroscopy and propeller imaging, could be leveraged to study metabolites and reduce motion artifacts. Additionally, perfusion imaging could be used for diagnosing the penumbra area. Further studies should also explore the effects of polydrug use with methadone compared to high-dose methadone use alone, to better understand the complexities of substance interactions.

In conclusion, our study highlights a significant risk of hypoxia in methadone users, particularly when combined with alcohol, and underscores the importance of MRI in diagnosing and monitoring this condition. The findings underscore the need for enhanced education and monitoring to prevent hypoxic brain injuries in this vulnerable population. Future research and policy initiatives should aim to mitigate these risks through better regulation, education, and advanced diagnostic techniques.

Author Contribution

Ali Shamooshaki: First author, responsible for analyzing data, writing the main sections of the article, and collecting the data.Fariborz Faeghi: Corresponding author, provided guidance throughout the study and manuscript preparation.Hossein Jomleh: Assisted in data analysis, contributed to writing the manuscript, and provided ideas for the study.Amin Aziziyan: Radiologist, reported the MRI scans, and provided guidance in writing the manuscript.Dayan Amanian: Radiologist, responsible for reporting the MRI scans.Reza Koohi: Assisted in collecting data for the study.

Data Availability

The data supporting the findings of this study are currently saved on the author’s computer. Due to concerns related to the privacy of study participants, the data cannot be shared openly. However, data will be made available upon reasonable request to qualified researchers. For access to the data or any further inquiries, please contact the corresponding author at [email protected]

Dinis-Oliveira RJ. Metabolomics of methadone: clinical and forensic toxicological implications and variability of dose response. Drug Metab Rev. 2016;48(4):568-76.
Dole VP, Nyswander M. A MEDICAL TREATMENT FOR DIACETYLMORPHINE (HEROIN) ADDICTION. A CLINICAL TRIAL WITH METHADONE HYDROCHLORIDE. Jama. 1965;193:646-50.
Kristensen K, Christensen CB, Christrup LL. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci. 1995;56(2):Pl45-50.
Peng PW, Tumber PS, Gourlay D. Review article: perioperative pain management of patients on methadone therapy. Can J Anaesth. 2005;52(5):513-23.
Hagen NA, Fisher K, Stiles C. Sublingual methadone for the management of cancer-related breakthrough pain: a pilot study. J Palliat Med. 2007;10(2):331-7.
Lugo R, Satterfield K, Kern S. Pharmacokinetics of Methadone. Journal of pain & palliative care pharmacotherapy. 2005;19:13-24.
Inturrisi CE. Pharmacology of methadone and its isomers. Minerva Anestesiol. 2005;71(7-8):435-7.
Brown R, Kraus C, Fleming M, Reddy S. Methadone: applied pharmacology and use as adjunctive treatment in chronic pain. Postgrad Med J. 2004;80(949):654-9.
Gudin J, Fudin J, Nalamachu S. Levorphanol use: past, present and future. Postgrad Med. 2016;128(1):46-53.
Ripamonti C, Zecca E, Bruera E. An update on the clinical use of methadone for cancer pain. Pain. 1997;70(2):109-15.
Kreek MJ. Biological correlates of methadone maintenance pharmacotherapy. Ann Med Interne (Paris). 1994;145 Suppl 3:9-14.
Gourlay GK, Willis RJ, Lamberty J. A double-blind comparison of the efficacy of methadone and morphine in postoperative pain control. Anesthesiology. 1986;64(3):322-7.
Kharasch ED. Intraoperative methadone: rediscovery, reappraisal, and reinvigoration? Anesth Analg. 2011;112(1):13-6.
Mizoguchi H, Watanabe C, Yonezawa A, Sakurada S. New therapy for neuropathic pain. Int Rev Neurobiol. 2009;85:249-60.
Schwartz RP, Brooner RK, Montoya ID, Currens M, Hayes M. A 12-year follow-up of a methadone medical maintenance program. Am J Addict. 1999;8(4):293-9.
BESWICK T, BEST D, REES S, COOMBER R, GOSSOP M, STRANG J. Multiple drug use: patterns and practices of heroin and crack use in a population of opiate addicts in treatment. Drug and Alcohol Review. 2001;20(2):201-4.
Gourevitch MN, Friedland GH. Interactions between methadone and medications used to treat HIV infection: a review. Mt Sinai J Med. 2000;67(5-6):429-36.
Taburet AM, Singlas E. Drug interactions with antiviral drugs. Clin Pharmacokinet. 1996;30(5):385-401.
Bruce RD, Altice FL, Gourevitch MN, Friedland GH. Pharmacokinetic drug interactions between opioid agonist therapy and antiretroviral medications: implications and management for clinical practice. J Acquir Immune Defic Syndr. 2006;41(5):563-72.
Schlatter J, Madras JL, Saulnier JL, Poujade F. [Drug interactions with methadone]. Presse Med. 1999;28(25):1381-4.
Hsu A, Granneman GR, Bertz RJ. Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet. 1998;35(4):275-91.
Gagajewski A, Apple FS. Methadone-related deaths in Hennepin County, Minnesota: 1992-2002. J Forensic Sci. 2003;48(3):668-71.
Ballesteros MF, Budnitz DS, Sanford CP, Gilchrist J, Agyekum GA, Butts J. Increase in deaths due to methadone in North Carolina. Jama. 2003;290(1):40.
Leonard J. Paulozzi M, Karin A. Mack, PhD, Christopher M. Jones, PharmD. Risk for Overdose from Methadone Used for Pain Relief. Div of Unintentional Injury Prevention, National Center for Injury Prevention and Control, CDC.: Morbidity and Mortality Weekly Report (MMWR); 2012 July 3.
Salgado RA, Jorens PG, Baar I, Cras P, Hans G, Parizel PM. Methadone-induced toxic leukoencephalopathy: MR imaging and MR proton spectroscopy findings. AJNR Am J Neuroradiol. 2010;31(3):565-6.
Carroll I, Heritier Barras AC, Dirren E, Burkhard PR, Horvath J. Delayed leukoencephalopathy after alprazolam and methadone overdose: a case report and review of the literature. Clin Neurol Neurosurg. 2012;114(6):816-9.
Bileviciute-Ljungar I, Häglund V, Carlsson J, von Heijne A. Clinical and radiological findings in methadone-induced delayed leukoencephalopathy. J Rehabil Med. 2014;46(8):828-30.
Corré J, Pillot J, Hilbert G. Methadone-induced toxic brain damage. Case Rep Radiol. 2013;2013:602981.
Vella S, Kreis R, Lovblad KO, Steinlin M. Acute leukoencephalopathy after inhalation of a single dose of heroin. Neuropediatrics. 2003;34(2):100-4.
Mittal M, Wang Y, Reeves A, Newell K. Methadone-induced delayed posthypoxic encephalopathy: clinical, radiological, and pathological findings. Case Rep Med. 2010;2010:716494.
Hunt G, Bruera E. Respiratory depression in a patient receiving oral methadone for cancer pain. J Pain Symptom Manage. 1995;10(5):401-4.
Sweeney MM, Antoine DG, Nanda L, Géniaux H, Lofwall MR, Bigelow GE, et al. Increases in body mass index and cardiovascular risk factors during methadone maintenance treatment. J Opioid Manag. 2019;15(5):367-74.
Fenn JM, Laurent JS, Sigmon SC. Increases in body mass index following initiation of methadone treatment. J Subst Abuse Treat. 2015;51:59-63.
Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, Robertson AD, Mehler PS. Torsade de pointes associated with very-high-dose methadone. Ann Intern Med. 2002;137(6):501-4.
Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol. 2005;95(7):915-8.
Garrido MJ, Trocóniz IF. Methadone: a review of its pharmacokinetic/pharmacodynamic properties. J Pharmacol Toxicol Methods. 1999;42(2):61-6.
Gorman AL, Elliott KJ, Inturrisi CE. The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett. 1997;223(1):5-8.
Schuckit MA. Treatment of Opioid-Use Disorders. New England Journal of Medicine. 2016;375(4):357-68.
Codd EE, Shank RP, Schupsky JJ, Raffa RB. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther. 1995;274(3):1263-70.
Ebert B, Andersen S, Krogsgaard-Larsen P. Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord. Neurosci Lett. 1995;187(3):165-8.
Davis AM, Inturrisi CE. d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia. J Pharmacol Exp Ther. 1999;289(2):1048-53.
Bravo L, Llorca-Torralba M, Berrocoso E, Micó JA. Monoamines as Drug Targets in Chronic Pain: Focusing on Neuropathic Pain. Front Neurosci. 2019;13:1268.
Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895-926.
Murphy GS, Wu CL, Mascha EJ. Methadone: New Indications for an Old Drug? Anesth Analg. 2019;129(6):1456-8.
Fudin HR BJ, Hong JT, KuJ, May AL, Wisner A, et al. Side Effects of Drugs Annual. 1 ed: Elsevier; 2018. 694 p.
George F. Koob MAAaMLM. Drugs, Addiction, and the Brain. Drugs, Addiction, and the Brain. 1 ed. Academic Press: Elsevier; 2014. p. 350.
Schlaug G, Siewert B, Benfield A, Edelman RR, Warach S. Time course of the apparent diffusion coefficient (ADC) abnormality in human stroke. Neurology. 1997;49(1):113-9.
Xu XQ, Cheng QG, Zu QQ, Lu SS, Yu J, Sheng Y, et al. Comparative study of the relative signal intensity on DWI, FLAIR, and T2 images in identifying the onset time of stroke in an embolic canine model. Neurol Sci. 2014;35(7):1059-65.
Gerbasi A, Konduri P, Tolhuisen M, Cavalcante F, Rinkel L, Kappelhof M, et al. Prognostic Value of Combined Radiomic Features from Follow-Up DWI and T2-FLAIR in Acute Ischemic Stroke. J Cardiovasc Dev Dis. 2022;9(12).
Muttikkal TJ, Wintermark M. MRI patterns of global hypoxic-ischemic injury in adults. J Neuroradiol. 2013;40(3):164-71.
Harris AD, Murphy K, Diaz CM, Saxena N, Hall JE, Liu TT, et al. Cerebral blood flow response to acute hypoxic hypoxia. NMR Biomed. 2013;26(12):1844-52.
Bonnitcha P, Grieve S, Figtree G. Clinical imaging of hypoxia: Current status and future directions. Free Radic Biol Med. 2018;126:296-312.
Carroll I, Heritier Barras A-C, Dirren E, Burkhard PR, Horvath J. Delayed leukoencephalopathy after alprazolam and methadone overdose: A case report and review of the literature. Clinical Neurology and Neurosurgery. 2012;114(6):816-9.
Meyer MA. Delayed post-hypoxic leukoencephalopathy: case report with a review of disease pathophysiology. Neurol Int. 2013;5(3):e13.
Cerase A, Leonini S, Bellini M, Chianese G, Venturi C. Methadone-induced toxic leukoencephalopathy: diagnosis and follow-up by magnetic resonance imaging including diffusion-weighted imaging and apparent diffusion coefficient maps. J Neuroimaging. 2011;21(3):283-6.
Aghabiklooei A, Edalatparvar M, Zamani N, Mostafazadeh B. Prognostic factors in acute methadone toxicity: a 5-year study. J Toxicol. 2014;2014:341826.
Zanin A, Masiero S, Severino MS, Calderone M, Da Dalt L, Laverda AM. A delayed methadone encephalopathy: clinical and neuroradiological findings. J Child Neurol. 2010;25(6):748-51.
Mills F, MacLennan SC, Devile CJ, Saunders DE. Severe cerebellitis following methadone poisoning. Pediatr Radiol. 2008;38(2):227-9.
Anselmo M, Campos Rainho A, do Carmo Vale M, Estrada J, Valente R, Correia M, et al. Methadone intoxication in a child: toxic encephalopathy? J Child Neurol. 2006;21(7):618-20.
Madjova C, Chokanov S, Milkov M. CORRELATION BETWEEN SLEEP APNEA AND METHADONE THERAPY. Journal of IMAB - Annual Proceeding (Scientific Papers). 2021.
Webster LR, editor Methadone Side Effects: Constipation, Respiratory Depression, Sedation, Sleep-Disordered Breathing, and the Endocrine System2013.
Correa D, Farney RJ, Chung F, Prasad A, Lam D, Wong J. Chronic opioid use and central sleep apnea: a review of the prevalence, mechanisms, and perioperative considerations. Anesth Analg. 2015;120(6):1273-85.
Charpentier A, Bisac S, Poirot I, Vignau J, Cottencin O. Sleep quality and apnea in stable methadone maintenance treatment. Subst Use Misuse. 2010;45(9):1431-4.
De Lima L, Pastrana T, Radbruch L, Wenk R. Cross-sectional pilot study to monitor the availability, dispensed prices, and affordability of opioids around the globe. J Pain Symptom Manage. 2014;48(4):649-59.e1.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Hypoxic Brain Damage in Methadone Misuse: Insights from MRI Imaging and Comparative Study

Status:

Version 1

Abstract

Figures

Introduction

Materials and Methods

Results

Discussion

Declarations

Author Contribution

Data Availability

References

Additional Declarations

Status:

Version 1