AUTHORS: Daguio K et al
Pract Pain Manage. 2023 July August 23(4).
Methadone is a mu opioid agonist that binds to receptors located in the central nervous system (CNS) and cardiovascular tissue. Classified as a synthetic opioid, methadone is known to reduce symptoms of narcotic withdrawal and decrease the euphoric effects of other narcotics, including opioids.1 Due to its twofeatures of a long half-life and high oral absorption,2 methadone is used as an alternative treatment to prevent or reduce withdrawal symptoms in the treatment of drug misuse,2 specifically for those unable to maintain abstinence from drug misuse.3
Specifically, MMT can lead to adverse effects of the cardiovascular, endocrine, renal, gastrointestinal, and neuro/psychiatric systems. Based on the current literature, this paper briefly explores these adverse effects and their management, as well as provides perspective on emerging alternatives to MMT that may have a more positive safety profile for people with OUD.5,6,8
Methadone maintenance treatment poses an increased general risk of cardiotoxicity. One of the more specifically identified adverse cardiac effects is QT prolongation caused by the inhibition of the delayed rectifier K+ currents. This inhibition causes a prolonged action potential duration (APD), which increases the risk for life-threatening arrhythmias including ventricular tachycardia and Torsades de pointes. Cardiac markers such as brain natriuretic peptide and atrial natriuretic peptide were also found in patients with dyspnea and edema. Screening for cardiac risk factors and a baseline ECG is recommended to initiate MMT with ongoing monitoring for continued therapy.5,6,8
Hormonal changes and biopsychological effects have been documented in patients on MMT. Research shows that methadone leads to dose-dependent damage to testosterone production (ie, the higher the dose of methadone the lower the testosterone production). In fact, decreased levels of plasma testosterone and increased levels of prolactin (PRL) contribute to neuroendocrine changes leading to decreased libido and erectile dysfunction.9,10
Of note, other factors commonly found in people with OUD, noted in the Childhood Experience of Care and Abuse Questionnaire (CECA-Q) and Diagnostic Statistic Manual of Disorders (DSM-5) respectively, showed that childhood adversities and comorbid psychiatric symptoms can also lead to sexual dysfunction. The complex etiology of methadone-related sexual dysfunction therefore often warrants a holistic treatment approach to address methadone-induced sexual dysfunction as well as other root causes.9-11
Rhabdomyolysis-induced acute kidney injury (AKI) is a direct nephrotoxic effect of methadone consumption and has been seen on MMT doses starting as low as 30 mg/day and up to 150 mg/day. The increased oxygen demand in muscles generates ischemia and the release of toxic intracellular components that damage the cell membranes of skeletal muscle. Myoglobin is the primary constituent associated with AKI.
Other notable mechanisms of nephrotoxicity include renal vasoconstriction, ischemia, myoglobin casts, and myoglobin cytotoxicity. Although methadone toxicity is an important factor in renal failure and rhabdomyolysis-induced AKI, other parameters such as age, gender, and psychological disorders can affect outcomes and therefore should be considered in medical care.12
Opioid-induced constipation (OIC) has been observed in patients on MMT. This is due to a decrease in gut motility. Oral-cecal gastrointestinal transit times were gathered using the lactulose hydrogen breath test. This approach measures exhaled hydrogen concentrations generated by the colonic bacterial fermentation of lactulose. The oral-cecal transit time spans between the digestion of lactulose and production of pulmonary hydrogen. A baseline of 110 minutes increased to 159 minutes for patients on MMT. Lastly, patients on MMT do not develop tolerance to the opioid-induced gut effects leading to decreased gut motility, increased constipation, and an increased reliance on laxative use.13
Despite the clear evidence that MMT was effective in its treatment of opioid dependence, one less desirable phenomenon associated with treatment was weight gain. A significant increase in BMI associated with MMT was consistent with previous research showing a 10-pound weight gain within the first 6 months and an approximate 17.8-pound increase within the first 2 years. Gender differences were also observed with females experiencing a three-fold increase in weight gain. This is an average of around 28 pounds. Research data demonstrates that many patients suffer from clinically significant increases in BMI,14 and a call for preventive measures that counter methadone associated weight gain.
Edema was also reported alongside weight gain. In a study done by the Hope Center methadone program in Tucson, AZ, showed that none of 420 patients exhibited a past medical history of edema, and the edema resolved with a reduction or discontinuation of MMT.15 This information, along with the aforementioned study about BMI, infer the importance of weight management, especially with the significant health and economic impacts of obesity.
Methadone can lead to sleep disturbance, which is a common pre-existing condition for many patients with OUD. The use of trazodone 50 mg/day in conjunction with MMT improved sleep, enhanced cognitive performance, and reduced symptoms of anxiety and depression. Sleep hygiene training in combination with or as a stand-alone with methadone can produce positive results as well.16 This further reinforces a need for holistic care for patients with OUD.
On top of the growing number of identified side effects summarized above, studies showed behavioral and neurochemical adaptations can occur during MMT that cause harmful effects, or even a return of adverse effects that initially resolved.7,17 Experiments quantified dopamine transporters using PET imaging revealed methadone’s ability to modify the density of dopamine transporters in the striatum and putamen. This type of neuroadaptation is correlated with a long-lasting dopamine neuron impairment and the dopamine-dependent reward system. Progress to the goal of MMT to reduce withdrawal and cravings while upholding patient health is often ineffective when the dopamine-dependent reward system is modified.7,17,18
While MMT has been historically considered a safe and effective treatment for OUD, long term efficacy has been questioned by patients, healthcare professionals, and the scientific community altogether.
In practice, patients undergoing MMT must present for daily dosing within clinic hours until approved for take-home doses. These doses are increased incrementally to satisfy cravings, which are associated with increased doses due to tolerance, adverse biopsychosocial effects, and drug-related death.5,6,12,1. While death from methadone toxicities is preventable through proper drug administration and monitoring, the long-term risks versus benefits should be weighed prior to initiation of MMT. Patient health and education should be prioritized,12 including an extensive talk about MMT policies.
Research by David Frank et al suggests that strict MMT policies may be more problematic than therapeutic.19 Lengthy wait-times for dosing administrations and unannounced mandatory counseling sessions often prevent patients from getting to work on time. Moreover, skipping doses or rescheduling counseling sessions are sometimes prohibited and met with the threat of disciplinary action, such as the loss of “take-home privileges.” Clinic permission and explanations for work trips and vacations are another added burden to patients.
These hardships highlight the need to amend overly restrictive and burdensome policies or seek more efficacious alternatives.19
Based on the concerns expressed above with MMT, exploring safe alternatives to opioid substitution therapies (OST) for OUD including MMT are crucial to improved treatment success.7 One possible option is the psychoactive indole alkaloid, ibogaine. Cessation or reduced OUD was reported after a single dose of ibogaine and has attained long-term remission after four days of treatment.20,21 It has also shown success where other therapies have failed, warranting that future studies should be performed to further evaluate its safety and efficacy prior to FDA approval.22
Another pharmaceutical, ketamine, has shown to decrease craving and increase abstinence in opioid use disorders. Ketamine is a NMDA-receptor antagonist that is postulated to be multifunctional due to its effectiveness as an anesthetic and antidepressant. Longer-lasting effects for the treatment of OUD may be seen with 3 sessions per month over a single randomized dose.23
Oxytocin is capable of receptor modulation and therefore repurposed for its use in the stress and reward pathways. Chronic administration of opioids down-regulated oxytocin receptors and increased oxytocin binding in the brain. The oxytocinergic system also interacts with the dopaminergic reward pathway linking natural and drug reward systems to reduce stress and reward-seeking behaviors by administering low doses of oxytocin.20 Besides its neuroendocrine effects, oxytocin is particularly notable for its role in regulating social and non-social behaviors including stress, anxiety, and aggression.24 Intranasal oxytocin influences social actions and is being studied as means to hamper the development of OUD.23,24
While the use of MMT has prevented risky behaviors and certain diseases, the long-term safety and efficacy of methadone is unclear due to numerous adverse and undesirable effects.5-7,12 Future research should be dedicated to discovering new therapy options that are devoid of harmful neuroadaptations and optimize efficacy while protecting the health of the patient.7,22
Medical experts and policymakers must ensure that treatment options are driven by the maximization of long-term success rates rather than the recurring revenue model seen in MMT. Alternatives such as ibogaine and its Schedule I status should be reconsidered given its success rates in its participants’ long-term sobriety, especially in the face of staggering overdose numbers.
- Makvand, M., Mirtorabi, S. D., Hassanzadeh, G., Campbell, A., & Ahangari, G. (2022). The Effectiveness of Methadone Maintenance Therapy (MMT) on Drug Tolerance, Mediated by Receptor Signaling, Signal Transduction and Intracellular Transport.
- Nazari H. Clinical approach to methadone toxication. J Addiction. 2007;2:18-20.
- Rezvanifar A. Cognitive impairments in methadone maintenance treatment. J Addiction. 2007;2:27-31.
- Howard J, Cimineri L, Evans T, et al. Medication-assisted treatment for opioid use disorder. 2019. DHHS (NIOSH) Publication No. 2019-133. https://doi.org/10.26616/NIOSHPUB2019133
- Chen A, Ashburn MA. Cardiac effects of opioid therapy, Pain Med. 2015;16;suppl 1:S27-S31. , https://doi.org/10.1111/pme.12915
- Rhodin A, Grönbladh L, Nilsson LH, Gordh T. Methadone treatment of chronic non-malignant pain and opioid dependence — A long-term follow-up. Eur J Pain. 2006;10:271-271. https://doi.org/10.1016/j.ejpain.2005.05.003
- Noble F, Marie N. Management of opioid addiction with opioid substitution treatments: Beyond methadone and buprenorphine. Front Psychiatry. 2019;9:742. Published 2019 Jan 18. doi:10.3389/fpsyt.2018.00742
- Maremmani I, Pacini M, Cesaroni C, et al. QTc interval prolongation in patients on long-term methadone maintenance therapy. Eur Addict Res. 2005;11(1):44-49. doi:10.1159/000081416
- Gerra G, Manfredini M, Somaini L, et al. Sexual dysfunction in men receiving methadone maintenance treatment: Clinical history and psychobiological correlates. Eur Addict Res. vol. 22, no. 3, 2016;22;3:163–175. https://doi.org/10.1159/000441470.
- Lankhorst MichaelA. Hypotestosterone and long-term opioid use. J Pain Palliative Care Pharmacother.2016;30;4:328–329. https://doi.org/10.1080/15360288.2016.1231738.
- Yee A, Loh HS, Loh HH, et al. A comparison of sexual desire in opiate-dependent men receiving methadone and buprenorphine maintenance treatment. Ann Gen Psychiatry. 2019;18:25. Published 2019 Oct 22. doi:10.1186/s12991-019-0249-z
- Alinejad S, Ghaemi K, Abdollahi M, Mehrpour O. Nephrotoxicity of methadone: a systematic review. Springerplus. 2016;5(1):2087. Published 2016 Dec 9. doi:10.1186/s40064-016-3757-1
- Yuan et al., Gut motility and transit changes in patients receiving long-term methadone maintenance. J Clin Pharmacol. Oct. 1998;38(10):931-5.
- enn JM, Laurent JS, Sigmon SC. Increases in body mass index following initiation of methadone treatment. J Subst Abuse Treat. 2015;51:59-63. doi:10.1016/j.jsat.2014.10.007
- Longwell B, Betz T, Horton H, Witte CL, Witte MH. Weight gain and edema on methadone maintenance therapy. Int J Addict. 1979;14(3):329-335. doi:10.3109/10826087909054585
- Alikhani M, Ebrahimi A, Farnia V, et al. Effects of treatment of sleep disorders on sleep, psychological and cognitive functioning and biomarkers in individuals with HIV/AIDS and under methadone maintenance therapy. J Psychiatr Res. 2020;130:260-272. doi:10.1016/j.jpsychires.2020.07.043
- Allouche S, Le Marec T, Coquerel A, et al. Striatal dopamine D1 and D2 receptors are differentially regulated following buprenorphine or methadone treatment. Psychopharmacology (Berl). 2015;232(9):1527-1533. doi:10.1007/s00213-014-3785-x
- Shi J, Zhao LY, Copersino ML, et al. PET imaging of dopamine transporter and drug craving during methadone maintenance treatment and after prolonged abstinence in heroin users. Eur J Pharmacol. 2008;579(1-3):160-166. doi:10.1016/j.ejphar.2007.09.042
- Frank D, Mateu-Gelabert P, Perlman DC, et al. It’s like ‘liquid handcuffs’: The effects of take-home dosing policies on methadone maintenance treatment (MMT) patients’ lives. Harm Reduct J. 2021;18(1):88. Published 2021 Aug 14. doi:10.1186/s12954-021-00535-y
- Zanos P, Georgiou P, Weber C, et al. Oxytocin and opioid addiction revisited: old drug, new applications. Br J Pharmacol. 2018;175(14):2809-2824. doi:10.1111/bph.13757
- Cloutier-Gill L, Wood E, Millar T, et al. Remission of severe opioid use disorder with ibogaine: A case report. J Psychoactive Drugs. 2016;48(3):214-217. doi:10.1080/02791072.2016.1180467
- Brown TK, Alper K. Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes. Am J Drug Alcohol Abuse. 2018;44(1):24-36. doi:10.1080/00952990.2017.1320802
- Lee YK, Gold MS, Fuehrlein BS. Looking beyond the opioid receptor: A desperate need for new treatments for opioid use disorder. J Neurol Sci. 2022;432:120094. doi:10.1016/j.jns.2021.120094
- Leong KC, Zhou L, Ghee SM, et al. Oxytocin decreases cocaine taking, cocaine seeking, and locomotor activity in female rats. Exp Clin Psychopharmacol. 2016;24(1):55-64. doi:10.1037/pha0000058
- Stauffer CS, Musinipally V, Suen A, et al. A two-week pilot study of intranasal oxytocin for cocaine-dependent individuals receiving methadone maintenance treatment for opioid use disorder. Addict Res Theory. 2016;24(6):490-498.