Side Effects of Chronic Methadone Use in Opioid Addiction: A Scoping
Review on Hematological Derangements

Karniza      Khalid; Amalina      Anuar; Wei   Chern   Ang; Ruzita      Jamaluddin

doi:10.2174/1574886317666220514154931

Abstract

Background: Per oral methadone maintenance therapy [MMT] was introduced as part of harm reduction strategy to manage rising numbers of HIV infections caused by intravenous use of illicit drugs.

Method: We aim to review published articles related to the side effects of long-term methadone therapy, focusing on hematological derangements in human studies published between 1 January 2000 till 31 January 2021.

Results: Our search databases include Web of Science, Scopus, and Medline. Our search yielded 971 articles, of which 55 articles were related to the effects of MMT on various organ systems: cardiovascular [n=12], respiratory [n=1], endocrine [n=10], central nervous system [n=12], neurobehavioral [n=10], gastrointestinal [n=1], and bone [n=1]. There were eight articles specifically related to the hematological side effects of chronic methadone therapy that include [i] immune system hyperactivation, [ii] reduced circulating lymphocytes, and [iii] increased blood viscosity.

Conclusion: In view of all foreseeable health risks seen with prolonged methadone therapy, pharmacological modulation is warranted to find a better substitute for managing patients with opioid dependence.

Keywords: Methadone, harm reduction, opiate substitution treatment, immune system, illicit drugs, circulating lymphocytes.

« Previous Next »

[1]
Cicero TJ, Ellis MS, Surratt HL, Kurtz SP, Kurtz SP, Cicero TJ. The changing face of heroin use in the United States: A retrospective analysis of the past 50 years. JAMA Psychiatry  2014; 71(7): 821-6.
 [http://dx.doi.org/10.1001/jamapsychiatry.2014.366] [PMID: 24871348]

[2]
Merz F. United Nations office on drugs and crime: World drug report 2017. 2017 SIRIUS - Zeitschrift für Strateg Anal  2018; 2(1): 85-6.

[3]
Barocas JA, White LF, Wang J, et al. Estimated prevalence of opioid use disorder in Massachusetts, 2011-2015: A capture-recapture analysis. Am J Public Health  2018; 108(12): 1675-81.
 [http://dx.doi.org/10.2105/AJPH.2018.304673] [PMID: 30359112]

[4]
WHO. World Health Organization Model List of Essential Medicines 2019.

[5]
Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence Cochrane Database of Systematic Reviews. John Wiley and Sons Ltd 2009.

[6]
Kapur BM, Hutson JR, Chibber T, Luk A, Selby P. Methadone: A review of drug-drug and pathophysiological interactions. Crit Rev Clin Lab Sci  2011; 48(4): 171-95.
 [http://dx.doi.org/10.3109/10408363.2011.620601] [PMID: 22035341]

[7]
Srivastava A, Kahan M, Nader M. Primary care management of opioid use disorders: Abstinence, methadone, or buprenorphine-naloxone? Can Fam Physician  2017; 63(3): 200-5.
 [PMID: 28292795]

[8]
Dinges HC, Otto S, Stay DK, et al. Side effect rates of opioids in equianalgesic doses via intravenous patient-controlled analgesia: A systematic review and network meta-analysis. Anesth Analg  2019; 129(4): 1153-62.
 [http://dx.doi.org/10.1213/ANE.0000000000003887] [PMID: 30418234]

[9]
Guzel D, Yazici AB, Yazici E, Erol A. Evaluation of immunomodulatory and hematologic cell outcome in heroin/opioid addicts. J Addict  2018; 2018: 2036145.
 [http://dx.doi.org/10.1155/2018/2036145] [PMID: 30631635]

[10]
Neri S, Bruno CM, Pulvirenti D, et al. Randomized clinical trial to compare the effects of methadone and buprenorphine on the immune system in drug abusers. Psychopharmacology  2005; 179(3): 700-4.
 [http://dx.doi.org/10.1007/s00213-005-2239-x] [PMID: 15806416]

[11]
Brejchova J, Holan V, Svoboda P. Expression of opioid receptors in cells of the immune system. Int J Mol Sci  2021; 22: 1-13.

[12]
Toskulkao T, Pornchai R, Akkarapatumwong V, Vatanatunyakum S, Govitrapong P. Alteration of lymphocyte opioid receptors in methadone maintenance subjects. Neurochem Int  2010; 56(2): 285-90.
 [http://dx.doi.org/10.1016/j.neuint.2009.10.013] [PMID: 19913582]

[13]
Quang-Cantagrel ND, Wallace MS, Ashar N, Mathews C. Long-term methadone treatment: Effect on CD4+ lymphocyte counts and HIV-1 plasma RNA level in patients with HIV infection. Eur J Pain  2001; 5(4): 415-20.
 [http://dx.doi.org/10.1053/eujp.2001.0262] [PMID: 11743707]

[14]
Mazahery C, Benson BL, Cruz-Lebrón A, Levine AD. Chronic methadone use alters the CD8+ T Cell phenotype in vivo and modulates its responsiveness ex vivo to opioid receptor and TCR Stimuli. J Immunol  2020; 204(5): 1188-200.
 [http://dx.doi.org/10.4049/jimmunol.1900862] [PMID: 31969385]

[15]
Schwartz K, Herman I, Peer G, Weizman A, Rehavi M. Elevated platelet vesicular monoamine transporter 2 in former heroin addicts maintained on methadone. J Neural Transm  2007; 114(2): 281-4.
 [http://dx.doi.org/10.1007/s00702-006-0527-1] [PMID: 16855915]

[16]
Zeiger AR, Patkar AA, Fitzgerald R, Lundy A, Ballas SK, Weinstein SP. Changes in mu opioid receptors and rheological properties of erythrocytes among opioid abusers. Addict Biol  2002; 7(2): 207-17.
 [http://dx.doi.org/10.1080/135562102200120433] [PMID: 12006216]

[17]
Hassan NM, Daud N, Aziz AA, Mat KC. Associated factors for relapse in opioid addicts undergoing therapy. Res J Pharm Technol  2018; 11(7): 2724-8.
 [http://dx.doi.org/10.5958/0974-360X.2018.00503.6]

[18]
Frank D. Methadone maintenance treatment is swapping one drug for another, and that’s why it works: Towards a treatment-based critique of the war on drugs. Int J Drug Policy  2020; 83: 102844.
 [http://dx.doi.org/10.1016/j.drugpo.2020.102844] [PMID: 32653670]

[19]
West SL, O’Neal KK, Graham CW. A meta-analysis comparing the effectiveness of buprenorphine and methadone. J Subst Abuse  2000; 12(4): 405-14.
 [http://dx.doi.org/10.1016/S0899-3289(01)00054-2] [PMID: 11452842]

[20]
Savov Y, Antonova N, Zvetkova E, Gluhcheva Y, Ivanov I, Sainova I. Whole blood viscosity and erythrocyte hematometric indices in chronic heroin addicts. Clin Hemorheol Microcirc  2006; 35(1-2): 129-33.
 [PMID: 16899916]

[21]
Bell D, Gaillard F. Virchow triad 2009. Available from: http://europepmc.org/books/NBK539697 (Accessed on 2022 Apr 11).
 [http://dx.doi.org/10.53347/rID-7113]

[22]
Pimentel L, Mayo D. Chronic methadone therapy complicated by torsades de pointes: A case report. J Emerg Med  2008; 34(3): 287-90.
 [http://dx.doi.org/10.1016/j.jemermed.2007.03.053] [PMID: 18022786]

[23]
Porter BO, Coyne PJ, Smith WR. Methadone-related Torsades de Pointes in a sickle cell patient treated for chronic pain. Am J Hematol  2005; 78: 316-7.

[24]
Cruciani RA, Sekine R, Homel P, et al. Measurement of QTc in patients receiving chronic methadone therapy. J Pain Symptom Manage  2005; 29(4): 385-91.
 [http://dx.doi.org/10.1016/j.jpainsymman.2004.06.012] [PMID: 15857742]

[25]
Lusetti M, Licata M, Silingardi E, Reggiani Bonetti L, Palmiere C. Therapeutic and recreational methadone cardiotoxicity. J Forensic Leg Med  2016; 39: 80-4.
 [http://dx.doi.org/10.1016/j.jflm.2016.01.016] [PMID: 26859696]

[26]
Housová J, Wilczek H, Haluzík MM, Křemen J, Krízová J, Haluzík M. Adipocyte-derived hormones in heroin addicts: The influence of methadone maintenance treatment. Physiol Res  2005; 54(1): 73-8.
 [PMID: 15717844]

[27]
Gerra G, Manfredini M, Somaini L, Maremmani I, Leonardi C, Donnini C. Sexual dysfunction in men receiving methadone maintenance treatment: Clinical history and psychobiological correlates. Eur Addict Res  2016; 22(3): 163-75.
 [http://dx.doi.org/10.1159/000441470] [PMID: 26595117]

[28]
Hallinan R, Byrne A, Agho K, McMahon CG, Tynan P, Attia J. Hypogonadism in men receiving methadone and buprenorphine maintenance treatment. Int J Androl  2009; 32(2): 131-9.
 [http://dx.doi.org/10.1111/j.1365-2605.2007.00824.x] [PMID: 17971165]

[29]
Galynker II, Watras-Ganz S, Miner C, et al. Cerebral metabolism in opiate-dependent subjects: Effects of methadone maintenance. Mount Sinai J Med  2000; 67(5-6): 381-7.

[30]
Wang GY, Kydd R, Wouldes TA, Jensen M, Russell BR. Changes in resting EEG following methadone treatment in opiate addicts. Clin Neurophysiol Off J Int Fed Clin Neurophysiol  2015; 126(5): 943-50.
 [http://dx.doi.org/10.1016/j.clinph.2014.08.021] [PMID: 25301768]

[31]
Wang D, Teichtahl H, Goodman C, Drummer O, Grunstein RR, Kronborg I. Subjective daytime sleepiness and daytime function in patients on stable methadone maintenance treatment: Possible mechanisms. J Clin sleep Med JCSM Off Publ Am Acad. Sleep Med  2008; 4(6): 557-62.

[32]
Bruera E, Sweeney C. Methadone use in cancer patients with pain: A review. J Palliat Med  2002; 5(1): 127-38.
 [http://dx.doi.org/10.1089/10966210252785097] [PMID: 11839235]

[33]
Fredheim OMS, Borchgrevink PC, Hegrenaes L, Kaasa S, Dale O, Klepstad P. Opioid switching from morphine to methadone causes a minor but not clinically significant increase in QTc time: A prospective 9-month follow-up study. J Pain Symptom Manage  2006; 32(2): 180-5.
 [http://dx.doi.org/10.1016/j.jpainsymman.2006.02.010] [PMID: 16877186]

[34]
Grodofsky S, Edson E, Huang S, et al. The QTc effect of low-dose methadone for chronic pain: A prospective pilot study. Pain Med  2015; 16(6): 1112-21.
 [http://dx.doi.org/10.1111/pme.12658] [PMID: 25644980]

[35]
Vallecillo G, Mojal S, Roquer A, et al. Risk of QTc prolongation in a cohort of opioid-dependent HIV-infected patients on methadone maintenance therapy. Clin Infect Dis  2013; 57(8): 1189-94.
 [http://dx.doi.org/10.1093/cid/cit467] [PMID: 23899678]

[36]
van den Beuken-van Everdingen MHJ, Geurts JW, Patijn J. Prolonged QT interval by methadone: Relevance for daily practice? A prospective study in patients with cancer and noncancer pain. J Opioid Manag  2013; 9(4): 263-7.
 [http://dx.doi.org/10.5055/jom.2013.0167] [PMID: 24353019]

[37]
Wilczek H, Haluzík M, Svobodová J, Parízková J. Serum Leptin levels in patients with heroin addiction the effect of one year of methadone substitutions  2004; 50(4): 282-5.
 [PMID: 15214298]

[38]
Yang J, Li J, Xu G, et al. Elevated hair cortisol levels among heroin addicts on current methadone maintenance compared to controls. PLoS One  2016; 11(3): e0150729.
 [http://dx.doi.org/10.1371/journal.pone.0150729] [PMID: 27010803]

[39]
Pacini M, Icro Maremmani AG, Rovai L, Bacciardi S, Rugani F, Maremmani I. Long-term replacement of methadone by equipotent buprenorphine for male heroin addicts with methadone-induced hyperprolactinaemia and sexual dysfunction. A case report. Heroin Addict Relat Clin Probl  2013; 15(4): 21-4.

[40]
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): 160-6.
 [http://dx.doi.org/10.1016/j.ejphar.2007.09.042] [PMID: 17977528]

[41]
Wang HC, Chen WL, Yao CT, Chen JH. Delayed hemothorax caused by thymic bleeding after blunt chest trauma. J Emerg Med  2015; 48(1): 77-8.
 [http://dx.doi.org/10.1016/j.jemermed.2014.09.003] [PMID: 25440861]

[42]
Teichtahl H, Wang D, Cunnington D, et al. Ventilatory responses to hypoxia and hypercapnia in stable methadone maintenance treatment patients. Chest  2005; 128(3): 1339-47.
 [http://dx.doi.org/10.1378/chest.128.3.1339] [PMID: 16162727]

[43]
Bracken BK, Trksak GH, Penetar DM, et al. Response inhibition and psychomotor speed during methadone maintenance: Impact of treatment duration, dose, and sleep deprivation. Drug Alcohol Depend  2012; 125(1-2): 132-9.
 [http://dx.doi.org/10.1016/j.drugalcdep.2012.04.004] [PMID: 22552256]

[44]
Nolan LJ, Scagnelli LM. Preference for sweet foods and higher body mass index in patients being treated in long-term methadone maintenance. Subst Use Misuse  2007; 42(10): 1555-66.
 [http://dx.doi.org/10.1080/10826080701517727] [PMID: 17918026]

[45]
Haber PS, Elsayed M, Espinoza D, Lintzeris N, Veillard AS, Hallinan R. Constipation and other common symptoms reported by women and men in methadone and buprenorphine maintenance treatment. Drug Alcohol Depend  2017; 181: 132-9.
 [http://dx.doi.org/10.1016/j.drugalcdep.2017.09.024] [PMID: 29054032]

[46]
Milos G, Gallo LM, Sosic B, et al. Bone mineral density in young women on methadone substitution. Calcif Tissue Int  2011; 89(3): 228-33.
 [http://dx.doi.org/10.1007/s00223-011-9510-4] [PMID: 21698454]

[47]
Beck M, Mirmohammadsadegh A, Franz B, Blanke J, Hengge UR. Opioid receptors on white blood cells: Effect of HIV infection and methadone treatment. Pain  2002; 98(1-2): 187-94.
 [http://dx.doi.org/10.1016/S0304-3959(02)00044-1] [PMID: 12098631]

Rights & Permissions Print Cite

Article Metrics

68

2

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1574886317666220514154931	Print ISSN 1574-8863
Publisher Name Bentham Science Publisher	Online ISSN 2212-3911

Current Drug Safety

Side Effects of Chronic Methadone Use in Opioid Addiction: A Scoping Review on Hematological Derangements

Abstract

Related Journals

Related Books

Related Articles