Abstract
Objective: Methylphenidate activates μ-opioid receptors, which are linked to euphoria. μ-Opioid antagonists, such as naltrexone, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential. This study assessed whether the combination of naltrexone with methylphenidate is well-tolerated while preserving the clinical benefits of stimulants in subjects with attention-deficit/hyperactivity disorder (ADHD). Methods: We conducted a 6-week, double-blind, placebo-controlled, randomized clinical trial of naltrexone in adults with DSM-IV ADHD receiving open treatment with a long-acting formulation of methylphenidate from January 2013 to July 2015. Spheroidal Oral Drug Absorption System (SODAS) methylphenidate was administered twice daily, was titrated to approximately 1 mg/kg/d over 3 weeks, and was continued for 3 additional weeks depending on response and adverse effects. Subjects were adults with ADHD preselected for having experienced euphoria with a test dose of immediate-release methylphenidate. The primary outcome measure was the Adult ADHD Investigator Symptom Report Scale (AISRS). Results: Thirty-seven subjects who experienced stimulant-induced (mild) euphoria at a baseline visit were started in the open trial of SODAS methylphenidate and randomly assigned to naltrexone 50 mg or placebo. Thirty-one subjects completed the study through week 3, and 25 completed through week 6. Throughout 6 weeks of blinded naltrexone and open methylphenidate treatment, the coadministration of naltrexone with methylphenidate did not interfere with the clinical effectiveness of methylphenidate for ADHD symptoms. Additionally, the combination of naltrexone and methylphenidate did not produce an increase in adverse events compared with methylphenidate alone. Conclusions: Our findings provide support for the concept of combining opioid receptor antagonists with stimulants to provide an effective stimulant formulation with less abuse potential.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 19-25 |
| Number of pages | 7 |
| Journal | Journal of Clinical Psychiatry |
| Volume | 79 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2018 |
Funding
2016. MGH Psychiatry Academy for tuition-funded CME Monogr. 1989;92:73–100.PubMed Online first:June 20, 2017. courses, and from Avekshan; received research Jasinski DR. An evaluation of the abuse support from Ironshore, Magceutics Inc, and potential of modafinil using methylphenidate Potential conflicts of interest:Dr T. J. Spencer VAYA Pharma/Enzymotec; in 2014, he received as a reference. J Psychopharmacol. receives research support from or is a consultant honoraria from the MGH Psychiatry Academy for 2000;14(1):53–60.PubMed doi:10.1177/026988110001400107 for Alcobra, Enzymotec Ltd, Heptares, Impax, tuition-funded CME courses; he received research Kollins SH, MacDonald EK, Rush CR. Assessing Ironshore,Lundbeck,ShireLaboratories,Sunovion, support from AACAP, Alcobra, Forest Research the abuse potential of methylphenidate in VayaPharma, Avekshan, the US Food and Drug Institute, and Shire Pharmaceuticals Inc; in 2013, nonhuman and human subjects: a review. Administration (FDA), and the US Department received an honorarium from the MGH Psychiatry PharmacolBiochemBehav. 2001;68(3):611–627.PubMeddoi:10.1016/S0091-3057(01)00464-6 of Defense; is on an advisory board for Alcobra; Academy for a tuition-funded CME course; Hamilton M. A rating scale for depression. and receives research support from Royalties received research support from APSARD, ElMindA, J NeurolNeurosurgPsychiatry.1960;23:56–62.PubMeddoi:10.1136/jnnp.23.1.56 and Licensing fees on copyrighted ADHD scales McNeil, and Shire; in previous years, received Beck AT, Ward CH, Mendelson M, et al. An through Massachusetts General Hospital (MGH) research support, consultation fees, or speaker’s inventory for measuring depression. Arch Gen Corporate Sponsored Research and Licensing; fees for/from the following additional sources: Psychiatry. 1961;4:561–571.PubMed doi:10.1001/archpsyc.1961.01710120031004 has a US Patent Application pending (Provisional Abbott, Alza, AstraZeneca, Boston University, Hamilton M. The assessment of anxiety states Number 61/233,686), through MGH corporate Bristol Myers Squibb, Cambridge University Press, by rating. Br J Med Psychol.1959;32(1):50–55.PubMeddoi:10.1111/j.2044-8341.1959.tb00467.x licensing, on a method to prevent stimulant abuse. Celltech, Cephalon, The Children’s Hospital of First MB, Spitzer RL, Gibbon M, et al. Structured Consultant fees are paid to the MGH Clinical Southwest Florida/Lee Memorial Health System, Clinical Interview for DSM-IV-TR Axis I Disorders, Trials Network and not directly to Dr Spencer. Drs Cipher Pharmaceuticals, Eli Lilly, Esai, Fundacion Research Version, Patient Edition (SCID-I/P). New Bhide and Zhuare founders and consultants at Areces (Spain), Forest, Fundación Dr.Manuel York, New York: Biometrics Research, New York AvekshanLLC,Tallahassee,Florida.DrFaraoneis Camelo A.C., Glaxo, Gliatech, Hastings Center, State Psychiatric Institute; 2002. supported by the K.G. Jebsen Centre for Research Janssen, Juste Pharmaceutical Spain, McNeil, Orvaschel H. Schedule for Affective Disorders onNeuropsychiatricDisorders,Universityof Medice Pharmaceuticals (Germany), Merck, MGH and Schizophrenia for School-Age Children Bergen, Bergen, Norway; the European Union’s Psychiatry Academy, MMC Pediatric, NARSAD, EpidemiologicVersion. 5th Edition. Ft. SeventhFrameworkProgrammeforresearch, National Institute on Drug Abuse, New River, Lauderdale, FL: Nova Southeastern University, technologicaldevelopmentanddemonstration National Institute of Child Health and Human Center for Psychological Studies; 1994. under grant agreement No. 602805; the European Development, National Institute of Mental Spencer T, Biederman J, Wilens T, et al. A large, Union’s Horizon 2020 research and innovation Health (NIMH), Novartis, Noven, Neurosearch, double-blind, randomized clinical trial of programmeundergrantagreementNo.667302; Organon, Otsuka, Pfizer, Pharmacia, Phase V methylphenidate in the treatment of adults and NIMH grant 5R01MH101519. In the past year, Communications, Physicians Academy, The with attention-deficit/hyperactivity disorder. Dr Faraone received income, potential income, PrechterFoundation,QuantiaCommunications, BiolPsychiatry.2005;57(5):456–463.PubMeddoi:10.1016/j.biopsych.2004.11.043 travel expenses, and/or research support from Reed Exhibitions, Shionogi Pharma Inc, Shire, the Biederman J, Mick E, Surman C, et al. A Rhodes,Arbor,Pfizer,Ironshore,Shire,Akili Spanish Child Psychiatry Association, The Stanley randomized, 3-phase, 34-week, double-blind, Interactive Laboratories, CogCubed, Alcobra, VAYA Foundation, UCB Pharma Inc, Veritas, and Wyeth. long-term efficacy study of osmotic-release Pharma, NeuroLifeSciences, and NACE; with his Dr Uchida and Mss Fitzgerald, Hall, and Koster oral system-methylphenidate in adults with institution, has US patent US20130217707 A1 for have no conflicts of interest. attention-deficit/hyperactivity disorder. J Clin Funding/support:This work was supported by the use of sodium-hydrogen exchange inhibitors Psychopharmacol. 2010;30(5):549–553.PubMed doi:10.1097/JCP.0b013e3181ee84a7 in the treatment of ADHD; in previous years, National Institute of Mental Health. CGI has received income or research support from grant W81XWH-12-1-0510 from the US Department (Clinical Global Impressions) Scale—NIMH. Shire, Alcobra, Otsuka, McNeil, Janssen, Novartis, Psychopharmacol Bull. 1985;21:839–844.of Defense. Pfizer, and Eli Lilly; receives royalties from books Walker E, Nowacki AS. Understanding Role of the sponsor: The funding supporter had published by Guilford Press: Straight Talk about equivalence and noninferiority testing. J Gen no role in the design, analysis, interpretation, or Your Child’s Mental Health, Oxford University Press: publication of this study. Intern Med. 2011;26(2):192–196.PubMed doi:10.1007/s11606-010-1513-8 Schizophrenia: The Facts, and Elsevier: ADHD: Previous presentation: Presented at the 8th Spencer TJ, Biederman J, Ciccone P, et al. Non-Pharmacologic Interventions; and is principal Annual Massachusetts General Hospital for Pharmacokinetics, detection, likeability and investigator of www.adhdinadults.com. Dr Children Research Day; March 29, 2016; Boston, dislikeability of two formulations of long- Yule received grant support from the American Massachusetts ▪ 60th Congress of Asociación acting oral methylphenidate. Presented at the Academy of Child and Adolescent Psychiatry Pilot Española de Psiquiatría del Niño y el Adolescente 53rd Annual meeting of the American Research Award for Junior Faculty supported and American Academy of Child and Adolescent Academy of Child and Adolescent Psychiatry. by Lilly USA, LLC, in 2012 and currently receives Psychiatry; June 1–4, 2016; San Sebastian, Spain. 2006; San Diego, California. research funding from the MGH Louis V. Gerstner III Faraone SV, Buitelaar J. Comparing the efficacy Research Scholar Award. In 2016, Dr A. E. Spencer of stimulants for ADHD in children and received honoraria for tuition funded Continuing adolescents using meta-analysis. Eur Child Medical Education (CME) courses and received Adolesc Psychiatry. 2010;19(4):353–364.PubMed doi:10.1007/s00787-009-0054-3 research support from Sunovion. Dr Biederman Peterson JB, Conrod P, Vassileva J, et al. is currently receiving research support from Differential effects of naltrexone on cardiac, the US Department of Defense, FDA, Lundbeck, subjective and behavioural reactions to acute Merck, Neurocentria, PamLab, Pfizer, Shire ethanol intoxication. J Psychiatry Neurosci. Pharmaceuticals, SPRITES, Sunovion, and National 2006;31(6):386–393.PubMed Institutes of Health; his program has received Cooper WO, Habel LA, Sox CM, et al. ADHD departmental royalties from a copyrighted rating drugs and serious cardiovascular events in scale used for ADHD diagnoses, paid by Ingenix, children and young adults. N Engl J Med. Prophase, Shire, Bracket Global, Sunovion, and 2011;365(20):1896–1904.PubMed doi:10.1056/NEJMoa1110212 Theravance (these royalties were paid to the Yen MH, Ko HC, Tang FI, et al. Study of Department of Psychiatry at MGH); in 2016, he hepatotoxicity of naltrexone in the treatment received honoraria from the MGH Psychiatry of alcoholism. Alcohol. 2006;38(2):117–120.PubMed doi:10.1016/j.alcohol.2006.05.003 Academy for tuition-funded CME courses and from Zhu J, Zhang X, Xu Y, et al. Prenatal nicotine Avekshan, Alcobra, and the American Academy exposure mouse model showing hyperactivity, of Child and Adolescent Psychiatry (AACAP); he reduced cingulate cortex volume, reduced has a US Patent Application pending (Provisional dopamine turnover, and responsiveness to Number #61/233,686), through MGH corporate oral methylphenidate treatment. J Neurosci. licensing, on a method to prevent stimulant 2012;32(27):9410–9418.PubMed doi:10.1523/JNEUROSCI.1041-12.2012
ASJC Scopus subject areas
- Psychiatry and Mental health