The current opioid crisis remains a significant public health issue and there is a critical need for biomedical research to develop effective and easily deployable candidate treatments. One emerging treatment strategy for opioid use disorder includes immunopharmacotherapies or opioid-targeted vaccines. The present study determined the effectiveness of a fentanyl-tetanus toxoid conjugate vaccine to alter fentanyl self-administration using a fentanyl-vs.-food choice procedure in male and female rats under three experimental conditions. For comparison, continuous 7-day naltrexone (0.01–0.1 mg/kg/h) and 7-day clonidine (3.2–10 μg/kg/h) treatment effects were also determined on fentanyl-vs.-food choice. Male and female rats responded for concurrently available 18% diluted Ensure® (liquid food) and fentanyl (0–10 μg/kg/infusion) infusions during daily sessions. Under baseline and saline treatment conditions, fentanyl maintained a dose-dependent increase in fentanyl-vs.-food choice. First, fentanyl vaccine administration significantly blunted fentanyl reinforcement and increased food reinforcement for 15 weeks in non-opioid dependent rats. Second, surmountability experiments by increasing the unit fentanyl dose available during the self-administration session 10-fold empirically determined that the fentanyl vaccine produced an approximate 22-fold potency shift in fentanyl-vs.-food choice that was as effective as the clinically approved treatment naltrexone. Clonidine treatment significantly increased fentanyl-vs.-food choice. Lastly, fentanyl vaccine administration prevented the expression of withdrawal-associated increases in fentanyl-vs.-food choice following introduction of extended 12 h fentanyl access sessions. Overall, these results support the potential and further consideration of immunopharmacotherapies as candidate treatments to address the current opioid crisis.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $43.69 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hedegaard H, Warner M, Minino AM Drug Overdose Deaths in the United States, 1999–2016. NCHS Data Brief. 2017:1–8.
Volkow ND, Frieden TR, Hyde PS, Cha SS. Medication-assisted therapies — tackling the opioid-overdose epidemic. New Engl J Med. 2014;370:2063–66.
Volkow ND, Woodcock J, Compton WM, Throckmorton DC, Skolnick P, Hertz S. et al. Medication development in opioid addiction: Meaningful clinical end points. Sci Transl Med. 2018;10:eaan2595.
Volkow ND, Collins FS. The role of science in addressing the opioid crisis. New Engl J Med. 2017;377:391–94.
Banks ML, Olson ME, Janda KD. Immunopharmacotherapies for treating opioid use disorder. Trends Pharmacol Sci. 2018;39:908–11.
Baehr C, Pravetoni M. Vaccines to treat opioid use disorders and to reduce opioid overdoses. Neuropsychopharmacology. 2019;44:217–18.
Bremer PT, Janda KD. Conjugate vaccine immunotherapy for substance use disorder. Pharmacol Rev. 2017;69:298–315.
Hwang CS, Bremer PT, Wenthur CJ, Ho SO, Chiang S, Ellis B, et al. Enhancing efficacy and stability of an antiheroin vaccine: examination of antinociception, opioid binding profile, and lethality. Mol Pharm. 2018;15:1062–72.
Sulima A, Jalah R, Antoline JFG, Torres OB, Imler GH, Deschamps JR, et al. A stable heroin analogue that can serve as a vaccine hapten to induce antibodies that block the effects of heroin and its metabolites in rodents and that cross-react immunologically with related drugs of abuse. J Med Chem. 2018;61:329–43.
Bremer PT, Schlosburg JE, Banks ML, Steele FF, Zhou B, Poklis JL, et al. Development of a clinically viable heroin vaccine. J Am Chem Soc. 2017;139:8601–11.
Bonese KF, Wainer BH, Fitch FW, Rothberg RM, Schuster CR. Changes in heroin self-administration by a rhesus monkey after morphine immunisation. Nature. 1974;252:708–10.
Schlosburg JE, Vendruscolo LF, Bremer PT, Lockner JW, Wade CL, Nunes AAK, et al. Dynamic vaccine blocks relapse to compulsive intake of heroin. Proc Natl Acad Sci USA. 2013;110:9036–41.
Nguyen JD, Hwang CS, Grant Y, Janda KD, Taffe MA. Prophylactic vaccination protects against the development of oxycodone self-administration. Neuropharmacology. 2018;138:292–303.
Pravetoni M, Pentel PR, Potter DN, Chartoff EH, Tally L, LeSage MG. Effects of an oxycodone conjugate vaccine on oxycodone self-administration and oxycodone-induced brain gene expression in rats. PLOS ONE. 2014;9:e101807.
Banks ML, Negus SS. Insights from preclinical choice models on treating drug addiction. Trends Pharm Sci. 2017;38:181–94.
Epstein DH, Heilig M, Shaham Y. Science-based actions can help address the opioid crisis. Trends Pharmacol Sci. 2018;39:911–16.
Banks ML. Utility of preclinical drug versus food choice procedures to evaluate candidate medications for methamphetamine use disorder. Ann New Y Acad Sci. 2017;1394:92–105.
Banks ML, Hutsell BA, Schwienteck KL, Negus SS. Use of preclinical drug vs. food choice procedures to evaluate candidate medications for cocaine addiction. Curr Treat Options. Psychiatry. 2015;2:136–50.
Negus SS, Banks ML. Medications Development for Opioid Abuse. In: Pierce RC, Kenny PJ, editors. Addiction. New York: Cold Springs Harbor; 2013.
Sullivan MA, Vosburg SK, Comer SD. Depot naltrexone: antagonism of the reinforcing, subjective, and physiological effects of heroin. Psychopharmacology. 2006;189:37–46.
Tanum L, Solli K, Latif Z, et al. Effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence: a randomized clinical noninferiority trial. JAMA Psychiatry. 2017;74:1197–205.
Mantsch JR, Baker DA, Funk D, Le AD, Shaham Y. Stress-induced reinstatement of drug seeking: 20 years of progress. Neuropsychopharmacology. 2016;41:335–56.
Kowalczyk WJ, Phillips KA, Jobes ML, Kennedy AP, Ghitza UE, Agage DA, et al. Clonidine maintenance prolongs opioid abstinence and decouples stress from craving in daily life: a randomized controlled trial with ecological momentary assessment. Am J Psychiatry. 2015;172:760–7.
Kowalczyk WJ, Bertz JW, Moran LM, Phillips KA, Ghitza UE, Epstein DH, et al. Clonidine increases the likelihood that abstinence can withstand unstructured time in buprenorphine-maintained outpatients. J Addict Med. 2017;11:454–60.
Ling W, Amass L, Shoptaw S, Annon JJ, Hillhouse M, Babcock D, et al. A multi-center randomized trial of buprenorphine–naloxone versus clonidine for opioid, detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Addiction. 2005;100:1090–100.
Wade CL, Vendruscolo LF, Schlosburg JE, Hernandez DO, Koob GF. Compulsive-like responding for opioid analgesics in rats with extended access. Neuropsychopharmacology. 2015;40:421–28.
Wurster RM, Griffiths RR, Findley JD, Brady JV. Reduction of heroin self-administration in baboons by manipulation of behavioral and pharmacological conditions. Pharmacol Biochem Behav. 1977;7:519–28.
Lenoir M, Cantin L, Vanhille N, Serre F, Ahmed SH. Extended heroin access increases heroin choices over a potent nondrug alternative. Neuropsychopharmacology. 2013;38:1209–20.
Negus SS, Banks ML. Modulation of drug choice by extended drug access and withdrawal in rhesus monkeys: implications for negative reinforcement as a driver of addiction and target for medications development. Pharmacol Biochem Behav. 2018;164:32–39.
Negus SS. Choice between heroin and food in nondependent and heroin-dependent rhesus monkeys: effects of naloxone, buprenorphine, and methadone. J Pharm Exp Ther. 2006;317:711–23.
Negus SS, Rice KC. Mechanisms of withdrawal-associated increases in heroin self-administration: pharmacologic modulation of heroin vs food choice in heroin-dependent rhesus monkeys. Neuropsychopharmacology. 2009;34:899–911.
Huskinson SL, Naylor JE, Townsend EA, Rowlett JK, Blough BE, Freeman KB. Self-administration and behavioral economics of second-generation synthetic cathinones in male rats. Psychopharmacology. 2017;234:589–98.
Townsend EA, Naylor JE, Negus SS, Edwards SR, Qureshi HN, McLendon HW, et al. Effects of nalfurafine on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone: modeling an abuse-deterrent opioid analgesic in rats. Psychopharmacology. 2017;234:2597–605.
Thomsen M, Barrett AC, Negus SS, Caine SB. Cocaine versus food choice procedure in rats: environmental manipulations and effects of amphetamine. J Exp Anal Behav. 2013;99:211–33.
Negus SS. Rapid assessment of choice between cocaine and food in rhesus monkeys: effects of environmental manipulations and treatment with d-Amphetamine and flupenthixol. Neuropsychopharmacology. 2003;28:919–31.
Banks ML, Blough BE. Effects of environmental maniuplations and bupropion and risperidone treatments on choice between methamphetamine and food in rhesus monkeys. Neuropsychoharmacology. 2015;40:2198–206.
Ossipov MH, Harris S, Lloyd P, Messineo E, Lin BS, Bagley J. Antinociceptive interaction between opioids and medetomidine: systemic additivity and spinal synergy. Anesthesiology. 1990;73:1227–35.
Bremer PT, Kimishima A, Schlosburg JE, Zhou B, Collins KC, Janda KD. Combatting synthetic designer opioids: a conjugate vaccine ablates lethal doses of fentanyl class drugs. Angew Chem Int Ed. 2016;55:3772–75.
Maguire DR, Gerak LR, Woods JH, Husbands SM, Disney A, France CP. Long-lasting effects of methocinnamox on opioid self-administration in rhesus monkeys. J Pharmacol Exp Ther. 2019;368:88–99.
Comer SD, Sullivan MA, Yu E, et al. Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2006;63:210–18.
Matthew L, Banks E, Andrew T, Negus SS. Testing the 10 most wanted: a preclinical algorithm to screen candidate opioid use disorder medications. Neuropsychopharmacology. 2019;44:1011–12.
Stowe GN, Vendruscolo LF, Edwards S, Schlosburg JE, Misra KK, Schulteis G, et al. A vaccine strategy that induces protective immunity against heroin. J Med Chem. 2011;54:5195–204.
Raleigh MD, Pentel PR, LeSage MG. Pharmacokinetic correlates of the effects of a heroin vaccine on heroin self-administration in rats. PLOS ONE. 2014;9:e115696.
Association AP. Diagnositc and Statistical Manual of Mental Disorders. Fifth Edition. Arlington, VA: American Psychiatric Association; 2013.
Spragg SDS. Morphine Addiction in Chimpanzees. Comparative Psychology Monographs. Baltimore, MD: The John Hopkins Press; 1940. p. 1–132.
Hwang CS, Smith LC, Natori Y, Ellis B, Zhou B, Janda KD. Efficacious vaccine against heroin contaminated with fentanyl. ACS chemical. Neuroscience. 2018;9:1269–75.
We appreciate comments from Dr. Steve Negus during the design of these experiments. We also acknowledge Kevin Costa for writing the original version of the behavioral program that was modified for the choice studies conducted in this manuscript.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Effectiveness and selectivity of a heroin conjugate vaccine to attenuate heroin, 6-acetylmorphine, and morphine antinociception in rats: Comparison with naltrexone
Drug and Alcohol Dependence (2019)
Utility of fentanyl vaccines: unique challenges posed by preventing opioid overdose and treating opioid use disorder