Prophylactic vaccination protects against the development of oxycodone addiction
Abstract: Abuse of prescription opioids is a growing public health crisis in the United States, with drug overdose deaths increasing dramatically over the past 15 years. Few preclinical studies exist on the reinforcing effects of oxycodone or on the development of therapies for oxycodone abuse. This study was conducted to determine if immunopharmacotherapy directed against oxycodone would be capable of altering oxycodone-induced antinociception and intravenous self-administration. Male Wistar rats were administered a small-molecule immunoconjugate vaccine (Oxy-TT) or the control carrier protein, tetanus toxoid (TT), and trained to intravenously self-administer oxycodone (0.06 or 0.15 mg/kg/infusion). Brain oxycodone concentrations were 50% lower in Oxy-TT rats compared to TT rats 30 minutes after injection (1 mg/kg, s.c.) whereas plasma oxycodone was 15-fold higher from drug sequestration by circulating antibodies. Oxy-TT rats were also less sensitive to 1-2 mg/kg, s.c. oxycodone on a hot water nociception assay. Half of the Oxy-TT rats failed to acquire IVSA under the 0.06 mg/kg/infusion training dose. Oxycodone self-administration of Oxy-TT rats trained on 0.15 mg/kg/infusion was higher than controls; however under progressive ratio (PR) conditions the Oxy-TT rats decreased their oxycodone intake, unlike TT controls. These data demonstrate that active vaccination provides protection against the antinociceptive and reinforcing effects of oxycodone. Anti-drug vaccines may entirely prevent repeated use in some individuals who otherwise would become addicted. Vaccination may also reduce dependence in those who become addicted and therefore facilitate the effects of other therapeutic interventions which increase the difficulty of drug use or incentivize other behaviors.
Summary (2 min read)
- Drug overdose deaths in the US have increased dramatically over the past 15 years with most of these attributable to opioids, including prescription drugs.
- This success encourages more comprehensive research on anti-oxycodone vaccines, to further general understanding of how anti-drug vaccinations function in addition to supporting an eventual clinical vaccine for oxycodone abuse.
- Prior studies of IVSA of oxycodone (Pravetoni et al, 2014) and methamphetamine (Duryee et al, 2009) suggest that increasing the workload (i.e., the number of lever responses required for each infusion) may decrease intake in the vaccinated groups relative to controls.
2. Materials and Methods
- Adult male Wistar (N=48; Charles River, New York) rats were housed in humidity and temperature-controlled vivaria (23+1oC) on 12:12 hour light:dark cycles.
- The solvents from the organic layer were dried with sodium sulfate (Na2SO4), filtered and evaporated.
- After completion of the reaction, NaBH(OAc)3 was quenched with water and the reaction was washed with saturated sodium bicarbonate (2 x 10 mL).
2.2.3 Synthesis of activated oxycodone hapten 7 and conjugation to carrier protein tetanus toxoid (TT) or
- The deprotection was allowed to proceed for several hours and was monitored by TLC (9:1 CH2Cl2:MeOH) and LCMS.
- To begin a session, the catheter fittings on the animals’ backs were connected to polyethylene tubing contained inside a protective spring suspended into the operant chamber from a liquid swivel attached to a balance arm.
- The eluted sample was evaporated using GENEVAC and taken up in MeOH for LCMS analysis.
3.1 Conjugation of Oxy-TT Vaccine
- The oxycodone hapten (Oxy) and Oxy-TT immunoconjugate were prepared as described previously (Kimishima et al, 2016) with minor modification detailed in the Experimental Section .
- MALDI-ToF analysis of Oxy-BSA confirmed successful conjugation with approximately 16 moles of Oxy hapten per mole of carrier protein.
- Following the vaccination regimen, rats in the Oxy-TT groups established plasma antibody titer .
3.2 Vaccination Protects Against Self-Administration of Oxycodone
- Using a threshold per infusion dose of oxycodone (0.06 mg/kg/inf; Cohort 1) under fixed-ratio (FR) schedule of reinforcement, rats steadily increased intake across the first 18 sessions of training .
- Only 58% of the Oxy-TT group met the acquisition criterion (average of 7 infusions across two sessions), whereas all of the TT animals met criterion .
- Under a higher per infusion dose (0.15 mg/kg/inf; Cohort 2), rats increased oxycodone intake over the first 18 sessions of acquisition, with the Oxy-TT group eventually obtaining more infusions .
3.3 Oxy-TT Vaccine Decreases Motivation for Oxycodone Self-Administration
- By increasing the workload required for reinforcement, the first PR probe (See details of PR schedule and j values in Materials and Methods) in Cohort 1 produced a significant reduction in the number of infusions earned for the Oxy-TT rats only ; there was a significant effect of schedule condition [F(1,21)=9.35; p=0.006] but not of vaccine Group.
- Oxy-TT rats trained under a higher per infusion dose (Cohort 2) also self-administered less oxycodone under the higher workload conditions of a PR schedule .
- In the subsequent FR, PRJ2, PRJ3, FR transitions fewer infusions were obtained in both PRJ2 and PRJ3 relative to each of the FR conditions within the Oxy-TT group .
3.4 Vaccine Attenuates Antinociceptive Effects of Oxycodone
- The effects of oxycodone on nociception were first determined prior to self-administration training in Cohort 1 (N=11-12) and Cohort 2 (N=12) rats.
- The dose-dependent attenuation of the antinociceptive effects of oxycodone in Oxy-TT rats persisted throughout the study .
- Post hoc analysis confirmed increased tail withdrawal latency in TT rats compared to Oxy-TT during the 30 and 120 min time points.
- Finally, Oxy-TT vaccination did not protect against heroin (1.0 mg/kg, s.c.)-induced antinociception which was assessed in Cohort 2 .
3.5 Vaccine Decreases Brain Penetration of Oxycodone
- Plasma oxycodone (ng/mL) was significantly higher in the Cohort 1 Oxy-TT rats compared to the corresponding TT group following injection of oxycodone , which was confirmed by an unpaired t-test [t(20)=7.708, p<0.0001].
- The Tukey post hoc test confirmed that Oxy-TT and TT oxycodone concentration levels found in plasma under all dose and time post-injection conditions were significantly different.
- This study provides evidence that active vaccination with Oxy-TT provides functional protection against the reinforcing effects of oxycodone.
- The tail-withdrawal test demonstrated that the Oxy-TT groups were less sensitive to the antinociceptive effect of injected oxycodone in a dose-dependent manner.
- This was observed in Cohort 2 despite the fact that more infusions were obtained by Oxy-TT rats when only one response was required.
- This ratio is cut in half for seniors endorsing past month use, suggesting a change in relative risk from prescription to illicit opioids in the more-frequently using population which would potentially pivot health care priorities from single drug prophylaxis to multi-drug prevention/therapy depending on exposure history.
- The increased intake of oxycodone in the Upper halves of each of the Oxy-TT vaccinated groups might be misinterpreted in a human clinical context as a significant failure, since drug-taking is usually the main outcome measure of clinical trials (Hoogsteder et al, 2014; Martell et al, 2009).
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Frequently Asked Questions (2)
Q1. What contributions have the authors mentioned in the paper "Prophylactic vaccination protects against the development of oxycodone self-administration" ?
Janda et al. this paper used a vaccine incorporating an oxycodone-hapten conjugated to fixmetetanus toxoid ( Oxy-TT ) to reduce voluntary drug-seeking in a rat model.
Q2. What future works have the authors mentioned in the paper "Prophylactic vaccination protects against the development of oxycodone self-administration" ?
Such consideration might include the likelihood of the individual requiring opioid medications in the near future and the availability of alternatives, as well as the relative risks of potentially using a higher dose of, e. g., oxycodone, in a very short course of pain management. This study was funded by grants from the USPHS R01 DA035281 ( M. A. T. ), R01 DA024705 ( M. A. T. ), UH3 DA041146 ( K. D. J. ) and F32 AI126628 ( C. S. H. ), which had no further input on the conduct of the work or the decision to publish results. Conversely it also underlines the potential need for multiple vaccines to address differing risk profiles with respect to abuse of multiple opioids, e. g. as modelled by Hwang and colleagues ( Hwang et al, 2018b ). This ratio is cut in half for seniors endorsing past month use, suggesting a change in relative risk from prescription to illicit opioids in the more-frequently using population which would potentially pivot health care priorities from single drug prophylaxis to multi-drug prevention/therapy depending on exposure history.