Opioid Dose- and Route-Dependent Efficacy of Oxycodone and Heroin Vaccines in Rats

Abstract

Heroin and oxycodone abuse occurs over a wide range of drug doses and by various routes of administration characterized by differing rates of drug absorption. The current study addressed the efficacy of a heroin vaccine [morphine hapten conjugated to keyhole limpet hemocyanin (M-KLH)] or oxycodone vaccine [oxycodone hapten conjugated to keyhole limpet hemocyanin (OXY-KLH)] for reducing drug distribution to brain after intravenous heroin or oxycodone, or subcutaneous oxycodone. Rats immunized with M-KLH or keyhole limpet hemocyanin (KLH) control received an intravenous bolus dose of 0.26 or 2.6 mg/kg heroin. Vaccination with M-KLH increased retention of heroin and its active metabolites 6-acetylmorphine (6-AM) and morphine in plasma compared with KLH controls, and reduced total opioid (heroin + 6-AM + morphine) distribution to brain but only at the lower heroin dose. Immunization also protected against respiratory depression at the lower heroin dose. Rats immunized with OXY-KLH or KLH control received 0.22 or 2.2 mg/kg oxycodone intravenously, the molar equivalent of the heroin doses. Immunization with OXY-KLH significantly reduced oxycodone distribution to brain after either oxycodone dose, although the magnitude of effect of immunization at the higher oxycodone dose was small (12%). By contrast, vaccination with OXY-KLH was more effective when oxycodone was administered subcutaneously rather than intravenously, reducing oxycodone distribution to brain by 44% after an oxycodone dose of 2.3 mg/kg. Vaccination also reduced oxycodone-induced antinociception. These data suggest that the efficacy of OXY-KLH and M-KLH opioid vaccines is highly dependent upon opioid dose and route of administration.

Fig. 1.

Effect of vaccination with M-KLH on heroin, 6-AM, and morphine concentrations after intravenous administration of a low or high heroin dose. Plasma (A–C) and brain (D–F) samples were collected 4 minutes following the end of 1-minute infusion of heroin. **P < 0.01; ***P < 0.001 for the difference between M-KLH and KLH control groups. Numbers above bars represent the percentage of difference from controls. Unpaired t tests with Welch’s correction were used to compare groups. Mean ± S.D., n = 8/group.

Fig. 2.

Effect of vaccination with M-KLH or OXY-KLH on opioid concentrations after intravenous administration of low or high heroin or oxycodone doses. Plasma (A) and brain (B) samples were collected 4 minutes following the end of 1-minute infusion of heroin, and serum (C) and brain (D) samples were collected 4 minutes following the end of 1-minute infusion of oxycodone. Plasma and brain drug concentrations after heroin administration represent total opioid (heroin + 6-AM + morphine); converted data from Fig. 1 and presented here for comparison. *P < 0.05; **P < 0.01; ***P < 0.001 for the difference between vaccinated rats and KLH controls. Numbers above bars represent the percentage of difference from controls. Unpaired t tests with Welch’s correction were used to compare groups. Mean ± S.D., n = 8/group.

Fig. 3.

Effect of vaccination with M-KLH on SaO₂ after intravenous administration of 0.26 mg/kg heroin. Heroin was infused intravenously for 1-minute following saline pretreatment. Vaccination with M-KLH significantly blunted the decrease in SaO₂ seen in the KLH control group. Both groups had significantly lower %SaO₂ levels following heroin administration (P < 0.01). **P < 0.01 for the difference between M-KLH and KLH control groups. Two-way analysis of variance with Sidak’s multiple comparisons test was used to compare groups. Mean ± S.E.M., n = 8/group.

Fig. 4.

Effect of vaccination with OXY-KLH on oxycodone concentrations following subcutaneous administration of a high oxycodone dose. Serum and brain oxycodone concentrations (A) and oxycodone-induced antinociception (B) 30 minutes following subcutaneous administration of 2.3 mg/kg oxycodone. **P < 0.01; ***P < 0.001 for the difference between OXY-KLH and KLH control groups. Numbers above bars represent the percentage of difference from controls. Unpaired t tests with Welch’s correction were used to compare groups. Mean ± S.D., n = 6/group.