BACKGROUND

Fentanyl is an effective synthetic opioid that is used legally as a schedule II prescription pain reliever. However, fentanyl presents a significant abuse liability due to the euphonic feeling it induces via activation of mu-opioid receptors (MOR) in the brain; the same pharmacological target as the illegal schedule I opioid, heroin.[1]Excessive activation of MOR results in respiratory depression which can be fatal.[2]Fentanyl exceeds the potency of heroin by >10-fold, and morphine by >80-fold posing a significant risk of overdose when it is consumed from unregulated sources.[3]Furthermore, the ease of fentanyl synthesis enables illegal production and the creation of designer drug analogues.[4]The fact that the pharmacology of these analogues has yet to be properly characterized makes them particularly dangerous, especially when certain modifications, even methyl additions, can increase potency, notably at the 3-position.[5]

Last July, the National Institute on Drug Abuse (NIDA) reported an alarming surge in fentanyl overdose deaths:[6]the latest update in a long stream of overdose cases starting with methylfentanyl aka “China White” in the late 1980s.[7]A newer designer analogue, acetylfentanyl, further exacerbates the opioid epidemic because of its deceptive sale as heroin or as a heroin mixture,[8]and it has been linked to a number of overdose deaths.[9]In addition to the US, fentanyl abuse is on the rise across Europe; while the most overdose deaths occurred in Estonia, the highest consumption of fentanyl per capita was reported in Germany and Austria.[10]

SUMMARY

The invention provides, in various embodiments, a hapten for generating, when conjugated with a carrier, a vaccine for raising IgG antibodies in vivo, with specificity for fentanyl class drugs, comprising a compound of formula (I)

wherein R1=CH2CH2C(═O)X and X═OH or an activated ester thereof; R2═H or a (C1-C4)alkyl group, R3═H or a (C1-C4)alkyl group, and R4═H or a (C1-C4)alkyl group; and a hapten conjugate for generating an in vivo ‘immunoantagonist’ to a fentanyl class drug, comprising a compound of formula (I) of claim1wherein X comprises a protein carrier or an amino-functionalized bead, the protein or the bead forming an amide bond with the hapten. For example, the protein carrier can be bovine serum albumin (BSA) or tetanus toxoid (TT), or the amino-functionalized bead can be a DYNABEADS® M-270 Amine.

The invention further provides a vaccine produced in a mammal by administration of an effective dose of the hapten conjugate described above. For example, the mammal used for vaccine production can be a mouse. The vaccine can comprise IgG type antibodies.

In additional embodiments, the invention provides a method of effectively minimizing a concentration of a fentanyl class drug at a site of action in a patient, comprising administration of an effective dose of the vaccine to the patient. Additionally, administration of the effective dose of the vaccine imparts significant protection to the patient from an otherwise lethal dose of a fentanyl class drug. Further, administration of the effective dose of the vaccine to the patient reduces the addiction liability and overdose potential of the fentanyl class drug.

