Can a Combination Formulation Containing a Neutral Opiate Antagonist Decrease the Abuse of μ-Agonist Opiates

DOI: 10.1007/978-1-59745-197-0_14


Dependence on and abuse of prescription opiate drugs is now a major health problem with initiation of prescription opiate
abuse exceeding cocaine in young people. Coincident with the emergence of abuse and dependence on prescription opiates there
has been an increased emphasis on the treatment of pain. Pain is now the “5th vital sign” and physicians face disciplinary
action for failure to adequately relieve pain. Thus, physicians are whipsawed between the imperative to treat pain with opiates
and the consequences of producing addiction in some patients. Novel approaches are needed to allow appropriate prescribing
yet diminish the risk of iatrogenic addiction. In this chapter, we propose a method to develop opioid medications that are
resistant to drug abuse and show reduced adverse effects. Among the various strategies to reduce addiction liability, the
addition of small doses of an opioid antagonist has received recent attention. This is done with the expectation that the
antagonist does not affect the analgesic actions if the combination is given for therapeutic purposes, but will accumulate
and then block the opioid effects when the drug is abused — either in high oral doses or by intravenous administration. However,
opioid antagonist engender strong adverse effects in opioid-dependent and tolerant subjects. Our method emerges from recent
advances in our understanding of the molecular pharmacology of opioid receptors, whereby antagonist can be classified into
inverse agonists (e.g., naltrexone) that block basal receptor activity, and neutral antagonists (e.g., 6β-naltrexol) that
block only the agonist-stimulated effects — thereby causing less withdrawal effects. Preclinical results indicate that 6β-naltrexol
(a main metabolite of naltrexone) has all the desired pharmacokinetic and pharmacodynamic attributes as an ideal candidate
for such a combination therapeutic, potentially yielding a significant advance in pain therapy with opiates. In this chapter,
we review the evidence for the unfolding prescription opiate epidemic and describe the potential of 6β-naltrexol, a neutral
opiate antagonist, in limiting maximal μ-agonist effects of oral opiate analgesics.

KeywordsPrescription opiate abuse–Combination formulation–Neutral opiate antagonist–6β-naltrexol

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