Medications Development for Opioid Abuse

Abstract

Here we describe methods for preclinical evaluation of candidate medications to treat opioid abuse and dependence. Our perspective is founded on the propositions that (1) drug selfadministration procedures provide the most direct method for assessment of medication effects, (2) procedures that assess choice between opioid and nondrug reinforcers are especially useful, and (3) the states of opioid dependence and withdrawal profoundly influence both opioid reinforcement and the effects of candidate medications. Effects of opioid medications on opioid choice in nondependent and opioid-dependent subjects are reviewed. Various nonopioid medications have also been examined, but none yet have been identified that safely and reliably reduce opioid choice. Future research will focus on (1) strategies for increasing safety and/or effectiveness of opioid medications, and (2) continued development of nonopioids such as inhibitors of endocannabinoid catabolic enzymes or inhibitors of opioid-induced glial activation.

Effects of the novel, selective and low-efficacy mu opioid receptor ligand NAQ on intracranial self-stimulation in rats

“…Mu opioid receptor agonists are used for a range of clinical applications that include treatment of pain, diarrhea and cough, and they are also used as maintenance medications to treat opioid addiction (Gutstein and Akil 2006; Negus and Banks 2013). Two important determinants of opioid action are selectivity for, and efficacy at, mu opioid receptors.…”

“…nalbuphine, pentazocine and butorphanol) also have low selectivity for mu receptors, especially for mu vs. kappa opioid receptors (Emmerson et al 1996; Emmerson et al 1994; Peng et al 2007; Raynor et al 1994; Selley et al 1998). Low-efficacy mu agonists may have clinical value for some indications because they might retain sufficient efficacy to produce therapeutic effects such as analgesia against modest pain or alleviation of opioid withdrawal, but they might lack sufficient efficacy to produce some side effects such as significant respiratory depression or lethality (Gutstein and Akil 2006; Hoskin and Hanks 1991; Negus and Banks 2013). However, kappa opioid receptors mediate dysphoric subjective effects and some other undesirable effects (Pfeiffer et al 1986; Walsh et al 2001), and kappa-mediated effects may be one factor that limits clinical utility of existing low-efficacy opioids.…”

Agonist Medications for the Treatment of Cocaine Use Disorder

“…Second, agonist medications have high probability of functioning as effective reinforcers in patients, and as a result, their delivery in a clinical context can be leveraged to promote compliance and reinforce other desirable behaviors (Preston et al, 2000). Third, agonist medications can alleviate withdrawal signs that contribute to relapse (Koob, 2009;Negus and Banks, 2013). The pharmacokinetic attributes of agonist medications enable their use by safer routes of administration (eg, oral and sublingual) than the intravenous or smoked routes common in drug abuse.…”

Predicting abuse potential of stimulants and other dopaminergic drugs: Overview and recommendations

“…In the case of opioids, a class of drug reinforcers for which physical dependence may be the most thoroughly characterized, overt and adverse signs of drug withdrawal are evident upon cessation of administration and are thought to be related to compensatory homeostatic adaptations that occur during chronic drug administration (Rehni et al, 2013). Drug withdrawal from opioids and other drugs with established physical dependence-inducing properties (e.g., ethanol, sedatives) can be alleviated by reestablishing administration of the drug, which is a likely contributor to continued drug-taking, or by administering another drug of comparable pharmacological effect (e.g., agonist substitution therapy; Kosten and O’Connor, 2003; Negus and Banks, 2013). During chronic drug administration, homeostatic adaptations also result in tolerance to the drug’s effects, which is manifest by a need to progressively increase the dose of the drug to maintain a stable level of effect.…”