One theoretical approach to end an epidemic is to eliminate the agent.

This is neither realistic nor in all likelihood would it be in the best interest of the host population, in many cases. First of all, the agents are ubiquitous. Secondly, most microbes play some role in the larger balance of the ecosystem, and their elimination may have far-reaching negative consequences. Thirdly, mutation rates coupled with short propagation times invariably result in new pathogenic strains, or antimicrobial-resistant strains, as we have learned over the last few decades in the infectious disease realm.

Many of these considerations apply to the opioid as agent as well. Blanket elimination is impossible without destroying every poppy plant and chemical laboratory on the planet. Opioids do provide a necessary and useful role, and their elimination would have far-reaching negative consequences. Human nature is such that when one abusable substance is rendered inaccessible, another is often substituted.

An alternate approach addressing the agent is to somehow attenuate its virulence without eliminating it. Since the post-World War II period and Dr. Jonas Salk’s inactivated and Dr. Albert Sabin’s “live-attenuated” poliovirus vaccines, alteration of normal microbial pathogenic capacity has been the mainstay of infectious disease prevention, by means of stimulating host immune defenses via vaccination. More recently, “antivirulence therapies ” aimed at altering agent virulence factor production, expression, regulation, etc. are under intensive research and development as classic twentieth century antimicrobial therapeutic approaches seem doomed to failure as resistance inevitably overcomes antibiotics. Some of these approaches include targeting adherence and protective (biofilm) mechanisms, enhancing competition for resources by increasing commensal organisms, interfering with “quorum sensing ” and signaling among pathogens, “quorum quenching” agents, and other novel approaches [1–3].

This sort of multifaceted “outside-the-box thinking” must be applied to the development of novel analgesics as well if we hope to reduce human dependence upon exogenous opioids. Classic approaches (such as extended-release/long-acting formulations and abuse-deterrent/tamper-resistant technologies, discussed in greater detail below) have not proven successful on a wide scale in containing the opioid epidemic.

Nora Volkow’s 2014 Congressional Address highlighted the need for the development of novel analgesic therapies that “circumvent the brain reward pathways, thereby greatly reducing abuse potential” [4]. In considering antivirulence strategies, one must first define and understand virulence. A succinct, recent definition highlighting both the concept of virulence along a spectrum and also its essentially broad context is “the relative capacity of a microbe to cause damage in a host [5].” These authors also make the point that the virulence of an agent may be dependent upon individual host vulnerability which varies as well. Host damage caused by opioids has been reviewed in Chap. 3 and ranges from mildly annoying side effects to death from respiratory depression and in some cases cardiac arrest. Significant morbidity affecting nearly every physiologic system is common but varies from individual to individual. Obese individuals with compromised airways and those with ultra-rapid CYP2D6 metabolizer status are more prone to respiratory arrest, and individuals with certain psychosocial risk factors (as discussed in greater detail in Chap. 9) are more prone to dependence and addiction. However, while the vulnerability to and outcome of opioid morbidity (including dependence and addiction) and mortality are variable, their correlation with increased exposure is not only intuitive but borne out in the literature. In addition, the correlation between abuse potential and increased exposure is well-established. Thus, while death (or addiction) may result from one single exposure and many chronic users survive and escape addiction, in general reducing abuse potential is a key strategy in attenuating virulence, as Dr. Volkow points out.

Before examining past, present, and future mechanisms of reducing opioid virulence, a cursory review of current neurobiological theory of (psychological) substance dependence and addiction, along with proposed mechanisms whereby opioids “hijack” the proposed circuitry, is in order. A more comprehensive overview is presented in Chap. 9, with behavioral and societal theories broadening the discussion. It should be noted at the outset of any exploration of proposed addiction biology that:

Current understanding of the neurobiology of reward motivation assigns a central role to dopaminergic neurons within the ventral tegmental area (VTA) of the midbrain. VTA dopaminergic neurons project superiorly along the medial forebrain bundle (nicknamed the “hedonic highway” [7]) to various limbic and executive areas including the:

Intracerebral dopamine agonists induce both self-administration and conditioned place preference (CPP) in rodents [9–12], and dopamine antagonism causes aversive behaviors in both animal and human subjects [13–15]. Virtually all drugs of abuse and other pleasurable stimuli are believed to exert hedonic effect via mesolimbic dopamine.

Opioid-induced reward (including euphoria) is thought to be mediated via cerebral mu-opioid receptors (MOR) [16–18]. MOR are ubiquitous throughout the brain, but extensive research in animal subjects has shown that there are specific regions, in particular the VTA, whose MOR appear particularly important to the reward/reinforcement phenomenon that is universally accepted as fundamental to the development of addiction [19–22]. Evidence for the centrality of the VTA in opioid dependence is both positive (intra-VTA opioid administration induces both self-administration and CPP in rodents [20, 22–24]) and negative (intra-VTA opioid antagonists or genetic MOR knockout results in loss of these behaviors [21, 25]).

Dopaminergic transmission to mesolimbic targets including the NAc is effected by VTA MOR agonism [26, 27], and thus a synthesis of these data has resulted in opioid-VTA MOR-mesolimbic dopaminergism being widely accepted as the foundational biologic paradigm for opioid addiction [28–30].

However, several recent lines of evidence indicate that the picture is much more complicated than this. First of all, ample evidence indicates that not all NAc dopaminergism is rewarding; several agents (delta-opioid receptor agonists, cholecystokinin, glial-derived neurotrophic factor) increase dopamine in the NAc but do not produce CPP [6], and furthermore even the administration of MOR antagonists sufficient to cause place aversion also results in NAc dopamine increases [31, 32]. Second, evidence is accumulating that opioid reinforcement can occur in the absence of mesolimbic dopaminergism [33–36]. Interestingly, dopaminergic neuronal activity in response to MOR agonism has been shown to increase in anesthetized animals but decrease in awake animals [6]. Similarly, MOR-mediated CPP inhibition by dopamine antagonism has been shown in opioid-dependent rodents whereas opioid-naïve animals do not lose CPP [37]. Finally, stimulation of VTA dopaminergic neurons has been shown to also result in release of other neurotransmitters including glutamate and GABA [38–40].

While our understanding of the complexities of addiction neurobiology (let alone behavior) is in its infancy, it is at least a useful construct to imagine a correlation between a substance’s capacity to agonize midbrain MOR and effect pleasurable dopaminergic (or other) transmission to limbic and higher cortical structures and its virulence.

Historic and current approaches to attenuating opioid virulence are organized in this chapter into two categories:

The second category is necessarily and by design broad, indicating the diversity of approaches available. It is also intended to highlight the distinction between “out-of-the-box” thinking and more restricted efforts typified by the first category. This is not to disparage efforts to reduce virulence by altering delivery of currently extant agents; there is great practicality in utilizing agents already known to be (relatively) safe and efficacious. Such approaches however have little promise for improvement over the current situation besides limiting the potential for non-sanctioned routes of abuse. Development of novel opioid-mediated strategies will be necessary to effectively harness the full, balanced potential of the intricate and wonderful endogenous analgesic system we possess. Development of non-opioid-mediated strategies (e.g., N-methyl d-aspartate blockers, cannabidiol analogs) of course will provide complementary or alternative means of potent analgesia but are outside the scope of this work.