Where do we stand in the field of anti-abuse drug discovery?

Abstract

Drug abuse and addiction to licit and illicit drugs constitute an almost worldwide health and socioeconomic problem. This problem can be addressed in a number of ways. As far as pharmaceutical development and drug therapy is concerned, abuse-deterrent formulations (ADF), substitution therapies, antagonist therapies, aversion therapies, and diverse novel approaches can be considered. ADF (or tamper-resistant formulations) are an important step towards preventing the abuse of medically used drugs, such as strong opioid analgesics, and some drug treatments are well established, such as substitution therapy in opioid dependence with methadone and buprenorphine. Nevertheless, a large medical need remains, and drugs that effectively curb opioid or psychostimulant addiction by promoting abstinence and preventing relapse have yet to be developed. Many different targets and mechanisms are currently being considered in preclinical research, but apart from repurposing or reformulating already known drugs, very little clinical development is currently ongoing. It is hoped that at least a few of the investigated approaches (e.g., various glutamate and GABA receptor modulators, nociceptin/orphanin FQ peptide receptor agonists, or histamine H3 receptor antagonists) reach the stage of clinical development and eventually reach regulatory approval.

Keywords::

• abuse
• abuse-deterrent formulation
• addiction
• dependence
• glutamate
• nociceptin orphanin FQ peptide
• relapse
• substitution

1. Introduction

Abuse of and addiction to legal and illicit drugs is a big health and socioeconomic problem in many countries worldwide. The abuse of legal drugs like alcohol and nicotine can cause substantial morbidities in significant parts of a population, with respective impact on health and economy. The abuse of illicit drugs such as heroin or cocaine is numerically a smaller problem, but with major consequences for the afflicted and their environment. The abuse of medical drugs (e.g., strong opioid analgesics) not only has negative consequences for the abusers, but bears the additional weight of potentially limiting access to these drugs for the general patient population because control measures (e.g., scheduling) are put in place to limit the illicit use of these drugs, and because doctors may be disinclined to prescribe opioids because of the associated regulatory issues.

Addiction and drug abuse is a complex, multifaceted phenomenon. Thus, when talking about ‘antiabuse drug discovery’, several lines of possible approaches have to be considered:

• Abuse-deterrent (ADF)/tamper-resistant formulations (TRF) (aimed at making it more difficult to abuse licit drugs).

• Substitution therapies (aimed at replacing an illicit drug by a licit drug and thus promoting illicit drug abstinence and resocialization).

• Antagonist therapies (including vaccinations) (aimed at blocking the effects of illicit drugs, thereby making their use undesirable).

• Aversion therapies (making the use of drugs undesirable because of acute negative consequences); as this is essentially a one-drug category (disulfiram for alcoholism) with no apparent new developments, this category will not be further considered below.

• Diverse novel approaches (mainly aimed at preventing craving and relapse by suppressing or erasing addiction memory and conditioned responses).

Furthermore, although probably all illicit and abused licit drugs eventually act, in principle, via the same neurobiological substrate in the brain, the different classes of drugs invoke distinct pharmacological and physiological mechanisms and have distinct consequences on physiology and behavior. Thus, when considering approaches to antiabuse treatments, each drug class probably needs to be considered separately, as a drug that may be effective in supporting opioid abstinence would not necessarily be expected to reduce craving for cocaine as well, and vice versa [1].

2. Abuse-deterrent/tamper-resistant formulations

The development of ADF (a.k.a. TRF) for therapeutically used drugs is an important building block in reducing overall drug abuse since abuse of licit drugs contributes a significant part to the overall drug abuse problem. In particular in the US, the abuse of narcotics and other scheduled medications is a major problem. Studies have shown that an ADF of a strong opioid can indeed be much less attractive for drug (ab-)users compared with the original, non-ADF formulation or compared with a non-ADF formulation of another strong opioid [2,3]. There are several companies that have developed or are still actively developing such novel formulations. A recent setback regarding the establishment of ADF formulations as a ’gold standard’ for strong opioids was an FDA ruling regarding oxymorphone/Opana® ADF, which does not prevent non-ADF oxymorphone generics from entering the market [4].

3. Substitution therapy

Substitution therapy is only available for opioid dependence (and smoking/nicotine addiction, when considering licit drugs as well). The only drugs approved for opioid dependence are (levo-) methadone and buprenorphine (apart from a few local or national heroin substitution programs). New developments in this field have largely been limited to novel formulations, particularly in the case of buprenorphine. A buprenorphine/naloxone buccal film is currently under regulatory review, and a buprenorphine implant and an injectable depot are in late stages of development. Both methadone and buprenorphine are well established in the treatment of opioid dependence, and both drugs can have beneficial effects. However, both drugs also have their shortcomings in terms of tolerability, compliance or effectiveness. Nevertheless, activities regarding the development of novel drugs for opioid dependence have been sparse in the past and still are. Most of these have been concerned with novel, mostly long-acting µ-opioid peptide (MOP) receptor agonists, although there is an increasing believe among experts and health authorities that classical MOP receptor agonist therapy for opioid addiction is merely replacing one addiction for another. This may indeed represent a problem for the future development of treatments for opioid dependence. A potentially interesting new development has been the discovery of drugs that bind not only to the classical MOP receptor, but also to the nociceptin/orphanin FQ peptide (NOP) receptor (e.g., [5]). In preclinical studies, selective NOP receptor agonists were shown to reduce the rewarding or reinforcing effects of drugs of abuse (see below), thus an additional NOP receptor agonistic activity may enhance the therapeutic value of a MOP receptor agonist. Whether this promise holds true remains to be determined.

More efforts have been devoted to finding a (substitution) treatment for cocaine dependence, particularly in the US, where large research and development programs, in part with substantial public funding, have produced a number of drug candidates, none of which, however, have thus far proceeded to the stage of regulatory approval [6].

4. Antagonist therapy

Naltrexone appears to be reasonably effective in supporting drug abstinence, but, not surprisingly for an antagonist treatment, compliance is a problem for the oral formulation, and together with the high price for the depot formulation makes it a good treatment option only for the most determined of patients.

Conceptually, vaccines may be considered under the heading of ’antagonist treatment’ since their aim is to neutralize a given drug, thus preventing interaction with its receptor. The development of vaccines against drugs of abuse first generated a lot of expectations in light of promising animal data, but clinical development proved difficult, and to date, no antidrug vaccine has been approved.

5. Novel approaches

The only currently approved drug that may fall into this category is acamprosate for alcoholism, which is moderately effective in promoting abstinence after withdrawal. The pharmacology of acamprosate is complex, but part of its activity may be related to blocking the glutamatergic NMDA receptor. Preclinical evidence suggests that there may be a dysregulation of glutamatergic signaling in addiction. Consequently, different types of antagonists (subtype-selective; low-affinity) of the glutamatergic NMDA receptor have been considered to have antiaddictive effects on various classes of abused drugs, based on substantial animal experimentation [7]. Unfortunately, most NMDA receptor antagonists in clinical development (regardless of the indication) have met with tolerability concerns, and clinical development activities for novel compounds in this field have more or less ceased. There is now a renewed interest in the old nonbenzodiazepine anxiolytic drug fenobam, which has recently been identified as a mGluR5-negative allosteric modulator (NAM). Since preclinical tool mGluR5 NAMs have shown promising effects in animal models of abuse and addiction, fenobam is currently being evaluated for its antiabuse potential, as is N-acetyl cysteine, which can be considered as a glutamate-normalizing agent. Other clinically available drugs for which currently a repurposing as antiabuse medication is considered include, for example, the spasmolytic baclofen, the atypical antidepressant mirtazapine and several antiepileptics.

A potentially promising new direction is the discovery and development of NOP receptor agonists. Although initially pursued for their potential anxiolytic effects, it was soon demonstrated that the prototypical NOP receptor agonists Ro64-6198 and Ro65-6570, and others, could reduce rewarding and reinforcing effects of essentially all classes of drugs of abuse (opioids, psychostimulants, nicotine, alcohol) in relevant animal models (e.g., [8]). Moreover, drug-induced reinstatement of drug-seeking behavior was also blocked by such compounds in animals, and there is some evidence that NOP receptor agonists might reduce physical dependence on opioids [9]. Unfortunately, clinical development programs of these compounds in other indications have been stopped due to efficacy or tolerability issues, and no clinical study in the addiction indication appears to be currently ongoing.

6. Conclusion

Drug abuse and addiction continues to be a worldwide health problem. ADF/TRF, substitution, antagonist and aversion therapies, as well as diverse novel approaches, are currently being used and/or investigated for their potential to treat addiction and dependence. Nevertheless, a clear medical need remains, and drugs effectively promoting abstinence and preventing relapse have yet to be developed. Many different targets and mechanisms are currently being considered in preclinical research, and it is hoped that at least a few of the investigated approaches reach the stage of clinical development and eventually become available on the market.

7. Expert opinion

So, where do we stand in the field of antiabuse drug discovery? Drug abuse and addiction continues to be a significant health issue with significant societal and economic implications. Some drugs for substitution, antagonist and aversion therapy exist, and quite a few patients can benefit from these drugs. Moreover, ADF/TRF, present and future, are an important step in limiting licit drug abuse. But as the clinical situation clearly shows, there is still an unmet medical need and a lot of room for the discovery and development of effective antiabuse treatments. Progress in the field is, to some extent, hampered by the difficulty and complexity of translating findings from animal experiments to the human clinical situation. There are several highly valuable animal models available, none of which however can mimic the full complexity of human addictive behavior, and developing better addiction models is almost a science in its own right [10,11]. Progress in antiabuse drug discovery is thus also closely linked to progress in developing animal models with better predictive and construct validity. Likewise, devising valid and predictive human laboratory models and refined clinical trial programs could facilitate successful drug development. Retention to pharmacotherapy remains a major issue. If patients drop out of therapy (be it due to lack of efficacy, lack of tolerability or due to personal circumstances), they are more likely to relapse. The biggest current gap is in the field of drugs that directly target the addiction as a disease. No effective treatments are available here, but basic research continues to identify targets and mechanisms that are promising and may become important for antiabuse drug discovery. These are as diverse as neuropeptide S, urocortins, glial modulators, histamine H3 receptor antagonists, kappa opioid receptor antagonists/partial agonists, various GABAergic and glutamatergic modulators, transcranial magnetic stimulation or pharmacologically manipulating extinction and reconsolidation processes, to name but a few [12-15]. Whether any of these approaches eventually leads to a breakthrough in antiabuse drug discovery and treatment of addiction remains to be seen.

Declaration of interest

TM Tzschentke is an employee of Grünenthal GmbH. The opinions expressed in this editorial, however, do not necessarily constitute the opinion of Grünenthal GmbH, but are the personal opinions of the author. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.