Challenges in Developing Therapeutics for Addiction and Pain

In light of the rapid increases in opioid overdose deaths, there is an urgent need to develop better treatment options for pain and addiction.

In light of the rapid increases in opioid overdose deaths, there is an urgent need to develop better treatment options for pain and addiction, according to a summary of key messages and discussion from a 2-day event titled “The Opioid Crisis and the Future of Addiction and Pain Therapeutics: Opportunities, Tools, and Technologies Symposium,” held at the National Institutes of Health in Gaithersburg, Maryland, which was published in the Journal of Pharmacology and Experimental Therapeutics.

In order to develop new pain treatments, it is imperative to have a better understanding of the circuits, pathways, genetics, transcriptional and epigenetic mechanisms, and targets involved in both pain and opioid addiction.

Opioid misuse and addiction now represent a public health crisis with a debilitating social and economic impact on individuals, and associated mortality. The symposium aimed to address concerns regarding pain and addiction and was unique in that it brought together experts from 2 research disciplines: addiction and pain.

Attempts to identify novel targets that could lead to effective pain treatments without involvement of the μ-opioid receptor were unsuccessful and only a limited number of targets exist for pain management, most which have been known for decades. It is important to recognize the complexity and diversity of pain and the pain experience, involving distinct mechanisms that require different therapeutic interventions.

Although drugs that have the potential for misuse initially act at the synapses, addiction requires repeated drug exposure and can therefore be considered drug-induced neural plasticity that involves changes in gene expression. Approximately half of the risk for addiction is thought to be due to genetic factors, with hundreds of genes each contributing a small fraction, and half due to environmental factors.

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Negative emotional states cause physical and emotional pain that may act as a driving force in addiction. There is significant overlap in the neural pathways that mediate negative emotional states (eg, hyperkatifeia) and pain.

Natural products, including capsaicin, menthol, isothiocyanates, and thiosulfinates, elicit irritation or pain by activating nociceptors. Studies examining the mechanisms of action of these compounds led to the identification of transient receptor potential (TRP) ion channels that represent promising targets for novel analgesics. Current work aims at identifying antagonist molecules to TRP channels that may represent alternatives to opioid analgesics.

Research into venomous toxins, including Hm1a/b spider toxins, has revealed a role for the Nav1.1 voltage-gated channel in pain. Cannabinoids and the opioid receptor agonist mitragynine (derived from kratom) are also gaining attention as potential targets for pain.

Efforts to identify inhibitors selective for the Nav1.7 channel have proved challenging due to factors that include the IC50 value of the receptor being inferior to concentrations required to block action potentials in nociceptors.

ĸ-opioid receptor antagonists may represent an effective therapeutic strategy to alleviate the affective dimension of chronic pain, as these can restore dopamine release.

Digital therapeutic options also lead to effective chronic pain therapy. With the use of data derived from smartphones, connected sensors, wearables, and voice input, there is the potential to better assess and understand a patient’s health and to identify biomarkers. Finally, behavioral epigenetics can be used to understand the interplay between life experience and brain function.

“Given the rapidly growing occurrence of opioid use disorder and associated overdose deaths, as well as the lengthy time required for new targets to reach patients in need, there is a renewed urgency to develop better treatments for pain and addiction,” concluded the authors.

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Coussens NP, Sittampalam GS, Jonson SG, et al. The opioid crisis and the future of addiction and pain therapeutics [Published online September 3, 2019]. J Pharmacol Exp Ther. doi: 10.1124/jpet.119.259408