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New Opioids Without Side Effects?

New opioid drugs with reduced side effects are in development.


Chronic pain is a serious and growing concern. It impacts 1/3 of Americans and severely degrades quality of life. To date, the best treatment to manage chronic pain are opioids such as morphine and fentanyl. Unfortunately, opioids have many side effects, including dependence, addiction, tolerance, constipation, nausea, respiratory depression, somnolence, and mental clouding.  These limitations reduce the quality of life of the patients, and there is a desperate cry for the development of a new therapeutic option.

Opioid drugs activate the mu opioid receptor (MOR), which leads to beneficial therapeutic effects as well as unwanted side effects. For instance, Barrestin2, which is stimulated upon opioid binding to MOR, dampens analgesic outcome of opioids and produces unwanted side-effects. To date, there are several different approaches to enhance analgesia and inhibit side-effect related signaling. In an effort to minimize unwanted side effects, scientists are focused on the following areas of drug development: 1) selective ligands, 2) signaling modulators, 3) multi-functional drugs, and 4) druggable peptides.

Selective ligands are biased ligands that bind to MOR but block the activation of side-effect signaling such as Barrestin2.  PZM21 and TRV130 are examples of MOR agonists with Barrestin2 blocker. In clinical Phase I trials, TRV130 has been shown to enhance analgesia and reduce nausea.

Signaling modulators directly target intracellular signaling molecules that are involved in MOR signaling. If targeted correctly, signaling modulators have the potential to selectively inhibit side-effect signaling. Some of the potential targets are heat shock protein 90, associated with dependency; ERK1/2, associated with opioid-induced tolerance; and TLR4, shown to disturb the analgesic effect of opioid. Potentially, targeting and blocking these regulators could enhance opioid analgesic signaling and reduce side effects.

Multi-functional drugs are meant to target the MOR to produce analgesia and prevent a negative feedback system. Tapentadol and tramadol are examples of multi-functional drugs that have reached the market and been shown to reduce addiction liability. Several other multi-functional drugs are in pre-clinical and early clinical development. Agonists at the cholecystokinin and neurokinin receptors have been shown to reduce tolerance and reward.

Druggable peptides is an approach to increase bioavailability and potency of endogenous opioids, such as endorphins, enkephalins, dynorphins, and endomorphins. The analgesic efficacy of endogenous opioids is comparable to morphine, and their side-effect profiles are superior to small molecule drugs like morphine. However, endogenous opioids have a short half-life, poor blood-brain barrier penetration, and poor bioavailability. Currently, there are several methods to modify the structure of endogenous peptides to combat this shortcoming.

These novel approaches are promising and may lead to a pain drug breakthrough. However, more research is needed to achieve successful development. Opioid addiction and drug overdose are prevalent and there is an urgent need for effective and safe novel analgesics.


Written By: Boram Ham, PhD



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