Preclinical studies and opioids: role in crisis management in the United States

Research into safer use of opioids

The development of new compounds with a better risk-benefit ratio is among the solutions to avoid opioid dependence, as well as their unsatisfactory safety profile. 

One such approach involves the design of biased μ-opioid receptor agonists, which aim to relieve pain without the full range of side effects associated with traditional opioids. For example, work by DeWire et al. (2013) showed that TRV130, a biased agonist, produced potent analgesia in rodent models with reduced respiratory depression and gastrointestinal side effects compared to morphine.

Many other strategies have been developed, including the use of activators of specific μ splice variants (Majumdar et al., 2011), a pH-dependent μ agonist (Spahn et al., 2017) or a dual nociceptin/μ agonist (Ding et al., 2018). A scientific team has developed an original design that is independent of the μ-opioid receptor. The researchers showed that targeting TREK1, the potassium channel involved in the antinociceptive activity of morphine, but not in its adverse effects, completely dissociates the antinociceptive and adverse effects of morphine.

Among the devices used, tests to evaluate motor coordination were also performed, such as the Rotarod, which measures the time it takes for an animal to fall from a rotating rod whose speed gradually increases. The mechanical pain thresholds were assessed using Von Fey filaments. The results of the study show that selective pharmacological activation of TREK1 is a promising and safe strategy for relieving pain.

Overview of research into non-opioid drugs

The search for non-opioid alternatives is also a major focus of preclinical studies. Given the addictive potential of opioids, there is an urgent need to develop effective pain treatments with a better safety profile. One promising approach to pain associated with certain pathologies, such as osteoarthritis, which is sometimes relieved by opioids, is the use of local anaesthetics (LA). University of Connecticut researchers (Kishnan et al., 2023), used a rodent model to compare the efficacy of periarticular versus intra-articular administration of LA in the management of osteoarthritis pain. They used the Electronic Von Frey device and a pressure sensor system from Bioseb to measure mechanical allodynia. The results showed that periarticular injections provided significantly longer-lasting pain relief, with a prolonged analgesic effect for up to 17 days, superior to traditional intra-articular injection, suggesting that LA could be a viable alternative to opioids for certain types of pain.

Neuropathic pain, caused by injury or dysfunction of the somatosensory system, is very difficult to treat without opioids. A study by Sun et al. (2022) investigated the PTPRD receptor, linked to addiction pathways, which could play a role in neuropathic pain. The results show that a small molecule (7-butoxy illudalic acid analogue: 7-BIA) reduces neuropathic pain in rats while activating a pathway involved in the immune response. The discovery of the possibility of using this compound could be a new therapeutic option for managing neuropathic pain without the risk of addiction, made possible by the animal model: pain sensitivity (temperature and thermal latency of paw withdrawal) assessed using a Cold Hot Plate test (Bioseb).

A French team (Girard et al., 2008) explored the antinociceptive synergy between nefopam, a centrally acting non-opioid that inhibits monoamines reuptake, and ketoprofen, a non-steroidal anti-inflammatory drug. The scientists used Bioseb's Smalgo device to accurately measure pain responses, demonstrating the increased efficacy of this combination in reducing pain while minimising side effects.