Opioid analgesics have been a mainstay of pain treatment for centuries but over the past few decades, their overuse for both medical and non-medical reasons has led to what has been described in the popular press as a worldwide opioid epidemic, and by the USA Department of Health and Human Services as a public health emergency. The USA statistics are staggering; since 1999, the amount of prescription opioids sold to pharmacies, hospitals and doctor’s offices has quadrupled with no overall change in the amount of pain that American patients reported. Deaths from overdoses of prescription opioids such as oxycodone, hydrocodone and morphine have also quadrupled since 1999, with over 42,000 fatalities in 2016 alone. Opioid dependency is an important associated social and medical problem with 2.1 million people in the USA reporting an opioid use disorder in the same year.
Opioids are clearly efficacious and appropriately prescribed for acute pain but their use in chronic non-cancer pain is controversial with recent meta-analyses concluding that opioids alone are ineffective. NICE guidance for chronic pain states such as neuropathic pain indicates that opioids should not be used unless patients are individually advised by a pain specialist. The provision by the NHS of universally accessible pain management services with non-opioid strategies perhaps explains, in part, why opioid over-prescribing in the UK is not at the level of that in the USA.
The commonly used opioid analgesics are poorly selective agonists of all three opioid receptors (μ, κ and δ) although, morphine, for example, is about 50 fold more potent at μ vs δ receptors. The well-known unwanted effects of morphine-like agonists including constipation, nausea, itching and potentially fatal respiratory depression are largely μ receptor-mediated as is the tendency to induce analgesic tolerance and physical/psychological dependence. Thus, maintaining a clinical balance between effective analgesia and adverse side effects with conventional opioids is extremely difficult.
One developmental approach for the opioid analgesic family is to design drugs that are selective for the κ and δ receptors and, indeed, there is excellent preclinical evidence that δ receptor agonists are effective analgesics in chronic pain states, although their effects on acute pain are limited. Early δ-selective compounds such as SNC80 were reported to be proconvulsant and this limited pharma companies’ enthusiasm for this approach. However, this property has since been found to be structurally dependent and not a universal class feature and newer agents such as JNJ-20788560, TAN-67 and KNT-127 are free from proconvulsant activity and are also devoid of the adverse μ receptormediated side effects. There is also evidence of δ-mediated anxiolytic and antidepressant activity which would be beneficial to patients suffering from chronic pain. κ-receptor agonists are also analgesic in preclinical models but compounds that enter the brain cause hallucination, dysphoric effects and aversion. However, the development of peripherally restricted agonists is a realistic research focus. At the present time, although they have considerable potential, very few clinical studies of κ or δ agonists have been conducted and none are currently marketed.
Perhaps an ideal situation would be to have opioids that retain the very effective analgesic properties of μ receptor agonists without their adverse effects. Recently, efforts have been made to achieve this by taking advantage of the potential for biased agonist signalling.
Agonists for the μ receptor can activate Gi/Go protein signalling and also arrestinassociated transduction pathways. Based largely on knockout studies, it is thought that G protein biased signalling is crucial for analgesia whilst arrestin-3 (β-arrestin 2) recruitment is related to unwanted side effects. Based on this hypothesis, Trevena Inc developed oliceridine (TRV130), a μ receptor agonist reported to be selective for G protein over arrestin signalling and this has been shown to be as effective as morphine with fewer opioid-like side effects in patients with moderate to severe pain following abdominoplasty. Manglik et al. reported the development of another G protein-biased μ receptor agonist, PZM21, which they reported to be as effective an analgesic as morphine but devoid of respiratory depression and Schmid et al. have recently described some other G proteinbiased μ receptor agonists that induce less respiratory depression than morphine at equi-antinociceptive doses. However, Hill et al. have carefully re-examined the properties of PZM21 and reported that it is a partial agonist for both G protein activation and arrestin recruitment, induces respiratory depression and rapid tolerance to analgesia, but not respiratory depression, similar to equi-antinociceptive doses of morphine. The reasons for the disparity between the studies of Manglik and Hill are unclear but the potential for exploitation of signalling bias to optimise agonist function is clearly worth further development.
Given the problems associated with existing opioid analgesic therapy it is perhaps attractive to consider completely different drug development targets. For example, considerable attention is being paid to the potential of ligands interacting with the NaV1.7 ion channels that are key players in controlling activity in pain pathways. Various strategies for inhibiting Nerve Growth Factor (NGF), particularly with regard to osteoarthritis pain, are also being pursued, although there are some concerns about the long-term safety of anti-NGF antibodies. Whatever new targets emerge, the centuries’ long dependence on opioid analgesic drugs is unlikely to diminish significantly in the near future and clinicians and drug discoverers must continue to focus on safe and effective alternatives.
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