Opioids have formed a mainstay of the analgesia ladder. They are commonly used in the anaesthesia setting in the treatment of post-operative pain but have widespread use in pain management and palliative care. Within the critical care setting often short acting opioids including codeine, oxycodone and morphine can be used as an infusion. Opiates have a wide range of side effects due to their narrow therapeutic window. Common side effects include nausea, vomiting, constipation, and drowsiness. More serious effects include opiate-induced respiratory distress and addiction. There is an urgent clinical need for safer opiates in analgesia. In this article we aim to address emerging opioids and their possible future use. Oliceridine is an opioid which has been approved by the Food and Drug Administration (FDA).
The concept of biased agonism and pharmaco-physiology of opioid receptors
Biased agonism is a term which describes a ligand selectively activating a receptor using one of several signalling pathways, largely within G-protein couple receptors (GPCR) (Gundry et al., 2017). The opioid receptor exists as four main types of receptors delta (δ), kappa (κ), mu (μ) and nociception receptor (Machelska et al., 2020). It is often the μ receptor which is the receptor of target in opioids treatment of analgesia. The activation of GPCR including opioid receptors leads to an activation of a signalling pathway. In the case of opioid receptors, the activation leads to downstream pathway of inhibition of adenylate cyclase and decrease in cyclic AMP leading to mitogen-activated protein kinase (MAPK) signalling via β arrestin (Connor & Christie 1999). Opioid activation of the opioid receptor leads to suppression of excitatory neurotransmitter release such as substance P, glutamate and calcitonin gene-related peptide. Oliceridine is described as an opioid analgesic which acts on the μ receptor (Ok et al 2018). Current literature also suggests that as oliceridine does not use the β arresting2 pathway thus not having harmful side effects of opioids (Gillis et al 2020). These side effects include nausea, vomiting, addiction, and tolerance. The mechanism of opioid agonist non-selectively activating G protein coupled receptor and β-arresting mediated signalling is explained in diagram 1.
Diagram-1 showing the stimulation of µ receptor by traditional opioids: both GPCRs and β-arrestin
pathways are recruited.
The specific pharmacological effects and mechanism of action are described as “OLICERIDINE”
An elusive identification pathway of specific opiate receptor agonists which could activate GPCR pathway targeting analgesia only pathway has proved to be the “holy grail” in opioid pharmacology. Oliceridine is an opioid of significant interest and currently studied in pre-clinical and clinical studies due to its pharmacological profile. The ATHENA-1, APOLLO-1 and APOLLO-1 clinical trials has shown that oliceridine has increased efficacy and favourable safety profile (Shah et al., 2021). Oliceridine is considered to have a different mechanism to other opioids and is explained using the mnemonic OLICERADINE and diagram 2. The side effect profile of oliceradine summarised also by the mnemonic OLICERADINE, interaction of drugs with oliceridine has also been highlighted below.
The way Oliceridine behaves differently is explained below; also see diagram -2
The mechanism of action is explained as follows
O Oliceridine is agonist at µ receptor
L Ligand biased (GPCR signalling pathway stimulated) leading to
I Inhibition of sensory neurons signals 20 to
C Cyclic AMP↓ due to Adenylate cyclase↓
E Efficacy is improved 20 to
R Reduced recruitment at β- arrestin (leading to)
I Internalisation of receptors ↓ and
D Desensitisation of receptors ↓(leading to)
I Improved side effects profile e.g. tolerance↓, OIH↓ and OIRD↓
N N-dealkylation, Glucoronidation → Inactive metabolites (300 times less active than parent drug)
E Excretion: Renal 70%, faecal 30%
Diagram-2 showing the mechanism of action of Oliceridine
Side Effects of OLICERIDINE
O Orthostatic hypotension
E ECG: long QT interval
R Respiratory (OIRD)
I Increased sleepiness
D Dependence and addiction, danger of tolerance
I Interaction with other drugs*
N N/V and anorexia
E Eyes: miosis
*Interaction with drugs
A Anti-retroviral drugs
F Fluoxitine, paroxitines and other SSRIs
G General anaesthetics
H HT3 antagonists
Macrolides, Rifampicin and Quinidine
Traditional opioids have provided the mainstay of analgesia and palliative care, but their side effects have left a need within medicine to target drugs which have better side effect profile. Oliceridine was approved by the FDA in 2020 for adult use only, with its contraindications in pregnancy and under 18. Due to its low oral bioavailability, it is used as injectable solution only. The discovery of oliceridine has led to the inspiration of new opioid agents such as PZM21N. It is believed that PZM21 acts in a similar mechanism to oliceridine by selectively acting on the μ receptors and activating G protein signalling pathway leading to fewer β-arrestin recruitment and thus fewer side effects. In the future, we hope the use of oliceridine will give future inspiration for opioid analgesics with fewer side effects. We also hope that oliceridine is used widespread and does not turn out to be a damp squib like rapacuronium and other anaesthetic agents.
Conflict of interest-none
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Machelska H, Celik MÖ. Opioid Receptors in Immune and Glial Cells-Implications for Pain Control. Front Immunol. 2020 Mar 4;11:300.
Ok HG, Kim SY, Lee SJ, Kim TK, Huh BK, Kim KH. Can oliceridine (TRV130), an ideal novel µ receptor G protein pathway selective (µ-GPS) modulator, provide analgesia without opioid-related adverse reactions? Korean J Pain. 2018 Apr;31(2):73-79.
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Shah A, Shah R, Fahim G, Brust-Sisti LA. A Dive Into Oliceridine and Its Novel Mechanism of Action. Cureus. 2021 Oct 27;13(10):e19076.
Dr Sher Mohammad1,Dr.Naghmana Iftikhar2, Dr Salman Yahya3, Dr Zain Ahmed Shah4 ,Abdul Alim Khan5
- Consultant Anaesthetist,Sheffield Teaching Hospitals, NHS Foundation Trust
- General Practitioner,Upwell Street Surgery,Sheffield
- Clinical Fellow Anaesthetics, Sheffield Teaching Hospitals, NHS Foundation Trust
- Foundation Year 2 trainee, RBH, NHS Foundation Trust
- Clinical Fellow Anaesthetics,Sheffield Teaching Hospitals,NHS Foundation Trust
Illustrations: Authors’ own.
Correspondence email: email@example.com