What is the mechanism of action (MOA) of opiates?

Mechanism of Action of Opioids

Opioids primarily exert their analgesic effects through agonist activity at mu opioid receptors (MORs), with some compounds also binding to delta and kappa opioid receptors to contribute to pain relief. 1, 2, 3

Primary Receptor Interactions

• Opioids bind to four types of opioid receptors: mu (MOR), delta (DOR), kappa (KOR), and nociceptin/orphanin FQ (NOP), with MOR being the most clinically relevant for analgesia 1
• Fentanyl and morphine are full opioid agonists that interact predominantly with the mu-opioid receptor, though they can bind to other opioid receptors at higher doses 2, 3
• The principal therapeutic action of opioids is analgesia, and as full agonists, they have no ceiling effect for pain relief 2

Anatomical Distribution of Receptors

• MORs are highly expressed in brain regions that regulate pain perception including the periaqueductal gray, thalamus, cingulate cortex, and insula 1
• MORs are also found in brain regions associated with reward (ventral tegmental area, nucleus accumbens), explaining their addictive potential 4, 1
• Opioid receptors are located throughout the central nervous system (brain and spinal cord) and in peripheral tissues 1
• The brainstem respiratory center (pre-Bötzinger complex) contains MORs, which explains opioid-induced respiratory depression 4, 5

Mechanism of Analgesia

• Opioids differ from other analgesics by reducing pain perception rather than antagonizing the transmission of pain signals 1
• Although sensory transmission remains intact, the subjective interpretation of pain is altered 1
• The precise mechanism of analgesic action involves activation of specific CNS opioid receptors distributed throughout the brain and spinal cord 2, 6

Systemic Effects of Opioid Receptor Activation

Central Nervous System Effects

• Respiratory depression occurs through direct action on brain stem respiratory centers, reducing responsiveness to carbon dioxide increases and electrical stimulation 2, 3
• Miosis (pupil constriction) occurs even in total darkness 2, 3
• Sedation and euphoria are common central effects 1

Gastrointestinal Effects

• Reduced GI motility with increased smooth muscle tone in the stomach and duodenum 2, 3
• Delayed digestion in small intestine and decreased propulsive contractions 2, 3
• Decreased peristaltic waves in the colon with increased tone leading to constipation 2, 3
• Other effects include reduced biliary and pancreatic secretions and spasm of sphincter of Oddi 2, 3

Cardiovascular Effects

• Peripheral vasodilation which may cause orthostatic hypotension or syncope 2, 3
• Manifestations of histamine release may include pruritus, flushing, red eyes, and sweating 2, 3

Endocrine Effects

• Inhibition of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) 2
• Stimulation of prolactin, growth hormone secretion, and pancreatic secretion of insulin and glucagon 2
• Chronic use may influence the hypothalamic-pituitary-gonadal axis, potentially leading to androgen deficiency 2

Pharmacokinetic Considerations and Tolerance

• Opioids vary in binding affinity and selectivity for different opioid receptors, affecting their potency 4, 1
• Pharmacokinetics and bioavailability determine the rapidity and duration of action 4, 1
• Route of administration affects onset of action - rapid delivery to the brain produces stronger reward and addiction potential 4
• With repeated administration, both physical and perceptual effects diminish, leading to tolerance 4
• Tolerance to analgesia develops faster than tolerance to respiratory depression, increasing overdose risk 4, 5
• Physical dependence manifests as withdrawal symptoms upon abrupt discontinuation 4

Receptor Interactions and Synergy

• Co-activation of mu and delta receptors can lead to synergistic effects, enhancing potency and efficacy 7
• Heterodimers of mu-delta receptors exhibit distinct ligand binding and signaling characteristics 7
• This receptor interaction may provide foundations for more effective pain therapies 7

Adverse Effects Related to Mechanism

• Opioid-induced hyperalgesia can develop with chronic use, mediated through MOR activation 8
• The morphine metabolite morphine-3-glucuronide (M3G) can contribute to hyperalgesia through MOR binding 8
• Chemokine signaling pathways involving stromal-derived factor 1 (SDF1/CXCL12) and its receptor CXCR4 may contribute to opioid-induced hyperalgesia 9