Mechanism of Action of Meperidine
Meperidine exerts its pharmacologic effects by binding to specific opioid receptors present throughout the central nervous system and peripheral tissues, producing analgesia and sedation as its principal therapeutic actions. 1
Primary Mechanism: Opioid Receptor Binding
Meperidine acts primarily as an agonist at mu (μ) opioid receptors (MORs), which are highly expressed in brain regions that regulate pain perception including the periaqueductal gray, thalamus, cingulate cortex, and insula. 2
The drug also demonstrates activity at kappa (κ) opioid receptors, which contributes to some of its unique clinical effects distinct from other opioids. 3
Unlike other analgesics, opioids like meperidine reduce pain perception rather than antagonizing the transmission of pain signals—sensory transmission remains intact while the subjective interpretation of pain is altered. 2
Secondary Mechanism: Alpha-2 Adrenergic Activity
Meperidine uniquely functions as a potent agonist at alpha-2 adrenoceptors, particularly the alpha-2B subtype, with binding affinity of 8.6 μM and achieving approximately 70% inhibition of cyclic AMP production. 4
This alpha-2B adrenoceptor activity is clinically relevant at therapeutic concentrations and likely explains meperidine's superior antishivering effects compared to other opioids. 4, 3
Morphine, in contrast, shows no binding affinity to alpha-2 adrenoceptor subtypes, highlighting meperidine's distinct pharmacologic profile. 4
Local Anesthetic Properties
Meperidine possesses local anesthetic-like properties, acting on nerve fibers similarly to local anesthetics, which distinguishes it from other opioid agents. 5
This mechanism has led to its use as an alternative for anesthetic blockade in certain clinical scenarios. 5
Clinical Pharmacology
The analgesic effects are most likely mediated through the periaqueductal gray (PAG) structure in the midbrain, caused by stimulation of descending inhibitory pathways. 2
Meperidine produces qualitatively similar actions to morphine, with 60-80 mg parenteral doses approximately equivalent to 10 mg of morphine in analgesic effect. 6
The onset of action is slightly more rapid than morphine (3-6 minutes), with duration of effect ranging from 1-3 hours. 1, 6
Important Clinical Caveats
The antishivering property of meperidine is NOT fully mediated by mu-receptors alone—low-dose naloxone (blocking mu receptors) only partially reduces meperidine's antishivering effect, while high-dose naloxone (blocking both mu and kappa receptors) nearly abolishes it. 3
The alpha-2 adrenoceptor activity does NOT contribute significantly to meperidine's analgesic action, as alpha-2 antagonists (yohimbine, RX821002) do not block meperidine analgesia, while naloxone does. 4
Meperidine undergoes N-demethylation by the liver to create normeperidine, an active metabolite with potent central excitatory toxicity—this is a pharmacologic consequence rather than part of the primary mechanism, but critically important for safety. 1