Mechanism of Action, Therapeutic Action, and Side Effects

Mechanism of Action

Before getting into the mechanism of action of opioid analgesics, we will first outline the process of nociception (the process by which the body senses and responds to pain). The process  most widely accepted is called the gate control theory of pain. This theory can be broken down into four steps: Transduction, Transmission, Perception, and Modulation.

The first step, transduction, relates to the transformation of noxious stimuli, whether it be mechanical, chemical, or thermal energy. Transduction takes these stimuli and converts them into electrochemical energy that can be transmitted by the nociceptors along sensory neurons. Transmission occurs because of chemicals released by damaged cells during the transduction phase; prostaglandins and serotonin are but two examples of the chemicals released (NSAIDs target prostaglandins and antidepressants target serotonin). An action potential initiated by these chemicals travels to the spine along nociceptive pain fibres. Perception of pain is subjective, and different reactions can be elicited from the identical stimuli. Pain signals from the spinal cord travel to the thalamus in the brain to be combined and assessed, then sent to the brain’s pain cortical structures.

Modulation, the process to control and suppress pain, then occurs. Signals that originate in the brainstem at the periaqueductal gray travel down the spine to the junction where the original transmission of pain occurred. These neurons release chemicals such as endogenous opioids (endorphins), serotonin, norepinephrine, etc, that bind to the spinal nerves’ opioid receptors and inhibit the initiation of an action potential in the nerves to create another painful stimulus. There are two primary types of opioid receptors that have been established as important for the analgesic effects of opioids, the Mu and Kappa receptors. Out of the two, Mu receptors are the most important in the regulation of pain. It has been found that if present in relatively high numbers, the individual has increased pain tolerance. Opioids, therefore, do not work to stop the pain itself, but instead work to prevent the pain signals from reaching the brain to be registered and 'felt'. 

Side Effects

As opioids are mu and kappa receptor agonists, their side effects correspond to other areas of the body where these receptors can be found. Mu receptors can be found throughout the digestive tract, inhibiting peristalsis (the constricting waves of the digestive tract that push food through), causing the most common side effect, constipation.

Mu receptors found throughout the central nervous system account for other side effects, such as miosis (constricting pupils), respiratory depression, and physical dependence. Respiratory and CNS depression may be further affected by simultaneous use of other depressants, such as alcohol.

Though opioids generally do not have a significant effect on heart rate and force of contractions, some opioids do release histamines, causing vasodilation (widened blood vessels) and hypotension (low blood pressure). Opiates combined with other medications such as benzodiazepines and blood pressure medications can cause significant bradycardias (low heart rate) and hypotension.


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