Pain and Opioids: From Mechanisms to Applications

Pain and Opioids: From Mechanisms to Applications

# Pain: A Complex Sensation

Pain is an unpleasant physical or psychological sensation associated with actual or potential tissue damage. According to the definition by the International Association for the Study of Pain (ISAP), pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”

The subjective nature of pain is evident in the fact that the same stimulus can evoke different pain sensations in different individuals. Pain threshold, or the level of stimulation required to elicit a pain sensation, varies depending on several factors, including:

• Emotions: Mental state can influence pain threshold.

• Gender: Women tend to have lower pain thresholds than men.

• Genes: Each individual has a different genetic predisposition to pain.

• Environment: The surrounding environment also affects pain perception.

Although pain is an unpleasant sensation, it plays a crucial role in protecting the body by warning of potential injury. Pain also acts as a motivator for learning, helping us avoid painful stimuli in the future. Ultimately, pain sets limits on bodily activity, signaling the need for rest and recovery.

# Pain Classification: Acute and Chronic

There are two main types of pain:

• Acute pain: The onset and end of pain are easily identifiable, usually with a clear cause and easily treatable.

• Chronic pain: Persists after the injury has healed, often with complex causes and more difficult to treat.

# The Somatosensory Pathway for Pain Signal Transmission

When a painful stimulus occurs, pain receptors (nociceptors) are activated and send signals through peripheral nerves (first-order neurons) to the spinal cord or brainstem.

• Thermal stimuli are transmitted to the spinal cord.

• Mechanical stimuli are transmitted to the brainstem.

In the spinal cord or brainstem, the first-order neurons synapse with second-order neurons, transmitting the signal to the thalamus. At the thalamus, the second-order neurons synapse with third-order neurons, conveying the signal to the cerebral cortex.

Finally, the cerebral cortex receives the pain signal, analyzes it, and generates an appropriate response.

# Types of Nerve Fibers Transmitting Pain Signals

The two main types of nerve fibers involved in pain signal transmission are A delta and C:

• A delta fibers: Have a smaller diameter, a thin myelin sheath, transmit pain signals faster, producing a sharp, localized pain sensation. Account for about 20% of total sensory pain fibers.

• C fibers: Have a smaller diameter than A delta, lack a myelin sheath, transmit pain signals slower, producing a burning, poorly localized pain sensation. Account for about 80% of total sensory pain fibers.

# The Central Pain Perception Center: Thalamus

The thalamus serves as the central pain perception center. It contains sensory third-order neurons, forming the thalamocortical tract, which transmits pain signals to the cerebral cortex, specifically the parietal lobe, for analysis and appropriate response generation.

# Pain Control Mechanisms: Gate Control Theory and Endogenous Pain Relief Theory

There are two primary mechanisms that help control pain:

• Gate Control Theory: When there is a painful stimulus, nociceptors send signals through afferent sensory pain fibers (A delta, C) to the dorsal horn of the spinal cord. Here, the signal encounters the T-cell (interneuron), acting as a “gatekeeper.”

In a normal state, the T-cell closes the gate, blocking the signal from the first-order neuron from transmitting to the second-order neuron. However, when there is a real painful stimulus, the signal inhibits the T-cell, opening the gate and allowing the pain signal to travel to the thalamus and cerebral cortex, causing pain perception.

• Endogenous Pain Relief Theory: Painful stimulation can also activate the midbrain periaqueductal gray (PAG), causing the release of endogenous opioid substances (similar to morphine), known as endogenous morphine or endorphins.

Endorphins act on the rostral ventromedial medulla (RVM), inhibiting pain transmission at the dorsal horn of the spinal cord, reducing pain and producing a feeling of euphoria. However, endorphins DO NOT cause addiction because they are easily degraded.

The common goal of these two pain relief theories is to prevent the pain signal from reaching the brain.

# Applications of Opioids

Opioids are a class of potent pain relievers used to treat severe, chronic, visceral pain, and during pre-anesthesia. However, opioids only treat symptoms and can be addictive.

Origin and History:

• Opium: is a substance extracted from the opium poppy plant. Since ancient times, opium has been used to relieve pain, sedate, treat diarrhea, and suppress coughs.

• Morphine: was isolated from opium in 1800.

Opioid Classification:

• Natural opium alkaloids: Morphine, Codeine.

• Semi-synthetic opiates: Diacetylmorphine (Heroin).

• Synthetic opiates: Pethidine, Fentanyl, Tramadol, Methadone, Dextropropoxyphen.

Mechanism of Action:

• Opioids act on GPCRs receptors, including:

• μ-receptor: Responsible for most of the central analgesic effects of opioids.

• κ-receptor: Responsible for analgesia in the spinal cord, with potential for good analgesia, non-addictive, and respiratory depression.

• δ-receptor: Responsible for peripheral effects, with less potential for side effects.

Mechanism of Negative Regulation: Opioids reduce calcium influx, inhibit neurotransmitter release (such as glutamate), block pain signals, and relieve pain.

# Side Effects of Opioids

• Central Nervous System (CNS) Effects of Morphine:

• Pain relief, euphoria.

• Sedation, drowsiness, potential amnesia.

• Respiratory depression (affecting the respiratory center in the medulla oblongata).

• Nausea and vomiting.

• Peripheral Effects:

• Histamine release: itching, bronchospasm, hives.

• Bradycardia.

• Hypotension (reflex tachycardia).

• Gastrointestinal Effects:

• Constipation.

• Pyloric spasm.

• Ileal sphincter spasm.

• Reduced intestinal fluid secretion.

# Opioid Dependence

• Tolerance: The body becomes accustomed to the drug, requiring higher doses to achieve the same effect.

• Dependence:

• Physical dependence: Reduced after 7-10 days of withdrawal.

• Psychological dependence: Prolonged, difficult to withdraw from.

# Common Opioids

• Codeine:

• Natural opium alkaloid.

• Metabolized from natural morphine.

• Well-absorbed orally.

• Uses: Suppress coughs and thin mucus (Terpin Codeine).

• Pethidine (Meperidine):

• Has a different chemical structure, similar side effects to morphine.

• Effective pain relief.

• Weak cough suppression.

• Intramuscular injection, rapid action.

• Used for postoperative pain relief, childbirth.

• Fentanyl:

• 80-100 times more potent than morphine.

• Short duration of action.

• Intravenous, transdermal administration.

• Used for anesthesia.

# Opioid Overdose and Antidote

• Toxic dose of morphine: 50mg.

• Lethal dose of morphine: 250mg.

• Antidote:

• Respiratory support, blood pressure maintenance.

• Gastric lavage within the first 4 hours.

• Naloxone: 0.4 – 0.8mg every 2-3 minutes to restore breathing.

# Opioid Withdrawal Syndrome

• Fever, sweating, nausea, insomnia, dilated pupils, diarrhea.

• A difficult phase experienced when the body physically withdraws from the drug.

# Ineffectiveness of Codeine in Some Patients: Causes and Solutions

• Cause: Some individuals lack the CYP2D6 enzyme, preventing the conversion of Codeine to its active form.

• Solution: Switch to using a lower dose of morphine.

Note: The information in this article is for informational purposes only and should not be considered a substitute for professional medical advice.