Medical Pharmacology Topics

Pain Management: Pain

Pain is a critical defense mechanism essential for survival. What is not of value is the intermediate and long term consequences of trauma and pain that results in chronic debilitating disorders like chronic pain.

Pain may be classified as acute cutaneous, acute visceral, chronic inflamatory or chronic neuropathic. Acute cutaneous pain is precisely localized and of immediate onset, i.e. an alarming sharp pain. Acute visceral pain is of immediate onset but poorly localized. Acute pain is usually responsive to non-steroidal antinflammatory drugs and to opioids.

Chronic pain involves numerous determinants including physiological, psychological and social, and may persist in the absence of significant pathology. Chronic inflammatory pain is persistent pain secondary to chronic inflammatory disease involve both peripheral sensitization and central sensitization. Chronic inflammatory pain usually responds to NSAIDs or opioids but relief of pain does not alter underlying disease.

Chronic neuropathic pain is a persistent pain in the absence of detectable injury or disease due to both peripheral sensitization and central sensitization. It is characterized by burning sensation with occasional shooting or stabbing component, and allodynia (i.e. non-painful stimuli perceived as painful). Chronic neuropathic pain usually does not respond to NSAIDs or opioids, and the current therapy is complex, including drugs like antidepressants, anticonvulsants, opioids, and other newer drugs.

There are two components to pain: sensory and affective. The sensory (or nociception) components relates to duration, intensity and pain threshold. The affective component involves perception of the sensation as unpleasant, escape threshold and the reaction to pain.

Pain Pathways

The pathways of pain perception and reaction can be divided into four areas: nociceptors and sensory neurons, dorsal horn and spinal chord, ascending pain pathways, and descending pain suppression systems.

Nociceptors are sensitive to thermal, mechanical and chemical stimuli that activates the peripheral nerve. Tissue damage can sensitize nociceptors largely by the activity of prostaglandins. Such process is known as hyperalgesia or allodynia. Blockade of prostaglandin synthesis is the likely mechanism for the analgesic action of non-steroidal antinflamatory drugs (NASIDs).

At the dorsal horn of the spinal cord, sensory neurons communicate with interneurons that excite or inhibit signals and with projection neurons that travel to the brain. This is a site of action for opioids and NSAIDs.

The ascending pain pathways have several components. The spinothalamic tract communicates pain signals to the thalamus, then the cortex. The pain signal projects from the thalamus to the somatosensory cortex. The spinoreticular tract communicates pain to the brainstem for modulation. The pain signal is also sent to the limbic area (emotional component). Pain from the head and upper neck is communicated by the trigeminal ascending pathway.

Stimulation of various sites in the brainstem result in activation of descending inhibitory pathways. Major neurotransmitters in these pathways are norepinephrine, serotonin (5-hydroxytrytamine, 5-HT), and endogenous opioids. These substances can block conduction of incoming pain signals by acting on sensory neurons or on neurons that carry the pain signal to the brain.

Several approaches can be taken to relief pain:

Heal Injury (doesn’t always relieve pain)
Prevent production of pain-producing chemicals
Block nerve conduction of the pain signal
Block release of pain transmitters
Block receptors of pain transmitters
Activate endogenous pain suppression systems

Drugs used to treat pain include: opioids, NSAIDs, COX2 Inhibitors, anticonvulsants (ex. gabapentin), antidepressants, steroids, and cytokine inhibitors (ex. etanercept).

Endogenous Opioids

Opioids are exogenous and endogenous compounds that act on opioid receptors throughout the pain pathways to block the release of pain transmitters and to inhibit the pain signal. Although their main effect is to relieve pain (analgesia) they have many other effects. Opioid receptors are G-protein linked.

The characteristics of opioids that suggested the existence of a receptor were: stereospecific action (only the levo- isomers cause analgesia), action blocked by antagonists, tolerance develops to specific effect, and similarity of chemical structure.

Currently we know there are at least three opioid receptors: mu, delta and kappa. The main selective agonists for these receptors are sufentanyl for mu, DPDPE and deltorphin for delta, and nalbuphine and dynorphin for kappa. Naloxone is an antagonist for all three receptor types.

Endogenous opioids arise from three separate gene products isolated from the pituitary. Proopiomelanocortin gives rise to b-endorphins. Proenkephalin gives rise to met-enkephalin (Tyr-Gly-Gly-Phe-Met) and leu-enkephalin (Tyr-Gly-Gly-Phe-Leu). Prodynorphin gives rise to dynorphins. Surprisingly, there is no good correlation between CNS distribution of the three classes of endogenous opioids and the three types of known opioid receptors.

It has been proposed that endogenous opioids have many functions in the brain, among them: pain regulation (analgesia), control of respiration, endogenous reinforcement (euphoria), stress, mental illness, shock and regulation of gut motility. At the cellular level, opioids generally inhibit, resulting in hyperpolarization of cells and decreased release of neurotransmitters. Proposed mechanisms include an increase in K conductance (hyperpolarizes and decreases Ca conductance), and a direct decrease of Ca conductance.

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