Opioid analgesics have been used for decades for the management of both acute and chronic pain.  Unfortunately, many patients do not receive adequate treatment for their pain and thus, are left to suffer.1-3  For example, the SUPPORT investigators found that 50% of seriously ill hospitalized patients reported pain with approximately 15% of patients reporting moderate to extremely severe pain at least half of the time and approximately 15% of those were dissatisfied with their pain control.2  This is one of many studies that have documented the need for better pain management strategies in community settings, hospitals and long-term care facilities.  In order to effectively manage acute and chronic pain, the clinician must not only recognize the various pharmacotherapeutic options for the different types of pain, but understand how they work to treat pain. 

In order to understand how opioids modulate the transmission of pain, it is important to recognize the pathway by which pain is transmitted from its site of origin to its site of interpretation and perception in the brain.  In regard to nociceptive pain transmission, acute pain is transmitted primarily by A-delta afferent sensory nerve fibers and chronic or slow pain is transmitted primarily by unmyelinated C sensory afferent nerve fibers (C nerve fibers) to the spinal cord (see figure 1).4 The smaller axonal diameter and the lack of myelination of C nerve fibers are why the pain is transmitted slower with C nerve fibers as compared to A-delta nerve fibers. Normally, free nerve endings (nociceptors) found in various somatic and visceral tissues throughout the body are stimulated by a number of different types of noxious stimuli.  These stimuli can be chemical, mechanical or thermal in nature and each has its own nociceptors for each type of stimuli.  Noxious stimuli typically result in the local release of bradykinin, histamine, leukotrienes, potassium ions, prostaglandins, and substance P.  These not only activate the nociceptor, but can also sensitize those same nociceptors to become activated by non-noxious or low intensity stimuli causing further activation (i.e., hyperalgesia).  This increased sensitivity to pain or non-noxious stimuli is especially common during periods of inflammation.  Upon activation of the nociceptors, an action potential is generated down the A-delta and/or C afferent sensory nerve fibers (i.e., 1storder neurons) towards the spinal cord.  Upon entering the dorsal gray horn of the spinal cord, these first order nerve fibers will synapse with second order nerve fibers by releasing substance P, glutamate, and calcitonin gene related peptide in the substantia gelatinosa division of the dorsal horn in the dorsal aspect of the spinal cord.4,5  The release of these neurotransmitters (especially glutamate and substance P) then cause the depolarization of the 2nd order neuron.  The 2nd order neuron crosses over to the other side of the spinal cord through the anterior commissure where it enters in the contralateral spinothalamic tract (LSTT) to ascend up the spinal cord and eventually into the brain causing the patient to perceive or experience pain.

• Additional details for those that want them:
• In addition to this direct crossing at the spinal cord level, the 2nd order neurons that are crossing can also ascend up 1-3 levels in the spinal cord before entering into the LSTT.4  Either way, once the 2nd order sensory nerve fiber crosses, it is now on the contralateral side of the pain response (i.e. pain in the right hand will eventually be interpreted by the postcentral gyrus in the left cortex of the brain).4    As the 2nd order neurons ascend the spinal cord via the LSTT, the tract changes in name upon entering the medulla of the brain stem and is now called the spinal lemniscus.  The 2ndorder pain nerve fibers then continue to ascend until they synapse with 3rdorder neurons in the ventral posterolateral (VPL) nucleus.  The 3rd order neurons then ascend through the posterior limb of the internal capsule up into the postcentral gyrus within the cerebral cortex where the initial stimuli is finally received and interpreted as pain.4  
• At this point, pain transmission can then be modified by descending pathways from the central nervous system.  This is where opioids exert their pharmacologic effects on pain.  The exact mechanisms for the modulation of pain are complex and are influenced by a number of interconnecting nerve pathways.6 However, there are some common pathways through which opioids can decrease the frequency of transmission into and throughout the spinal cord.  Within the brain stem, the periaqueductal gray (area surrounding the duct that connects the third ventricle within the brain to the 4th ventricle in posterior compartment of the brain) receives information from the hypothalamus, amygdala, frontal and insular cortex of the brain and from the nucleus cuneiformis, pontine reticular formation and locus coeruleus in the brain stem.6,7  The information received influences the activity of endogenous opioid-containing neurons.  The endogenous opioids involved in pain regulation are called endorphins and enkephalins.6 These interneurons regulate the activity of nerve fibers that leave the periaqueductal gray and descend down the brainstem to synapse on neurons in the raphe nuclei in the medulla.8 Normally these interneurons release the inhibitory neurotransmitter, GABA, which causes a decrease in descending pathway activity.  Decreased descending pathway activity allows for more ascending activity (i.e. pain transmission) up the spinal cord and into the brain.6,8,9  From the raphe nuclei, nerve fibers descend to the dorsal horn of the spinal cord.  These also regulate the activity of interneurons containing endorphins; however, these directly impact pain transmission at the level of the spinal cord before the impulse ascends into the brain and is interpreted as pain.  

How do opioids influence this descending pathway and ultimately reduce pain transmission into the brain?
Assuming oral or parenteral administration, the opioid agonist (e.g., hydromorphone, morphine, oxycodone) will bind to mu-opioid receptors in a number of places.  Within the midbrain of the brainstem, opioids will bind to mu-opioid receptors located presynaptically on the inhibitory interneurons that are maintaining an inhibitory effect on the neurons leaving the periaqueductal gray.  The opioid agonist activity at these neurons causes a decrease in the inhibitory effects on the nerve fibers leaving the periaqueductal gray. Therefore, they cause disinhibition of these descending nerves resulting in an increase in their activity or communication to the raphe nuclei within the medulla.9 Disinhibition of neurons in the raphe nuclei as a result of opioid activity is also likely to occur.  This will cause an overall activation of the descending nerve fibers going down the spinal cord via the lateral funiculus where they ultimately influence activity in the dorsal horn of the spinal cord (the location where the initial pain stimuli enter into the spinal cord for its ascent up into the brain).6 

So far, the descending pathways within the spinal cord have been activated through a presynaptic inhibition of inhibitory interneurons (i.e. via disinhibition).6,8,9  At the level of the dorsal horn of the spinal cord, opioids also inhibit afferent sensory (pain) nerve fibers that are on their way up the spinal cord towards the brain; these effects are both presynaptic and postsynaptic as well as direct and indirect.10-12  Opioids directly bind to presynaptic mu-opioid receptors causing inhibition of pain transmission via the 1st order (afferent sensory) nerve fibers entering into the spinal cord.10-12  This direct inhibition results in a decrease in the release of substance P needed for the activation of 2nd order neurons.12  In addition, opioids can directly bind to postsynaptic mu-opioid receptors on other ascending nerve fibers which further decreases communication to the ventral posterolateral nucleus and subsequently the cerebral cortex.  Indirectly, opioids inhibit the 2nd order ascending neurons within the spinal cord by modulating the release of serotonin  (5-HT) and substance P from the activated descending nerve fibers from the raphe nuclei within the medulla that control endorphin containing neurons within the dorsal horn.6  The net effect of the direct and indirect effects of opioids on the nerves within the dorsal horn is inhibition of pain transmission to the brain and a decrease in the perception and experience of pain by the patient.6 

• Additional details for those who want them:
• Mu-opioid receptors are 7 transmembrane inhibitory G-coupled protein receptors (Gi) found presynaptically and postsynaptically on various nerve fibers in both the brainstem and spinal cord.13 Binding of an opioid agonist to this Gi-receptor causes a reduction in cAMP which decreases intracellular calcium levels thereby resulting in the release of that nerve fiber's primary neurotransmitters.  At the level of the periaqueductal gray and raphe nuclei within the spinal cord, this is the mechanism by which opioids cause a decrease in GABA release from the interneurons resulting in disinhibition of the descending pathway. 
  
• The other effect of mu-opioid receptor activation is an increase in potassium efflux out of the nerve fiber causing hyperpolarization (i.e., inhibition) of the nerve.  This is another mechanism of opioids that results in the net inhibition of interneurons within the brainstem as well as inhibition of afferent nerve fibers transmitting pain stimuli. 
  
• Therefore, all mu-opioid receptors function the same way (net inhibition), but the location of the nerve fibers and their connections results in some nerve fibers becoming activated while others are inhibited. 

Conclusion

In summary, opioid analgesics decrease pain transmission to the brain by activating the descending nerve fibers from the periaqueductal gray within the midbrain and raphe nuclei within the medulla that control the endogenous opioid containing interneurons within the dorsal horn of the spinal cord.  In addition, opioids directly inhibit afferent nerve transmission by binding to mu-opioid receptors presynaptically and postsynaptically within the dorsal horn of the spinal cord.  As a result of these various mechanisms, the ascending pathways for pain stimuli are inhibited and pain relief is provided to the patient.

References:

1. Gallagher RM.  Primary care and pain medicine.  A community solution to the public health problem of chronic pain.  Med Clin North Am  1999;83:555-83. 
   
2. Desbiens NA, Wu AW, Broste SK et al.  Pain and satisfaction with pain control in seriously ill hospitalized adults: findings from the SUPPORT research investigations.  For the SUPPORT investigators.  Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment.  Crit Care Med  1996;24:1943-4.  
   
3. Bernabei R, Gambassi G, Lapane K et al.  Management of pain in elderly patients with cancer.  SAGE Study Group.  Systematic Assessment of Geriatric Drug Use via Epidemiology.  JAMA  1998;279:1877-82.  
   
4. Snell RS.  Chapter 4. The Spinal Cord and the Ascending Pathway and Descending Tracts.  In: Clinical Neuroanatomy.  6^th Ed.  Snell RS eds.  Lippincott Williams and Wilkins.  Philadelphia, PA.  2006.
5. Saria A, Gamse R, Petermann J et al.  Simultaneous release of several tachykinins and calcitonin gene-related peptide from rat spinal cord slices.  Neurosci Lett  1986;63:310-4.  
6. Basbaum AI, Fields HL.  Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry.  Annu Rev Neurosci  1984;7:309-38. 
7. Mantyh PW.  Connections of midbrain periaqueductal gray in the monkey. II. Descending efferent projections.  J Neurophysiol  1983;49:582-94.

• EBM Focused Topic: Chance of Survival from Opioid Overdose and in Cardiac Arrest
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• Drug Monograph:  Naloxone (Narcan)
  
• Reference Tool:  Sedative Hypnotics Used in RSI or Procedural Sedation

Opioid Analgesics, Opiate Analgesia, Mechanism of Opioids, Mechanism of Opiates