A lecture on PAIN AKA a painful lecture by Colleen Blanchfield, MD Full Circle Neuropsychiatric Wellness Center 1
Overview of the lecture Anatomy of the Pain Tract How a painful stimulus travels from the great toe to the brain Neurochemistry of the Pain Tract Which neurochemicals arepresent at which neuroanatomical locations Ways to alleviate pain neuropsycopharmacology 2
IN ENGLISH Find a partner or two. The lecture will be given in 3 sections 25 minutes each After each 25 minute section you will be given 3 5 minutes to discuss with ihyour partners what you have learned. FABULOUS discussions will occur. I will review the take home points. 3
Neuroanatomy of PAIN ACUTE PAIN A tissue insult occurs Pain receptors known as freenerve endings are located in the skin The receptors areactivatedactivated by thermal or mechanical (pressure) stimuli Thefreenerve endings areconnected to pain fibers that bring the pain signal to the spinal cord. 4
A delta fibers Are connected to free nerve endings that respond to sharp pricking pain. Conduct at 5 30 meters/second d(f (fast). Small in diameter and thinly myelinated Their cell bodies are located in the dorsal root ganglion g Terminate in the dorsal horn of the spinal cord 5
a delta and c fibers 6
C fibers The C fibers are unmyelinated. Small in diameter Conduct slowly l 0.5 2 meter/second Respond to a variety of high intensity mechanical, thermal (greater than 45 degrees Celsius) or cold stimuli Are widely distributed in skin and deep tissues 7
How does it work? How does it work? A noxious stimuli activates the nociceptor by depolarizing the membrane of the sensory nerve ending. Depending on what type of stimulus it is, it will activate A delta fibers, C fibers or both A delta and C fibers carry the impulse to the dorsal horn of the spinal cord 8
Tract of Lissauer A delta and C fibers bifurcate and ascend or descend for a few levels of the spinal cord as part of the tract of Lissauer. This is the origin of referred pain. Fibers then terminate in lamina I (marginal zone) or lamina II (substantia gelatinosa) 9
Secondary Neurons 1. Projection Neurons: connect to higher brain structures. These are the majority of second order neurons. They ascend to the brain in five different tracts. 1. Spinothalamic (Major) 2. Spinoreticular 3. Spinomesencephalic 4. Spinocervical 5. Dorsal Column of the spinal cord 2. Local Excitatory Interneurons: relay sensory inputto to projection neurons. 3. Inhibitory Neurons: regulate the flow of nociceptive information to higher brain centers. 10
Spinothalamic Tract Fibers from Lamina I or Lamina II cross anteriorly to the central canal in the ventral white commissure and form the lateral spinothalamic tract on the opposite side of the pain stimulus. The sensation is now carried on the opposite side of the body: left foot pain travels in the right spinothalamic tract and ends on the right side of the brain. Pain Crosses Over The lateral spinothalamic tract ascends through the medulla, pons and midbrain. It runs in the lateral leminiscus and terminates in the Ventral Posteriolateral Nucleus of the Thalamus (VPN). Third order neurons start in the thalamus and project to the primary sensory cortex located in the posterior central gyrus of the parietal lobe. 11
The other four tracts Travel to the brain and send branches to different areas of the brain. Two are clinically and pharmacologically relevant to the study of pain. The reticular formation: responsible for the maintainance of wakefulness and alertness during pain. Activates consciousness. The periaqueductal gray area: has reciprocal connections with thelimbic system through thehypothalamus. hypothalamus. Thus,one has an emotional response to pain via the limbic system. Responsible for the sympathetic response of increased heart rate, blood pressure, sweating, and GI system shutdown that leads to nausea. 12
The remaining secondary neurons Local excitatory interneurons Higher intensity pain causes the firing of more excitatory interneurons. This has pharmacologic consequences. Inhibitory neurons Regulate the flow of excitatory output from the dorsal horn to the higher brain centers. These neurons kick in after the initial pain stimulus. Descending pain pathway: Begins in the thalamus and terminates onthe inhibitorysecond order neuron. Stimulation of this neuron inhibits transmission of the pain stimulus. Pharmacologically, this is relevant as the site of action of the SNRIs. 13
What did you learn? Pain receptors have 2 different fibers: A delta (myelinated and fast) and C (unmyelinated and slower) Both enter the spinal cord and ascend or descend d1 2 levels, l finally synapsing on Lamina I (marginal zone) or Lamina II (substantia gelatinosa) Second order neurons start in Lamina I or Lamina II and then Ascend to the cortex via one of the five different tracts Act as excitatory interneurons Act as inhibitory interneurons to decrease the painful stimulus The majority of neurons form the spinothalamic tract, cross to the opposite side of the cord and ascend to the thalamus. Third order neurons connect the thalamus with the sensory cortex (posterior central gyrus of the parietal lobe). 14
What you learned, continued There are four other tracts that ascend to the brain. Spinoreticular tract Spinomesencephalic tract Spinocervical tract Dorsal Column of the Spinal Cord The clinically relevant part of this is that they activate the hypothalamus, the limbic system and the reticular activating system. Clinically, i ll this leads to a change in: Emotional state (limbic system) Increase inalertness/activation (reticular activatingsystem) Increase in sympathetic output (hypothalamus) 15
Neurochemistry At every synapse, one or more neurochemicals is present to transmit or to inhibit the pain signal. There are many neurochemicals; I will discuss only those that are clinically ll significant and pertinent to today s topic. Several neurochemicals are active in other areas of the CNS and therefore cannot be pharmacologically increased or decreased because of the effect this would have on the rest of the system. 16
Neurochemistry We will look at five sites: 1. The site of the injury 2. The afferent nerve (A delta and C fibers) 3. The dorsal horn of the spinal cord 4. The periaqueductal grey area/cortex 5. The descending pathway 17
Neurochemistry At the site of inflammation or injury there are several neurochemicals released. Bradykinin Substance P Serotonin Prostaglandins Histamine Substance P 18
Neurochemistry Theprostaglandins cause thepain receptors to be more sensitive to bradykinin. In other words, prostaglandins increase thepain signals into the dorsal horn. If we decrease prostaglandins we can decrease the signal into the dorsal horn and decrease pain level overall. 19
Neurochemistry Arachidonic acid is the precursor of prostaglandins. Cyclooxygenase is an enzyme required to convert arachidonic acid to prostagladins. NSAIDs and aspirin both inhibit the formation of prostaglandins by inhibiting cyclooxygenase at two different steps. 20
Neurochemistry Arachidonic acid is metabolized to several inflammatory mediators using enzymes. The enzymes are targets for pharmacologic intervention. NSAIDs and Aspirin both inhibit the synthesis of prostaglandins from arachidonic acid. 21
Neuropsychopharmacology A delta and C fibers conduct the pain impulse from the site of injury to the dorsal horn of the spinal cord. Although they conduct at specific speeds, pain transmission can be affected by medications that slow the impulse. Medications that inhibit the Na/K pump slow transmission of the signal. Examples include Dilantin, i Tegretol and other antiepileptic il i medications. 22
Neurochemistry The dorsal horn is the Grand Central Station of pain. Most modulation occurs here. The pain impulse can act on an inhibitory interneuron to decrease the intensity ofthe stimulususing using serotonin, norepinephrine, dynorphin, enkephalin, acetylcholine, neurotensin or GABA as the neurochemical The pain impulse can act onan excitatory neuron to increase the intensity of the pain signal using Substance P, glutamate, glycine or an excitatory amino acid as the neurochemical The pain impulse can cross over and ascend to the thalamus as part of the spinothalamic tract. 23
Periaqueductal Grey Area and Cortex The final ascending branch of the pain pathway ends here. This is an area of intense research. The periaqueductal grey area has the highest concentration of mu receptors in the CNS. There aremureceptors receptors in the cortex as well. Mu receptor 24
Neuropsychopharmacology: Opioidsand d the mu receptor Opioids bind to mu receptors and decrease the interpretation of pain by decreasing the impulses at the level of the thalamus and cortex. The entire pain process is still present. But you don t feel it! Some people then get up and do the hip hop hip flop dance because they feel so good until the opioid dissociates from the mu receptor and the pain returns. Opioids also act in the dorsal horn to increase impulses to the inhibitory interneuron. 25
Descending pathways that modulate pain TheLocus Ceruleus produces norepinephrine and modulates the descending pathway through the inhibitory interneuron in the dorsal horn. The Dorsal Raphe Nucleus produces serotonin and modulates the descending pathways through the inhibitory interneuron in the dorsal lhorn This is where the SNRIs are effective. 26
Pharmacologic Overview There are 5 opportunities to interrupt the pain signal. Acute pain management does not need to address all 5. Chronic pain management should address the 5 locations or should alternate medications among the different locations. 27
Level 1: the site of tissue injury Goal is to decrease the injury to the tissue: first attempt to remove or repair the offending stimuli. Herniated disc in the spinal canal Broken bone A pressure point 28
Level 2: tissue inflammation Reduce inflammation using NSAIDs, COX 2 inhibitors and aspirin systemically and in form of patches. These medications work by preventing the formation of inflammatory mediators from arachidonic acid metabolism. Examples of topical patches: Flector Patch Lidocaine Patch Voltaren Cream Creams prepared by a compounding pharmacy I have found that using an Anti inflammatory patch during the day when one is moving around more and a Lidocaine patch at night is a good combination. 29
Antispasmodics and Muscle Relaxants Valium Flexeril Soma 30
To decrease the injury to the tissue first attempt to remove/repair the offending stimuli. Herniated disc in the spinal canal Broken bone A pressure point 31
Level of Peripheral Nerve The goal is to slow the transmission of the nerve impulse from the receptor to the spinal cord. Use medications that will inhibit the Na/K pump; Dilantin 100mg TID Tegretol 200mg TID Depakote 250 mg TID Topamax 50mg BID Gabitril 4mg BID 32
Dorsal Horn Increase the inhibitory input by increasing both serotonin and norepinephrine. This is best accomplished by medications that block the re uptake of serotonin and norepiephrine Savella Cymbalta Or through serotonin alone; Baclofen 33
Dorsal Horn Or through an opioid Oxycodone Morphine Hydromorphone Hydrocodone Methadone Fentanyl Demerol Talacen 34
Periaqueductal Gray/Sensory Cortex Decrease the perception of pain through activation of the mu receptor. A mu receptor agonist Oxycodone Morphine Hydroorphone, Ect. Or though hypnosis/relaxation response/meditation which will change one s perception p of the pain 35