1. Drugs (Pregabalin) Modulates Hyperexcited Neurons
The key points on this slide are as follows:
The mechanism of action of pregabalin is distinct from the several known mechanisms of action of other antiepileptic and analgesic drugs.
Pregabalin modulates hyperexcited neurons via the following mechanism:
pregabalin binds to presynaptic neurons at the 2-d subunit of voltage- gated calcium channels
drug binding reduces calcium influx into presynaptic terminals
decreased calcium influx reduces excessive release of excitatory neurotransmitters (e.g., glutamate, substance P, noradrenaline).
Preclinical animal studies indicate that this mechanism of action is responsible for the anticonvulsant, analgesic, and anxiolytic activity of pregabalin.
These findings are derived from work in preclinical experimental models. The clinical significance in humans is not known.
Reference
1. Data on file, Pfizer Inc, NY, USA.
(See previous slides on the effects of pregabalin on calcium influx and neurotransmitter release for additional references)
Additional key words: mechanism of action, MOA, pharmacology, norepinephrine, calcium ion
*Does not affect Ca++ influx in normal neurons

2. (4) Central Reorganization (Spinal Cord Injury)Ab
Superficial C
Dorsal root ganglion
Deep
After nerve injury
Finally, pain fibers within the spinal cord may reorganize such that sections of the spinal cord that normally receive only noxious input from the periphery via C fibers begin to receive information regarding non-noxious stimuli from A fiber terminals that sprout into the superficial dorsal horn. Thus, even light touch may be perceived as painful.
References:
Attal N, Bouhassira D. Mechanisms of pain in peripheral neuropathy. Acta Neurol Scand. 1999;100(Suppl):12-24.
Woolf CJ, Doubell TP. The pathophysiology of chronic pain—increased sensitivity to low threshold. A beta-fibre inputs. Curr Opin Neurobiol. 1994;4:
 Sprouting of injury fiber alter the relationship and modified the pain between stimulant and response
Woolf, 1994.

3. (5) Loss of Inhibitory Control (Descending disinhibition)
Central
Descending
local To
brain
NORMAL
Dorsal horn neuron
Central
Descending
Local To
brain
INJURED
Excitatory as well as inhibitory input determines what information is transferred from the periphery to the brain.
Normalwill be gated control impulse to brain sti, when inj inhibition loss impulse overflow exciting neuron.
Inhibition 可來自兩處 local (spinal cord)-- GABA, Glycine, descending pathway (medulla- to spine) serotonin and nonadrenaline
Inhibitory influences may arise from inhibitory interneurons at the level of the spinal cord, mediated by neurotransmitters such as  aminobutyric acid (GABA) and glycine.
Also, inhibitory influences may arise from descending pathways from the brain, mediated by endogenous opioids or neurotransmitters like serotonin and noradrenaline. 
Either one of these inhibitory controls may be lost or impaired, causing the dorsal horn neuron to fire in an exaggerated way in response to afferent input, and the patient may develop allodynia. 
References:
Attal N, Bouhassira D. Mechanisms of pain in peripheral neuropathy. Acta Neurol Scand. 1999;100(Suppl):12-24.
Siddall PJ, Cousins MJ. Spinal pain mechanisms. Spine. 1997;22:
Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet. 1999;353:
Innocuous or noxious stimulus
Exaggerate pain response
Excitatory synapse
Inhibitory synapse
Mechanoreceptor
Woolf, 1999.

4. Brain-Gate Theory (閘門理論)
Melzack and Wall (1965)
Melzack-wall-Casey (1982)--- modified theory: cognitive control+ descending brain-stem control
1.C/A fiber can have control to thalamus, when together, A fiber will inhibit the C fiber t express the pain transmission gate control theory
2.In 1982, NEW GATE- CONTROL THEORY 加入descending brain stem control 及cognitive control…> 是近代pain 理論的始祖.
3.還有pattern theory, central summation theory, sensory interaction theory….都不及gate theory 重要. 雖然目前已知,, gate control 仍不足以解釋完全pain 的mechanism…
*滿清十大酷刑,拔指甲-Rx: 1)轉移注意力. 2)crude press 可以減輕mall fiber pain transmission. (小孩打針時,可以在旁邊press, or massage)

5. block NE and serotonin reuptake
TCAs, more than blocking NE and serotonin re-uptake of anti-depression characater, but also increasing the inhibitory descending modulation control of pain in BS.

7. LISTEN LOCATE LOOK 臨床診斷 (3L) Nervous system lesion / dysfunction
Sensory abnormalities, pattern recognition
Patient verbal descriptors, Q & A
The 3L approach (Listen, Locate and Look) will facilitate the assessment and successful diagnosis of neuropathic pain in the limited consultation time available in general practice.
The 3L approach involves the following steps:
Listen to patients’ verbal descriptors of their pain; ask appropriate questions and note their responses.
Locate the area of pain and/or determine the nervous system lesion/dysfunction.
Look for sensory abnormalities and recognize its distribution pattern. Also look for abnormal behavior or guarding of the affected area.
A differential diagnosis of neuropathic pain is dependent on the combined outcomes from the 3L approach.

8. 神經評估 Neurological Assessment
History: onset, duration, character…
Landmark of S level, distribution, location…
Intensity, quality of pain
Associated s/s, aggravated factors…
T10
LANDMARK., 如T2上接C4. (非T1)., 是否COMPARTMENT SSYND, scitica, sensory neuritis…..(畫出範圍).
Duration-sec’,neuralgia, throbbing—vascular. HIVD—aggravating factors.
CTS. ulnar neuropathy, 各有其distribution 區域
Holmes GM. Introduction to Clinical Neurology. Baltimore: Williams & Wilkins, 1952.

9. 病史: 問診還是最主要的 Use scales to aid in defining pain
Complete information regarding pain
Use scales to aid
in defining pain
McGill pain Questionnaire
Visual analog scale (VAS)
Activities of daily living scales (ADS)
Neuropathic pain scale (NPS)
Quality
Intensity
Location
pattern
Macgill—where, what, how, how strong, (78items).
VAS(看治療如何).ADS, NPS.

10. 也可利用疼痛問卷

11. Visual Analog Scales (VAS-疼痛評分)
No pain
Excruciating pain
100
0-100, 由pt 自己畫出位置 , (適合pain intensity, or pain relieve scoring). ..
Complete pain relief
No pain relief
100
Note: Lines must be exactly 100 mm long
McQuay, 1998.

12. Neuropathic Pain Scale (NPS)
1. Tell us how intense your pain is.
The most intense pain sensation imaginable
2. Tell us how sharp your pain feels.
The most sharp
Not sharp sensation imaginable (“like a knife”)
3. Tell us how hot your pain feels.
The most hot
Not hot sensation imaginable
(“on fire”)
No pain 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10
HA就是用此scales, Tension headache 就偏向mild to moderate degree HA. 1 2 3 4 5 6 7 8 9 10
Dull, cold,
sensitive, itchy
Galer, 1997.

13. 臉部表情評分表

14. NCV(神經傳導) 脕隧道症候群(Carpal tunnel syndrome)
For example, in carpal tunnel syndrome there is a constriction of the carpal tunnel by the reticulatum affecting the passage of motor and sensory fibers through this entrapment.
Recordings are taken at the abductor muscle of the thumb. The median nerve is stimulated through the skin by surface electrodes, and the resulting motor action potential is recorded.
Diagnosis of carpal tunnel syndrome would require the demonstration of focal slowing through the carpal tunnel. This can be achieved by stimulating the median nerve at the palm and recording proximally or stimulating at the wrist and recording distally.
Reference:
Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill; 1998:2286.
However, small fiber disease can not be detectable
(亦即神經傳導正常,不代表神經沒有病變)

15. EMG(肌電圖) (neurogenic or myogenic)
Full
Interference
Intermediate
Pattern
Single Unit
Pattern
The EMG may provide additional information on axonal loss.
Normal muscle is electrically silent when it is at rest, but when it is voluntarily contracted, motor unit action potentials are recorded. As a slowly progressive pattern begins, action potentials of 1 motor unit appear at rates of about 4 to 5 per second and increase to 8 to 10 per second. As the power of the contraction increases, a second or third unit slightly larger in size than the first will be recrutied. As the contraction becomes even stronger, more and larger motor units are recruited and their potentials begin to overlie each other until there are a disorderly crowd of action potentials of many sizes and shapes firing at about 20 per second. Individual motor units can no longer be distinguished and the pattern that results is called a complete or full interference pattern.
A muscle contracting weakly from central or peripheral motor sytem disease or muscle disease will have fewer active fibers and, therefore, will produce a smaller total number of motor unit action potentials than normal. This reduction in output may be sufficient to break up the interference pattern. An intermediate pattern may result when there is some axonal loss; a single unit pattern results when there is extensive axonal loss with few axons spared.
Reference:
Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill; 1998.
(肌電圖更難以判斷=正常反應,不代表神經肌肉正常)