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Pharmacology for Pharmacology for
Pain and AnalgesiaPain and Analgesia
Dept of Pharmacology
Shi-Hong Zhang ( 张世红 )
What is What is painpain
An unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Pain is always subjective. Each individual learns the application of the word through experiences related to injury in early life. It is unquestionably a sensation in a part of the body, but it is also unpleasant, and therefore also an emotional experience. Many people report pain in the absence of tissue damage or any likely pathophysiological cause; usually this happens for psychological reasons. There is no way to distinguish their experience from that due to tissue damage, if we take this subjective report……
IASP. Pain 1979(6)249-252
Physiology of PainPhysiology of Pain
Pain sensation First pain ： sharp, pricking, well defi
ned ， A fibers
Second pain ： dull, aching, poorly localized, C fibers
Milligan et al, 2009
Types and reasons Neuropathic pain Inflammatory pain Bone cancer pain Fibromyalgia Migraine Psychogenic pain
Chronic Pain
Mechanisms ： Peripheral input Central sensitization
Chronic Pain
Plus dysfunction in inhibitory systems, including opioids, cannabinoids, norepinephrine, adenosine…
Analgesics (pain killer)
NSAIDs and other anti-inflammatory drugs
Opiates and morphinomimetics Some tricyclic antidepressants Some antiepileptic drugs Local anesthetics Others: ketamine, mexiletine, etc
Antipyretic, Analgesic, and Anti-inflammatory Drugs
(Non-steroidal anti-inflammatory drugs, NSAIDs)
Arachidonic acid
Phospholipase A2
Corticosteroids ⊕ BradykininAngiotensin
Cyclooxygenase (COX)
PGG2Prostacyclin(PGI2)
PGE2
PGF2α
Thromboxane A2
Dipyridamole
hydroperoxidase
NSAIDs
Leukotrienes
5-lipoxygenase
Phospholipid
PGH2
COX-1 COX-2
Synthesis intrinsic induced
Functions physiological:
gastrointestinal protection
platelet aggregation regulation
vascular resistance regulation
renal blood flow regulation
physiological: production of PG elevated during pregnancy
pathological:
producing proteinase, PG, and other inflammatory mediators
Characteristics comparison between COX-1 and COX-2
Aspirin and other salicylates （阿司匹林及水杨酸类）
Aniline derivatives （苯胺类衍生物）
Indole derivatives （吲哚类衍生物）
Propionic acid derivatives （丙酸类衍生物）
Others ( 烯醇酸类，灭酸类，杂环芳基乙酸类，茚乙酸类，吡唑酮类，以及选择性 COX-2 抑制剂 )
Classification of NSAIDs :
The mechanism of aspirin: acetylating COX enzyme irreversibly
1. Aspirin
1.1 Actions and therapeutic uses:
A Antipyretic and analgesic actions:
-- resets the thermostat toward normal and lowers
the body temperature by increasing heat dissipation;
-- alleviates pain of low to moderate intensity arising
from integument, especially with inflammation.
1. Aspirin
1.1 Actions and therapeutic uses:
B Anti-rheumatic actions: at large dose (4-6 g/d).
C Anti-aggregation of platelets and vasoconstric
tion: at small dose (~100 mg/d), irreversibly inhi
bits thromboxane production in platelets witho
ut markedly affecting PGI2 in the endothelial cell
s of the blood vessel.
1. Aspirin
1.2 Adverse effects:
Gastrointestinal effects: epigastric distress,
nausea and vomiting, bleeding, ulcer.
Allergic effects:
Urticaria （风疹）Bronchoconstriction (aspirin asthma) angioneurotic edema
1. Aspirin
1.2 Adverse effects:
Prolonged bleeding time
Excessive ventilation: respiratory alkalosis Salicylism ( 水杨酸反应 ) ： toxicity in the CNS (headache, dizziness, nausea, vomiting, tinnitus)
Reye’s syndrome: liver and brain injury in children with virus infection
1. Aspirin
2. Acetaminophen （对乙酰氨基酚） Slow and prolonged antipyretic and
analgesic effects No obvious anti-inflammation effect Less stimulation to gastrointestinal tract Damage of liver and kidney if used for a
long time and at high dose
3. Indomethacin （吲哚美辛）
One of the most potent inhibitors of COX High potency of anti-inflammatory, analgesic, and anti
pyretic activity Used for ankylosing spondylitis ( 强直性脊柱炎 SA) ，
Osteoarthritis ( 骨关节炎 OA) and gout ( 痛风 ) Effective in treating patent ductus arteriosus （动脉导
管未闭）
High incidence of adverse effects like:
central nervous system effect
gastrointestinal complaints
allergic reactions
hematopoietic reactions
Sulindac ( 舒林酸 ) and Etodolac ( 依托度酸 ) are less toxic and used for OA, RA, SA and acute gout.
3. Indomethacin
4. Propionic acid derivatives （丙酸类）
Anti-inflammatory, analgesic and antipyretic activity
Less gastrointestinal effects Change platelet function and prolong bleedin
g time Used for the treatment of various arthritis an
d dysmenorrhea ( 痛经 )
5. Inhibitors of TNF-
TNF- is the predominant factor in inflammatory reaction.
Include infliximab, adalimumab and IgG1 Used for the treatment of rheumatoid arthritis,
spondylitis ankylosans ( 强直性脊柱炎 ) and other autoimmune diseases.
Opioid analgesics (narcotic analgesics) and
antagonists
Collecting resin of opium poppy
Crude opium
Opium flowers
Seeds of opium poppy
• Natural opiates: morphine, codeine, papaverine and thebaine;
• Semi-synthetic opiates: hydromorphone, hydrocodone, oxycodone, oxymorphone, desomorphine, diacetylmorphine (Heroin), nicomorphine, dipropanoylmorphine, benzylmorphine and ethylmorphine;
• Fully synthetic opioids: fentanyl, pethidine, methadone, tramadol and propoxyphene;
• Endogenous opioid peptides: endorphins, enkephalins, dynorphins, and endomorphins.
1. Classification of opiates
2. Opioid receptors
2. Opioid receptors
2.1 Distribution and physiological effects:
A Certain cells in the CNS:
Brainstem: mediate respiration, cough, nausea and vomiting, maintain blood pressure, pupillary diameter and control of stomach secretions.
Medial thalamus: modulate deep pain that is poorly localized and emotionally influenced.
2.1 Distribution and physiological effects :
A Certain cells in the CNS:
Spinal cord: involved in the reception and integration of incoming sensory information and attenuate painful afferent stimulation.
Hypothalamus: affect neuroendocrine secreti
on.
Limbic system: influence emotional behavior.
2. Opioid receptors
2.1 Distribution and physiological effects :
B Periphery:
--- Inhibit the release of excitatory, proinflamm
atory substances from nerve endings, which contribute to the anti-inflammatory effect of opioids.
C Immune cells: immune depression
2. Opioid receptors
2.2 Signal transduction:
2. Opioid receptors
In the Spinal Cord
In the Brain Stem
2. Opioid receptors
Summary of opioid analgesics and antagonists:
Strong agonists: fentanyl, heroin, pethidine, methadone,
morphine
Moderate agonists: codeine
Mixed agonist-antagonists: pentazocine
Antagonists: naaloxone, naltrexone
3. Opioids
Mainly agonist action atμreceptors, but some actions on other receptors•Morphine•Heroin•Codeine•Fentanyl
⊕
Agonist action at κreceptors,with partial antagonist action at μ receptors•Pentazocine
⊕⊕
μ opioid receptor
κ opioid receptor
opioid receptor
AnalgesiaRespiratory depressionEuphoria/sedationPhysical dependenceDecreased GI motilityPupil constriction
AnalgesiaSedation/dysphoriaPupil constriction
Analgesia
Antagonist act at μ, κ, receptors•Naloxone•Naltrexone
low
highEfficacy
Addiction/abuse
Morphine Pethidine Methadone Fentanyl Codeine
A comparison of the maximum efficacy and addiction/abuse liability of commonly used
narcotic analgesics
20min4 hours
15min2 hours
5min45min
Morphine
Pethidine
Fentanyl
Time to peak effectDuration of action
Time to peak effect and duration of action of several opioids administered intravenously
4. Morphine
4.1 Pharmacological effects:
A Analgesia:
- Raises the pain threshold at the spinal cord level, alters nociception in the brain.
- Relieves anxiety and fear
B Euphoria:
- Produces a powerful sense of contentment and well-being by stimulation of the ventral tegmentum.
C Respiration:
- Causes respiration depression by reduction of the sensitivity of respiratory center neurons to carbon dioxide.
D Depression of cough reflex:
- May allow accumulation of secretions and thus lead to airway obstruction and atelectasis ( 肺不张 ).
-Replaced by other safer antitussives .
4. Morphine
E Miosis:
- The pinpoint pupil is the characteristic of morphine use, little tolerance.
F Emesis:
- Causes vomiting by stimulating the CTZ in the medulla but with no unpleasant sensations.
4. Morphine
G Sedation:
- Causes drowsiness and clouding of mentation, even disrupting sleep
H Gastrointestinal effect:
- Decreases motility of smooth muscle and increases tone, which causes constipation and increases pressure in the biliary tract (worsens abdominal colic, eg. Sphincter oddi contraction).
4. Morphine
I Cardiovascular :
- Has no major effects on the cardiovascular system.
- Is usually contraindicated in individuals with severe brain injury (because that increased PCO2 induced by
respiration depression leads to cerebral vasodilation and consequential increase in cerebral blood flow and intracranial
pressure).
- Causes postural hypotension sometimes.
4. Morphine
J Histamine release:
- Causes pruritus, urticaria, sweating, vasodilation and bronchoconstriction.
K Hormonal actions:
- Inhibits release of LH ( 黄体生成素 ).
- Increases GRH ( 促生长激素 ), ADH ( 抗利尿激素 ), PRL ( 催乳素 )
M Immune depression
4. Pharmacodynamics- morphine
4.2 Therapeutic uses: A Analgesia:
- Used for various pain, especially acute, obstinate constant pain (e.g. burn, cancer pain);
- Fixed interval of administration reduces tolerance and dependence;
- Severe pain of renal and biliary colic + MR blockers.
4. Morphine
B Cardiac asthma:
- Acute left ventricular heart failure induces pulmonary edema
- Reduces anxiety, cardiac preload and afterload.
- Particularly useful for painful myocardial ischemia with pulmonary edema.
C Treatment of diarrhea: synthetic surrogates （ eg. 地芬诺酯） .
4. Morphine
D Relief of cough: synthetic antitussives （ eg. 右美沙芬）
E Premeditate drugs before anesthesia : sedative, anxiolytic, and analgesic properties. For high-risk surgery administered systemically; for local (epidural) anesthesia.
Caution: respiratory suppression
4. Morphine
4.3 Adverse effects:
- Respiratory depression
- Vomiting, constipation, biliary colic
- Dysphoria
- Allergy-enhanced or postural hypotensive effects
- Urinary retention (prostatic hypertrophy)
- Elevation of intracranial pressure (head injury)
- Immune depression
4. Morphine
Tolerance and Physical Dependence
Repeated use produces tolerance to the respiratory depression, analgesic, euphoric and sedative effects, but not to pupil-constricting and constipating effects.
Physical and psychologic dependence readily occur for strong μagonists, especially used on necessities.
4. Morphine
Tolerance and Physical Dependence
Withdrawal symptoms: a series of autonomic, motor and psychological response that incapacitate the individual (rhinorrhea, lacrimation, yawning, chills, gooseflesh, hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety, and hostility).
4. Morphine
Druggy Malformation
4.4 Contraindications: Women during labor or lactation New-born infants Chronic obstructive pulmonary disease (COPD)
Asthma
4. Morphine
5. Pethidine (meperidine)
5.1 Actions and mechanisms: Binds to opioid receptors, particularly
receptor. Actions similar to but less potent than
morphine.
----Transient decrease of gastro-intestinal motility and increase of the tone
---- Indistinctly central depression of cough reflex.
5. Pethidine (meperidine)
5.2 Therapeutic uses: Analgesia: various severe pain, including during obst
etric labor (less depression of respiration in newborn infants)
Cardiac asthma Administration before anesthesia and artificial hibern
ation, combined with chlorpromazine （氯丙嗪） and promethazine （异丙嗪）
6. Pentazocine
An agonist on receptor, but a weak antagonist at and receptors (partial agonist).
Actions (less potent compared with morphine): analgesia and respiratory depression, indistinct euphoria and dependence. Dysphoria, hallucinations and hypertension in high dose
Used for moderate or chronic pain.
7. Naloxone
Competitive blocker of opioid receptor, with ten-fold higher affinity for receptor than for .
Actions:
--- precipitates withdrawal symptoms;
---reverses the coma and respiratory depression of opioid overdose (short action duration! Naltrexone with much longer action duration);
--- eliminates some adverse effects with opioids
8. Other analgesics
Tramadol: weak receptor agonist, inhibits uptake of NA and 5-HT, effective on moderate to severe acute and chronic pain.
Tetrahydropalmatine ( 延胡索乙素 ): effective on persistent blunt pain
Guidelines for neuropathic pain
WHO guidelines for cancer pain
