
Pharmacology for Pain and Analgesia. Dept of Pharmacology Shi-Hong Zhang ( 张世红 ) shzhang713@zju.edu.cn. What is pain.
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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
Pain sensation
First pain:sharp, pricking, well defined,A fibers
Second pain:dull, aching, poorly localized, C fibers
Types and reasons
Neuropathic pain
Inflammatory pain
Bone cancer pain
Fibromyalgia
Migraine
Psychogenic pain
Plus dysfunction in inhibitory systems,
including opioids, cannabinoids, norepinephrine, adenosine…
(Non-steroidal anti-inflammatory drugs, NSAIDs)
Bradykinin
Angiotensin
⊕
Corticosteroids
Phospholipase A2
Arachidonic acid
Cyclooxygenase (COX)
NSAIDs
5-lipoxygenase
PGG2
Prostacyclin(PGI2)
hydroperoxidase
PGE2
PGF2α
PGH2
Leukotrienes
Thromboxane A2
Dipyridamole
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)
The mechanism of aspirin: acetylating COX enzyme irreversibly
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.
1.1 Actions and therapeutic uses:
B Anti-rheumatic actions:atlarge dose (4-6 g/d).
C Anti-aggregation of platelets and vasoconstriction:at small dose (~100 mg/d), irreversibly inhibits thromboxane production in platelets without markedly affecting PGI2 in the endothelial cells of the blood vessel.
1.2 Adverse effects:
Gastrointestinal effects:epigastric distress, nausea and vomiting, bleeding, ulcer.
Allergic effects:
Urticaria (风疹)
Bronchoconstriction (aspirin asthma) angioneurotic edema
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
central nervous system effect
gastrointestinal complaints
allergic reactions
hematopoietic reactions
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 secretion.
Limbic system:influence emotional behavior.
2.1 Distribution and physiological effects :
B Periphery:
--- Inhibit the release of excitatory, proinflammatory substances from nerve endings, which contribute to the anti-inflammatory effect of opioids.
C Immune cells: immune depression
In the Brain Stem
Summary of opioid analgesics and antagonists:
Strong agonists: fentanyl, heroin, pethidine, methadone, morphine
Moderate agonists: codeine
Mixed agonist-antagonists: pentazocine
Antagonists: naloxone, naltrexone
Mainly agonist action atμreceptors,
⊕
⊕
⊕
μopioid
receptor
κ opioid
receptor
opioid
receptor
Analgesia
Respiratory depression
Euphoria/sedation
Physical dependence
Decreased GI motility
Pupil constriction
Analgesia
Sedation/dysphoria
Pupil constriction
Analgesia
high
Addiction/abuse
low
Morphine Pethidine Methadone Fentanyl Codeine
A comparison of the maximum efficacy and
addiction/abuse liability of commonly used
narcotic analgesics
Duration of action
20min
Morphine
Pethidine
Fentanyl
4 hours
15min
2 hours
5min
45min
Time to peak effect and duration of action of
several opioids administered intravenously
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 .
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.
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).
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.
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
4.2 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.
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).
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
4.3 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
Malformation
4.4 Contraindications:
5.1 Actions and mechanisms:
----Transient decrease of gastro-intestinal motility and increase of the tone
---- Indistinctly central depression of cough reflex.
5.2 Therapeutic uses:
--- 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