pharmacology for pain and analgesia dept of pharmacology shi-hong zhang ( 张世红 )...

Pharmacology for Pharmacology for

Pain and AnalgesiaPain and Analgesia

Dept of Pharmacology

Shi-Hong Zhang ( 张世红 )

shzhang713@zju.edu.cn

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