Analgesics

Zhang, Bin

Pain transmission pathway

Noxious stimuli

PGs

K+ 、 H+

BK

5-HT

Primary afferent fibres

nociceptor

Spinal cord

Limbic system

Somato-sensory cortex

mood effect, the affective aspect of pain

the sensory aspect of pain

Dorsal horn

severe pain Opioids (eg. Morphine)

inflammatory pain NSAIDs (eg. Aspirin)

local anaesthesia

smooth muscle colic

angina pectoris induced by coronary artery spasm

trigeminal pain

Drug treatment of pain

cholinoceptor-blocking drugs

vasodilator drugs (eg. Nitroglycerin)

Carbamazepine

Local anaesthetics

Cortex

Spinal cord

Dorsal horn

Ventral caudal thalamus

PGs

K+ 、 H＋

BK

5-HT

NSAIDs

Opioids

Sites of action of different drugs

Non-opioid for mild pain

Pain persisting or increasing

Weak Opioids for moderate pain

Pain persisting or increasing

Strong Opioids for severe pain

Freedom from cancer pain

NSAIDs e.g. aspirin, acetaminophen

e.g. codeine ，tramadol

e.g. morphine, fentanyl, methadone

WHO analgesic ladder

Three steps analgesia therapy for cancer patientsThree steps analgesia therapy for cancer patients

opioid analgesics(narcotic analgesic, addictive analgesics)

Opium ( 阿片 ) is the dried exudate obtained from unripe seedpods of the poppy Papaver somniferum, containing morphine, codeine, and other alkaloid substances.

Opiate ( 阿片剂 ) means that a substance is extracted from opium or is similar in structure to natural substances present in opium.

Opioid ( 阿片样物质 ) is a term that designates substances that are not derived from opium. It refers particularly to opioid peptides, i.e. endogenous compounds that bind to opioid receptors and mimic the effect of morphine-like compounds. Widely use

term

Opium

The flower of papaver

The plant of joy

Opium ( 阿片 )

Opiate (阿片剂 )

• Morphine• Codeine• Papaverine … …

Opioid ( 阿片样物质 )

Endogenous opioid peptides:

Enkephalins

Endorphins

Dynorphins

Nociceptin and nocistatin

Endomorphin-1/2

Others:

1992~1993

1973

1962

1975

analgesic site is laminae III of periventricular and periaqueductal gray area

put forward “receptors” for opiate analgesics in brain

isolated the first “endogenous opioid peptide” and named enkephalin

Cloned opioid receptors: μ κ δ

Research history

Extracellular

Cytoplasmic

NH2

HOOC

Opioid receptors

G protein-coupled receptors

The cellular mechanisms

• Presynaptic inhibition: activation of opioid receptors on presynaptic nerve terminals. Close a voltage-gated Ca2+ channel, decrease Ca2+ input, and thereby reduce transmitter release (Ach, NA, Glu, 5-HT, P).

• Postsynaptic inhibition: activation of postsynaptic opioid receptors. Open K+ channels on postsynaptic neurons, increase K+ output , and thereby cause hyperpolarization and thus reduce postsynaptic neuronal excitability.

Spinal cord

Dorsal hornenkephalins

Ca2+

Ca2+

Presynaptic terminal

Postsynaptic neuron

enkephalins

enkephalins

Presynaptic terminal

Postsynaptic neuron

The cellular mechanisms

morphine

Pharmacological actions

1. CNS

2. Smooth muscles

3. Cardiovascular system

4. Others

1.CNS effects: principal effects

Analgesia Sedation & euphoria Respiratory depression Cough suppression Others: miosis, nausea, hormone

2. Smooth muscle system

Gastrointestinal system

Biliary tract

Urinary system

genital system

orthostatic hypotension

Mechanisms:

release of histamine

vasomotor center

3. Cardiovascular system

(1) peripheral arterial and venous dilatation

(2) intracranial pressure

secondary to respiratory depression

Clinical uses

• Analgesia

• Cardiac asthma

• Antidiarrhea

• Antitussive

1.Analgesia (severe pain)

terminal cancer

myocardial infarction

renal and biliary colic (atropine)

trauma, burn, operation

• at regular time and quantity

Pulmonary edema

dyspnea

Acute left ventricular dysfunction

short of breath (respiratory center)

CO2 retention

anxiety and distress

Alveolar hypoventilation

morphine

Reduce cardiac preload and afterload

Reduce the sensitivity of the respiratory center to increased CO2

Sedation

Cardiac asthma and morphine therapy

2. Cardiac asthma

Opioid analgesic drugs

• Morphine ( 吗啡 )• Codeine ( 可待因 ) • Pethidine ( 哌替啶 ) • Methadone ( 美沙酮 )• Fentanyl ( 芬太尼 )• Tramadol ( 曲马多 )

absorption excretion distribution

free drug

oral First pass elimination

sc. im.

blood

liver

placental fetuslittle cross

the BBB, but enough for its function

metabolism

morphine-6-glucuronide

kidney, breastiv.

activeBioavailability25-30%

Morphine

美施康定（硫酸吗啡控释片） 1. 强效，作用持续 12 hr 。主要用于晚期

癌症患者第三阶梯止痛。 2. 抑制呼吸，可引起恶心、呕吐、便秘及

排尿困难，长期应用可产生耐受性、身体依赖性和成瘾性。

Codeine

1. has a higher1. has a higher oral efficacy, demethylation to efficacy, demethylation to morphinemorphine

2. lower efficacy than morphinelower efficacy than morphine

3. 3. mainly use as antitussive, severe severe dry cough. cough.

联邦止咳露联邦止咳露 ：麻黄碱 + 可待因 + 氯苯那敏 + 氯化铵

注意事项• 抑制支气管腺体分泌，使痰液粘稠难以咳出，

不宜用于痰多粘稠者。连续应用不宜 2 周，因久用可成瘾。 7 岁儿童禁用。

Pethidine (dolantin)

• Synthetic substance• Weaker potency than Morphine, no antitussive

action• More sedative, more rapid onset and shorter

duration (2-4h) than morphine• Metabolite: normeperidine convulsion • Lyticcocktail

Methadone

1. synthetic compound, oral bioavailability is 80%

2. milder physical abstinence syndrome

3. routinely used in detoxification of the morphine

and heroin addicts

Fentanyl

1. more analgesic potentcy than morphine: 100 times

2. rapid onset and short duration of action

3. fentanyl, alfentanil, remifentanil: adjunctive drug

for general anaesthesia

4. breakthrough cancer pain:癌症患者的突发性疼痛，突然出现，不能被患者的常

规疼痛治疗方案缓解。

口腔经粘膜芬太尼拘橼酸盐(Oral Transmucosal Fentanyl Citrate, OTFC)

Fentanyl lollipop

ACTIQ

芬太尼口腔粘膜贴片(Fentanyl sublingual tablets) ABSTRAL

适应证：年龄 18岁以上，已连续 24小时使用阿片类药，对高剂量阿片类药物耐受者。

Tramadol

• Atypical opioid

• Weak μ activation, also interacts with monoaminergic systems

• Alternative to traditional opioid analgesics (improved side effect profile)

1. Tolerance

2. Dependence

physical dependence ： withdrawal syndrome

psychological denpendence:

compulsive drug- seeking behavior

When are used for the relief of pain, tolerance and dependence are not significant and prevalent problem

Adverse effects

3. General adverse effects

1 Constipation 5 Respiratory depression

2 Biliary colic 6 Postural hypotension

3Nausea and

vomiting7 Increased intracranial pressure

4 Urinary retention 8 Dysphoria

• Clinical overdose• Accidental poisoning in addicts• 30mg – toxic threshold• 120mg – lethal threshold

Pinpoint pupilsDeep respiratory depressionComa

Treatments: Establish patent airway Adequate ventilation Naloxone iv.

The triad ：

4. Acute Morphine Poisoning

Naloxone

1. competitive full antagonist for opioid R (μ)

2. Uses: opioid overdose

3. short t1/2 (1h) , repeated injections

Contraindications

obstetric labor, breasting period

obstructive airway disease, bronchial

asthma

head injuries

seriously impaired hepatic or renal function

Mode of administration of opioids

• Oral administration

• Sublingual administration

• Rectal administration

• Intravenous administration

• Intramuscular administration

• Intrathecal and epidural administration

• Transdermal patch administrationPatient Controlled Analgesia

( 病人自控镇痛， PCA)

Non-opioid analgesics

Introduction Non-steroidal anti-inflammatory

drugs (NSAIDs)

Antipyretic-analgesic and anti-

inflammatory drugs

Aspirin-like drugs

共同作用机制 :

Inhibition of cyclo-oxygenase enzymes (COX), and resulting inhibition of the

synthesis of prostaglandins (PGs)

花生四烯酸的代谢途径及主要代谢产物的生物活性

保护胃粘膜

比较 COX-1 & COX-2生物学作用

COX-1 COX-2

类型 结构型 ( 血管，肾脏，胃 ) 诱导型作用 保护胃粘膜 调节血小板聚集 发热、疼痛、致炎 调节外周血管阻力 调节肾血流量作用类型 生理性作用 病理性作用 NSAIDs 不良反应 解热、镇痛、抗炎

【 COX isoforms: 】 COX-1 COX-2

production Constitutive Inducible

functions

Physiological ： GI protection

Regulation of platelet aggregation

Regulation of kidney blood flow

Regulation of peripheral vascular

resistance

Pathological ： Inflammation

Pain

Fever

NSAIDs effects

Side effectsTherapeutic effects

【 Three major actions of NSAIDs 】

Antipyretic effect

Analgesic effect

Anti-inflammatory effect

heat production

heat dissipation

pathogen and toxins

neutrophils

endogenous pyrogens (ILs, TNF)

set point body temperature

cox NSAIDsPGE2 (hypothalamus)

Antipyretic effect

Characteristics

① Central

② “Elevated” temperature — reduced

“Normal ” temperature — no influence

Clinical applications symptomatic treatment

Pain transmission pathway

Noxious stimuli

PGs

K+ 、 H+

BK

5-HT

nociceptor

Spinal cord

Limbic system

Somato-sensory cortex

Dorsal horn

NSAIDs

Analgesic effect

Characteristics

① Peripheral (probably also inhibit pain stimuli at a subcortical site)

② mild to moderate pain

③ No addiction or respiratory inhibition

Clinical applications

① have good effects on chronic dull pain— headache , toothache, neuralgia, muscle

pain, arthralgia, dysmenorrhea

② are not very effective for traumatic pain, severe visceral pain—myocardial infarction or renal or biliary colic

• Three steps analgesia therapy for cancer patientsThree steps analgesia therapy for cancer patients

Drug location mechanism characteristics representative

Analgesics

NSAIDs

CNS

periphery

(+)opium receptor

(-)PG synthesis

morphine

aspirin

powerful dull and sharp pain inflammatory pain cause euphoria and addiction respiratory inhibition

moderate chronic dull pain cancer pain not addictive no respiratory inhibition

比较 NSAIDs 和吗啡的镇痛作用

Mechanism of inflammation:Mechanism of inflammation: phospholipids injury factor PLA2

neutrophilic arachidonic acid granulocyte cytokines induce COX-2

( ILs, TNF) PGs

inflammation ( redness, swelling, heat and pain )

Anti-inflammatory effect :

According to selectivity for COX:

①Non-selective COX inhibitors

②Selective COX-2 inhibitors

According to chemical structures :

【 NSAIDs classifications 】

化学分类 非选择性 COX 抑制药 选择性 COX-2 抑制药

水杨酸类 阿 司 匹 林苯胺类 对乙酰氨基酚吲哚类 吲哚美辛 依托度酸芳基丙酸类 布洛芬 芳基乙酸类 双氯芬酸烯醇酸类 吡罗昔康 美洛昔康吡唑酮类 保泰松烷酮类 奈丁美酮二芳基吡唑类 塞来昔布二芳基呋喃酮类 罗非昔布磺酰苯胺类 尼美舒利

(1) Antipyretic-analgesic effect

(2) Anti-inflammatory and antirheumatic effects

(3) Platelet effect

Aspirin (Acetylsalicylic acid)

PGI2 TXA2

Platelet effect : thrombosis inhibition

AA

TXA2PGI2

(-) platelet aggregation vascular dilation

(+) platelet aggregation vascular constriction

血小板血管内皮

AA

TXA2PGI2

(-)platelet aggregation vascular dilation

(+)platelet aggregation vascular constriction

血小板血管内皮

Aspirin小剂量

thrombosis inhibition:

AA

TXA2PGI2

(-)platelet aggregation vascular dilation

(+)platelet aggregation vascular constriction

血小板血管内皮

Aspirin大剂量

Aspirin irreversibly acetylates and blocks platelet COX1 → TXA2 biosynthesis(-) → platelet aggregation(-) → thrombosis (-).

TXA2↓ Low dose thrombosis is inhibited PGI2 not affected TXA2↓ High dose unbeneficial for thrombosis inhibition PGI2↓

Clinical uses:

① low dose (40~100mg) is recommended

② prevent thrombosis:

cardiac or brain ischemic diseases

angioplasty( 血管成形术 )

coronary artery bypass grafting

③ Pregnancy-induced hypertension syndrome (PIH)

【 Adverse effects 】

Gastrointestinal side effects

Disturbance of blood coagulation

Salicylism reaction

Hypersensitivity reactions

Reye’s syndrome

Nephrotoxicity

Salicylism reaction

Large dosage (>5g/d)

headache, vertigo, nausea, vomiting, tinnitus, decreased vision and hearing ；hyperpnea, acid-base disturbance, insanity.

Therapy: ① aspirin must be stopped at once

② sodium bicarbonate infusions.

Reye’s syndrome

Severe hepatic dysfunction with

complication of encephalopathy

Substitute aspirin with acetaminophen

Nephrotoxicity acute renal failure by reducing renal blood flow.

chronic renal failure due to development of interstitial nephritis. 复方药物滥用

Similar antipyretic and analgesic effects to aspirin, no significant anti-inflammatory effect

Less frequent gastrointestinal irritationToxicity to liver and kidney after

prolonged use

Acetaminophen (paracetamol):

Paracetamol overdose is treated with N-acetylcysteine

Acetaminophen (paracetamol):

对乙酰氨基酚是现在常用感冒药的主要成分

常用复方制剂

白加黑：白片：扑热息痛＋盐酸伪麻黄碱＋氢溴酸右美沙芬

黑片：白片＋苯海拉明

Ibuprofen( 布洛芬 ) ： Anti-inflammatory, analgesic, antipyretic effects similar

to Asp It can be slowly released into synovial fluid and

remains there with a high concentration

Widely used in RA and osteoarthritis, mild and moderate pain

Less frequent gastrointestinal irritation 芬必得布洛芬缓释胶囊 芬必得布洛芬乳膏 芬必得酚咖片新头痛装

Selective COX-2 inhibitors

Celecoxib ( 塞来昔布 )

Rofecoxib( 罗非昔布 )

Nimesulide( 尼美舒利 )

2004年 9 月 30日 , 由于“连续服用 18个月会增加病人心血管事件的风险”，美国默沙东公司宣布将其治疗风湿性关节炎的王牌药物“万络” (罗非昔布 ) 实施全球召回。

美国辉瑞公司“西乐葆”（塞来昔布）被披露存在同样的安全隐患。

• The security of selective COX-2 inhibitors is not absolute !

Attention