Analgesics Zhang, Bin

pain a. Acute pain (sharp pain) b. Chronic pain (dull pain) two components somatic sensation affective (emotion) pain a. Acute pain (sharp pain) b. Chronic pain (dull pain)

Pain transmission pathway mood effect, the affective aspect of pain PGs K+、H+ BK 5-HT Limbic system Somato-sensory cortex the sensory aspect of pain Primary afferent fibres Dorsal horn Noxious stimuli Spinal cord nociceptor Pain transmission pathway

Drug treatment of pain severe pain Opioids (eg. Morphine) inflammatory pain NSAIDs (eg. Aspirin) local anaesthesia smooth muscle colic angina pectoris induced by coronary artery spasm trigeminal pain Local anaesthetics cholinoceptor-blocking drugs vasodilator drugs (eg. Nitroglycerin) Carbamazepine

Sites of action of different drugs Cortex Opioids NSAIDs Dorsal horn PGs BK Spinal cord 5-HT K+、H＋ Sites of action of different drugs

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 (阿片) The flower of papaver Opium

Opiate (阿片剂) Morphine Codeine Papaverine (罂粟碱) … …

structure-activity relationship OH 海洛因 吗啡 纳洛酮

Opioid (阿片样物质) Endogenous opioid peptides: Enkephalins Endorphins Dynorphins Orphanin

Research history 1992~ 1975 1973 1962 Cloned opioid receptors: μ κ δ  isolated the first “endogenous opioid peptide” and named enkephalin 1973 put forward “receptors” for opiate analgesics in brain 1962 analgesic site is laminae III of periventricular and periaqueductal gray area

Opioid receptors     G protein-coupled receptors NH2 Extracellular Cytoplasmic NH2 HOOC    G protein-coupled receptors

Opioid receptors supraspinal analgesia, sedation, euphoria, dependence, respiratory depression, miosis : : spinal analgesia, sedation : spinal analgesia, sedation, euphoria, dependence, respiratory depression : dysphoria (烦躁不安), hallucination

The cellular mechanisms Presynaptic terminal Ca2+ Postsynaptic neuron Ca2+ Dorsal horn enkephalins enkephalins Spinal cord

The cellular mechanisms morphine Presynaptic terminal Postsynaptic neuron enkephalins The cellular mechanisms

The cellular mechanisms Morphine + receptors postsynaptic presynaptic Open K+channel Close Ca2+channel Ach, NA, Glu, 5-HT, P release  Excitability  抑制冲动传导

The cellular mechanisms Presynaptic inhibition: activation of opioid receptors on presynaptic nerve terminals. Close 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.

Pain Descending pain inhibitory pathways Endogenous opioid peptides Descending pain inhibitory pathways Ascending pain transmission pathways Pain Local inhibitory interneuron in spinal cord

Pharmacological actions CNS Smooth muscles 3. Cardiovascular system

1.CNS effects: principal effects Analgesia Sedation & euphoria Respiratory depression Cough suppression Others: miosis, nausea, hormone

1. CNS (1) Analgesia insensitive: muscle spasms pain, deafferentation pain partially sensitive: nerve pain, CNS compression injury, bone cancer sensitive: myocardial infarction, other types of cancers relieve anxiety and distress, tolerance of pain 灼性神经痛(causalgia)系指在明确的神经损伤后，与损伤神经支配范围相一致的区域内出现的以剧烈灼样疼痛主要症状，表现为痛觉异常、痛觉过敏、交感神经机能障碍、血流障碍、出汗异常、骨、肌肉萎缩，有时表现出水肿性改变的慢性顽固性疼痛综合征。

(2) Sedation and euphoria drowsiness and clouding of mentation sleep induced and aroused easily Sedation: a sense of contentment and well-being Euphoria the main reason for drug abuse Site: limbic system and locus ceruleus

(3) Respiratory depression respiratory rate ，tidal volume the most common cause of death from acute poisoning influenced by stimulus Mechanisms:  the sensitivity of respiratory center to increased CO2 tension

(4) Cough suppression antitussive effect by inhibiting cough center codeine antitussive effect by inhibiting cough center (5) Other CNS effects Miosis: pinpoint pupils Nausea and vomiting: CTZ  muscular tension:限制 胸廓活动,影响呼吸 Hormone: ↓ LH ,FSH, ↑ prolactin, GH, ADH

2. Smooth muscle system Gastrointestinal system Biliary tract Urinary system genital system

constipation (1) Gastrointestinal tract delays passage GIT tone GIT motility absorption of water constipation secretion of digestive gland indigestion a call of nature defecation reflex central inhibition

(2) Biliary tract biliary colic constrict biliary smooth muscle constrict Oddi's sphincter pressure in the biliary tract biliary colic

(3) Urinary tract (4) Genital tract urinary retention prolong labor constrict ureteral smooth muscle bladder sphincter tone urinary retention (4) Genital tract uterine tone prolong labor

3. Cardiovascular system (1) peripheral arterial and venous dilatation orthostatic hypotension Mechanisms: release of histamine vasomotor center (2) intracranial pressure secondary to respiratory depression

Clinical uses Analgesia Cardiac asthma Antidiarrhea Antitussive Combined anesthesia

myocardial infarction renal and biliary colic (atropine) Analgesia terminal cancer myocardial infarction renal and biliary colic (atropine) trauma, burn, operation at regular time and quantity

Reduce cardiac preload and afterload 2. Cardiac asthma Acute left ventricular dysfunction Reduce cardiac preload and afterload morphine Pulmonary edema Alveolar hypoventilation CO2 retention Reduce the sensitivity of the respiratory center to increased CO2 Sedation dyspnea short of breath (respiratory center) oxygen consumption anxiety and distress Cardiac asthma and morphine therapy

Cardiac asthma (1) Mechanisms: ① peripheral arterial and venous dilation preload and afterload pulmonary edema ② sedation anxiety and distress oxygen consumption ③ the sensitivity of respiratory center to CO2 shortness of breath

Opioid analgesic drugs Morphine (吗啡) Heroin (海洛因，二醋吗啡) Codeine (可待因) Pethidine (哌替啶) Methadone (美沙酮) Fentanyl (芬太尼) buprenorphine (丁丙诺啡) Tramadol (曲马多)

Morphine 1803 Serturner isolated a pure active alkaline substance from opium. He proposed the name “morphine” for it after Morpheus.

little cross the BBB, but enough for its function distribution absorption excretion placental fetus little cross the BBB, but enough for its function blood kidney, breast oral First pass elimination sc. im. free drug iv. morphine-6-glucuronide liver metabolism Bioavailability25-30%

美施康定（硫酸吗啡缓释片） 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。

Heroin (diamorphine) Semisynthetic substance, prodrug of morphine More lipid soluble than morphine More rapid onset 德国拜尔公司 heroin在德文中意为英雄 万能药 药品转变为毒品 白粉

Codeine higher oral efficacy 2. lower efficacy than morphine 3. use as antitussive, severe dry cough. 联邦止咳露 ： 麻黄碱+可待因+氯苯那敏+氯化铵 注意事项 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) Weaker potency than Morphine, no antitussive action More rapid onset and shorter duration (2-4h) than morphine Metabolite: normeperidine  convulsion Lyticcocktail

Methadone 1. synthetic compound, equal analgesia to morphine 2. milder abstinence syndrome 3. routinely used in detoxification of morphine addicts

Fentanyl 1. more analgesic potentcy than morphine: 2. rapid onset and short duration of action 3. fentanyl, alfentanil, remifentanil: adjunctive drug for general anaesthesia 4. Fentanyl + Droperidol (氟哌利多): neuroleptanalgesia (神经阻滞镇痛术) Used for minor surgery 5. breakthrough cancer pain:

口腔经粘膜芬太尼拘橼酸盐 (Oral Transmucosal Fentanyl Citrate, OTFC) ACTIQ Fentanyl lollipop high lipid- soluble 芬太尼口腔粘膜贴片 (Fentanyl sublingual tablets) ABSTRAL 芬太尼透皮贴剂 (Fentanyl transdermal system) 多瑞吉

Pentazocine κ,  agonist , μ partial agonist weak action on μ : analgesia and respiratory depression : weaker weak action on μ : little addictive liability precipitate withdrawal syndrome of morphine abuser increase blood pressure and cause tachycardia ( NA) 列入非麻醉药品。但久用仍会成瘾！

Tramadol Atypical opioid: weak μ activation, also interacts with monoaminergic systems (inhibit NA and 5-HT reuptake) Alternative to traditional opioid analgesics 2008年1月1日国家将曲马多列为精神药品进行管理

延胡索乙素和罗通定 罗通定为左旋体的延胡索乙素，是有效部分。 镇静安定镇痛和中枢性肌肉松弛作用 解热镇痛抗炎药＜镇痛作用＜哌替啶，镇痛作用与阿片受体及前列腺素均无关 无明显成瘾性 口服后10-30min起效，维持2-5h，对慢性持续性钝痛效果好 不影响产程

Adverse effects 1. Tolerance large doses at short intervals readily cross tolerance full agonist: more obvious

Adverse effects 2. Dependence physical dependence： withdrawal syndrome psychological denpendence: compulsive drug- seeking behavior

依赖性 精神依赖性 身体依赖性 渴求 戒断综合征 强迫性用药 药物滥用

药物滥用（drug abuse）: 非医疗目的反复使用具有依赖性潜能的精神活性物质。体验该物质产生的特殊精神效应。 药物误用(drug misuse)：用药适应证选择不当 / 用量过大、疗程过长等错误用药行为。

gooseflesh (piloerection) Withdrawal syndrome of Opioid rhinorrhea Lacrimation chills gooseflesh (piloerection) yawning sweating muscular ache vomiting diarrhea anxiety hostility hyperventilation

Respiratory depression 3. General adverse effects 1 Constipation 5 Respiratory depression 2 Biliary colic 6 Postural hypotension 3 Nausea and vomiting 7 Increased intracranial pressure 4 Urinary retention 8 Dysphoria

4. Acute Morphine Poisoning

Naloxone 1. competitive full antagonist for opioid R (μ) 2. opioid overdose: reverses coma and respiratory depression 3. differential diagnosis in morphine abuser : precipitates withdrawal symptom 4. short t1/2 (1h) , repeated injections

Contraindications obstetric labor, breasting period obstructive airway disease, bronchial asthma head injuries seriously impaired hepatic or renal function

联合国禁毒机构估计全球约2亿人在滥用四类毒品，占全球15~64岁人口的5%。 阿片类 苯丙胺类 大麻 可卡因

Mode of administration of opioids Oral administration Sublingual administration Rectal administration Intravenous administration Intramuscular administration Intrathecal and epidural administration (鞘内给药) (硬膜外给药) Transdermal patch administration (透皮贴剂)

Patient Controlled Analgesia (病人自控镇痛，PCA) 根据病人对镇痛药需求的个体差异，使用专门设计的具有安全控制系统的微电脑输液泵，由医生设定给药剂量，病人可以根据个人需要，通过按压给药按扭自行给药，以满足镇痛治疗个体化需要。术后镇痛很多采取这种方法。医生会根据您的情况设置一个安全剂量范围，不必担心按压次数过多而引起药物过量。

Strong Opioids for severe pain Freedom from cancer pain WHO analgesic ladder e.g. morphine, fentanyl, methadone Strong Opioids for severe pain Pain persisting or increasing e.g. codeine， tramadol Weak Opioids for moderate pain Pain persisting or increasing NSAIDs e.g. aspirin, acetaminophen Non-opioid for mild pain Three steps analgesia therapy for cancer patients

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