Analgesics 镇痛药 Opioid analgesics Synthetic opioid analgesics Other analgesics 汤慧芳 浙江大学医学院 药理系 2018-11-7

Pain Classification 躯体痛 An adverse or unpleasant reaction plus the reactions evoked by it Pain Acute Headache (migraine) Chronic Injury Postoperative Flare Nociceptive 躯体痛 Neuropathic Mixed Visceral 内脏痛 Irritable bowel syndrome,IBS肠易激综合征 Diabetic neuropathy (DN) Post-herpetic neuralgia (PHN) Radiculopathy 神经根痛(RADIC) Cancer pain Low back pain Osteoarthritis Rheumatoid arthritis Fibromyalgia纤维肌痛 IBS Pancreatitis Bladder pain Noncardiac chest pain Abdominal pain syndrome

General Considerations Pain (疼痛)： 躯体痛(somatic pain) －快痛，慢痛 内脏痛(visceral pain) 神经性痛 Analgesia (镇痛)： 选择性抑制疼痛感觉， 不影响意识和其他感觉

Peripheral mechanisms of pain

Thalamus Conduction pathways of pain

General Considerations Classification of analgesics： Opioid analgesics (centrally acting) Opiates Synthetic agents Antipyretic, analgesic, and anti-inflammatory drugs (peripherally acting) aspirin, indomethacin Other drugs (for special types of pain) Carbamazepine, atropine, etc.

Aspirin Opiates Diazepam, Indomethacin Opiates Synthetic agents Diazepam, Anti-depressents, etc. . Others：Carbamazepine, Atropine, Nitroglycerin, etc.

A. Opioid Analgesics Morphine 吗啡 B D C Morphine 吗 啡 Heroin 海洛因

Morphus, the Greek god of dreams Morphine: Morphus, the Greek god of dreams

Opium

The first publication of opioid receptor was in 1971 A.Opioid Analgesics 1. Pharmacological effects (1) Mechanisms of actions Acting on central opioid receptors  receptors, morphine  receptors, ketocyclazocine δ receptors, receptor was first identified in mouse vas deferens tissue(输精管组织) ORL1, opiate receptor-like 1 The first publication of opioid receptor was in 1971

(脑啡肽) (内啡肽) (强啡肽)

Peripheral mechanisms of morphine actions

Central mechanisms of morphine actions

A. Opioid Analgesics (2) Central nervous system effects A. Analgesia：maximal analgesic efficacy； relieving unpleasant sensation; euphonia（欣快） and potential of dependence B. Depression of respiration: reducing the sensitivity of respiratory center to CO2 C. Depression of cough reflex D. Other central effects: miosis（瞳孔缩小）, emesis

A. Opioid Analgesics (3) Cardiovascular effects A. Postural hypotension： Releasing histamine; depressing CVS centers B. Increase of intracranial pressures： Respiratory depression  brain CO2 increase  vasodilatation in the brain

A. Opioid Analgesics (4) Effects on smooth muscles A. GI tract： Contispation: increasing resting tone of smooth muscles and sphincters, decreasing propulsive peristalsis and secretions; Biliary tract：Oddi’s sphincter contraction, increasing the pressure in the biliary tract B. Respiratory tract：bronchoconstriction C. Urinary tract：increasing vesical sphincter tone  urinary retention D. Uterus

A. Opioid Analgesics (5) Other effects A. Immune depression B. Endocrine effects

A. Opioid Analgesics 2. Clinical uses (1) Analgesia Cautions: the pain of high intensity and the pain of terminal illness Cautions: a) obscure the symptoms and the progress of the disease; b) dependence or addiction; c) biliary colic: combined with atropine d) not used for long-term if no clear indications

A. Opioid Analgesics (2) Cardiac asthma (acute left ventricular failure) As an adjuvant treatment A. Vasodilatation: after-load  B. Sedation: anxiety  C. Respiratory depression: breathing slowly and deeply (3) Diarrhea

A. Opioid Analgesics 3. Adverse effects (1) Side effects (2) Tolerance and dependence psychological and physic dependence: addiction withdrawal syndromes or abstinance syndromes(戒断症状)

Opiate withdrawal syndrome

A. Opioid Analgesics (3) Acute intoxication coma, respiratory depression, hypotension, pinpoint pupils reversed by naloxone, an opioid receptor antagonist Pinpoint pupils

(4) Contraindications Labor and lactation; Bronchial asthma and cor pulmonal; Increased intracranial pressures; Severe hepatic damage

A. Opioid Analgesics Codeine 可待因 Analgesia; central antitussive

B.Synthetic Analgesics Pethidine 哌替啶 Dolantin 度冷丁

Structures of natural opioid (morphine) and synthetic analgesics (pethidine) 哌啶环中的叔氮 与叔氮相隔两个碳原子的季碳 与季碳相连的苯环 Morphine Pethidine

B.Synthetic Analgesics Pethidine 1. Pharmacological effects Similar to morphine but ineffective for cough and diarrhea, and its metabolite normeperidine has central stimulant effect 2. Clinical uses analgesia; cardiac asthma; preanesthetic medication or artificial hibernation; 3. Adverse effects similar to morphine, convulsion (overdose)

B.Synthetic Analgesics Fentanyl （芬太尼） high efficacy combined with droperidol (氟哌利多): 1:50 neuroleptanalgesia 神经安定镇痛术 Methadone （美沙酮） orally effective long-acting also used for displacement in heroin or morphine detoxication 美沙酮替代治疗，用于戒毒！

B.Synthetic Analgesics Pentazocine （喷他佐辛, 镇痛新） κ receptor agonist / μ receptor partial agonist; non-narcotic analgesic drug psychotomimetic effects: anxiety, nightmare, hallucinations Tramadol （曲马朵） Relatively weak efficacy and dependence

丁丙诺啡 丁丙诺啡 Buprenorphine – an attractive opioid with underutilized potential in treatment of chronic pain. J Pain Res. 2015;8:859-870.

Opioid receptor antagonists 附： 阿片受体拮抗药 Naloxone （纳洛酮） Naltrexone （纳曲酮） Antidotes for acute intoxication of opioids Treatment of shock and other diseases

Summary of opioid receptor ligands

C.Other Analgesics Rotundine （罗通定） dl-Tetrahydropalmatine （延胡索乙素） chronic pain sedative effects no addiction

WHO Analgesic Ladder

附：癌痛的镇痛治疗 三级止痛阶梯治疗： 轻度：解热抗炎镇痛药 中度：加用或改用弱阿片药 重度：强阿片药 应用原则： 尽可能口服用药 按时规则用药，剂量个体化 辅助措施

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