Part 12AnalgesicsOpioid analgesicsSynthetic opioid analgesicsOther analgesicsGeneral ConsiderationsPain ( (疼痛疼痛疼痛疼痛) )： 躯体痛快痛，慢痛躯体痛快痛，慢痛躯体痛快痛，慢痛躯体痛快痛，慢痛 内脏痛内脏痛内脏痛内脏痛 情绪反应情绪反应情绪反应情绪反应Analgesia ( (镇痛镇痛镇痛镇痛) )： 选择性抑制疼痛感觉，选择性抑制疼痛感觉，选择性抑制疼痛感觉，选择性抑制疼痛感觉， 不影响意识和其他感觉不影响意识和其他感觉不影响意识和其他感觉不影响意识和其他感觉Pain ClassificationHeadacheHeadache(migraine)(migraine)AcuteAcuteChronicChronicPainPainNociceptiveNociceptiveMixedMixedNeuropathicNeuropathicVisceralVisceralDiabetic neuropathy (DN)Post-herpetic neuralgia (PHN)Radiculopathy (RADIC)Cancer painLow back painOsteoarthritisRheumatoid arthritisFibromyalgiaIBSPancreatitisBladder painNoncardiac chest painAbdominal pain syndromeInjuryInjuryPostoperativePostoperativeFlareFlareAn adverse or unpleasant reactionplus the reactions evoked by itPain generation and reactionsPain generation and reactionsStimulation and depolarization of sensory nerve endingsStimulation and depolarization of sensory nerve endingsPain: peripheral sensory reflex Peripheral mechanisms of painPeripheral mechanisms of painPrimary & secondary hyperalgesiaThe perception of somatic painThe perception The perception and conduction and conduction of somatic painof somatic painConduction pathways of painCortical locations of pain The fMRI imaging of painClassification of analgesics：Opioid analgesics (centrally acting) opiatesopiates synthetic agentssynthetic agentsAntipyretic, analgesic, and anti-inflammatory drugs (peripherally acting) aspirin, indomethacinaspirin, indomethacinOther drugs (for special types of pain) carbamazepine, atropine, nitroglycerin, carbamazepine, atropine, nitroglycerin, etc.etc.General ConsiderationsMorphine 吗啡吗啡Morphine Morphine 吗吗吗吗 啡啡啡啡Heroin Heroin 海洛因海洛因海洛因海洛因A. Opioid AnalgesicsOpiumOpiumMorphine:Morphus, the Greek god of dreams1. Pharmacological effects(1) Mechanisms of actions Acting on central opioid receptors receptors receptors receptorsA. Opioid AnalgesicsATPcAMPGiACOpioid Receptors and Endogenous Ligands EndorphinEndorphinEnkephalinEnkephalinDynorphinDynorphinK+abgabgGi=Mechanisms of morphine actionsPeripheral mechanisms of morphine actionsCentral mechanisms of morphine actions: Central mechanisms of morphine actions: Pain inhibitory systemPain inhibitory system(2) Central nervous system effectsA. Analgesia：maximal analgesic efficacymaximal analgesic efficacy； relieving unpleasant sensation; relieving unpleasant sensation; euphoniaeuphonia and potential of dependence and potential of dependenceB. Depression of respiration: reducing the sensitivity of respiratory center to reducing the sensitivity of respiratory center to COCO2 2C. Depression of cough reflexD. Other central effects: miosis, emesismiosis, emesisA. Opioid Analgesics(3) Cardiovascular effectsA. Postural hypotension： Releasing histamine; depressing CVS centers Releasing histamine; depressing CVS centersB. Increase of intracranial pressures： Respiratory depression Respiratory depression brain CObrain CO2 2 increaseincrease vasodilatation in the brain vasodilatation in the brainA. Opioid Analgesics(4) Effects on smooth musclesA. A. GI tractGI tract： Contispation:Contispation: increasing increasing resting resting tone tone of of smooth smooth muscles muscles and and sphincters, decreasing propulsive peristalsis and secretions; sphincters, decreasing propulsive peristalsis and secretions; Biliary Biliary tracttract：Oddis Oddis sphincter sphincter contraction, contraction, increasing increasing the the pressure in the biliary tractpressure in the biliary tractB. B. Respiratory tractRespiratory tract：bronchoconstrictionbronchoconstrictionC. C. Urinary Urinary tracttract：increasing increasing vesical vesical sphincter sphincter tone tone urinary retentionurinary retentionD. D. Uterus Uterus A. Opioid Analgesics(5) Other effectsA. Immune depressionB. Endocrine effectsA. Opioid Analgesics2. Clinical uses(1) Analgesia the the pain pain of of high high intensity intensity and and the the pain pain of of terminal terminal illnessillnessCautions: a) obscure the symptoms and the progress of the disease; a) obscure the symptoms and the progress of the disease; b) dependence or addiction; b) dependence or addiction; c) biliary colic: combined with atropine c) biliary colic: combined with atropine d) not used for long-term if no clear indications d) not used for long-term if no clear indications A. Opioid Analgesics(2) Cardiac asthma (acute left ventricular failure) As an adjuvant treatmentAs an adjuvant treatment A. VasodilatationA. Vasodilatation: : afterload afterload B. SedationB. Sedation: : anxiety anxiety C. C. Respiratory Respiratory depressiondepression: : breathing breathing slowly slowly and deeplyand deeply(3) Diarrhea Mixture containing opiate Mixture containing opiate A. Opioid Analgesics3. Adverse effects(1) Side effects(2) Tolerance and dependence psychological and physic dependence: psychological and physic dependence: addictionaddiction withdrawal syndromes or abstinance syndromeswithdrawal syndromes or abstinance syndromesA. Opioid Analgesics(3) Acute intoxication coma, respiratory depression, coma, respiratory depression, hypotension, pinpoint pupils hypotension, pinpoint pupils reversed by naloxone, an opioid receptor antagonistreversed by naloxone, an opioid receptor antagonist(4) Contraindications labor and lactation; labor and lactation; bronchial asthma and cor pulmonal; bronchial asthma and cor pulmonal; increased intracranial pressures; increased intracranial pressures; severe hepatic damage severe hepatic damageA. Opioid AnalgesicsMorphine toxicity can Morphine toxicity can be reversed by opioid be reversed by opioid receptor antagonistreceptor antagonist (naloxone)(naloxone)Analgesia; central antitussiveCodeine 可待因可待因A. Opioid AnalgesicsB. Synthetic AnalgesicsPethidine 哌替啶哌替啶Dolantin 度冷丁度冷丁度冷丁度冷丁PethidinePethidineMorphineMorphineStructures of Structures of natural opioid natural opioid (morphine) and (morphine) and synthetic analgesics synthetic analgesics (pethidine)(pethidine)哌啶环中的叔氮哌啶环中的叔氮哌啶环中的叔氮哌啶环中的叔氮与叔氮相隔两个碳与叔氮相隔两个碳与叔氮相隔两个碳与叔氮相隔两个碳原子的季碳原子的季碳原子的季碳原子的季碳与季碳相连的苯环与季碳相连的苯环与季碳相连的苯环与季碳相连的苯环B. Synthetic AnalgesicsPethidine1. Pharmacological effects Similar Similar to to morphine morphine but but ineffective ineffective for for cough cough and and diarrhea, diarrhea, and and its its metabolite metabolite normeperidine normeperidine has has central central stimulant effects.stimulant effects.2. Clinical uses analgesia; analgesia; cardiac asthma; cardiac asthma; preanesthetic medicationpreanesthetic medication or artificial hibernation; or artificial hibernation; 3. Adverse effects similar to morphine, convulsion (overdose) similar to morphine, convulsion (overdose)Fentanyl （芬太尼芬太尼芬太尼芬太尼） high efficacyhigh efficacy combined with combined with droperidol: droperidol: neuroleptanalgesianeuroleptanalgesiaMethadone （美沙酮美沙酮美沙酮美沙酮） orally effectiveorally effective long-actinglong-acting also used for displacement in heroin or also used for displacement in heroin or morphine detoxicationmorphine detoxicationB. Synthetic AnalgesicsPentazocine （喷他佐辛喷他佐辛喷他佐辛喷他佐辛, , , , 镇痛新镇痛新镇痛新镇痛新） receptor agonist / receptor agonist / receptor partial agonist; receptor partial agonist; low-narcotic analgesic druglow-narcotic analgesic drug psychotomimetic effects: anxiety, nightmare, hallucinationspsychotomimetic effects: anxiety, nightmare, hallucinationsTramadol （曲马朵曲马朵曲马朵曲马朵） Relatively weak efficacy and dependenceRelatively weak efficacy and dependenceB. Synthetic AnalgesicsSummary of opioid receptor ligands附：附： 阿片受体拮抗药阿片受体拮抗药Naloxone （纳洛酮纳洛酮纳洛酮纳洛酮）Naltrexone （纳曲酮纳曲酮纳曲酮纳曲酮）Antidotes for acute intoxication of opioidsAntidotes for acute intoxication of opioidsTreatment of shock and other diseasesTreatment of shock and other diseasesOpioid receptor antagonistsSummary of opioid receptor ligandsRotundine （l l-tetrahydropalmatine,-tetrahydropalmatine, 罗通定罗通定罗通定罗通定）dl-Tetrahydropalmatine （延胡索乙素延胡索乙素延胡索乙素延胡索乙素） chronic painchronic pain sedative effects sedative effects no addiction no addictionC. Other Analgesics附：癌痛的镇痛治疗附：癌痛的镇痛治疗WHO提出的目标：提出的目标： 2000年，使癌症病人不痛！年，使癌症病人不痛！附：癌痛的镇痛治疗附：癌痛的镇痛治疗三级镇痛阶梯治疗：三级镇痛阶梯治疗： 轻度：轻度：轻度：轻度：解热抗炎镇痛药解热抗炎镇痛药解热抗炎镇痛药解热抗炎镇痛药 中度：中度：中度：中度：加用或改用弱阿片药加用或改用弱阿片药加用或改用弱阿片药加用或改用弱阿片药, , 辅助治疗药辅助治疗药辅助治疗药辅助治疗药 重度：重度：重度：重度：强阿片药，强阿片药，强阿片药，强阿片药，加非阿片及辅助治疗药加非阿片及辅助治疗药加非阿片及辅助治疗药加非阿片及辅助治疗药 应用原则：应用原则： 尽可能口服用药尽可能口服用药尽可能口服用药尽可能口服用药 按时规则用药，剂量个体化按时规则用药，剂量个体化按时规则用药，剂量个体化按时规则用药，剂量个体化 辅助措施辅助措施辅助措施辅助措施WHO Analgesic LadderWHO Analgesic Ladder