pain10 11(%c1%a4%c7%f6)
TRANSCRIPT
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Ch.10Opioid Receptors
Pain conference
R2 최 정 현
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Pharmacology - pharmacodynamics
• Analgesia from opioid varies greatly between individuals– d/t the difference in morphology and physiology of opioid sys.
Ex) c/sec 후 adequate analgesia 위한 PCA morphine 요구량 study
0.6 ~ 5.2 mg/hr 로 variation 이 심함
• 3 receptor : mu, kappa, delta– Widely distributed in the brain, spinal cord, pph norciceptors
• pre and postsynaptic sites of ascending pain transmission sys in the dorsal horn of the spinal cord, the brain stem, thalamus, the cortex
• also found in the midbrain periaqueductal gray, the nucleus raphe magnus, rostal ventral medulla
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Pharmacology - pharmacodynamics
• Opioid receptor activated by exogenous opiates or endogenous peptide
• 3 major groups of endogenous opioid peptide
– Endorphin Mu receptor : mechanical, chemical, thermal norciception at spinal level
– Dynorphin Kappa receptor : spinally mediated thermal norciception and chemical visceral pain
– Enkephalin Delta receptors : mechanical norciceptions and inflammatory pain
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Pharmacology
1. Opioid agonist analgesics
2. Opioid agonist-antagonist analgesics
3. Opioid partial-agonist analgesics
4. Opioid antagonist
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Opioid agonists
• 주로 mu receptor 에 bind – 3 chemical class
1. phenanthrene opioid agonists : morphine, hydromorphone, codeine, oxycodone, oxymorphone, hydrocodone
2. phenylpiperidine opioid agonists : meperidine, fentanyl, sufentanyl, alfentanil, remifentanyl
3. diphenylhepatane opioid agonists : methadone, propoxyphene
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Opioid agonists
• Mu receptor activation analgesia (desired effect)
constipation (side effect)
• Research : 각각의 3 가지 receptor 를 연구 (mu, kappa, delta)
– Knockout mice(lacking mu receptor) 를 이용 : morphine 을 주어도 analgesia, respiratory depression, constipation, physical dependence, reward behavior 가 나타나지 않음
– central role Mu receptor
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Opioid Agonist-Antagonist Analgesics
• one opioid receptor 에 binding- agonist activity
• Binding another opioid receptor – producing no or low receptor activity
• Butorphanol, nalbuphine, pentazocine– agonist at kappa receptor and antagonit at mu receptor
• Chronic use, physical dependence 환자에게 투여시 withdrawl symptom을 촉진시킬 수 있다
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Opioid Antagonists
• Full agonist response 의 일부만 나타남• Buprenorphine : addiction history 있는 환자에게 유용
Opioid Partial-Agonist Analgesics
• Naloxone, naltrexone, nalmefene
• Naloxone, nalmefene : opioid- induced sedation 이나 respiratory depression 을 reverse 하는데 유용
• Naltrexone : opiate and alcohol addiction 치료에 사용
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Opioid Pharmacokinetics
• Opioid analgesics 는 uptake 나 clearance 에 개인마다 많은 차이가 있다 - 개인마다 dose titration 필요
• Hydromorphone, morphine - liver 에서 uridine diphosphate glucuronosyl transferase(UDT) enzyme 에
의해 대사되서 hydromorphone-3-glucuronide, morphine-6-glucuronide, morphine-3-glucurinode 로 대사됨
- renal excretion : severe renal dysfunction 환자에서는 undesirable effect 나타날 수 있다
• Fentanyl, methadone - cytochrome P450 enzyme(CYP3A4) 에 의해 대사되어 norfentanyl, EDDP,
N-demethylated methadone 으로 됨 - macrolide antobiotics : CYP3A4 를 inhibition 해서 fentanyl, methadone 의
clearance 를 감소시킴 - Anticonvulsant phenytoin 은 fentanyl, methadone 의 clearance 를 증가시킴
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Adverse effectCommon side effects
Constipation
• m/c opioid side effect• Abd. pain, bloating, nausea, vomitting, urinary retention 을
발생시킬 수 있음
• Mechanism – Gastric antrum 과 proximal duodenum 에 opioid receptor 가 high co
ncentration 으로 존재 opioid 가 intestinal motility 를 감소시켜 colonic transient time 을 증가
• Tx : stool softner, laxative
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Nausea and vomitting
• 다행히도 보통의 환자들은 rapid tolerance 를 가짐
• Opioid induced nausea & vomiting 에는 여러 mechanism 이 관련
1. Stimulating the vestibular apparatus : tx with meclizine, promethazine, scopolamine
2. Stimulation of chemoreceptor trigger zone : controlled with droperidole, prochlorperazine, ondansetron, hydroxyzine
3. constipation
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Sedation
• 특히 Opioid 를 처음 사용하는 환자나 chronic therapy 중에 증량중인 환자에서 sedation 과 drowsiness 발생할 수 있다
• Pain 이 sedation 을 antagonize 할 수 있음
• Stable dose 로 사용기간이 길어지면 보통 sedating effect 에 tolerance 가 생김
• sedation intolerance 의 contributing factor– CNS depressant medication, renal and/or hepatic dysfunction, neuropathic pain, disease r
elated fatigue, or intracerebral metastasis
• Chronic opioid theraphy 필요한 환자에서 sedation 을 경감시키기 위해서 – 다른 CNS depressant medication 를 감량– opioid dose 를 감량– mephylphenidate 같은 psychostimulant 를 사용하는것이 도움될수 있다
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Itching
• Oral or parenteral route 로 투여받는 환자보다 neuraxial opioid 사용한 환자에서 더 흔하다
• 보통 증상은 mild 해서 치료 필요치 않음
• Morphine produce histamine release - itch-specific C fiber 에 있는 H1 receptor 를 자극• Fentanyl 은 histamine release 하지 않지만 다른 기전으로 itching 발생
• Serotonergic receptor and mu and kappa receptor 가 관계되는 것으로 생각됨– 최근 study 에서 ondansetron 이 intrathecal morphin, fentanyl 에 의한 itching 을
감소시킨다는 보고가 있음
• Nalbuphine : analgesia 에 영향없이 epidural or intrathecal morphine 에 의해 생긴 itching 치료에 유용
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Less common side effects
Respiratory depression
• Rare, opioid-naive patient 에서 급속주입시에 나타날 수 있음 .• Brainstem respitatory center 에 있는 mu receptor 를 자극해 hypoxic and hyperc
apnic respiratory drive 를 억제• Pain 은 physiological antagonist : pain relief 시에는 dose reduction 해야
• Tx - naloxone 0.4mg 을 N/S 10cm3 에 dilution 해서 2 분마다 0.5cm3 씩 투여 - 소아나 40kg 미만의 성인은 0.5μg/kg IV 2 분마다 투여 - naloxone 이 대부분의 opioid 보다 action duration 이 짧으므로 투여후에도 clos
e observation 필요
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Cognitive dysfunction
• Opioid analgesics 를 처음 시작하는 환자에서 reaction speed 감소 보일 수 있음
• 수일동안 opioid therapy 지속하면 tolerance 생김• Opioid 투여 시작 , 증량시 7 일간은 drive 금지
Delirium
• 주로 terminal cancer pts 에서 흔함• 특히 renal function 감소한 환자에서 delirium 의 원인이 됨• Morphine 과 meperidine 의 metabolite 인 Morphine-3-glucuronide, Morphine-
6-glucuronide, normeperidine 등이 원인이 됨• Delirium 의 risk 가 높은 환자나 cognitive impairment sign 있는 환자
– fentanyl, methadone 같이 active metabolite 가 신장에서 배설되지 않는 약제– oxycodone, hydromorphone 과 같은 less active metabolite 생기는 약제 사용
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Myoclonus
• High dose 로 사용시 모든 opioid analgesics 가 유발 가능
• 신기능 감소한 환자에서 morphine and meperidine 을 higher dose 로 투약한 경우 metabolite 인 morphine-3-glucuronide, normeperidine 이 accumulation 되어 발생하는 경우가 가장 흔함
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Ch.11Major Opioid in Pain Management
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Rationale
• Acute and chronic pain management 에서 opioid theraphy 는 필요
• 그러나 chronic nonmalignant pain(CNMP) 에서 opioid 를 1st line Tx 로 사용할지에 대해서는 아직 논란이 있음
• Health care professionals : 2nd line 으로 사용하는 경향– Arthritic pain & neuropathic pain 에서는 NSAIDs, anticonvulsant, TCA 가 efficacious– CRPS type I,II 등에서는 injection therapy 가 more effective– Side effect 로 인한 risk-benefic ratio 고려시 alternative Tx. 가 사용될 수 있다 .
• Opioid trial 은 alternative analgesics, interventional pain procedure, and physical and psychological theraphy 가 부적절하거나 금기인 경우 사용
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Administration
• short acting opioid 는 pain relief 와 악화를 반복하는 “ roller coaster”effect 생길 수 있음 .
Chr. Pain Tx 에서 Opioid 투여의 goal 은 regular interval 로 sustained analgesia 유지
• Fixed dose > as needed(PRN)
• Oral administration : convenience, prefferd route• IV or SQ : commonly used in cancer pts• SQ : faster onset than most oral preparations (slower than IV) venous access 어려운 환자에 유용 Bleeding disorder pts 나 muscle mass 감소된 환자에서 안전• PCA : morphine, hydromorphone, fentanyl 사용 주로 Postoperative pain management 에서 사용• Alternatives : rectal, sublingual, buccal, intranasal, transdermal, epidural, i
ntrathecal
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Selected opioidsMeperidine ( demerol )
• Weak mu-receptor agonist• IM 으로 흔히 사용되지만 neurotoxicity potential 때문에 사용 점점 감소
• Morphine 과 비교해서 potency 1/10, slightly more rapid onset, shorter duration of action
– Equianalgesic dose 에서 less sedation and prurutis, more effective in neuropathic pain
• Significant cardiac, anticholinergic, and local anesthetic property 가 있기 때문에 therapeutic window 감소
• Postanesthetic shivering Tx. 에 유용• Prolonged adm.(3 일 이상 ) 시 neurotoxic metabolite(normeperidine) 의 accum
ulation – CNS hyperactivity seizure• MAO inhibitor 와 같이 투여시 치명적일 수 있다• SSRI, tramadol, methadone 과 함께투여시 주의
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Morphine
• Prototypical mu agonist, 다른 opioid 의 equianalgesic potency 비교기준
• IV, epidural, intrathecal• Oral formulation : sustained release(SR), immediate-release(IR)
• Hydrophilic : BBB 통과가 지연되서 다른 opioid 보다 onset 느리다– Brain 에서 low solubility & slower elimination Plasma half life(2~3.5 hrs) 보다 analgesic effect 가 더 길다 (4~5 hrs)
-• 2 major metabolite : morphine-3-glucuronide(M3G), morphine-6-glucuronide(M6G) - M3G : 50% of morphines metabolite 동물실험에서 generalized hyperalgesia, CNS irritability, seizure, myoclonus 등을
일으키는것으로 보고됨 human chronic use 환자에서 side effect 와 관련이 있을 것으로 추정
- M6G : 5~15% Intrinsic opioid agonism 으로 analgesic effect 있다
• Hepatic mech. 의해 elimination 되므로 cirrotic pts 에서 주의• Morphine metabolite 들은 신장에서 배설되므로 kidney dysfunction 있는 환자에서
용량조절
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Oxycodone
• Morphin 의 semisynthetic congener
• SAO, IR preparations (single agent or compounded with AAP or aspirin)• SR fomulation(oxycontin)
• SR oxycodone– no ceiling dose, minimal side effect, absence or minimal active metabolite, eas
y titration, rapid onset of action, short half life, long duration of action, predictable pharmacokinetics
• Oxycodone 은 prodrug 으로 hepatic metabolism(via cytochrome P450 2D6 enzyme) 에 의해 2 가지로 대사됨 .– oxymorphine :mu-opioid agonist property 를 갖는 active metabolite– noroxycodone : inactive metaboliote
• SSRI, TCAs, neuroleptics 복용중인 환자에서 용량 주의해 사용
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Hydromorphone
• Morphin 의 hydrogenated ketone analogue• Oral ,IV, epidural, intrathecal 로 사용 가능
• Strong mu-opioid receptor agonist activity• Morphine 과 비교해서
– similar duration of analgesic effect(3~4 hrs)– less frequent side effect(pruritis, sedation, N/V)– Hydrophilic 하지만 morphin 보다 10 배 lipid soluble 5~7 배 potency
• Onset : oral – 30min, IV – 5min
• Impaired GI function 있는 hospice pts 에서 안전하게 SQ 로 사용 가능• Hepatic biotransformation 에 의해 hydromorphone-3-glucuronide(H3G) 로
대사되어 renal excretion• M3G 와 같이 H3G 도 neurotoxicity 있어 neuroexcitation(seizure, allody
nia, myoclonus) 유발 가능– 하지만 renal insufficiency 가 있는 환자가 아니면 양이 적으므로 negliable
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Methadone
• 장점– Low cost
– high bioavailability with absorption and activity within 30 min
– multiple receptor affinity
– lack of known metabolite that produce neurotoxicity
• 단점– Unpredictable bioavailability, high interindividual variability
• Liphophilic 2 isomer– D-isomer : NMDA receptor antagonize, 5-hydroxytryptamine, norepi. Reuptake inhibit
– L-isomer : opioid receptor agonist
• Mu receptor 에 morphin 보다 lower affinity side effect 적음• Greater affinity than morphine for delta-opioid receptor
- opioid-induced tolerance and dependence 를 desensitization 시킬 수 있다
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Fentanyl
• Perioperative and postop pain management 에서 IV, epideral, intrathecal 로 사용• Predominantly mu-opioid agonist property• Morphine 보다 faster onset, 75~125 배 potent• Transdermal and transmucosal application 가능
• Transdermal fentanyl (Duragesic Patch)– Chronic or cancer patient 에만 쓰도록 권고
• Postop pain Mx. 에 사용시 20% 의 hypoventilation 발생 보고됨– Therapeutic serum level 도달까지 1~30 시간 ( 평균 13 시간 ) 걸리므로
도달할때까지 SAO, IV PCA 처방 .– GI tract 을 지나지 않아 이론적으로 oral opioid 보다 constipation 적게 발생– oral medication 불가능한 환자에서 사용할 수 있다– transdermal rate absorption, skin temp, fat stores, muscle bulk 등 의 개인차로 dose titr
ation 어려울 수 있다– m/c side effect : erythema , itching, pustule formation
• Oral transmucosal fentanyl citrate– rapid onset(5~10 min), short duration of action– Impaired swallow or GI tract 에서 breakthrough pain 시 사용하기 좋음
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Sufentanil (sufenta)
• Fentanyl 의 thiamyl analogue
• 주로 operative setting 에서 iv or neuraxial analgesics 로 사용
• 주로 CYP3A4 isoezyme 에 의한 hepatic metabolism
• Fentanyl 보다 greater analgesic potency, shorter half-life, rapid onset , shorter duration of effect
• Dose related skeletal m. rigidity 유발 가능
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Alfentanil (alfenta)
• iv or neuraxial analgesics 로 사용
• Short elimination half life, rapid onset of analgesia, short duration of effect
• Repeated dose 나 continuous infusion 으로 사용해도 accumulation 적다 Ideal in operative setting
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Remifentanil (ultiva)
• Most potent mu-opioid receptor agonist• Adm. IV for induction and maintenance of anesthesia
• Larger volume of distribution• more rapid distribution and metabolism• shorter elimination half life(3~10min)• more rapid analgesic onset(1min)• shorter duration of effect(5~10min)
• Liver 에서 대사되지 않고 tissue and plasma esterase 에 의해 degradation 후 renal excretion renal or hepatic insufficiency 에 영향받지 않음
• Continuous infusion 으로도 accumulation effect 없다 .
• Brisk clearance and lack of accumulation operative setting 에서의 장점이됨 . But Infusion 을 중지하면 rapid loss of analgesia