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Opioid Analgesics

H.Y Yang

Institute of Pharmacology, NYMU

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Opioid & Opiopeptin

Opioid 類嗎啡樣物質 : a. all drugs, natural & synthetic, with morphine-like

action (opiate )

b. all exogenous substances that bind

specifically to any subtype of opioid receptor and

produce some agonistic action

Opiopeptins 類嗎啡樣多胜: all endogenous

opioid peptides ( -endorphin, Leu-enkephalin, Met-

enkephalin, Dynorphin, etc )

Narcotic : imprecise term

opioid system : 4 major opioid receptors

1. Sensory, GI, endocrine, ANS

2. Emotion : rewarding and addictin

3. cognitive : leaning & memory

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Pain痛覺 & nociception傷害性感受

Definition :實質或潛在的組織之直接傷害或有關此傷害所敘述之不愉快的感覺和情緒的經歷；大多數我們所謂之痛，包括情緒上的反應，都是主觀、後天學來的，不是本能的反應。

"poine" in Greece, "poene" in Latin, meaning "penalty贖罪" or "punishment" from the gods. Pain is a complex experience encompassing sensory, affective, and cognitive elements.病患多用比喻性字眼形容；如偏頭痛會說好像有人用針刺我的眼睛。我們報告刺傷的痛楚時，想像一把利刀直刺入肌膚，而那些曾被刺傷的所表達的是完成不同之感覺；不是強力快速刺入，而像被揮一拳後，久久不能散去。如凍傷後2~3分鐘後所呈現的是燒炙感，接著是疼痛感。

Acute, chronic & neuropathic pain

Referred pain 牽連痛for visceral pain

Hyperalgesia 痛覺過度Phantom pain 截肢幽靈痛

Allodynia 觸物感痛Compartment :

1. Sensation 感覺 & sensitization 致敏 nociception傷害性感受 ;

2. Recognition 認知3. Discrimination 辨識

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Pain sensation Mixed function polymodal nociceptor : type C , A fiber

1. thermoreceptor :vanilloid receptor subtype 1 (VR1 or capsaicin receptor , a ligand-gated, non-selective cation channel) which is involved in noxious heat

2. Chemosensitive nociceptor and algesic致痛substance: K+, 5-HT ( 5HT1a ), PGs, kinins, ATP, NMDA (not hist), nerve growth factor, neuropeptides (Sub.P, calcitonin gene-related peptide, IL-1( IL-1), neutrophil-chemotactic peptides, and NGF-octapeptide

3. TTX-resistant Na+ channel ( Nav1.8 , termed PN3 or sensory-neuron specific, SNS) may play

a key role in neuropathic and chronic inflammatory pain

4. PKC-knock-out mice display intact acute pain responses but reduced thermal and mechanical

allodynia after nerve injury.

Tissue injury induced hyperalalgesia ( receptor hypersensitivity ) involved

A. Neuronal factor ( NMDA, sub. P , neurokinin-1)

B. Ciculating factors ( TNF-, IL-1 )

C. Kinases ( PKC) , PLase-A2, COX2

D. Channels ( Ca, TTX-resistant Na ) &

receptors ( NMDA )

PG & sub. P: enhance sensitivity,

NOT direct excitation

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Molecular mechanisms involved in pain

Transcription factors and second messenger molecules : expression of c-fos, CREB ( cAMP response element binding protein ), ERK

(extracellular signal-regulated protein kinases ) as a molecular marker for

noxious stimulation

Neurotrophic factors (neurotrophins) : NGF (nerve growth factor),

GDNF ( glial-cell-derived neurotrophic factor ) & BDNF (brain-derived neurotrophic

factor )

Cytokines and inflammatory pain : Pro-inflammatory ( TNF-, IL-1,

IL-6, IL-8, etc) and anti-inflammatory ( IL-4, IL-10, IL-13, etc.) cytokines

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傷害性信息上行傳導路徑 Med (Paleo) ST tract, relays in reticular

formation to Intralaminar thalamic N. and end in limbic system ( ant. Cingulate gyrus) : polysynaptic, diffuse, emotional component involved, lack of somatotopic representation

The majority of these spinal m- & -receptor ligand-binding sites are located presynaptically on the terminals of primary afferent nociceptors.

Neurotransmitter in

PAG : 5-HT, NT, SP, VIP, Enk, Dyn, GABA.

NRM : Enk, SP, SOM, TRH ,5HT ( colocalized with Enk )

LC : NA ( 2 ), NPY, galanin.

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Pain Recognition 上行性路徑 :

Primary sensory component of m-opioid receptor : ipsilateral nucleus accumbens and amygdala

pain-specific affective component of m-opioid

receptor : dorsal anterior cingulated

旁支: Enkephalinergic local circuit neuron could "gate" the activation of the spinothalamic pathway

牽連: Neurochemical changes in sensory neurons and spinal cord, e.g.

Inflammation sub P & CGRP in SG

Neuropathy sub P & CGRP; where galanin, NPY, GAP-43

Bone cancer glial fibrillary acidic protein ( GFAP )

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Opioid receptor-evoked cellular responsesDirect G-protein or a subunit-mediated effects

activation of an inwardly rectifying K channelinhibition of voltage operated Ca channels (N, P, Q and R type)inhibition of adenylyl cyclase

Responses of unknown intermediate mechanismactivation of PLA2 , PLC ( possibly direct G protein subunit activation), MAPKinase, large conductance Ca-activated K channels, L type voltage operated Ca channels, inhibition of T type voltage operated Ca channelsdirect inhibition of transmitter exocytosis

Responses which are a consequence of opioid-evoked changes in other effector pathwaysactivation of voltage-sensitive K channels (activation of PLA2)inhibition of M channels ( activation of PLA2)inhibition of the hyperpolarisation-activated cation channel (reduction in cAMP levels following inhibition of adenylyl cyclase)elevation of intracellular free Ca levels (activation of PLC, activation of L type voltage operated Ca conductance)potentiation of NMDA currents (activation of protein kinase C)inhibition of transmitter release (inhibition of adenylyl cyclase, activation of K channels and inhibition of voltage operated Ca channels)decreases in neuronal excitability (activation of K channels)increases in neuronal firing rate ( inhibition of inhibitory transmitter release - disinhibition)changes in gene expression : long-term changes in adenylyl cyclase activity, elevation of intracellular Ca levels, activation of cAMPresponse element binding protein (CREB)

unique receptor mechanisms are achieved through alternative splicing within its C terminus :

1. k and opioid receptors have been shown to exist as homodimers & heterodimer to alter their pharmacological properties

2. m and receptors recognize principally the Tyr-Gly-Gly-Phe core of the endogenous peptide, whereas the k receptor requires this core and the arginine in position 6 of dynorphin A and other prodynorphin products

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Pain Discrimination

Descending inhibitory pathway : med &

intralaminar thalamic N , PAG , through dorsal raphe magnus (NRM), Nucleus reticularis gigantocellularis (NRGC) to dorsolat. funiculus to laminar I, II of spinal

dorsal horn.

Pain experience involved in primarily sensory (e.g., ipsilateral nucleus accumbens and amygdala) or affective

and unpleasantness (e.g., dorsalanterior cingulate, prefrontal cortex ) components in the brain

Opioid peptides and their receptors are found throughout these descending pain control circuits

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Pain anatomy system 痛覺之接受 ( perception of pain) : laminae I and II of the spinal

cord, the spinal trigeminal nucleus, and the periaqueductal gray

感受與行為(affective behavior)之調適 : amygdala, raphenucleus, hippocampus, locus ceruleus, and the frontal cerebral cortex

動作( motor control )之調適 : caudate nucleus and globuspallidus

自主神經之協調: medulla oblongata

神經內分泌之協調 : median eminence.

Sites of opioid (MOR )-induced analgesia :

a) Endorphins are found in all regions where pain is modulated, i.e. the

descending inhibitory pathway and the peripheral tissues.

b) Periaqueductal gray (PAG)

c) Nucleus raphe magnus (NRM)

d) Spinal cord dorsal horn, trigeminal nerve

e) Peripheral afferent terminal

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Action site in CNSLocalization Functions

Spinal Cord: Laminae I,& II modulation of pain perception

Brain Stem: Sub. gelatinosa of spinal tract of caudal trigeminal N. modulation of pain perception

N. solitary Tract, N commissuralis, N ambiguus taste, vagal reflex, cough suppression, respiration, orthostatic hypotension, inhib. of gastric secretion, EEG synchronization and sleep induction

Area postrema nausea and vomiting

Locus ceruleus arousal, attentiveness, muscle inhibition during REM sleep

Habenula-interpeduncular N-fasciculus retroflexus emotional behavior, site of action between limbic area and basal ggl

Pretectal area ( Med. & Lat optic N. ) Upward eye movements and pupillary reflexes

Superior colliculus Orienting movements of head & eyes to sensory targets

Ventral N. of lat. geniculate central modulation of visual input

Dorsal, Lat, med terminal N of accessory optic pathway entrainment of endocrine rhythms by light, fine adjust of head-eye

Dorsal cochear N modulation of auditory input

Parabrachial N. Resp., breathing pattern, & modulation of taste and pain

Diencephalon: Infundibulum oxytocin and vasopressin secretion

Thalamus : Med Lat N, int.,ext, & intra laminae N, periventricular N modulation of pain and other somatic sensory , arousal, attention

Telencephalon : Amygdala emotional , fear and aversively motivated behaviors

Caudate putamen, globus pallidus motor coordination

N. accumbens locomotion, psychomotor ,reinforcing activity

Subfronical organ water balance

Interstitial N of stria terminals olfactory control of male sexual behavior

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Pain is suffering : 癌轉移之

1. 骨痛:持續、鈍、深部痛；夜晚、運動加劇

2. 臟痛: 間歇、悶、拉扯、深部痛；伴有噁心、嘔吐

3. 神經痛: 灼熱、刺麻感；伴有感覺遲鈍

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Chronic Severe painkiller : Opioids

Contraindication for head injury

Neuropathic pain not effective

1st choice for terminal stage in

cancer –induced pain

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Epidural & subdural injection for Cancer pts

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Preoperative & adjunctive in anesthesia Heart surgery : fentanyl, (i.v.), morphine

(epidural ) for regional anesthesia

Analog der. : Alfentanyl, Sufentanil , Remifentanil ( Ultiva , with higher affinity, rapid recovery, for neurosurgery; elimination by plasma esterase ) ultra short duration (duration: 15', T½ : 5' ), resp. depression (1/4 of morphine, 1/10 of fentanyl )

Illicit analog, e.g.-methylfentanyl "China White"; 3-methylfentanyl ( more potent than morphine, lethal dose: mM range.

Obstetric analgesia : be caution of meperidinepass cross placenta

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New analgesics

Epibatidine

- Source : 南美厄瓜多爾之毒青蛙Epipedobates tricolor表皮腺

體萃取之生物鹼

- nonopioid analgesic : n-AChR 4(2)2 receptor agonist, ggl blocker

- Potency : 200-500 X of morphine,

- toxicity : resp. arrest in analgesic dose

- patent : ’93 年由Syntex之 Broka及Corey, Fletcher完成其結構及全合成

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Chronic pain Characteristics :

1. Activation of NMDA Receptors

2. Activation of neurokinin-1 ( NK-I ) Receptors

3. Neurogenic Inflammation

4. Hyperalgesia and Allodynia

So morphine1. Not suitable for Migraine

2. Not effective to Neuropathic pain

3. Not recommended for RA

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情緒影響力

疼痛之正常反應 : 焦慮、害怕、驚嚇、與

痛苦(suffering)

疼痛增強之負面情緒 : 恐懼、憤怒、罪惡感、孤獨與無助

疼痛舒緩之正面情緒 : 希望、信心、愛、快樂、生存意念、創造力、嘻鬧

但情緒反應亦非唯一必備的條件

Pain may be a symptom of an underlying

problem, and proper treatment may require

more than pain relief.

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Ｒｅｗａｒｄ ＰａｔｈｗａｙRED : Results from self-administration experiments.

BLUE：Results from conditioned place preference

Amyg（Amygdala）

Hipp （Hippocampus）

LH （Lateral Hypothalamus）

mPFC （Medial Prefrontal Cortex）

NAc （Nucleus Accumbens）

PPT（Pedunculo-Pontine Tegmental Nucleus）

VTA （Ventral Tegmental Area）

Endogenous reward center ( e.g. VTA, NAc, mPFC,

Lat. hypothalamus, Olfactory tubercle,

hippocampus, and Ven pallidum as critical

areas等回饋性原始神經迴路 ) mediated

natural reinforcers (food , sex) and artificial

reinforcers ( drugs )；衍生的 biobehavioral

dysregulation問題如暴食、好賭成性、瘋狂購物或運動過度等

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Pain Assessment & Clinical Diagnosis

McGill Melzack Pain Questionnaire ( Pain Rating Index ),

Westhaven-Yale Multidimentional Pain Inventory ( WHYMPI ) for chronic pain

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Symptom release or cure ?

Pain experience

includes sensory ,

affective , and cognitive

dimension.

In clinical practice :1. i.m. inj. ( qid ) or patch

2. Patient control analgesia : iv

infusion

3. Recommend : Subdural injection:

with Port-M Cath. system

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Chronic neuropathic pain

Colorful symptoms ( 群症狀 ) :

糖尿病、甲狀腺功能低下、尿毒症、營養不良、化療( 長春花鹼、順鉑等)相關之神經障礙；格巴二氏徵候群、帶狀泡疹後神經痛、進行性神經肌肉萎縮症、複合式局部疼痛徵候群( CRPS ) 、第I型和缺血性神經病變等等所引發之hyperalgesia痛覺過度, allodynia觸物痛 , spontaneous pain 無名痛+ paraesthesias感覺缺失, dysesthesias感覺障礙與 affective disturbances感覺異常

Complex Pathophysiology :1. Change in expression of channel- , receptor-proteins and neurotransmitter production. e.g.

Type III Na channel ectopic spontaneous firing , N-type VOC ( esp. 2 sununit )neurotransmitter release

2. Neuronal loss, synaptic reorganization & rearrangement ( e.g. sprouting , „92); glutamate may damage GABA neuron ( „90)去抑制之興奮

3. CCK, VIP, galanin, NO; sub. P, Neurokinin A, CGRP (‟94 )sub. P discharge from large fiber ,and small fiber release VIP, CGRP & galanin {但allodynia 可能與主要調飾者NPY及galanin無關, 而CCK則確認會抑制opioid }

4. neurotrophin; BDNF (‟99 )

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Neuropathic Pain: A Guide to Comprehensive Assessment. Pain Management Nursing, 5 (4) suppl. 1: 9-18, „04

Diagnosis and Treatment of Neuropathic Pain. Journal of Pain and Symptom Management , 25: 5S ,’03

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Drugs for neuropathic pain

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Adjuvant Therapy for Neuropathic Pain

Medication Starting dosage* Maximum per day*

Carbamazepine (Tegretol)† 200 mg twice daily 1.6 g

Clonazepam (Klonopin)‡ 0.5 mg three times daily 20 mg

Divalproex (Depakote)‡ 10 mg per kg per day 60 mg / kg

Gabapentin (Neurontin)§ 100 mg three times daily 3.6 g

Lamotrigine (Lamictal)† 50 mg once daily 500 mg

Phenytoin (Dilantin)‡ 100 mg three times daily 600 mg

Baclofen (Lioresal)§ 5 mg three times daily 80 mg

*--Reduce dosage in children and the elderly.

†--Reduce dosage in patients with hepatic and/or renal impairment.

‡--Reduce dosage in patients with hepatic impairment.

§--Reduce dosage in patients with renal impairment

COMMON TARGET : Na Channel

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New Intervention for Neuropathic Pain GluR5 receptor antagonist : Ketamine, memantine, and dextromethorphan derivatives.

1. In chronic pain, the phenomenon of "wind-up", can be abolished with CPP.

2. The major limitation with NMDA antagonists is that their psychotomimetic actions provide unacceptable risk-benefit profiles.

3. LY382884, exhibited antinociceptive actions without ataxia.

P2X3 receptor antagonist :

1. selectively localized to sensory pathways in trigeminal, nodose, and DRG .

2. P2X3 receptor knock-out mice display reduced nociceptive responses.

3. Suramin are antinociceptive

Acid Sensing Ion Channels (ASIC's) blocker :

1. ASIC3 (DRASIC) and ASIC-ß are selectively expressed in sensory ganglia and/or the spinal cord.

2. Amiloride derivatives

Voltage-dependent Na channel blocker : c-fiber specific TTX-resistant

1. novel subtypes of voltage-gated Sodium channels rNav1.5a

2. lamotrigine and gabapentin ( anticonvulsant ) & amitriptyline ( antidepressant )

derivative

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Morphine "window into the brain"

Morpheus: in Greek means the son of god of dreams ( Somnus )

Gk. Opion = poppy juice

The alkaloid isolated from unripe seedpod ofPapaver somniferum

Indications : 1. severe burn, postoperative and chronic pain ( >

6M )associated with renal or biliary colic, malignant disease ( e.g. cancer ), and acute myocardial infraction

Contraindication for head injury where there is a potential for raised intracranial pressure

2. acute pulmonary edema :Nitroglycerin is more effective

3. preoperative medication and adjunctive agents in anesthesia

4. Heart surgery & anesthesia : fentanyl, i.v., morphine (epidural ) for regional anesthesia

Obstetric analgesia : be caution of meperidine pass cross placenta

5. maintenance programs for addicts : e.g. methadone, LAAM ( L--acetyl-methadol), buprenorphine, dihydroetorphin

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Mood effect

Euphoria : “rash” followed by a

“ high” ( as a “ +” reinforcer )

Tranquility & sleepiness : “ nod “

Last about 3-5 hr.

令人飄飄欲仙的感官奇旅，不可思議的罪惡幻夢!

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1. GI Constipation : act on myenteric plexus, inhibiting propulsive peristaltic contractions.

Characteristics : little tolerance develops, stimulative laxatives are almost always prescribed as an adjuvant medication to pt‟s with chronic pain . A newer therapy involves the co-administration of IV morphine with oral naloxone in addition to stimulative laxatives.

2. Nausea : directly stimulate the chemoreceptor trigger zone for emesis in the area postrema of the medulla.

Characteristics : Since the incidence of nausea is so high (about 50%), antiemeticsare prescribed as an adjuvant medication in about 2/3 of patients . To treat nausea: cholinergic such as scopolamine, or dopamine antagonists such as droperidol and ondansetron are often used .

3. Sedation : caution with drug interaction with alcohol, hypnotics

4. Pruritus (itching) : Occurs more frequently with epidural or intrathecal , not a drug allergy, due to histamine release from the mast cells. Treatment : antihistamine and low dose naloxone

5. Miosis : excite the oculomotor nerve. Not develop tolerance, Usually it does not interfere with the patient‟s vision.

Opioid Effect

–continuous

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6. Confusion, hallucinations : a problem with mixed agonists-antagonists ( e.g.

pentazocine, butorphanol, or Nalbuphine). Elderly patients are much more

susceptible. Hydromorphone and meperidine are usually better tolerated in those pts.

7. Euphoria : as a desired therapeutic effect in terminal pain, but many patients experience

dysphoria instead. IV injection has a much higher incidence .

8. Hypotension : with rapid iv morphine, meperidine, and hydromorphone . Fentanyl would

be the preferred analgesic agent in patients with compromised hemodynamics.

9. Respiratory depression : The most important adverse effect , Mediated at brainstem

respiratory centers, reduce responsiveness of respiratory centers to increase in

PCO2. as a intoxication marker( dose-dependent fashion).

10. The Toxicity triad

a) Catastrophic respiratory depression, as low as 2-4 breaths per minute: patient may

be conscious

b) Stupor or coma

c) Pinpoint pupils

Treatment : IV inj naloxone

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Meperidine (Pethidine, Demerol): prototype of synthetic

phenylpiperidine

劑量 : 1/10 x, short duration (T½ :2-4 hr), atropine-like ( higher incidence of nausea and vomiting than morphine).

使用於: It should be used only for short-term ( <48 hr, < 600 mg/D )treatment of acute pain, It‟s a poor choice in the management of cancer pain

注意: In patients taking a MAO inhibitor, meperidine can cause excitation, convulsions, hyperpyrexia, respiratory depression , hypotension, even severe encephalopathy and death

similar euphoric effect, less antitussive, constipation, urinary retentionl, short intense withdrawal

normeperidine (demethylated excitatory metabolite): > 200 mg, p.o. induce hallucination tremor & m. twitch rather than sedation. { naloxone insentive; diazepam or phenytoin sensitive }

medical professions are most frequently subjected to meperidine dependence

衍生物 : MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), an analogue of meperidine, a by-product that was formed during synthesis of MPPP. Is was found in San Jose, Califoria, 1982 as a neurotoxin and selective destroys neuronal tracts in sub. nigra and induced Parkinsonism.

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Fentanyl: phenylpiperidine der. synthetic

50~100 x ( tail flick test 295 x ), rapid onset ( crosses the BBB easily , peak : 3~5 min , T½ : 20' )

selective mu receptor agonist

S.E.: muscle rigidity in therapeutic doses

Clinical Use: cardiac anesthesia( iv, epidural & intrathecal ), and cause less hemodynamic disruption ( without histamine release) than morphine

neuroleptic analgesia (+ droperodol :Inovar) with nitrous oxide for anesthesia by Stanlegused in 1978

analog der. : Alfentanyl, Sufentanil , Remifentanil ( Ultiva , with higher affinity, rapid recovery, for neurosurgery; elimination by plasma esterase ) ultra short duration (duration: 15', T½ : 5' ), resp. depression (1/4 of morphine, 1/10 of fentanyl )

Illicit analog, e.g.-methylfentanyl "China White"; 3-methylfentanyl ( more potent than morphine, lethal dose: mM range.

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Pentazocine (Talwin, 速賜康 ), benzomorphane der.

1967, Partial angonist, p.o.

kappa agonist, mu receptor antagonist; spinal analgesia,

more rapid onset and a short duration than morphine , potency = 1/3 morphine

psychomimetic : dysphoria with nightmare & hallucination, rather than euphoria are the most predominant psychomimetic effect

T's+B's ( pentazocine 50 mg + tripelennamine 50 mg): immediate "flash" or euphoria, followed a "well-being" for 4-6 hr

a ceiling ( i.e. limitation) to analgesic effect ; At higher doses, it causes only a slight resp. depression

Toxic symptoms ( > 60 mg)

Behavior: anxiety, feeling of depersonalization, nightmare, visual hallucination

Respiration: dec resp rate & tidal vol, incr PCO2 level, apnea

Cardiovascular: incr systolic & diastolic BP, tachycardia

Nonspecific: nausea, vomiting, dizziness, lethargy, paresthesia, abdominal pain, tonic-clonic seizure

Clinical: not use in cancer-induced pain by p.o., poor oral efficacy, psycomimetic, & ceiling effect.

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Tramadol ( Ultran )

orally effective for moderate to moderalely severe pain

Not chemically related to opiates, an centrally acting analgesic,

bind to mu- opioid receptor, inhibit 5-HT & NE uptake,

low abuse liability ( may be due to the delay necessary for metabolism)

less respiratory depression than opiates

dizziness, somnolence, nausea, constipation, sweating and pruritis.

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ANTAGONISTS : Naloxone ( Narcan ) & Natrexone (Trexan)

mu receptor specific antagonist ( 1-4 nM for mu, 5-15 nM for kappa, 15-40 nM for delta receptor, mu : delta : kappa = 1: 15 : 40 ); GABA antagonist at high conc.

short T 1/2, repeat inj

reverse resp. depression, hypotension in spinal and endotoxic shock

precipitates abstinence ( 0.4-0.8 mg, iv, 2-3 dose/2-3 min ). Be caution of the "overshooting phenomenia"

Na shift theroy: increase [Na+] cause antagonist binding inc, agonist binding dec

Analog & Specific antagonists:1. Natrexone (Trexan): p.o., long acting ( T1/2= 10 hr ), for heroin dependence &

alcoholism

2. Nalmefene, Cypridime, ß-funaltrexamine : specific for mu receptor

3. Naltrindole : specific for delta receptor

4. Nor-binaltorphimine : specific for kappa receptor

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Selectivity of opioid drugs and peptides for different receptors

Compound m k

Opiopeptins

-endorphin 3+ 3+ -

Leu-enkephalin 2+ 3+ - -

Met-enkephalin 2+ 3+ - -

Dynorphin 2+ 3+ -

Opioid drugs

Morphine 3+ 1+ -

Fentanyl 3+ -

DMAGO 3+

Sufentanil 3+ 1+ 1+ -

Methadone 3+

Etorphine 3+ 3+ 3+ -

Codeine 1+ 1+ 1+ -

Meperidine 2+ 1+ 1+ -

Pentazocine 1 1+ 2+ 1+

Cyclazocine 1 1+ 2+ 1+

Nalorphine 2 2 2 1+

Buprenorphine 3 - - -

Meptazinol 2 - - -

Naloxone 3 2 2 -

Natrexone 3 2 2 -

+ : agonist; : antagonist; : partial agonist

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Chronic adverse effects & intoxication

addition, tolerance, psychological & physical dependence, constricted pupils,

constipation or diarrhea, skin infection, scars, abscess.

Extent of tolerance developed to some of the effects of the opiates -------

High degree Moderate degree Minimal or No

Analgesia Bradycardia Miosis ( pinpoint pupils)

Euphoria, Dysphoria Constipation

Mental clouding Convulsion

Sedation Antagonist effect

Resp. depression

Antidiuresis

Nausea, Vomiting

Cough suppression

Not to be confused with “addiction,” a negative term associated with psychological dependence and addictive behavior.

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Tolerance

a) Defined as a gradual loss in effectiveness with frequently repeated administration

b) Marked tolerance develops to the analgesic, euphoric, and respiratory depressant

effects of mu agonists

c) Tolerance does not develop to morphine-induced miosis and constipation

d) No tolerance develops to antagonists

e) Cross-tolerance develops between drugs that act at the same receptor types, e.g.

pts tolerant to morphine are tolerant to the other opioid agonist drugs. Cross tolerance

may not be complete, and therefore one needs to be more careful when switching

from one opioid to another.

f) Tolerance is often mistaken for worsening pathology that then leads to dose escalation.

g) For unknown reasons, pain actually contributes to tolerance of the respiratory system. Thus,

if the cause of the pain is eliminated, tolerance may not protect the patient from opioid

toxicity. In such cases, the opioid dose must be reduced quickly.

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Withdrawal脫癮( Abstinence戒斷, Rebound hyperexcitability ) Syndrome

Diagnosis: Himmelbach Scoring System of Abstience Syndrome of morphine ( methadone)

Criteria : 3 of 1). dysphoric mood 2).nausea or vomiting 3) muscle ache 4) lacrimation or rhinorrhea 5) pupillary dilation, piloerection, or sweating 6) diarrhea 7) yawning 8) fever 9) insomia

Unlike the sedative-hypnotic drugs, opioid withdrawal symptoms are seldom life-threatening

action site: locus ceruleus( LC ) is postulated to play a critical role in feeling alarm, panic, fear, and anxiety ( negative-reinforcement ) in morphine clonidine , opioidGrade Sign Time after last dose

0 Craving, anxiety 6 (12) hr

1 Yawning呵欠, perspiration流汗, running nose流鼻涕, lacrimation流淚 14 (34-48 )

2 Incr above sign + mydriasis散瞳, piloerection豎毛 (gooseflesh雞皮疙瘩)

tremor, hot-cold flushes, aching m & bone, anorexia食慾不振 16 (48-72)

3. Incr above sign + insomia, incr BP, BY, Resp rate &

depth, restlessness, nausea 24-36

4. Incr above sign + febrile發燒facies, position (curled

up on hard surface), vomiting, diarrhea, weight

loss, spontaneous ejaculation or organism, leuko-

cytosis, eosinopenia, blood sugar incr 36-48

Morphine or heroin withdrawal syndrome: Onset: 6-10 hr, peak: 36-48 hr, duration : 5 D

methadone withdrawal : Onset : 12-48 hr, peak 6 d, less serious, duration: 2 weeks

methadone + Naloxone : Onset : 2-5 min, peak: 10-20 min, duration: 1 hr

meperidine withdrawal : Onset: 3 hr, peak : 8-12 hr, duration: 24 hr, more severe muscle twitching & restlessness, and fewer ANS signs ( lacrimation, rhinorrhea, yawning, sweating, pupillary dilation) than morphine

42

Tolerance & PKC

PKC is key to the development and maintenance of pathological pain states.

1. PKC-mediated phosphorylation of Ca channel associated with the NMDA receptor.

2. Phosphorylation of the μ-opioid receptor by PKC may uncouple the receptor from its G-protein or alter the properties of its associated K+ channel.

3. activation of PKC decreases μ-receptor mRNA levels, suggesting that PKC also inhibits μ-opioid-receptor turnover

4. Administration of GM1 ganglioside blocks both the translocation of PKC from cytosolto membrane and the development of analgesic tolerance to morphine. Additionally, GM1 ganglioside prevents the development of thermal hyperalgesia associated with morphine tolerance

Two G-protein-coupled receptor kinases, β-adrenergic receptor kinase 2 and β-arrestin 2, also synergistically desensitize μ-opioid receptors.

1. Enhanced analgesia in mice lacking -arrestin 2 .

2. β-arrestin 2 knock-out mice display neither μ-opioid-receptor desensitization nor tolerance to the antinociceptive effects of chronically administered morphine.

Opioid tolerance may not be related to receptor desensitization but rather to a lack of desensitization.

43

44

DRUG DEPENDENCE(藥物依賴性) & Substance Abuse( 物質濫用)

其衍生的有問題有Tolerance ( 耐受性 ), Sensitization( 致敏性或 reverse tolerance ), Dependence(依賴), 及Withdrawal ( 脫癮 )；牽涉之惡性循環有preoccupation-anticiptation(先入為主), binge-intoxication( 沉迷中毒) 及 withdrawal-negative ( 脫癮負向 )

Physical dependence & withdrawal是某些濫用藥物(非必備)衍生的問題；但其核心問題是psycho-dependence之craving 與relapse 之難以克服.

endogenous reward center ( e.g. VTA, N accumbens, prefrontal cortex, Lat. hypothalamus, Olfactory tubercle, hippocampus, and Ven pallidum as critical areas等回饋性原始神經迴路 ) mediated natural reinforcers (food , sex) and artificial reinforcers ( drugs )；衍生的biobehavioral dysregulation問題如暴食、好賭成性、瘋狂購物或運動過度等。 e.g. Positive motivational effects of opioids are mediated partially by dopamine release at the level of the NAcc.

CERB (cAMP-response element binding protein) -like binding protein regulated the c-fos, BDNF , RGS4 ( regulator of G-protein signaling 4 ) gene expression為重心u Reduction the CREB in the nucleus accumbens enhancing reward (Science 282: 2272, 1998 )

NPY mRNA ( gene expression ) is significantly increased in striatum, not in hippocampus

uncoupling of receptor from effectors, e.g. adenylate cyclase等G protein調節性訊息。 -arrestin-2導致m receptor之desensitization 與morphine 之 tolerance有關， 但與

dependence 無關( Nature 408: 720-723, 2000 )

Long-term adaptation : G protein receptor kinase(GRKs), arrestins, G protein -subunits :

phosducins ,

45

46

47

48

49

50

Schedule I

1-(1-Phenylcyclohexyl)pyrrolidine : PCPy, PHP, rolicyclidine

1-[1-(2-Thienyl)cyclohexyl]piperidine : TCP, tenocyclidine

1-Methyl-4-phenyl-4-propionoxypiperidine : MPPP, synthetic heroin

1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidine : PEPAP, synthetic heroin

1-[1-(2-Thienyl)cyclohexyl]pyrrolidine : TCPy

2,5-Dimethoxy-4-ethylamphetamine : DOET

2,5-Dimethoxyamphetamine : DMA, 2,5-DMA

3,4-Methylenedioxyamphetamine : MDA, Love Drug

3,4-Methylenedioxy-N-ethylamphetamine : N-ethyl MDA, MDE, MDEA

3,4,5-Trimethoxyamphetamine : TMA

3,4-Methylenedioxymethamphetamine : MDMA, Ecstasy, XTC

3-Methylfentanyl : China White, fentanyl

3-Methylthiofentanyl : Chine White, fentanyl

4-Bromo-2,5-dimethoxyphenethylamine : Nexus, 2-CB, sold as Ecstasy

4-Methyl-2,5-dimethoxyamphetamine : DOM, STP

4-Bromo-2,5-dimethoxyamphetamine : DOB, 4-bromo-DMA

4-Methoxyamphetamine : PMA

4-Methylaminorex (cis isomer) : U4Euh, McN-422

5-Methoxy-3,4-methylenedioxyamphetamine : MMDA

Acetyl-alpha-methylfentanyl : Acetylcodone

Acetylmethadol : Methadyl acetate

Allylprodine

Acetorphine

Acetyldihydrocodeine

Alphacetylmethadol except levo-alphacetylmethadol

Alpha-Ethyltryptamine : ET, Trip

Alphamethadol

Alpha-Methylthiofentanyl : China White, fentanyl

Alphameprodine

Alpha-Methylfentanyl : China White, fentanyl

Aminorex : has been sold as methamphetamine

Benzethidine

Betacetylmethadol

Beta-Hydroxyfentanyl : China White, fentanyl

Benzylmorphine

Beta-Hydroxy-3-methylfentanyl : China White, fentanyl

Betameprodine

Betamethadol

Bufotenine : Mappine, N,N-dimethylserotonin

Clonitazene

Betaprodine

Cathinone : Constituent of "Khat" plant

Codeine methylbromide

Codeine-N-oxide

Desomorphine

Diampromide

Cyprenorphine

Dextromoramide : Palfium, Jetrium, Narcolo

Diethylthiambutene

Diethyltryptamine : DET

Dihydromorphine

Dimepheptanol

Difenoxin : Lyspafen

Dimenoxadol

Dimethylthiambutene

Dimethyltryptamine : DMT

Dipipanone : Dipipan, phenylpiperone HCl, Diconal, Wellconal

Ethylmethylthiambutene

Dioxaphetyl butyrate

Drotebanol : Metebanyl, oxymethebanol

Etonitazene

Etorphine (except HCl)

Fenethylline : Captagon,amfetyline,ethyltheophylline amphetamine

Gama Hydroxybutyric Acid (GHB) : gama hydroxybutyrate, Na oxybate

Etoxeridine

Furethidine

Heroin : Diacetylmorphine, diamorphine

Hydromorphinol

Ibogaine : Constituent of "Tabernanthe iboga" plant

Levomoramide

Hydroxypethidine

Ketobemidone : Cliradon

Levophenacylmorphan

Lysergic acid diethylamide : LSD, lysergide

Mecloqualone : Nubarene

Methaqualone : Quaalude, Parest, Somnafac, Opitimil, Mandrax

Marihuana : Cannabis, marijuana

Mescaline : Constituent of "Peyote" cacti

Methcathinone : N-Methylcathinone, "cat"

Methyldesorphine

Morpheridine

Morphine methylsulfonate

Methyldihydromorphine

Morphine methylbromide

Morphine-N-oxide CONTINOUS………

51

Myrophine

N-Ethyl-1-phenylcyclohexylamine : PCE

N-Ethylamphetamine : NEA

N,N-Dimethylamphetamine

N-Ethyl-3-piperidyl benzilate : JB 323

N-Hydroxy-3,4-methylenedioxyamphetamine : N-hydroxy MDA

Nicocodeine

N-Methyl-3-piperidyl benzilate : JB 336

Norlevorphanol

Nicomorphine : Vilan

Noracymethadol

Normethadone : Phenyldimazone

Normorphine

Para-Fluorofentanyl : China White, fentanyl

Peyote : Cactus which contains mescaline

Norpipanone

Parahexyl : Synhexyl,

Phenadoxone

Phenampromide

Phenoperidine : Operidine, Lealgin

Piritramide : Piridolan

Phenomorphan

Pholcodine : Copholco, Adaphol, Codisol, Lantuss, Pholcolin

Proheptazine

Properidine

Psilocybin : Constituent of "Magic mushrooms"

Racemoramide

Propiram : Algeril

Psilocyn : Psilocin, constituent of "Magic mushrooms"

Tetrahydrocannabinols : THC, Delta-8 THC, Delta-9 THC and others

Thebacon : Acetylhydrocodone, Acedicon, Thebacetyl

Tilidine : Tilidate, Valoron, Kitadol, Lak, Tilsa

Thiofentanyl : Chine white, fentanyl

Trimeperidine : Promedolum

52

Key neural circuits of addictionDotted lines indicate limbic afferents to the nucleus accumbens (NAc).

Blue lines represent efferents from the NAc thought to be involved in

drug reward.

Red lines indicate projections of the mesolimbic dopamine system

thought to be a critical substrate for drug reward. Dopamine neurons

originate in the ventral tegmental area (VTA) and project to the NAc

and other limbic structures, including the olfactory tubercle (OT),

ventral domains of the caudate-putamen (C-P), the amygdala (AMG)

and the prefrontal cortex (PFC).

Green indicates opioid-peptide-containing neurons, which are

involved in opiate, ethanol and possibly nicotine reward. These opioid

peptide systems include the local enkephalin circuits (short segments)

and the hypothalamic midbrain -endorphin circuit (long segment).

Blue shading indicates the approximate distribution of GABA A ( -

aminobutyric acid) receptor complexes that might contribute to

ethanol reward.

Yellow solid structures indicate nicotinic acetylcholine receptors

hypothesized to be located on dopamine- and opioid-peptide-

containing neurons. (ARC, arcuate nucleus; Cer, cerebellum; DMT,

dorsomedial thalamus; IC, inferior colliculus; LC, locus coeruleus; LH,

lateral hypothalamus; PAG, periaqueductal grey; SC, superior

colliculus; SNr, substantia nigra pars reticulata; VP, ventral pallidum.)

53

Regulation of CREB by drugs of abuse

The figure shows a dopamine neuron of the VTA innervating a class of GABA projection neuron from the nucleus accumbens that expresses dynorphin . Dynorphin constitutes a negative feedback mechanism in this circuit: dynorphin, released from terminals of the NAc neurons, acts on -opioidreceptors located on nerve terminals and cell bodies of the DA neurons to inhibit their functioning. Chronic exposure to cocaine or opiates upregulates the activity of this negative feedback loop through upregulation of the cAMP pathway, activation of CREB and induction of dynorphin.

54

Comparison of mu opioid receptor binding concentrations in a healthy control and a heroin-

addicted volunteer two weeks after detoxification and placebo administration. Large increases in

mu opioid receptor binding are detected in a number of brain regions, most prominently in

anterior cortical regions, such as the prefrontal cortex and anterior cingulate.

55

Drug Treatment for chronic dependence

1. Methadone ( 1mg can substitute for

4 mg morphine, 2 mg heroin, or 20

mg meperidine ) or -acetyl-

methadol (USA )

2. Buprenorphine ( Buprenex,

Subutex ) substitution (UK, US in

2000 )

3. Etorphine ( China )

4. Ibogaine (Endabuse) :an NMDA

antagonist ( alternative therapy )

Acamprosate ( alternative therapy )

5. Therapeutic Communities治療性社區 ( adjuvant therapy )

56

Opioid receptor morphine-induced analgesia, reward effect and

withdrawal symptoms in mice lacking the m-opioid-

receptor gene ( Science 383: 819-823, 1996 )

In the human genome, the gene encoding the

receptor is located on chromosone 1( mice in 4D), kreceptor is located on the proximal long arm of

chromosone 8, m receptor is located on the distal arm

of chromosone 6.

1. m-opioid receptor mRNA : dorsal root ganglia (DRG),

dorsolateral PAG

2. -Opioid receptor mRNA : ventral and ventrolateral

quadrants of the PAG, the pontine reticular formation,

and the gigantocellular reticular nucleus, but only low

levels are seen in the median raphe and nucleus raphe

magnus.

3. k-Opioid receptor mRNA and ligand binding are

widespread throughout the PAG, pontine reticular

formation, median raphe, nucleus raphe magnus, and

adjacent gigantocellular reticular nucleus.

57

Molecular mechanism of opioid receptor

MOR : the major molecular target for morphine activity in vivo

MOR-/- : abolition of morphine-induced analgesia, place preference and physical dependence,

as well as morphine respiratory depression and immunosuppression.

By contrast, the analgesic efficacy of heroin and the major morphine metabolite M6G remains

intact in exon 1-deficient mice

DOR : its activity contributes to improve mood states.

DOR-/- (Deletion of exon 2) : consistent anxiogenic- and depressive-like responses , basal pain

sensitivity is unaffected

KOR : a prominent role in the perception of visceral pain.

KOR-/- (deletion of the initiation codon and N-terminal coding region ): hyperalgesic for HAc-

induced writhing test

58

Characteristics of the cloned opioid receptors

Mu (MOR ) Delta (DOR ) Kappa ( KOR )

Effector 7TM; Gi/o coupled 7TM; Gi/o coupled 7TM; Gi/o coupled

Gene organization Intronic Intronic Intronic

6q24-25 1p34.3-36.1 8q11.2

mRNA Size 10-16 kb 4.5, 11.0 kb 5.2 kb

Structure , Human 400a.a 372a.a 380a.a.

Number of glycosylation 5 2 2

mRNA distribution thalamus cortex hypothalamus

striatum striatum N accumbens

locus ceruleus let reticular sub. nigra

N of solitary tract Vent tegmental area N of solitary tract

Selective agonist DAMGO DPDPE U50488

sufentanil DSBUET ICI197067

Selective antagonist CTOP Naltrindole nor-binaltorphine

59

Action Mechanisms of Opioid Receptor

Increase K+ conductance ( µ inhibit

locus coeruleus by activating an

inward-rectifying K+ current

hyperpolarization

Inhibit N-type Ca2+ channels ( k in dorsal

root ganglion cells ) inhibit neural

transmission

Inhibit of ( PGE1, forskolin-induced )

adenylyl cyclase ( µ ,k in different

nucleuslong term adaptation;

60

Delta Kappa

Mu Orphan

61

62

interactions of calmodulin and G proteins with the i3 loop of the µ opioid receptor (MOR). Calmodulin is thought to

block basal G protein coupling, but it is released upon receptor activation by an agonist such as morphine. After

chronic morphine pretreatment, calmodulin is depleted from the plasma membrane, which appears to permit

enhanced access of G proteins to the receptor and, paradoxically, increase basal G protein coupling after

morphine pretreatment. Receptor phosphorylation at S268 (a CaM-kinase II consensus site) might play a role in

regulating access of G proteins and calmodulin. The i3 loop of MOR contains a calmodulin-binding motif in its C

terminal portion, consisting of a predicted amphipathic -helix with several positively charged residues. Adapted

from J Biol Chem. 1999;274:22081-22088; J Neurochem. 2000;75:763-771; J Neurochem. 2000;74:1418-1425.

63

Opiopeptins : Endogenous Opioid Peptides

64

Hans Kosterlitz & Solomon SynderIn 1971, first by Solomon Snyder and his student, Candice Pert of John Hopkins University using a technique developed by Avram

Goldstein of Stanford Univ., to evaluation opiate receptor . That same year two other groups headed by Eric J. Simon of New York

Univ. (1973) and Lars Terenious in Uppsala, Sweden (1973) demonstrated specific opiate binding in nervous tissue. The“ morphine-

like substance“ treasure hunt had begun .

In the mid-1960s Choh Li of the Univ.California at Berkeley had isolated a pituitary hormone which he named B-Lipotropin (Li, 1964).

He noted that one portion of this hormone had analgesic properties. One year after the discovery of the receptor sites John Hughes

at the laboratory of Hans Kosterlitz in Aberdeen, Scotland reported the existence of an endogenous morphine-like substance which

they later purified and named Enkephalin for "in the head" (Hughes, 1975a; Hughes, 1975b; Kosterlitz, 1976) The Aberdeen group

recognized that the peptide sequence of Enkephalin was contained within Li's B-Lipotropin. Li would later name the other

endogenous morphine-like peptides, which also come from his pituitary hormone, Endorphin for "morphine within."

Today all endogenous morphine-like substances, including Dynorphin found by Avram Goldstein (Goldstein, Tachibana, Lowney,

Hunkapiller & Hood, 1979). In 1978 Solomon Snyder, John Hughes and Hans Kosterlitz shared the Lasker Award for their discoveries.

65

Enkephalin "endogenous analgesics"

Precursor: pro-enkephalin ( proenkephalin A )

Proenkephalin : 267 aa, 27kD, yields 4 met-enkephalin (Tyr-Gly-Gly-Phe-Met) , 1-leu-enkephalin, 1 hepapeptide (Me-Arg6- Phe7 ) and 1 octapeptide ( Met-Arg6-Gly7-Phe8 )

Affinity : delta > mu >> kappa , binds to delta-opioid receptors . These receptors are usually

localized on presynaptic vesicles containing neurotransmitters.

Physiological effects : regulating pain perception and accupuncture analgesia, responses to stress( negative feedback control of anxiety & fear-related behavior ), aggression and dominance, GI peristaltic movement

Distribution:

1. 1. CNS: widely, interneuron, basal ggl; e.g. perception of pain ( Laminae I & II, Spinal trigemebinal N,

periaqueductal gray ), modulation of affective behavior ( amygdala, hippocampus, LC & cerebral

cortex ) , modulation of motor control ( caudate N , globus pallidus ), regulation of ANS ( medulla

oblongata )& neuroendocrine function ( median eminence )

2. Peripheral : adreneral medulla , enteric N system

Neuronal function: as neurotransmitter .direct synaptic contact with the spinal cord neurons

projecting to the thalamus

ANALOG or derivative

1. synthetic :DADLE

2. enkephalinase inhibitor: kelatorphan, thiorphan, acetorphan

66

Endorphine "endogenous morphine” Precursor: pro-opiomelanocortin (POMC) same as corticotropin & melanotropin

POMC: major in ant. & intermed. pituitary, arcuate N., N. tractus solitarius; 267 aa;

POMC precursor of ß-lipotropin, ß-endorphin, adenocorticotropin (ACTH) , -melanocyte-stimulating hormone (-MSH ) , - MSH

-Endorphin bears a met-enkephalin sequence at N terminals, however each from different precursor

Affinity : mu = delta = kappa, 1). binding to µ-opioid receptors on the presynaptic terminals of nociceptors and the postsynaptic surfaces of dorsal horn neurons. 2). bind to delta-opioid receptors on inhibitory interneurons in the substantia gelatinosa of the dorsal horn, causing release of gamma-aminobutyric acid (GABA)

Physiological effects:

Antinociception ( icv , spinal) , hyperactivity, seizure, catalepsy & sedation )

Antinociception In supraspinal via epison receptor & Met-enkephalin release; in spinal : via

mu & kappa receptor,

Distribution: restricted area ( ant & intermed lobe of pituitary, arcuate N of hypothalamus & N

tractus solitarius )

Neuronal function: as neurohormone

ANALOG & Derivative :

Most recently, 2 mu-selective new tetrapeptides , endomorphine-1( tyr-pro-trp-phe-NH2), and endomorphine-2 ( tyr-pro-phe-phe-NH2) were isolated from bovine brain. ( Zadina JE, Hackler L, GeL-J, Kastin AJ. Nature 386: 499-502, 1997 )

67

Dynorphin 強啡 Isolated from porcine pituitary, active form : A (1-17) cleaved to B (1-13)

Precursor : prodynorphin ,widespread distribution

* 254 aa, bears of 3 Leu-enkephalin, dynorphin,

dynorphin N and -neoendorphin

Affinity : kappa > mu >> delta , via activates kappa-opioid receptors and leads to closure of N-type calcium channels

Physiological effects:

1. Lack of analgesia (icv); biphasic antinociceptive response ( intrathecal ).

2. inhibiting pain signals in acute injury, but having an intensifying effect on

neural transmission in persistent, chronic pain.

3. modulated in chronic inflammation rather then direct action, reduced the

SE in dependent, enhance psychological

Distribution: widely, synapsed directly onto the thalamic projection neurons, spinal interneuron

Neuronal function: neuromodulator

Dynorphin A(1–17) and its excitatory metabolites(1-13) potentiationNMDA-activated current interact with a glycine-binding site on the

NMDA receptor and with the glycine residues in positions 2 and/or 3.

twin phosphorylation and dephosphorylation reactions of promoter genes

CREB and TATA regulate the transcription of dynorphin.

68

Selected Reading

Willis W (ed). Hyperalgesia and Allodynia. Raven

Press, New York, „92

Max M (ed ). Pain 1999- An updated review. IASP

Press, „99

Hunt SP, & Mantyh PW. The molecular dynamics of

pain control. Nature Rev. Neurosci. 2: 83- 91, „01

Waldhoer M, Bartlett SE & Whistler JL. Opioid

Receptors. Annu Rev Biochem. 73: 953-90, „04