181lec8 - Psych 181 Dr Anagnostaras Lecture 8 OPIATES...

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Unformatted text preview: Psych 181: Dr. Anagnostaras Lecture 8 OPIATES Opioids Opiates q alkaloids alkaloids found in the opium poppy (Papaver somniferum) (Papaver q [Gk. opion = “poppy juice”] Opioids q compounds compounds with opiate-like actions, including, but not confined to opiates (e.g., synthetic, endogenous opioids) synthetic, Types of opioids 1. Naturallyoccurring q opium opium q sap from opium poppy Two major active alkaloids q morphine q codeine 25 x more potent than paregoric Morphine Morphine q q Morpheus (god of Dreams) -son of Hypnos ~ 10% of opium by weight N H CH 3 HO O OH Morphine Codeine q q methylmorphine ~ 0.5% of opium 2. Semi-synthetics 2. Semi-synthetics Heroin q diacetylmorphine q addition of two acetyl groups to morphine q ~ 10x more potent than morphine q pharmacological effect usually thought to pharmacological be identical to morphine be q in brain: heroin > morphine (new data suggest morphine and heroin may have different actions; 1999) Semi-synthetic analgesics q q q Hydromorphone (Dilaudid®) Hydrocodone (Hycodan®, Vicodin®) Oxycodone (Percodan®, Oxycontin®) 3. Synthetics Phenylpiperidines q Fentanyl “china white” q Carfentanil (Wildnil®) q Meperidine (Demerol®) (MPPP) Methadone & Congeners q Methadone (Dolophine®) q Propoxyphene (Darvon®) Benzomorphans Benzomorphans q Pentazocine (Talwin®) N CH 3 C O O CH 2 CH 3 Pethidine (Meperidine) H 3C N H (CH 3)2 C O CH 2 CH 3 Methadone Analgesic potency Analgesic Mild to moderate pain potency codeine, propoxyphene (Darvon®) Moderately severe pain meperdine (Demerol®) Severe pain heroin, hydromorphone (Dilaudid®) "Perc-a-pop" 4. Opioid antagonists q q naloxone (Narcan®) naltrexone Suboxone® (buprenorphine + naloxone) q 5. Endogenous opioids q q Enkephalins, endorphins and dynorphins Morphine & codeine? History of use - opium Since recorded history Ingredient in all sorts of medicinal preparations History of use - morphine “Soldiers disease” History of use Ads for heroin Major effects Analgesia q Relief Relief of pain in absence of impairment in other sensory modalities other Euphoria - Pleasure q Produce Produce sense of well being, reduce anxiety, positive feelings anxiety, Other effects q Nausea & vomiting q Respiratory depression q Miosis (opposite of mydriasis) q Gastrointestinal effects q Cough Suppression q Motor effects Effects of repeated administration Tolerance, withdrawal & sensitization Tolerance and withdrawal Behavioral withdrawal score 8 20 LC unit activity 6 4 2 0 1 46 Naltrexone Morphine Control 10 0 1 4 6 24 72 24 72 Time (hr) 12.18 Sensitization q Psychomotor stimulant effects q Rewarding effects (conditioned place preference) Mechanisms of action q Primary action on opioid receptors located in Primary CNS +/or periphery CNS Different effects due to action at q Different receptor subtypes q Receptors in different locations Endogenous opioids Classical transmitter Production of (1) Synthesizing enzymes (2) Storage vesicles Peptide transmitter Production of (1) Peptide (precursor) (2) Storage vesicles (3) Converting enzymes Axonal transport of (1) Storage vesicles Translation Axonal transport of (1) Synthesizing enzymes (2) Storage vesicles Supply by (1) Axonal transport + storage (2) New synthesis (3) Reuptake Release Release Post-translational processing Supply by (1) Axonal transport + storage 11.4 Opioid peptide gene families Three different gene families q Proopiomelanocortin q Proenkephalin q Prodynorphin Signal NH2 g-MSH (POMC) (‘proenkephalin B’) ΑΧΤΗ α−ΜΣΗ ΧΛΙΠ Μετ−ενκ 4 β−ΜΣΗ β−Ενδορπηιν ΧΟΟΗ β−ΛΠΗ (Αργ6∠ Πηε7) Proopiomelanocortin Proenkephalin Signal NH2 12 3 (Αργ6∠ Γλψ7∠ Λευ8) Μετ−ενκ 7 5 6 ΧΟΟΗ Prodynorphin Signal NH2 β−Νεοενδορπηιν α−Νεοενδορπηιν ∆ψν Α ∆ψν Β ΧΟΟΗ 12.5 Precursor gene families Proopiomelanocortin (POMC) Proopiomelanocortin q ß-endorphin q ACTH, melanocortin SH & 2 extended met-enk Proenkephalin -> Enkephalins Proenkephalin q met-enkephalin q leu-enkephalin q Prodynorphine - forms of leu-enkephalin Prodynorphine q Dynorphins, A and B q Neoendorphins, µ and β Neoendorphins, Differential distribution Endorphins q discrete q hypothalamic - endocrine related Enkephalins and Dynorphins q wide wide distribution, local circuit and short axon projections axon Opioid receptors Opioid receptors Subtype Mu (µ) Delta (δ) Kappa (κ) q Preferred Ligand Morphine & endorphins Enkephalins Ketocyclazocine & dynorphins Each subtype has subtypes Opioid receptors μ δ κ Cellular actions q q G protein coupled receptors inhibitory Οπιοιδ ρεχεπτορ γ β Adenylyl cyclase β γ α α Γι ATP cAMP Γσ Negatively-coupled 12.4 Protein kinase A Role in drug action Analgesia Analgesia Spinal actions q q Dorsal horn of Dorsal spinal cord spinal primary pain primary afferents afferents Dorsal horn Ventral horn 4.2 Analgesia Spinal actions q inhibit incoming pain signals Projection neuron Opioid receptor + Spinal cord 12.8 Sensory neuron Analgesia Analgesia Supraspinal actions Brain area Diencephalon Descending pathways PVG Midbrain PAG DLPT LC Rostroventral medial medulla (RVM) Spinal cord NR NP Dorsal horn 12.10 Analgesia Analgesia Supraspinal actions Brain area Diencephalon Descending pathways PVG Midbrain PAG Stimulation > analgesia and inhibit cells in dorsal horn DLPT LC Rostroventral medial medulla (RVM) Spinal cord NR NP Dorsal horn 12.10 Analgesia Analgesia Supraspinal actions Brain area Diencephalon Descending pathways PVG Lesion > block analgesia to systemic or local morphine DLPT LC Midbrain PAG Rostroventral medial medulla (RVM) Spinal cord NR NP Dorsal horn 12.10 Analgesia Supraspinal actions Supraspinal q µ1 sites seem most important q Specific blockade of µ1 shifts doseresponse curve for morphine analgesia up response to 12 fold to right to Analgesia Analgesia Heroin vs. Morphine q difference pharmacokinetic? recent evidence for different receptors - MOR-1 knockouts q Analgesia - MOR1 knockouts MOR1 Schuller et al., Nature Neurosci. (1999) heroin > 6-acetylmorphine in vivo Analgesia (%) Morphine, but not heroin, analgesia abolished in Mor1 knockout mice Reinforcing effects Reinforcing effects q All classical opioid drugs of abuse have a All preference for µ sites (e.g., morphine, heroin, methadone, fentanyl etc.) methadone, q δ may contribute, but little known κ compounds are not self-administered q psychomimetic and aversive in humans q Opioid/DA interaction q q q Intra-VTA opioid support SA and CPP DA antagonist or 6-OHDA lesion impair SA DA antagonist into VTA or ACC impair SA Mechanism Mechanism µ compounds: q q q Increase DA cell firing Increase DA release in ACC Accompanied by locomotor activation Model for reinforcing effects Site of action q VTA – accumbens DA system μÐ β−ενδορπηιν Ð “Disinhibition” ΓΑΒΑ Μεσολιµβιχ δοπαµινε DA ςεντραλ παλλιδυµ 12.16 ςεντραλ τεγµενταλ αρεα (ςΤΑ) Νυχλευσ αχχυµβενσ κ compounds q q q Decrease DA cell firing Decrease DA release Decrease locomotion Respiratory depression µ2 sites? q q q Specific µ1 antagonist (naloxonazine) shifts Specific analgesia dose - response curve for morphine to right to Not shift dose-response curve for: q elevation of pCo2 q depression of pO2 Respiratory neurons in medulla in region of n. Respiratory solitary tract solitary Gastrointestinal effects µ and κ sites q In stomach, small and large intestine q Decreased motility q Common bioassay > ability to inhibit Common intestinal contractions intestinal MOR Knockouts q Morphine has affinity for all opioid receptor Morphine subtypes (much stronger for mu) subtypes Evidence for site of action from Evidence pharmacological experiments with drugs that may act at multiple sites may Which effects due to action at which receptpr Which subtypes? subtypes? q q MOR Knockouts (MOR -/-) Morphine effect Spinal analgesia Supraspinal analgesia Reward Withdrawal Respiratory depression Inhibition GI motility Psychoactivating effect Abolished Abolished Abolished Abolished Abolished Abolished Abolished (all effects maintained in DOR-/- and KOR-/-) Brigitte L. Kieffer, Opioids: first lessons from knockout mice, Brigitte Trends in Pharmacological Sciences, 20 (1999) 19-26. Trends The Politics of Pain The and Pain Management Introduction q q Prevalence q Pain accounts for 80% of all medical Pain complaints (30% debilitated at some time) complaints q Pain is patient's #1 reason why they fear Pain disease disease q Pain affects 90% of patients with terminal Pain disease (50% of ambulatory patients) disease Obstacles for treatment q Fear—patient, prescriber Social and Legal obstacles q Lack of education Political and Social Obstacles • Overstated abuse potential of opiate drugs has been a serious obstacle to pain treatment treatment • Pain patients have been a casualty of the war on drugs war • No field to study pain until the 1970s No (opiate receptor cloned) • Very little formal training on pain management as part of medical school curriculum (often 1 hour) curriculum Politics of pain • Most doctors misinformed about the addictiveness of therapeutic opiates (e.g., vicodin v heroin or significance of routes of administration in addiction) of • Even when habit-forming this addiction outweighed thinking about patient's quality of life. quality • Fear of reprisals on license by DEA a major issue major • Drug companies avoided new opiates Drug Politics of pain • Pain patients looked down upon for complaining about pain (especially chronic pain) pain) • Pain treated as a valuable diagnostic indicator by doctors "don't want to cover up the pain" (even chronic neuropathic pain) (even Politics of pain • Revolution in pain management had multifaceted roots- began in 1970s roots• conference on Pain formed unified field to study Pain, 1977 - American Pain Society ( www.ampainsoc.org) 28-3600 • discovery of endogenous opioids discovery • activism by Bonica, Liebeskind, etc. activism • revolt by San Francisco cancer doctors revolt • Centers for Pain Management Policy (e.g., Wisconsin) Wisconsin) Politics of pain • Several states enacted legislation to protect doctors and patients (e.g., California's "pain patients bill of rights") patients • Softening of war on drugs by Clinton administration administration • Doctor's take back their rights Doctor's (Doctor's make medical decisions) • Medical marijuana acts Medical Politics of pain • In cancer was clear need to treat pain outweighed any addiction outweighed • It became clear most pain patients either didn't become addicted at all or developed mild dependence mild • Pain management clinics have appeared all over the place (including Emory) over • Still many obstacles to adequate pain management, e.g., patient access is still very low and too many drug side-effects low Many obstacles remain • Still difficult for patients to get treatment Still • triplicate prescriptions triplicate • cannot be called in • cannot be refilled cannot • policing by DEA policing • few experts in pain few • strong slow-release drugs are expensive strong • pain patients often poor, uninsured, and cannot travel or work cannot What is Pain? q Medical Definition “Pain is an unpleasant sensory and emotional Pain experience associated with actual or potential tissue damage or described in terms of such damage” damage” International Association for the Study of Pain, International 1979 1979 q Operative Definition “Pain is whatever the experiencing person says it Pain is, existing whenever he/she says it does.” is, •patient's appearance can be very deceptive What is Pain? Current definitions of pain don't work well Current for: for: • children who can't speak or even older ones who can't express themselves well ones • those who are mute or mentally ill those • animals animals • those who hide their pain those •• emphasis on pain behaviors emerging •• emphasis Pain is a perception, nociception is the sensation Reflection tells me that I am so far from being able to define pain, of which I here write, that the attempt could serve no useful purpose. Pain, like similar subjective things, is known to us by experience and described by illustration. Thomas Lewis. Pain. New York, The MacMillan Company, 1942. PAIN BEHAVIOR SUFFERING PAIN NOCICEPTION Definitions Nociception: Potentially tissue damaging thermal, mechanical or chemical energy impinging upon specialized nerve endings of A-δ and C fibers. Pain: Perceived nociceptive input to the nervous system. Pain can occur without nociception! Pain syndromes without nociception Thalamic syndrome Tic douloureux Postherpetic neuralgia Postparaplegia pain Postthoracotomy pain Phantom limb pain Arachnoiditis Atypical facial pain Nerve root avulsion pain Neuropathic pain Pain is a major cause of suffering! Suffering: Negative affective response generated in higher nervous system regions in response to pain and other situations including fear, anxiety, isolation, depression, etc. Pain behavior All forms of behavior generated by the individual that are commonly understood to reflect the presence of nociception; for example, grimacing, saying ouch, limping, lying down, taking medicines, seeking health care, refusal to work. Types of Pain q Nociceptive Pain q Stimulation Stimulation of somatic and visceral peripheral nociceptors by stimuli that damage tissue damage resulting from non-inflammatory dysfunction of the peripheral/central nervous system in the absence of stimuli stimuli q Neuropathic Pain q Pain Pain Neuropathic Pain q Prevalence q General population 0.6-1% Compression/infilitration of nerves by: q Tumors q Nerve Nerve q Causes q Trauma secondary to procedures procedures q Nervous System Injury q E.g., phantom-limb pain, neuralgia back injury, post-surgical pain back Types of Pain Transient Pain • Studied extensively in man and animals Studied q Does not involve tissue damage q Activation of nociceptors in resting state Not clinically relevant, save for procedural Not pain such as venipuncture, LP pain q Types of Pain Acute Pain q Activation of nociceptors in region of Activation tissue damage tissue q Nociceptor function is altered by tissue Nociceptor changes changes q Healing processes can eliminate tissue Healing damage; nociceptor function returns to baseline baseline Types of Pain Chronic Pain q Activation of nociceptors in region of tissue Activation damage damage q Nociceptor function is altered by tissue Nociceptor damage; CNS adapts permanently damage; q Body cannot heal injury, or damage to Body nervous system q Organic cause unknown and untreatable Organic (often iatrogenic) (often Chronic pain is a special problem Chronic Pain q Associated with a social stigma q people expect you to get over illness q "get back to work" q associated with a lot of hiding of pain q Debilitating and depressing producing lots of Debilitating psychological problems psychological • Especially poorly treated Especially • lack of expertise and desire to treat by docs lack • lack of effective treatment lack Afferent pain transmission q q q Afferent fibers go to the CNS transmitting Afferent nociceptive message from trauma to dorsal horn of spinal cord horn A alpha, A beta, A gamma, A delta, B, or C Nociceptive transmission takes place in Nociceptive the A delta fibers (well-localized pain); C fibers (persistent pain) fibers Transduction of nociception q q Conversion of stimuli into electrical action Conversion potential potential What types of stimuli? q Heat or cold (e.g. radiation damage) (e.g. tumor infiltration into q Pressure Pressure bone) bone) q Chemical (e.g. chemotherapy) Peripheral Nociceptors q What is a nociceptor? q Not spontaneously active q Level of stimulation must exceed threshold q Sensitization produces hyperalgesia q Tissue damage changes the sensitivity q Sensitization is manifested as: q Decreased threshold q Increased intensity-prolonged firing q Spontaneous activity Pain Theories and Pathways q Spinal cord transmission–spinothalamic Spinal tract carries pain impulses; the lateral pathway (sharp, localized pain), the vental pathway (dull, nonlocalized pain) pathway Pathways merge in thalamus and connect in Pathways cortex cortex Ant Cingulate cortex–pain perception area q q Types of Peripheral Nerve Fibers q A Fibers (Fast Transmission) Fibers q Alpha - Proprioception (Muscles & Joints) q Beta - Mechanoreception (Cutaneous Beta Tissue) Tissue) q Delta - Primary nociceptive neurons C Fibers (Slow Transmission) Fibers q Primary nociceptive neurons q Neuronal Activities in Normal States Stimulus Low Intensity High Intensity Pri Afferent Sensation A-Beta A-Delta/C Innocuous Pain (nociception) Neuronal Activities in Pain States Stimulus Low Intensity High Intensity Pri Afferent A-Beta A-Delta/C Sensation Pain (allodynia) Hyperalgesia Pain Theories and Pathways q q Clusters of opiate receptors throughout Clusters ascending and descending pain pathways descending endogenous opioids also in brain Opiate receptors--µ (µ1 and µ2), δ (delta), Opiate (delta), κ (kappa), (σ, sigma and ε,epsilon) sigma • µ1 are primarily responsible for analgesic µ1 effects (but maybe also δ, κ, ε) q Opioid (Narcotic) analgesics q q q q q q q q q q Morphine Meperidine (Demerol) Codeine (Tylenol-3) Hydromorphone (Dilaudid) Hydrocodone and acetaminophen (Vicodin) Methadone (Dolophine) Fentanyl, alfentanil, sufentanil, remifentanil (e.g., sublimaze & duragesic) Oxycodone (Percodan) Oxycodone and acetaminiphen (Percocet) Propoxyphene (Darvon) Opioids q q q Inhibit the transmission of pain impulses in Inhibit sensory pathways in the spinal cord sensory Reduce cortical responses all over the brain Alter behavioral responses to pain Tolerance & dependence may develop, not Tolerance necessary a sign of abuse or addiction necessary q Opioids q Despite reports of abuse vast majority of Despite pain patients use chronically without addiction or dependence addiction Long-acting much better than short-acting Long-acting (prevents on-off and sensitization) (prevents ATC (around-the-clock) preferable to PRN ATC q q Non-narcotic analgesics q Salicylates (aspirin–historically there Salicylates were several derivatives) were Aniline derivatives (Tylenolacetaminophen) acetaminophen) Non-steroidal anti-inflammatory Non-steroidal agents (NSAIDS) agents q q NSAIDs COX 1 & COX 2 inhibitors q ibuprofen (Motrin, Advil) q naproxen (Aleve) q diclofenac (Voltaren) q indomethacin (Indocin) q ketorolac (Toradol) q sulindac (Clinoril) q mefanamic (Ponstel) q piroxicam (Feldene) q flurbiprofen (Ansaid) q ketoprofen (Orudis) Selective COX 2 Selective inhibitors inhibitors q celocoxib (Celebrex) q rofecoxib (Vioxx) q valdecoxib (Bextra) Celebrex & Vioxx q q q q Aspirin and most commonly used NSAIDs Aspirin nonselectively inhibit COX 1 and COX 2 nonselectively COX 2 agents have a lower incidence of the COX ulcerogenic side effects (they increase the risk of heart attack, stroke, and clotting disorders, however) disorders, Identified by genetic screen of aspirin side effects include headache Therapeutic effects of NSAIDs q q Antipyretic Analgesic--low to moderate pain intensity; lack Analgesic--low unwanted CNS effects of opioids unwanted Antiinflammatory Side effects still include ulcers, blood-thinning. Side and sensitivity and Only aspirin proven to show anti-MI effects and Only still in its own category q q q Aniline derivatives– Acetaminophen (Tylenol) q q q Centrally mediated hypothalamic Centrally stimulation to alter pain perception stimulation Clinical use–analgesic, weak antipyretic No action as anti-inflammatory Overdosage is associated with hepatic Overdosage necrosis/must be treated within 10 hours SERIOUS PROBLEM SERIOUS q Pain adjuvants q Tricyclic antidepressants and SSRIs Anticonvulsants Corticosteroids Muscle relaxants Capsaicin Local anesthetics (lidocaine, benzocaine) Non-pharmacologic therapies NMDA receptor antagonists (ketamine, DXM, CPP) Patient-controlled analgesia/epidural analgesia q q q q q q q q Clinical applications q q Review history (drug abuse, allergy) Assess level of function and pain level Monitor patient pain relief, tolerance Level of function after treatment Surgical treatment of chronic pain is a last Surgical resort (exception = pumps, stimulators, rhizotomy), usually makes things worse rhizotomy), q q q ...
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