opioid pharmacology - ucla ctsi | accelerating · pdf fileopioid pharmacology f. michael...
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Opioid Pharmacology
F. Michael Ferrante, MD Director, Pain Management Center
Professor of Clinical Anesthesiology and Medicine David Geffen School of Medicine at UCLA
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Nomenclature
• Opium is the dried powdered mixture of 20 alkaloids obtained from the unripe seed capsules of the poppy • Opiate refers to any agent derived from opium
• Opioid refers to all substances (exogenous or endogenous) with morphine -like properties • The generic term for the class of agents is “opioid”
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Opium Poppy
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Structure-Activity
• Alkaloid: derived from the poppy • morphine
• codeine
• Semisynthetic: modification of morphine functional groups:
• diacetylmorphine (heroin) • hydrocodone • hydromorphone • oxycodone • oxymorphone
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Morphine (Phenanthrene Ring)
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Semisynthetic Opioids
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Structure-Activity
• Synthetic: progressive reduction in the number of fused rings in phenanthrene moiety:
Morphinan Phenylpiperidine Propioanilide
• levorphanol • meperidine • fentanyl • sufentanil • alfentanil
• methadone • propoxyphene
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Synthetic Opioids
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Pharmacodynamics
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Opioid Receptors
Opioid receptors serve two functions: • Recognition: only L-isomers exhibit analgesic activity
• Biologic action: The strength of attachment (binding affinity) correlates with analgesic potency ⇓adenylate cyclase ⇑presynaptic Ca
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µ-Receptor Binding Affinities
Opioids Binding Affinity Sufentanil 0.1 Fentanyl 1.6 Morphine 5.7 Alfentanil 19.0 Meperdine 193.0
Binding Affinity is measured by the equilibrium inhibition constant (Ki) for [H*] sufentanil (nM). The lower the value of (Ki), the Higher the binding affinity for the µ-receptor.
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Opioid Receptor Classification
Receptor Prototypic drug Proposed actions Most endogenous , naturally- occurring or synthetic opioids Morphine Enkephalins Ketocyclazocine and dynorphin N - allylnormetazocine
Supraspinal analgesia Respiratory depression Cardiovascular effects Spinal analgesia Spinal analgesia Sedation, miosis Psycotomimetic effects
µ1 µ2
δ κ σ
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Major Groups of Endogenous Opioids
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Secretion as Prohormones
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Localization in CNS
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Intrinsic Activity
The relationship between receptor binding and response
• Agonists produce a maximum biologic effect • Antagonists have no intrinsic activity and prevent
the access of agonists to the receptors
• Partial agonists have a submaximal response
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Intrinsic Activity
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Partial Agonists
• Less steep dose-response curve than agonists
• Ceiling effect
• Concomitant administration of a partial and full agonist reduces (antagonizes) the effect of the full agonist
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Mixed Agonist-Antagonists
• Partial antagonism: interaction at a single receptor type
• Agonist-antagonists:have divergent activities at different receptors, acting simultaneously as an agonist at one and an antagonist at another
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Mixed Agonist-Antagonists
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Mixed Agonist-Antagonists
Buprenorphine partial
Butorphanol antagonist agonist agonist -
Nalbuphine antagonist partial agonist -
Pentazocine antagonist agonist agonist -
µ κ σ δ Receptor Type Opioid
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• Less steep dose-response curve than agonists
• Ceiling effect
• Concomitant administration of a partial and full agonist reduces (antagonizes) the effect of the full agonist
• Addictive potential
Mixed Agonist-Antagonists
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Mixed Agonist/Antagonists
Butorphanol (Stadol): – Potency: 5X Morphine (parenteral) – Nasal spray: 1mg per spray
• Headache – 50% less nausea/vomiting than Morphine – Sedating
Nalbuphine (Nubain): equipotent to Morphine
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Buprenorphine
Semisynthetic derivative of thebaine. Highly lipophilic. Prolonged and avid binding to µ-receptor 20-30X potency of MS (0.2-0.3mg = 10mg MS) Formerly, most common route: parenteral Well absorbed sublingually
– Opioid detoxification – Maintenance programs
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Pharmacologic Considerations: Opiates
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Morphine
Routes: PO, IM, IV, SQ, nebulized & rectal Sustained release preparations:
– MS Contin – Oramorph – Kadian – Avinza (true qd dosing)
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Morphine Metabolites
Morphine: conjugated in the liver Metabolites include:
– Morphine-3-glucuronide (M3G) – Morphine-6-glucuronide (M6G)
Metabolites are cleared in kidneys M6G:
– Active metabolite, – Accumulates in CNS
M3G – May affect tolerance
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Dextromethorphan
d-isomer of morphine No classic analgesic effects (only L-isomer) NMDA antagonist (neuropathic pain)
– Need “industrial” doses: impractical
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Codeine Opiate (naturally occurring in poppy) Low affinity for opioid receptors 10% of dose demethylated to morphine
– Fraction responsible for analgesia? Schedule II Most prescribed opioid in the world. Probably the most widely used analgesic
– (Excluding aspirin) Limited by:
– Low potency (do not use for severe pain) – Perceived frequency of nausea/ vomiting
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Pharmacologic Considerations: Semisynthetics
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Hydrocodone Combinations
With acetaminophen – Norco (5,7.5,10/325) – Anexia (5/500;7.5/650) – Lortab (2.5,5,7.5,10/500) – Vicoden (5/500) – Vicoden-ES (7.5/750) – Lorcet (7.5, 10/650)
Vicoprofen (ibuprofen 200/7.5 mg hydrocodone)
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Oxycodone Combinations
Percocet/ Tylox: – oxycodone 5/acetaminophen500
Percodan: – oxycodone 5/ASA 325
Roxycodone/ Oxy IR OxyContin
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Oxymorphone (Opana)
Opana ER: 5, 10, 20, 40 mg tabs Opana (IR): 5 and 10 mg Oral: 3x potency of morphine Old N/A IV: 10X potency of morphine “Tamper-proof” gum RF: OK in mild-mod (CC > 30 mL/min) Dose 1h before or 2hr s/p eating
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Pharmacologic Considerations: Synthetics
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Methadone
Dolophine: incorrectly attributed to Hitler 10 mg tabs & 40 mg wafers Half-life:
– Acute: 1o t1/2 = 14 h; 2o t1/2 = 55h – Chronic: t1/2 = 23h
Analgesic duration <<< t1/2 (slow terminal elimination) – Sequestered & unavailable for analgesia – Dose q6-q8
Beware accumulation
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Methadone
Stigma of heroin maintenance Must write: “for pain” in some states
– Special license for methadone maintenance Inexpensive d-isomer = NMDA antagonist (neuropathic pain)
– Available as racemic mixture in US – Available as l-enantiomer in Europe
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Meperidine and Congeners Meperidine (Demerol/Mepergan)
– Structurally similar to atropine • Tachycardia (unlike most opioids: bradycardia)
– Problems with MAO inhibitors – Normeperidine metabolite (CNS excitation)
• Renally cleared • “Slow excretors”: normal creatinine clearances
– Very short duration of action ≅ 3 h Diphenoxylate (Lomotil, with atropine): 20mg/ d ÷ doses Loperamide (Imodium): 4-8mg/ d, max 16mg
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Propoxyphene
Unique: – d-isomer has analgesic properties
Darvocet/ Darvon/ Darvon Compound Potency ≅ 2x codeine More effective in combination
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Tramadol Dual mechanism of action
– μ-opioid activity (30%) – inhibition of serotonin/NE re-uptake (70%)
Nonscheduled opioid
– Less abuse potential
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Tramadol-IR and –ER Dosing
Usual Dosing Adverse Events
Tramadol IR Start at 25 mg once daily; titrate up by 25-mg increments every 3 days to 100 mg/d (25 mg qid); thereafter titrate up as necessary every 3 days to 200 mg/d (50 mg qid); do not exceed 400 mg/d
Dizziness/vertigo, nausea, constipation, headache, somnolence
Tramadol ER
Start at 100 mg qd, titrate up as necessary by 100-mg increments every 5 d–not to exceed 300 mg daily
Dizziness, nausea, and constipation
ACR Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum. 2000;43:1905-1915; Ballantyne JC, Mao J. N Engl J Med. 2003;349:1943-1953.
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Concept: Equianalgesic Dosing
“ All opioids can be made equipotent or equianalgesic by adjusting for physicochemical and pharmacokinetic differences among individual opioids by correcting for dose and route of administration.”
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Opioid Analgesic Equivalents
Opioid Route Equianalgesic dose Morphine Parenteral 10 mg oral 30 mg Hydromorphone Parenteral 2 mg oral 4 mg Meperidine Parenteral 75 mg oral 300 mg Methadone Parenteral 10 mg oral 20 mg
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ORAL PARENTERAL EPIDURAL SUBARACHNOID ICV
ACUTE 600: 100 : 10 : 1 0.1 CHRONIC 300:
Equianalgesia: Route of Administration
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Scheduling
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Controlled Substances Act 1970
Concept of balance Intro of scheduling "Narcotic drugs"
defined, not by pharmacology
Defined by law enforcement needs
Analgesia Abuse Abuse
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Schedule I
No accepted medical use in the US – Heroin – LSD – Peyote – Mescaline – Marihuana (except for refractory nausea)
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Schedule II
High abuse potential: – Morphine – Codeine
• Add ASA or acetaminophen = Schedule III • Add expectorant = Schedule V
– Hydromorphone – Methadone – Oxycodone
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Schedule III Hydrocodone + acetaminophen
– Norco (5/325, 10/325) – Anexia (10/660) – Lortab (2.5, 5, 7.5, 10/500) – Lorcet (7.5, 10/660) – Vicoden (5/500, 7.5/750, 10/660) – Vicoprofen (ibuprofen 200/7.5 hydrocodone
Tylenol #x (codeine)
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Abuse Potential
Actual abuse not directly tied to schedule Schedule II abuse < Schedule III or IV In past, Schedule II monitored closely:
– Couldn’t be refilled – Couldn’t be prescribed by telephone – Why Vicodin (III) popularity c/w Percocet (II)
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Schedule IV and V
Schedule IV: Benzodiazepines Schedule V:
– Antitussive – Antidiarrheal – Analgesic
• e.g., Buprenorphine
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Scheduling: No Relation Pharmacology
Codeine: – Schedule II – + Acetaminophen or ASA = Schedule III – + Cough syrup = Schedule V
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Tolerance, Physical Dependance, Addiction
Definitions &
Concepts
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Tolerance
With continued use, progressively more and more opioid is necessary to produce the same effect
Pharmacologic property of a class of
agents Incomplete cross tolerance
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Physical Dependence A state of adaptation that is manifested by a
drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.
Not synonymous with tolerance or addiction
.
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“Cold Turkey”: Opioid Withdrawal
Symptoms of opioid withdrawal: • Diaphoresis • Lacrimation • Coryza • Tachycardia • Abdominal cramps • Nausea • Vomiting
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Other Withdrawal Syndromes
Rebound hypertension Exacerbations of asthma after stopping
steroids in steroid-dependent patients Rebound insomnia Discontinuation syndrome with SSRIs Rebound anxiety Seizures after D/C benzodiazepines
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Addiction
A psychic and physical state characterized by compulsive behavior to obtain a drug in order to experience its psychic effects, despite full knowledge of its harmful effects
Not a pharmacologic property Not synonymous with tolerance or physical dependence
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Physical Dependence & Addiction
Physical Dependence Addiction
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Addiction
Compulsive desire to obtain drugs for their euphoric effect despite full knowledge of the action
Behavioral
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Addiction: 5“Cs”
Chronic Compulsive use Control impaired Craving Continued use despite harm