Opioid Pharmacology: an overview with emphasis on clinical relevance
Dr. Dhrubajyoti BhuyanAssistant Professor
Department of PsychiatryAssam Medical College, Dibrugarh
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Plan of presentation
• Introduction• Basic Overview• Opioid Receptors• Classification of Opioids• Pharmacokinetics & Pharmacodynamics• Etiological basis & Treatment Implication• Treatment options• Summary
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Introduction
“Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium”
Sydenham (1680)
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Introduction• The word opium is derived from opos, (juice) • Derived from the Papaver somniferum.• Opioid refers broadly to all compounds related to
opium• Opiates refers to synthetic opioids.
(Baltieri DA 2001)• Endogenous opioid peptides are the naturally
occurring ligands for opioid receptors
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Introduction
• The term narcotic was derived from the Greek word for "stupor."
• At one time, the term referred to any drug that induced sleep, but then it became associated with opioids.
• It often is used in a legal context to refer to a variety of substances with abuse or addictive potential.
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Opioid Receptors
• Classical Receptorsµ (Mu) receptorδ (Delta)κ (Kappa)
• Non-Classicalopioid-receptor-like 1 (ORL-1) receptor or
"orphan" opioid receptor
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Opioid Receptors
Receptor IUPHAR* Origin of nameδ (DOP) OP 1 first isolated from, vas Deferens
κ (KOP) OP 2 first ligand, Ketocyclazine
μ (MOP) OP 3 Morphine, proposed 1976,cloned 1993
(IUPHAR = International Union Of Pharmacology
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Opioid ReceptorsReceptor CNS Location Response on activationμ Brain (laminae III and
IV of the cortex, thalamus, periqueductal gray), spinal cord (substantia gelatinosa)
μ1 supraspinal analgesia, physical dependence; μ2-Respiratory depression, miosis, euphoria, reduced gastrointestinal motility, physical dependence
κ Brain (hypothalamus, peri-aqueductal gray, claustrum), spinal cord (substantia gelatinosa)
Spinal analgesia,.diuresis,, dysphoria, sedation, miosis, depersonalization and derealization
δ Brain (pontine nucleus, amygdala, olfactory bulbs, deep cortex
Analgesia, may be associated with mood change
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Affinity, Intrinsic Activity & Dissociation
• Affinity: strength of drug binding to receptor• Intrinsic activity: The degree to which a drug
activates its receptors. • Dissociation : measure of the uncoupling of
the drug from the receptor
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Affinity, Intrinsic Activity,& Dissociation
• Affinity for a receptor and activation of the receptor are two different qualities of a drug.
• A drug can have high affinity for a receptor but not activate the receptor (e.g.antagonist).
• agonists, partial agonists, and antagonists can vary in their affinity
• In addition to variations in affinity and intrinsic activity, drugs also vary in their rate of dissociation from receptors..Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
• Dissociation is not the same as affinity—a drug can have high affinity for a receptor, but it still dissociates or uncouples from the receptor with some regularity. Buprenorphine’s slow dissociation contributes to its long duration of action.
Affinity, Intrinsic Activity,& Dissociation
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
• Most of the clinically used opioids are relatively selective for µ receptors, reflecting their similarity to morphine However, it is important to note that drugs that are relatively selective at standard doses will interact with additional receptor subtypes when given at sufficiently high doses, leading to possible changes in their pharmacological profile.
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Classification of opioids
• Traditional: based upon analgesic potency• Origin of drug: i.e naturally occurring or
manufactured• Function: their action at the opioid receptor
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
TraditionalStrong1. Morphine2. Pethidine3. Fentanyl4. Alfentanil5. Remifentanil6. SufentanilIntermediate1. Buprenorphine2. Pentazocine3. Butorphanol4. NalbuphineWeak1. Codeine
OriginNaturally occurring1. Morphine2. Codeine3. Papavarine4. ThebaineSemisynthetic1. Diamorphine2. Dihydrocodeine3. BuprenorphineSynthetic1. Phenylpyperidines:
pethidine, fentanyl, alfentanil, sufentanil
2. Diphenylpropylamines: methadone, dextropropoxyphene
3. Morphinans: butorphanol, levorphanol
4. Benzomorphans: pentazocine
FunctionPure agonists1. Morphine2. Fentanyl3. Alfentanil4. Remifentanil5. SufentanilPartial agonist1. BuprenorphineAgonists-antagonists1. Pentazocine2. Nalbuphine3. NalorphinePure Antagonists1. Naloxone2. Naltrexone
Classification
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Opioids with their selectivity for different opioid receptors
RECEPTOR TYPEOpioid MOP KOP DOP NOPEndogenousBeta-endorphin +++ +++ +++ -Leu-enkaphalin + - +++ -Dynorphin A& B ++ +++ + +N/OFQ - - - ++++ = low affinity; ++ = moderate affinity; +++ = high affinity; -= no affinity
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Opioids with their selectivity for different opioid receptorsRECEPTOR TYPE
Opioid MOP KOP DOP NOPClinical drugsAgonistsMorphine +++ + + -Pethidine +++ + + -Diamorphine +++ + + -Fentanyl +++ + - -Partial agonistsBuprenorphine ++ + - -Pentazocine - ++ - -AntagonistsNaloxone +++ ++ ++ -Naltrexone +++ ++ ++ -+ = low affinity; ++ = moderate affinity; +++ = high affinity; - = no affinity
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Partial vs. Full Opioid Agonist
Dose of Opiate
OpiateEffect
death
Full Agonist(e.g., methadone)
(e.g. Naloxone)Antagonist
Partial Agonist(e.g. buprenorphine)
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
© AMSP 18
Pharmacodynamics: CNS
Undesirable:• Euphoria• Respiration• Sedation• Endocrine effects
Desirable:• Analgesia• Cough suppression
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
© AMSP 19
Pharmacodynamics: GI
Undesirable:• Nausea, vomiting • Constipation
Desirable:• Antidiarrheal• Inhibit peristalsis
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Effects of Opiates in Body
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Pharmacokinetics
• absorbed readily from GIT; • absorption through the rectal mucosa is adequate.• lipophilic opioids also are absorbed readily through
the nasal or buccal mucosa (Weinberg et al., 1988). • Those with the greatest lipid solubility also can be
absorbed transdermally (Portenoy et al., 1993).• Opioids are absorbed readily after subcutaneous or
intramuscular injection• Biotransformation: liver • Excretion: kidney and GI (bile)Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Opiates And Opioid Metabolism
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Pharmacokinetics
• With most opioids, including morphine, the effect of a given dose is less after oral than after parenteral administration because of variable but significant first-pass metabolism in the liver.
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Opioids: Pharmacokinetic AspectsDrug Dosing Route PharmacokineticAspectsMorphine Oral (including slow release
form), IV, IM intrathecalt½ = 3 -4hr. Converted to active metabolite ( morphine6 –glucuronide)
Heroin IV,IM, smoked, oral chasing ½ = <1 hr. Partly metabolized to morphine
Methadone Oral, IV, IM ½ = >24 hr. No active metabolite
Pethidine Oral, IM ½ = 2 – 4hr. Active metabolite (norpethidine)
Buprenorphine Sublingual, Intratheacl, sc, iv, im ½ = 40 hrFentanyl IV, epidural, transdermal ½ = 1- 2 hrCodeine Oral Acts as pro-drug. Metabolized
to morphine & other activeopioids
Crude opium Oral Varies according to concPresented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Pharmacologic & physiochemical properties and addiction
• Liposolubility increases the passage through the blood-brain barrier
• Water solubility facilitates injection• Heat resistance favours smoking• Rapid onset and intensity of effect increase
the potential for abuse• A short half-life produces abrupt & intense
syndromes of withdrawalPresented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Etiological Basis & Treatment Implication
Pre Frontal CortexRegulates judgement, planning and other executive functions
Helps to overcome some of our impulses for immediate gratification
Ventral Tegmental area
Release of Dopamine
Feeling of pleasure
Opiates
- ve
+ ve
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Etiological Basis & Treatment Implication
DA neurons become dysfunctional
Alteration in baseline level of electrical activity and DA release
Grace 2000
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Resting Dopamine release in Nucleus accumbens
Cortical excitatory neurons (Glutamate)
Autoreceptors
Opiates
Bypasses
Increases release of Dopamine
Pleasure
Activation
When drug is stopped there is low DA level leading to dysphoria
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
• Increased sensitivity to environmental cues lead to craving rather than just reinforcement and withdrawal
Breiter et al 1997)• When drug is not available, brain can remember the
drug and there is increased cortical glutamate secretion which leads to increased Dopamine level (Craving) and this inturn leads to increased NA from LC (withdrawal)
• Inhibition of glutamate (excitatory amino acid antagonists) a major area of research
Etiological Basis & Treatment Implication
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Etiopathogenesis & Treatment Basis
Locus ceruleus
Release of NA
Widely distributed in cerebral cortex, brain stem and various sub cortical areas
wakefulness breathing Blood pressure General alertness
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Etiological Basis & Treatment Implication
Opiates binds to mu receptors
adenyl cyclase
ATP
C AMP
Locus ceruleus
Noradrenergic secretion
On repeated use of opiates there is compensatory up regulation of c AMP
Inhibits
Sudden stoppage of
opiate leads to un opposed action of NA
Intoxication leads to
drowsiness, slowed
respiration and low BP
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Current Pharmacotherapy Treatment Options for Opioid Addiction
• Three traditional types of pharmacotherapyagonist treatment (e.g. methadone) antagonist treatment (e.g., naltrexone), and use of these and other agents (e.g., clonidine)
• Newer Option: Partial agonist treatment: Buprenorphine
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Heroin (opiate) addiction is a disease – a “metabolic disease” – of the brain with resultant behaviors of “drug hunger” and drug self-administration, despite negative consequences to self and others. Heroin addiction is not simply a criminal behavior or due alone to antisocial personality or some other personality disorder.
Hypothesis (1964)Leading to Development of Methadone
Maintenance Treatment
Dole, V.P., Nyswander, M.E. and Kreek, M.J.: Narcotic blockade. Arch. Intern. Med., 118:304-309, 1966; 2006
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Agonist Pharmacotherapy• Methadone is the most commonly used
medication for opioid addiction treatment• Demonstrated todecrease heroin use and related crime, increase
employment, improve physical and mental health (McLellan et al. 1993),
incidence of needle sharing (Metzger et al. 1991) and HIV transmission (Metzger et al. 1993).
• Methadone suppresses opioid withdrawal, blocks the effects of other opioids, and decreases craving for opioids.Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Methadone Long-acting µ-receptor agonist with
pharmacological properties qualitatively similar to those of morphine. The outstanding properties of methadone analgesic activity, efficacy by the oral route, extended duration of action in suppressing
withdrawal symptoms in physically dependent individuals, and its tendency to show persistent effects with
repeated administration Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Antagonist Pharmacotherapy• Naltrexone - blocks the effects of heroin and
other opioids.• No addictive properties no physical dependence,
and tolerance• long t½, and its therapeutic effects can last up to
3 days• Not a stigmatized treatment. • Decreases the likelihood of alcohol relapse
when used to treat alcohol dependence
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Antagonist Therapy
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Antagonist Pharmacotherapy
• From a purely pharmacological point of view, naltrexone would appear to have the properties of a useful medication for the treatment of opioid addiction.
• Its usefulness in the treatment of opioidaddiction, however, has been limited because of certain disadvantages.
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Agents Used To Assist With Withdrawal From Opioid Drugs
• Medically supervised withdrawal from opioids is an initial component of certain treatment programs but, by itself, does not constitute treatment of addiction
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Agents Used To Assist With Withdrawal From Opioid Drugs
• These include methadone dose reduction, the use of clonidine (0.1 -0.3 mg/d) and other alpha-adrenergic agonists to suppress withdrawal signs and symptoms, and rapid detoxification procedures (e.g., with a combination of naltrexone or naloxone and clonidine and, more recently, buprenorphine).Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Buprenorphine
• Synthetic Thebaine coneger• Highly lipid soluble µ analgesic • High affinity/occupancy (95% at 16mg)• 25 to 50 times more potent than morphine • t½ ≈ 40 hours• relatively well absorbed by most routes. • Peak plasma level at 5 mins following i.m & 1 –
2 hr following sublingual administrationPresented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Properties of Buprenorphine
• Partial mu – opioid agonist• Moderate Intrinsic Activity• Kappa antagonist
Greenwald et al, 2003Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Buprenorphine
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Effect of Buprenorphine
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Buprenorphine Vs Methadone
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Naloxone:
• Competitive antagonist on all types of opioidreceptors
• Blocks mu receptors at much lower doses than those needed to block κ and δ receptors
• Devoid of any kind of agonist action
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Naloxone:
• No dependence or withdrawal syndrome• i.v .04 - .08 mg promptly antagonizes all
actions of morphine• At 4 – 10 mg doses antagonises agonist actions
of nalophine, pentazocine but the dysphoricand psychomimetic effects are not completely suppressed
• Naloxone insenitive component is through sigma receptorPresented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Naltrexone
• Chemically related to naloxone• Pure opioid antagonist• More potent than naloxone• Orally active and long duration of action (1
– 2 days)
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Nalorphine• First antagonist introduced in 1951 which
could reverse morphine action.• Later on found to have agonist action• Agonist action at k receptor• At low doses approx equipotent to Morphine.• With increasing dose this relation is not
mainained• Nalorphine 15 mg = morphine 10 mg
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Comparison of various Treatment ModalitiesTYPE OF TREATMENT
ADVANTAGES DISADVANTAGES
Substitution Treatment
Strong evidence of capacity to reduce opioid usedecrease mortalityimprove quality of lifeCapacity to retain patients in Rx
Expense to patient (daily travel dispensing fees)Side effects, StigmaProlonged withdrawal on cessation
Detoxification Short-term commitmentAttractive to consumerLow threshold easy accessEntry point to treatment
Poor long-term outcomes if stand-alone treatmentIncreased overdose risk following withdrawalCan lead to destabilisation of other health conditions
Antagonist treatment (naltrexone)
Effective in decreasing opioid use in highly motivated well-supported people Opioid-free’ medication
Poor retention for most peopleLimited acceptanceComplicates pain managementCost to patientRequires detoxification prior to initiating naltrexoneIncreased overdose risk following cessation due to loss of tolerance
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Opioid Receptor system & Related Pharmacological Treatment
Neurotransmitter Dopamine, Noradrenaline and 5HTReceptor types µ, κ, δRole in addiction µ, & possibly δ receptor
OpioidMedication
Mechanism of action
Therapeutic dosage
Buprenorphine Partial opioidagonist
FDA labeled indication for opioiddependence. Dosage: 4 – 24 mg/d
Methadone Opioid agonist FDA labeled indication for detoxification & maintenance opioid abuse, 15 – 40 mg/d
Naloxone µ antagonist FDA labeled indication for opioiddependence, overdose of opiates and reversal of opiate activity, 0.1 – 0.2 mg/day
Naltrexone µ antagonist FDA labeled indication for opioiddependence, overdose and reversal of opiate activity, reduction alcohol consumption & craving, 50 mg/d
Nalmefen Opioid antagonist Experimental agent alcohol relapsePresented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Pharmacologic Agents Used to Treat Opioid Dependance
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Name Onset Duration t1/2 of parent drug
Dose range morphine equivalent PO mg/d
Methdoneequivalent PO mg/d
Fentanylpatch
12-24 h 60- 72 h 7 h 25 – 300 mcg
150 - 200 60 – 80
FentanylTransmucosal
5 – 15 min 4 – 8 h 17 hr 200 – 1600 mcg
45 – 60 18 – 24
Hydromorphone oral
15 – 30 min 4 – 6 h 2- 4 h 2 – 8 mg 64 26
Meperidineoral
10 – 15 min 2 – 4 h 3 – 4h 50 – 100 mg 40 16
Methadone oral
30 – 60 min 4 – 8 h 15-29 h 10 – 100 mg 150 60
Morphine oral 15- 60 min 3- 6 h 2 – 4 h 5 – 20 mg 60 24
Morphine oral LA
2 – 3 h 8 – 14 h 2 – 4h 15 – 100 mg 120 48
Codeine oral 30 -60 min 4 – 8 h 3 – 4 h 15 – 60 mg 20 8
Propoxyphene oral
30 – 60 min 4 – 6 h 3 – 15 h 50 – 100 mg 60 24
Opioid Conversion Data
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi
Summary:Successful Pharmacotherapy
• Clinical efficacy and safety• Patient and provider acceptance• Public health significance• Powerful advocacy and strong leadership• Favorable societal attitude
– The role of the clinicians; we must change before our patients’ lives can change.
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi