Opioid pharmacology an overview with emphasis on clinical relevance

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


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)


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


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.


Opioid Receptors

• Classical Receptorsµ (Mu) receptorδ (Delta)κ (Kappa)

• Non-Classicalopioid-receptor-like 1 (ORL-1) receptor or

"orphan" opioid receptor


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


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


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


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


• 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.


Classification of opioids

• Traditional: based upon analgesic potency• Origin of drug: i.e naturally occurring or

manufactured• Function: their action at the opioid receptor


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


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


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


Partial vs. Full Opioid Agonist

Dose of Opiate

OpiateEffect

death

Full Agonist(e.g., methadone)

(e.g. Naloxone)Antagonist

Partial Agonist(e.g. buprenorphine)


© AMSP 18

Pharmacodynamics: CNS

Undesirable:• Euphoria• Respiration• Sedation• Endocrine effects

Desirable:• Analgesia• Cough suppression


© AMSP 19

Pharmacodynamics: GI

Undesirable:• Nausea, vomiting • Constipation

Desirable:• Antidiarrheal• Inhibit peristalsis


Effects of Opiates in Body


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


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.


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


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



DA neurons become dysfunctional

Alteration in baseline level of electrical activity and DA release

Grace 2000


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


• 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



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



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


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


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


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


Antagonist Therapy


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.


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


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


Effect of Buprenorphine


Buprenorphine Vs Methadone


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


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)


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


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


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


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


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.



Opioid pharmacology an overview with emphasis on clinical relevance

Health & Medicine