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OPIOID PHARMACOLOGY

PCTH 300/305Andrew Horne, PhD

andrew.horne@ubc.caMEDC 309

THE OPIUM POPPY

� Papaver somniferum� Sleep-bringing poppy

� Poppy Seeds

� Opiates� Opium

� Poppy Straw

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OPIATES VS. OPIOIDS

�Opiates:� Any of the narcotic alkaloid isolates from P. somniferum

� Primarily morphine, codeine and thebaine

�Opioids� Formerly, all non-opiate narcotic agents

� Now, generally includes opiates, and all semisynthetic and synthetic narcotics� E.g. heroin, methadone, fentanyl, mepiridine

ENDOGENOUS OPIOID PEPTIDES� Exogenous opioid alkaloids aim to mimic this endogenous peptide system� Modulation of painful stimuli, GI, endocrine and autonomic functions

� Endorphins� Enkephalins� Dynorphins� Nociceptin/Orphanin FQ

� 5-31 amino acids in length� Common N-terminal homology à “opioid motif ”

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THE RECEPTORS

� GPCRs, high homology� 3 “classical” opioid receptors…

� µ (Mu)

� δ (Delta)

� κ (Kappa)

� …plus splice variants

� Primarily responsible for most clinical effects (particularly µ-ORs)

� Nociceptin/orphanin FQ (N/OFQ) receptor� Minimal affinity for most conventional opioid ligands

� Vary in expression throughout brain, spinal cord and periphery

Granier et al. 2012. Nature 485

OPIOID AGONIST VARIETY

http://www.fastol.com/~renkwitz/Opiate_Receptors_and_Actions.html

http ://thebrain .mcgill.ca/flash/i/i_03/i_03_m/i_03_m_dou/i_03_m_dou.html

� Endogenous opioid agonists (EOPs): 5-31 amino acids long

� Exogenous opioid agonists:non-proteinaceous polycyclic molecules� Alkaloids

� …yet one receptor handles both!

� Common motif for both, with perhaps additional interactions for EOPs?

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OPIOID DRUGS

Drug µ δ κ

Morphine +++ +

Methadone +++

Fentanyl +++

Sufentanil +++ + +

Buprenorphine P --

Pentazocine P ++

Nalbuphine -- ++

Naloxone --- - --

Naltrexone --- - ---

Source: Goodman & Gilman, 10th Ed

OPIOID RECEPTOR CASCADES

� Aimed at diminishing excitability and/or neurotransmission

� Gi-mediated inhibition of adenylate cyclase

� Presynaptically:� Suppression of Ca++ conductance

� Reduced vesicle fusion/NT release

� Postsynaptically:� Activation of K+ conductance

� Hyperpolarization of membrane

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EFFECTS (OVERVIEW)

�Analgesia

�CNS effects

�Gastrointestinal Effects

ANALGESIA

� Primarily effective against nociceptive pain

� Intense, constant pain > sharp intermittent pain� Acute or Chronic

� Moderate/Severe pain associated with Cancer� Gradually gaining more acceptance in treatment of

chronic pain

� Primary sensation of pain, as well the suffering� All evoked reactions upon experiencing this sensation

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THREE MODES OF ANALGESIA

1. Direct inhibition of ascending nociceptive transmission from spinal cord dorsal horn

2. Activation of pain control circuits descending to dorsal horn from midbrain

3. Decreases release of sensitizing/modulating agents (e.g. Substance P)

ANALGESIA

� Treatment will vary depending on many factors, including:� Severity of pain

� Concomitant conditions/disease

� Whether opioid-naïve or opioid-tolerant

� Coprescribe with other analgesics where possible

� Strive for dosing stability rather than on an “as needed” basis

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CNS EFFECTS

� Respiratory Depression� Far and away the most dangerous possible opioid-related effect

� Rarely relevant unless pre-existing pulmonary dysfunction and/or supratherapeutic doses

� Miosis� Constrictor effect separates class from most other coma/RD-inducing agents

� Direct effects on relevant centers in brain to cause:� Nausea/Emesis

� Cough Suppression (antitussive effects)

� Euphoria and/or Tranquility

GI SYSTEM

� Delays intestinal peristalsis and decreases sensitivity to rectal distention à constipatory effect� Side effect, or utile diarrhea treatment

� If side effect, can treat with stool softeners and/or laxatives

� Can delay gastric emptying à Reflux disease/heartburn

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CHEMICAL CLASSES (AGONISTS)

�Phenanthrenes� Morphine, Codeine� Heroin, Oxycodone, Hydrocodone� Most mixed agonist/antagonist drugs

�Phenylpiperidines� Fentanyl, Sufentanil, Mepiridine

�Diphenylheptanes� Methadone

Morphine

Fentanyl

MethadoneNaturalSemisyntheticSynthetic

MORPHINE

�Gold standard in opioid analgesia

�Effective via enteral and parental administration�More Hydrophilic than most opioids�Renal excretion

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CODEINE

� Increased oral bioavailability

� Low affinity for opioid receptors

� Antitussive effects at sub-analgesic doses� non-opioid receptor?

Gasche et al. 2004. NEJM 351

HEROIN

� a.k.a. diacetylmorphine� Semisynthetic, ~3x more potent than morphine

Bencharit et al. 2003. Nature Structural Biology 10

Very lipophilic

à Rapid hydrolysis à

Increased [morphine]CNS

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FENTANYL AND SUFENTANIL

� Rapid onset (~5 minutes)

� Very lipophilic

� Termination via redistribution, unless already saturated

� Muscle rigidity common, especially in core trunk muscles

� Not cross-tolerant with morphine/codeine

Sufentanil 0.02

METHADONE

� Long-acting morphine-like µ-OP agonist� Less euphoria, but longer duration

� Very lipophilic� Reversal of tissue accumulation protracts

plasma concentrations

� Reduces withdrawal symptoms� Addiction/dependence treatment

http://stonybrookcenter.com/heroin-vs-methadone/

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MIXED AGONIST/ANTAGONIST DRUGS

�Partial agonists of (some) opioid receptors� In opioid-naïve à sub-maximal analgesia

� In opioid-tolerant à reduced efficacy compared to morphine (or other) precipitates withdrawal

BUPRENORPHINE

� Antagonist – κ-OP receptors� Partial agonist – µ-OP receptors

� Acts like morphine in naïve patients

� Available as a “take-home” oral detox option� (+) Reduced risk of respiratory depression

� (-) Slower reversal of addiction

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ANTAGONISTS

� Naloxone� Competitive antagonist of all three classic receptors, highest affinity for µ-OP

� Higher receptor affinity than most agonists

� Rapid relief of opioid-induced respiratory depression

� Approximate duration of 1-4 hours, risk of relapse if opioids still present

� Extensive first-pass metabolism

� Naltrexone� Similar actions to naloxone, with a longer duration (up to 48 hours)

� Approved by US FDA for treatment of alcoholism, through unknown mechanism

CONTRAINDICATIONS

�Head Injuries

�Pregnancy

�Impaired Pulmonary Function

�Impaired Hepatic/Renal Function

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CHRONIC OPIOID USE LEADS TO:

� Tolerance

� Dependence

� Withdrawal

� Common features of opioids, to all degrees� Extent may vary between different effects

TOLERANCE

� Usually over 2-3 weeks of therapeutic dosing� Remifentanil à tolerance within hours

� Onset and dissipation of tolerance varies� Respiratory depression à days

� Emesis à months

� Does not occur equivalently for all effects� Miosis, Constipation far less likely to show tolerance

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WITHDRAWAL

Lippincott’s I llustrated Reviews

TOLERANCE AND WITHDRAWAL

�Where their use is otherwise appropriate/indicated, opioids should never be avoided on the fear of tolerance or dependence/withdrawal

� Tolerance: Opioid rotation� Progressive treatment plan involving regular rotation between

equianalgesic (or equieffective) doses of opioids

� Dependence/Withdrawal: Controlled cessation regiment� Usually limited by a 10-20% reduction in daily dose until drug-free