Download Opioids

Pharmacology: Opioid Drugs (Bannon)
INTRODUCTION TO OPIOIDS:
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Neurobiology of Opioid Receptors and Peptides:
Opiate Receptors:
o Mu: for morphine (endogenous ligands are beta-endorphin and more recently recognized
endomorphins)
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Encoded by MOP gene
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Many opioid agonists and antagonists show preference here
o Kappa: for ketoclazocine (endogenous ligand is dynorphin)
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Encoded by KOP gene
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Partial agonists relatively strong here
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May have more importance in spinal anesthesia
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In some cases, have actions opposite to mu receptors
o Delta: for vas deferens (endogenous ligand is enkephalin)
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Encoded by DOP gene
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Morphine and other opioid drugs weaker here
Opioid-Like Receptor NOP: nociceptin/orphanin FQ peptide receptor
o Insensitive to classical opioid antagonists
o Elicits hyperalgesia (increased sensitivity to pain) and anti-opiod effects suprasinally
o Elicits antinociceptive spinal effects
Single Gene Results in Several Receptor Subtypes Seen Pharmacologically:
o Example: MOP gene elicits μ1, μ2, and μ3
o Possible Explanations:
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Alternative splicing of common gene products (really not important)
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Receptor dimerization to give different subtypes (may be important)*
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Interaction of common gene product with signaling proteins (may be important)*
 For example, drug dependent activation of signaling pathways (which pathway gets
activated depends on which drug bind)
OPIOID DRUGS:

Morphine (Gold Standard):
Pharmacokinetics:
o Absorption: well absorbed by multiple routes of administration (oral, IM, IV, subQ, rectal, epidural or
intrathecal)
o Metabolism: extensive first-pass metabolism limits oral use (~35% bioavailability)
o Excretion:
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Polar metabolites excreted in the urine
 After chronic use, polar metabolite morphine-6-glucuronide is responsible for
analgesic effects
 Therefore, toxicity may result in renal insufficiency due to decreased clearance of
this active metabolite (confusion, agitation)
 Morphine-3-glucuronide is another minor metabolite that may be proconvulsant
(CNS excitatory properties; again, take care with renal insufficiency)

Glucoronide conjugates also secreted in bile
Formulations:
o Long-Acting SR Beads: to be swallowed; if chewed or combined with alcohol, can cause release of too
much morphine
o Morphine SR + Naltrexone (Embeda): for continual use with decreased risk of abuse (if crushed,
opioid antagonist naltrexone will be freed)
o Post-Surgical Formulations (DepoDur): single liposomal injection (last 48 hours)
o Infumorph/Astromorph/Duramorph: continual epidural or intrathecal infusion formulations
Uses/Effects of Morphine:
o Analgesia:
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Basics:
 Pain relief without general sensory loss or loss of consciousness
 Pain reported as present but no longer bothers the patient
 Better against continuous dull pain than sharp, intermittent pain
 Multiple supraspinal (ie. brain) and spinal sites of action
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Issues:
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SIGNIFICANT tolerance to this effect (as well as most others)
Paradoxical hyperalgesia may occur (MOA unclear- possibly increased glutamate
transmission in the dorsal horn)
Use: surgical anesthesia (in combination with other drugs- multimodal anesthesia)
Mood and Cognitive Effects:
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Basics: cause euphoria and tranquility
 Normal (Pain-Free) Individuals: often unpleasant
o Dysphoria (intense feelings of depression or discontent)
o Difficulty thinking
o Drowsiness
o Nausea
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Site of Action: unclear (locus ceruleus, mesolimbic DA, nucleus accumbens all possible)
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Side Effects: confusion and sedation (especially in the elderly)
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Use in Combat Injured Subjects: prompt administration of morphine reduced risk for PTSD
Miosis:
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Cause: excitation of the PS innervation to the pupil
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Sign of Toxicity/Abuse: little/no tolerance to this effect with chronic use
Cough Inhibition:

Mechanism: depression of cough reflex mediated by medullary cough center (can administer
a dose that easily provides cough suppression without respiratory depression)
Respiratory Depression:
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Mechanism: dose-related depression mediated via brainstem centers
 Decreased response to CO2
 Synergistic depression seen with many other CNS drugs
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Importance: especially of concern in patients with COPD and pain
Increased Intracranial Pressure:
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Mechanism: due to increased pCO2 (causes cerebrovascular dilation)
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Importance: needs to be taken into consideration with head trauma
Nausea/Emesis:
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Mechanism: mediated by area postrema chemoreceptor trigger zone
 Relatively uncommon in supine patients but common in ambulatory patients (hints
at possible vestibular component to mechanism)
 Tolerance to this effect develops rapidly
Cardiovascular:

Effects: peripheral vasodilation (reduced peripheral resistance) and inhibition of
baroreceptor reflex
 Not evident in supine patient, however, orthostatic hypotension and fainting can
be seen upon standing
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Mechanism: may be due in part to histamine release

Use: IV morphine used for immediate relief of dyspnea from acute pulmonary edema
associated with left ventricular failure
 Decreases anxiety, venous tone and peripheral resistance
GI
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Effects: decreased propulsive contractions (leads to increased water absorption and
constipation)
 Little tolerance to this effect and therefore can be a problem with chronic use
Other:
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Ureter: increase sphincter tone to decrease urinary output (especially in the elderly)
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Uterus: leads to prolongation of labor (also need to worry about fetal effects)
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Itching: due to effects on CNS and peripheral nerves
 Mechanism: probably substance P and/or histamine related
Toxicity:
o Causes: clinical overuse, renal insufficiency, accidental OD or suicide attempt
o Key Signs: coma, respiratory depression and pinpoint pupils

Other Important Opiates:
Heroin:
o Potent and fast-acting (“heroic”)
o Converted to morphine by deacetylation in vivo
Oxycodone:
o Use: painkiller (has a morphine backbone) for the short-term relief of moderate pain
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Cancer patients (ER release form)
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In combination with aspirin (Percodan)
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In combination with acetaminophen (Percocet)
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In combination with ibuprofen (Combunox)
o Absorption: more orally active than morphine
o Efficacy: roughly equivalent maximal efficacy to oral morphine
o Popular Drug of Abuse: possibly lethal
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Acurox: recently FDA approved drug used as a deterrent for abuse
 Combination of niacin (unpleasant effects) and inactive ingredients that convert to
a gel upon attempted extraction
 Unfortunately, has driven up abuse of other opiates
Meperidine:
o Use: painkiller whose use is now limited to acute pain management (ie. post-surgical)
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Rapid onset and short duration of action
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Irritating to tissue if given IM
o Unique Toxicity:
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Seizures, twitching, delirium and psychiatric changes
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Due to accumulation of a long-lived metabolite
Codeine:
o MOA: weak full agonist with modest analgesic activity after deacetylation to morphine
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However, 10% of the population lack the enzyme for coversion
o Pharmacokinetics:
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Absorption: good oral absorption
 Highly protected from first pass glucuronidation
 High oral:parenteral potency ratio
o Use:
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Most often given in combination formulations (ie. Tylenol 3)
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Also a sustained release formulation
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Antitussive effects (possibly through distinct receptors; efficacy questioned for this use)
Fentanyl:
o Pharmacokinetics:
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Potency: 80-100x more potent than morphine (effective but potentially dangerous)
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Duration of Action: short (with no active metabolites)
o Use:
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IV use for surgical anesthesia (often with droperidol)
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Acute post-op pain (patient controlled analgesia by transdermal iontophoresis)
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Other unique delivery routes for pain in opioid-tolerant patients:
 Transdermal patch (change every 48-72 hours)
o Be careful of exposure of patch to heat
o Be careful with concurrent use of CYP3A4 inhibitors (ie. clarithromycin,
ketoconazole)
 Effervescent buccal tablet, buccal film or lonzenge on a stick (for breakthrough
pain)
Propoxyphene (Darvon):
o MOA: partial agonist painkiller
o Efficacy: very low
o Safety: low therapeutic index (not very safe)
o Formulations:
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Combinations with aspirin/caffeine (Darvon compound)
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Combinations with acetaminophen (Darvocet)
o Toxicity: accumulation of a toxic metabolite can lead to a variety of effects
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Cardiotoxicity, convulsions, OD (being pulled from the market!)*
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Nalbuphine/Butophanol/Pentazocine:
o MOA: kappa agonists and weak mu mixed agonists or antagonists
o Effects:
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Less analgesia
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Less respiratory depression
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Less tolerance
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Less naloxone reversibility*
o Side Effects:
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More adverse behavioral symptoms (psychomimetic effects/Salvinorin-A like effects)
Tramadol:
o Structure: synthetic codeine derivative
o MOA: active metabolite is a weak mu agonist
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Also blocks 5HT and NE uptake
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Some GABA mechanisms also suspected
o Use: should be limited to chronic neuropathic pain (due to need for slow titration); however, being
seen more and more for use in acute pain
o Formulations:
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Extended release
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In combination with aceptaminophen (Ultracet)
o Side Effects:
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Reports of increased frequency of seizures
 Esp. in patients with seizure history or on antidepressant medications
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DDIs may lead to serotonin syndrome (buildup of serotonin)
Tapentadol:
o Structure: tramadol-like compound
o MOA: weak mu agonist (also a NE reuptake inhibitor; NOT 5HT)
o Risks: risk of abuse and serotonine syndrome unclear at this point
Methadone:
o MOA: full agonist
o Pharmacokinetics:
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Long Half-Life: slow metabolism in most people and high fat solubility
 Need careful initial titration
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Hepatic metabolism: no active metabolites, and therefore safe in patients with renal
problems
o Use:
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Chronic pain (esp. in patients with renal issues)
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Addict detoxification or maintenance
Buprenorphine:
o MOA: partial agonist at mu receptor (but more potent than full agonist methadone)
o Pharmacokinetics:
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Long Duration of Action: very slow dissociation from receptor (resistance to naloxone
receptor)
o Use:
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Opiate dependence (can be prescribed in office setting)
o Formulations:
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Sublingual formulation
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Combination with naloxone (Suboxone) to prevent abuse
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Sustained release formulation (once a month dosing) currently being tested
Naloxone and Naltrexone:
o MOA: opiate receptor antagonists (mu > kappa and delta)
o Naloxone:
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ER form for opiate OD
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Blocks antidiarrheal, antitussive and analgesic effects of opioids
o Naltrexone:
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Oral form used for prevention of relapse to heavy drinking
 Poor compliance
 Hepatotoxicity if taken at 3-4x the recommended dose
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Recently approved injectable ER formulation (once a month) to maintain alcohol abstinence
o
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Naltrexone SR + Buprenorphine SR (Contrave): recently approved for obesity treatment
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Modestly effective
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Concerns about cognitive and CV side effects
Methylnaltrexone:
o MOA: opiate antagonist that does NOT cross BBB (therefore, will not affect analgesia)
o Administration: injectable
o Use: approved recently for opioid-induced constipation in terminal patients under palliative care
Diphenoxylate/Loperamide:
o MOA: mu receptor agonists
o Action: meperidine congeners that have very poor absorption from the gut (exclusive use in diarrhea)
o Formulations:
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Diphenoxylate + Atropine (Lomotil)
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Loperamide (Immodium)
Dextromethorphan:
o Structure: D isomer of methylated levorphanol (does not have typical opioid effects)
o MOA: NMDA receptor antagonist and sigma receptor agonist
o Use:
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Antitussive (MOA unclear, efficacy questioned but seems to work)
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Abuse potential now evidence
o Contraindications: young children; also discouraging use of combination products (ie. with
antihistamines etc.)
Nalfurafine:
o MOA: new kappa opioid receptor agonist (no action at mu receptors)
o Use: relief of itching
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However, taking a kappa agonist should be VERY unpleasant (recall psychomimetic effects)
Current Investigative Uses of Opioid Drugs:
Antidepressants
Anti-addiction
Cardioprotection
General Principles of Therapeutic Use of Opioids:
Only symptomatic relief: do not treat underlying disease
Tolerance: repeated administration can lead to tolerance and physical dependence; however, important to note
that most people that are using prescribed opioids do NOT become addicts