7 Opioids and Antagonists Flashcards
Opium is from the _________ plant and contains…
Papaver somniferum
10% morphine
0.5% codeine
What are the endogenous opioid peptides?
Enkephalins
Beta-endorphin
Dynorphin
Endogenous opioid peptides are ______ in response to pain
Released —> decreased responsiveness to pain
Derived from opium
Opiate
Having properties similar to drugs derived from opium
Opioid
Term that technically means “sleep inducing” but is commonly taken to mean “opioid”
Narcotic
Endogenous opioids are found in…
Areas of the brain involved in pain and in the reward system
_________ decrease pain transmission in the spinal cord and facilitate dopamine in the reward system, causing euphoria
Beta-endorphins
______ decrease pain transmission in the spinal cord
Enkephalins
_______ bind to kappa receptors, may produce analgesia, but also dysphoria
Dynorphins
What are the three opioid receptors
Mu (µ)
Kappa
Delta
(Sigma is not an opioid receptor, it binds to PCP)
Which opioid receptor does most of the things
Mu
All opioid receptors are coupled to _______ and decrease ________
G-i/o
cAMP
All subtypes of opioid receptors close _____________ on presynaptic nerve terminals
Voltage gated Ca2+ channels —> decreases neurotransmitter release and decreases neuronal activity in these pathways
In addition to closing voltage gated Ca2+ channels, µ receptors…
Open K+ channels, causing hyperpolarization —> inhibition of nerve transmission
Opioid receptor stimulation decreases the release of NTs by…
Inhibiting Ca2+ influx on the presynaptic terminal
Also µ receptors open K+ channels —> hyperpolarization —> harder for neurons to respond to pain signals
Effects of µ receptor stimulation
Analgesia
Euphoria
Sedation
Side effects
Effects of kappa receptor stimulation
Analgesia in some people, dysphoria in others
Effects of delta receptor stimulation
Dysphoria
What are the three ways opioids effect the transmission of pain?
Direct action at inflammed and damaged tissue
Inhibition of release of excitatory transmitters in the dorsal horn (spinal anesthesia)
Thalami action
How do opioids modulate pain
Periaqueductal gray, may cause release of endogenous opioids as well
Rostral ventral medulla
NE pathway from locus coeruleus to dorsal horn may also decrease pain
Inhibition of neurons may increase the activity of pathways that inhibit pain
What is the relationship between opioids and GABA?
GABA normally inhibits descending neuronal pathways that modulate pain
Opioids decrease the release of GABA, allowing the pathways to be activated
This decreases pain transmission in the dorsal horn of the spinal cord
Describe the analgesic effects of opioids
Decreases sensation of pain - not numb but they don’t mind it as much
Decreases reaction to pain - relieves SUFFERING from pain
Tolerance develops to the analgesia
What type of pain do opioids not work well for?
Nerve pain
Gabapentin is better
What are the sedative effects of opioids?
Not used as sleep aids - different quality of sedation (floating, dream-like state)
Disrupts REM
Morphine causes CNS depression in overdose
Codeine, meperidine may cause excitement in overdose
Some species become excited rather than sedated
While morphine causes CNS depression in overdose, _______ and ______ can cause excitation
Codeine
Meperidine
What are the different grades of CNS depression you see in opioid overdose?
Mental clouding/sedation —> hypnosis or stupor —> coma —> death
What are the effects of opioids on your mood?
Can cause a sense of euphoria (floating, pleasure) - researchers trying to dissociate euphoria from analgesia
Some find the experience dysphoric (unpleasant) - kappa and delta receptors are involved in dysphoria
Effect probably depends on receptor distribution in different individuals
Individuals who experience dysphoria while using opioids like have more ________ receptors
Kappa and delta
Which opioid causes the worst nausea?
Injected morphine
Why do opioids cause emesis?
Stimulate chemoreceptor trigger zone (CTZ)
Take with food!
What are the antitussive effects of opioids?
Lower doses than those used for analgesia
CODEINE and DEXTROMETHORPHAN most commonly used and very effective for depression of cough reflex
___________ is not an analgesic but works great as an antitussive agent
Dextromethorphan
_______ doesn’t suppress cough at all but is a great analgesic
Meperidine (Demerol)
What are the effects of opioids on the respiratory system?
Respiratory depression more common in overdose but also occurs with therapeutic doses
Decreases response of brain stem to elevated CO2
USEFUL IN PULMONARY EDEMA
Not good in people with pulmonary disease (Ie COPD)
May also cause bronchoconstriction
Effect of opioids on intracranial pressure
Increases ICP
Increased CO2 causes vasodilation, increases cerebral blood flow, and increases pressure
Watch out in patients with head trauma
Why would you want to avoid opioids in patients with head trauma?
B/c they increase intracranial pressure
All opioids cause miosis except…
Meperidine (which actually dilates the pupils
Tell me more about opioids and miosis
No tolerance develops (useful when people lie to you about having taken them)
Due to parasympathomimetic - blocked by atropine
Common in overdose but may convert to dilation in comatose patients
Why do you get decreased body temperature when you take opioids?
Dysregulation in the hypothalamus
Problematic for those addicts living on the street in winter…
Effects of opioids on the skeletal muscles
Supraspinal effect increases tone of the large trunk muscles —> truncal rigidity
May interfere with respiration or with attempts to ventilate patient
Most common with highly lipid soluble drugs like fentanyl
Inject slowly or use neuromuscular blockers to prevent this effect
Truncal rigidity is most common in…
Highly lipid soluble drugs like fentanyl
What are the cardiovascular effects of opioids?
No direct effect but bradycardia may occur
Decreased BP common
May result from CNS vasomotor depression and/or release of histamine (vasodilators)
Tachycardia may occur with meperidine
What’s the one opioid that causes tachycardia rather than bradycardia?
Meperidine
GI effects of opioids
Decreased gastric activity both CNS and local inhibition of transmitter release
CONSTIPATION
Decreased gastric motility
Biliary colic, constriction of sphincter of Oddi
Decreased biliary, pancreatic, and intestinal secretions
What patient ed is important when starting a patient on opioids?
Warn them about constipation and be pro-active in preventing it - maybe give them a stool softener at the same time
GU effects of opioids
Antidiuretic effect —> decreased urine output
Decreases renal blood flow
Increases sphincter tone —> harder to urinate (worst for those with BPH)
Increases urethral tone —> harder to pass kidney stones
Why don’t you give opioids to someone with kidney stones?
They increase urethral tone making it harder to pass the stone
Effects of opioids on the uterus
May prolong labor
Endocrine effects of opioids
Increases ADH, prolactin, somatotropin
Inhibits luteinizing hormone
People will often claim that they are allergic to opioids when they are really just….
Reacting to the histamine release that occurs in some people (—> flushing, itching, sweating)
True opioid allergies are very rare
More common when opioids are injected, especially morphine
Generally treated or prevented with antihistamines like Benadryl
_____ commonly develops when opioids are used chronically
Tolerance
Higher doses will be needed to control pain
Occurs very rapidly - within days
More common with drugs that have lower efficacy
How does physical dependence occur with opioids?
May result from desensitization of mu receptors or receptor uncoupling
NMDA receptor antagonists may decrease development of tolerance
Hyperalgesia with long-term opioid use may be mediated by…
Increases in spinal cord dynorphin in that it makes pain transmission more effective
Decreased by NMDA receptor antagonists
While tolerance to analgesia, sedation, euphoria, N/V, and respiratory depression do develop with opioids, no tolerance will develop to…
Miosis
Constipation
Seizures
Urinary retention as a result of opioid use will be worse in…
Men with BPH due in part to constriction of urinary sphincter
Adverse effects of opioids
N/V (take with food) Constipation Urinary retention Itching/hives Respiratory depression*** Postural hypotension Restlessness and hyperactivity Dysphoria in some people
Tolerance to opioids results from …
Receptor desensitization
Down regulation
Uncoupling from G-proteins
(Occurs in thalamus and spinal cord)
Patients who develop tolerance to opioids __________ addiction, but patients with addiction ________
Do not necessary have addiction
Patients with addiction are also tolerant
The reward pathway is involved in addiction, different from the tolerance areas
Why are opioids addictive?
Opioids increase firing in the reward system, leading to euphoria and reinforcement
Opioid abuse and addiction has become a major problem in the US
______ and ______ occur in anyone who uses opioids chronically for any reason
Tolerance and physical dependence
Addiction is most common when opioids are used for euphoric effect but an occur with medical use as well
Addiction is more likely if _________
UNDERprescribed
If the patient develops severe pain, which is relieved by an opioid, this provides reinforcement
Reward pathway activated
If opioids given before the pain gets too severe, it bypasses the reward pathway —> STAY AHEAD OF THE PAIN!
Compulsive use of drugs athat are no longer required medically, in spite of adverse consequences
Addiction
Other signs of addiction
Abandoning responsibilities Constipation Depression Mood swings Slurred speech Poor coordination Needle marks from injection Infections from injection
SSx of withdrawal
Dysphoria, anxiety, insomnia Anorexia, yawning Chills, goose bumps Vomiting, diarrhea Rhinorrhea, lacrimation Increased BP, HR, Temp Muscle aches and twitches
Symptoms of withdrawal can be reduced by use of …
Clonidine or another opioid (methadone)
Opioid antagonists can precipitate withdrawal if dependent though
SSx of opioid overdose
CNS depression
Respiratory depression
Pin point pupils (may dilate if severely hypoxic)
Treat by supporting respiration (ABCs)
Use of opioid antagonist naloxone (Narcan)
What are the different routes of administration for opioids
Patient controlled analgesia Transdermal patch Intranasal spray Buccal (lollipop) Sublingual
Keys to remember when using opioids to control pain
Sedation will be common (can become tolerant)
Stay ahead of the pain - dose around the clock
Combine with non-opioids when possible to maximize effectiveness
Titrate opioid to degree of pain - strong for severe pain, moderate for less severe
Patient controlled analgesia often used post-op
How are opioids used in acute pulmonary edema?
To relieve dyspnea (mechanism unclear)
Which opioids are used for the relief of cough
Codeine and dextromethorphan
What are the opioids used for treatment of diarrhea?
Loperamide (Imodium)
Diphenoxylate/atropine (Lomotil)
Opioids + sedative-hypnotics
Increased CNS and respiratory depression
Opioids + antipsychotics
Sedation, maybe respiratory depression
Opioids + MAO inhibitors
Esp Meperidine/dextromethorphan
May inhibit serotonin reuptake to some degree
BUT - best to avoid ALL opioids with MAOIs
Opioids + CYP2D6 inhibitors
Inhibit metabolism of codeine, oxycodone, hydrocodone to active compounds
Fluoxetine, paroxetine are the worst for inhibition
Contraindications for the use of opioids
Use of partial agonist with full agonist - can impair analgesia and cause withdrawal
Patients with head injuries (b/c increase ICP)
Pregnancy (esp at delivery)
Impaired pulmonary function
Impaired hepatic or renal function
Some endocrine diseases
Use opioids with caution in patients with …
Severe liver/kidney disease Pulmonary disease Biliary tract problems Seizures (esp meperidine) Pain of unknown cause (esp abdominal) Head trauma Chronic non-terminal pain Inflammatory bowel disease Pregnancy/breast feeding Urinary retention/BPH
Morphine stimulates _______ receptors
All opioid receptors
Strong agonist
Produces all of the effects of opioids
Useful in severe pain
Morphine is more effective when…
Injected, due to high first-pass metabolism (~75%) if taken orally
Extended release long-acting oral preparation used in chronic/terminal pain
Onset and duration of action for morphine
Rapid onset with parenteral admin - max action within one hour
Duration of analgesia is approx 4-6 hours (half-life 2-3 hours, longer in elderly)
The standard therapeutic dose of morphine is…
10mg SC or IM
This is the dose to which all other analgesic drugs are compared
Morphine is metabolized …
In the liver by CYP2D6
Conjugated to glucuronide compounds
Morphine-6-glucuronide is very potent analgesic
Morphine-3-glucuronide may cause adverse effects as it accumulates
Why don’t you give morphine to pregnant women?
Morphine and other opioids readily cross the placental barrier and can affect the fetus resulting in respiratory depression or even drug dependence with chronic use
Hydromorphone (Dilaudid) is a ________ analgesic
Very strong - more potent than morphine
Very effective for moderate to severe pain
Metabolites don’t accumulate so good if there is renal dysfunction
Less likely to cause histamine release and itching than morphine
MOA for Methadone (Dolophine)
Long half life and duration of action
Stimulates mu receptors
May also block NMDA receptors and inhibit NE/serotonin reuptake
How is Methadone (Dolophine) used?
Traditionally used for maintenance treatment of addicts
•Low doses used to prevent withdrawal symptoms
• Withdrawal thought to be milder, but very prolonged
Now commonly used in long-term control of pain
Effective in hard-to-treat types of pain
When should Meperidine (Demerol) NOT be used?
For more than 48 hours
In high doses
In renal failure (due to accumulation of metabolite, normeperidine)
As a cough suppressant (don’t work)
Metabolite of meperidine that causes seizures
Normeperidine
Meperidine (Demerol) is the one opioid you might use in obstetrics because…
Less respiratory depression in baby
Meperidine + MAOIs
Serotonin syndrome
Very lipid soluble and highly potent opioid with a high abuse potential
Fentanyl (Sublimaze)
Very commonly used in short surgical procedures, often with midazolam
Popular in longer surgeries b/c of good CV profile
May cause truncal rigidity if given rapidly via IV
________ is used for moderate to severe pain, often in combo with acetaminophen
Hydrocodone
Generally given orally, well absorbed
Don’t give to patients on SSRIs (esp fluoxetine/paroxetine) b/c they need to be converted by CYP2D6 for effect
Probably shouldn’t give the combo with acetaminophen but whatever
Percocet is _____ + ________
Oxycodone + acetaminophen
Percodan = ______ + ________
Oxycodone + aspirin
Naloxone or naltrexone are often added to ________ if injected to decrease abuse potential
Oxycodone
Codeine is _____ if alone, _____ if less than 90mg combined with acetaminophen or aspirin, _______ when less than 2mg/ml in cough suppressants
Schedule II
Schedule III
Schedule V
Which opioids have CYP2D6 interactions?
Codeine, oxycodone, hydrocodone
Less pain relief if 2D6 is inhibited
Codeine may be toxic if 2D6 extensive metabolizers
What is Pentazocine/naloxone (TalwinNX)
Kappa receptor agonist and mu receptor partial agonists
Moderate pain
May be less sedating than other opioids
May have less resp distress, GI effects
May cause dysphoria
May cause withdrawal
What is Buprenorphine?
Partial agonists on mu and maybe on kappa
Has ceiling effect - doesn’t cause much euphoria (so low abuse potential)
Now used for maintenance treatment of opioid addiction - decreases craving for drug
Can be injected, sublingual, or intranasal
Combined with naloxone
New maintenance drug for opioid addiction
Buprenorphine
Tramadol + antidepressants
Seizures
Tramadol should not be combined with these drugs because it may cause serotonin syndrome
MAOIs
TCAs
SSRIs
MOA for tramadol
Weak mu agonist
Inhibits NE/serotonin reuptake, contributing to analgesic effect
Generally mild side effects
______ is not an analgesic but works as a cough suppressant
Dextromethorphan
Dextromethorphan is frequently combined with _________
Guafenisen (expectorant)
What is robotripping?
Dumb ass kids taking too much dextromethorphan
How do opioid antagonists work?
Pure antagonists bind to opioid receptors and prevent agonists from acting
Mixed agonists/antagonists
• Generally partial agonists
•Alone will cause stimulation of receptor
• Antagonism if other stronger agonists are being used concurrently
May precipitate withdrawal in opioid-dependent individuals
Drug of choice for opioid overdose
Naloxone (Narcan)
Can reverse respiratory depression, consciousness, awareness of pain, miosis, constipation
Injected or intranasal
Short duration of action (2 hours)
How much naloxone should you give a druggy who is ODing?
Keep giving it until pupils dilate
Repeated dosing may be required
What is Naltrexone (ReVia)
Used in treatment of opioid addicts, esp health care professionals
Will precipitate withdrawal
Decreases craving in recovering alcoholics
May cause liver toxicity when used chronically
