Opioids and Drug Addiction Flashcards
How is pain transmitted?
- Stimulation of pain receptors (nociceptors)
- Sub P released and activates ascending pathways
- Glutamate activates AMPA and NMDA receptors
- Pain sense is projected to brain
Where is the perception of pain occurring?
Thalamus
Where is the localization of pain occurring?
Somatosensory cortex
Where are the behavioral and emotional responses to pain occurring?
Hypothalamus and limbic system
How do endogenous opioids and opioid meds treat pain?
- Inhibit ascending pain transmission from spinal cord (mu, delta, kappa receptors)
- Activates descending inhibitory pathways
- Agonism at mu and delta receptors stimulates release of dopamine (leads to euphoria, activation of “reward center”)
What receptors increase the pain threshold resulting in dulling of the pain sensation?
Mu, delta, kappa
What do mu, delta, and kappa receptors do?
- Part of inhibiting ascending pain transmission from spinal cord
- Increase pain threshold
- Dulls pain sensation
What are the types of mu receptors and what do they do?
Mu 1: analgesia
Mu 2: sedation, vomiting, respiratory depression, pruritus, euphoria, anorexia, urinary retention, physical dependence
None of our opioid meds are mu-1 selective unfortunately!
What are the naturally occurring opiates?
Morphine and codeine
What do opioid meds bind to?
G-coupled opiate receptors in brain, spinal cord, periphery (GI)
What are the primary actions of opioid meds?
- Close presynaptic Ca channels (results in decreased NT release including Sub P)
- Open K channels (hyperpolarize and inhibit postsynaptic neurons)
Which neurotransmitters are inhibited when opioid meds close Ca channels?
- Glutamate
- Norepi
- ACh
- 5HT (serotonin)
- Sub P
Opioid meds pharmacokinetics (generally)
- Extensive 1st pass with oral formulations
- Distributes well into highly perfused areas (brain, kidney, liver, lungs, spleen)
- Highly lipophilic (accumulate in adipose tissue)
Opioids metabolism
- CYP2D6 (MC esp codeine, hydrocodone)
- CYP3A4 (mainly fentanyl, methadone)
What is important to remember regarding CYP2D6 metabolism of opioids?
- Some individuals have NO CYP2D6 activity leading to NO metabolism
- Some have high levels leading to rapid metabolism
- Codeine has to be converted to morphine
Which opioids should be used in patients with renal dysfunction?
Methadone and fentanyl
Which opioids do not go through phase 1 CYP metabolism?
Morphine, hydromorphone, oxymorphone
Describe opioids analgesia effect
Decreases both sense and affect of pain
CNS effects of opioids
- Analgesia
- Euphoria
- Respiratory depression
- Cough suppression
- Miosis
- Truncal rigidity
- N/V
CV effects of opioids
- Bradycardia
- Hypotension (likely from histamine release)
GI effects of opioids
Constipation:
- Decreased motility, HCl secretion
- Increased tone and H2O reabsorption
Biliary tract effects of opioids
- Contracts smooth muscle (colic)
- Increases pancreatic enzymes
Renal effects of opioids
- Decreased plasma flow
- Antidiuretic effect (increased reabsorption of Na)
- Urinary retention
Uterine effects of opioids
May prolong labor (unknown mechanism)
Skin effects of opioids
Pruritus (due to histamine release)
Describe codeine
- Pro drug, weak opioid agonist
- Requires conversion to morphine via CYP2D6
- Antitussive, not a great pain reliever
- ADEs limit use
Metabolism of hydrocodone
- Weak opioid agonist
- Metabolized to hydromorphone via CYP2D6
Describe oxycodone (formulation, metabolism, etc.)
- Weak opioid agonist
- PO formulation only
- CYP2D6 to oxymorphone
- Addiction potential higher than morphine
- Commonly sold on street (hillbilly heroin)
- Often paired with acetaminophen (Percocet)
Describe morphine
- Strong opioid agonist
- Metabolized by glucoronidation to M3G (side effects) and M6G (analgesia)
Special considerations of morphine
- Consider d/c at CrCl less than 50
- IV form CI in sulfa allergy
- Long acting formulations available
Morphine drug interactions
- CNS depressants
- Diuretics (decreases effect)
- Muscle relaxants (increases effect)
Describe Avinza
- Long acting morphine
- Black box warning of ETOH consumption
What is the preferred agent in post-MI pain and why?
Morphine
-Histamine release causes peripheral vasodilation which will decrease preload and oxygen demand of the heart
Describe meperidine (demerol)
- Strong opioid agonist
- Not recommended for chronic use
- Most hospitals only use for post-anesthesia rigors (or OB labor pains)
Why has meperidine (demerol) fallen out of favor?
- Analgesic effect only lasts 3 hours but half life is 15 hours so it accumulates widely and fast
- Active toxic metabolite (normeperidine): causes intractable seizures
What is normeperidine?
- Active toxic metabolite of meperidine
- Can cause intractable seizures
Describe fentanyl
- Strong opioid agonist
- 100x more potent than morphine
- CYP3A4 to inactive metabolites
- More lipid soluble (quicker onset and resolution of resp. depression)
- Little to no histamine release (go to for pts w/itching on other agents)
What is the fentanyl formulation of choice for chronic pain patients?
Transdermal patch
- 12-24 hrs time to peak (cover this time period w/a short acting opioid)
- Reservoir remains up to 24 hrs post removal of patch
- Do NOT apply heat to patch area (rapid increase in absorption)
Primary use of methadone?
Chronic cancer pain
How does methadone work?
- Acts on all opiate receptors
- Antagonizes NMDA
- Blocks serotonin and norepi
Describe methadone
- Strong opioid agonists
- High lipid solubility (half life can be 15-150 hrs)
- Must be prescribed Q8h or Q12h
When is methadone prescribed Q24h?
Detox only (otherwise, must be Q8h or Q12h)
Advantages of methadone
- Can be used in someone with a true opioid allergy (less than 1% of pts)
- Long acting w/o special formulation
- Excreted in feces instead of urine
- Causes less constipation than other opioids
- Cheap
- Less euphoria
- Respiratory depression is less pronounced
Disadvantages of methadone
- Can cause Torsades
- CYP3A4
- Difficult to convert this to other opioids
What is tramadol?
- Mu receptor agonist/serotonin reuptake inhibitor/norepi reuptake inhibitor
- Can lower seizure threshold in pts w/seizures
What is tapentadol?
- Mu receptor agonist/norepi reuptake inhibitor
- Can lower seizure threshold
Describe weak opioid agonists/NT reuptake inhibitors
- Thought to be less addictive
- Less concern w/drug interactions
Describe nalbuphine
- Mixed agonist/antagonist
- IV only
- Has a ceiling effect
- Not commonly used
- Should be used in someone w/substance abuse history (or strong fam hx)
Describe buprenorphine
- Mu agonist/K antagonist
- Sublingual and IV
- Preferred for detox (esp in pregnant women)
- Should be used in someone w/substance abuse history (or strong fam hx)
What is the only opioid currently formulated intranasally?
Butorphanol (mixed agonist/antagonist)
*Should be used in someone w/substance abuse history (or strong fam hx)
Monitoring opioid use
- Analgesia
- Affect (depressed?)
- Activities of daily living
- Adverse effects
- Aberrant behaviors
Absolute contraindications to opioid use
- Severe resp instability
- Acute psych instability or suicide risk
- Diagnosed non-nicotine substance abuse disorder not in remission or treatment
- True allergy
- Co-administration of drugs capable of fatal interactions
- QTc greater than 500 ms (avoid methadone)
- Active diversion
Relative contraindications
Anything with respiratory issues
Preventing opioid induced constipation
- Typically occurs w/in 3-5 days
- Tolerance does not usually occur
- Combo of stimulant laxative (Senna) and stool softener (Docusate)
- Titrate to 1 soft BM every 1-2 days
How do opioids induce respiratory depression?
As dose increases, brain’s response to CO2 decreases
Treatments of opioid induced respiratory depression
- Naloxone (Narcan)
- Naltrexone
- Nalmefene
Describe naloxone (narcan)
- Antidote to opioid induced respiratory depression
- Pure competitive opiate receptor blocker
- No PO bioavailability
- Onset is 5-10 secs
- Half life 30-90 mins
Describe naltrexone
- Treatment of opioid induced respiratory depression
- Pure opiate antagonist
- PO and IM bioavailability
- Longer acting than naloxone
- Not typically used in acute emergencies, more in curbing dependence and cravings
Describe nalmefene
- Treatment of opioid induced respiratory depression
- Synthetic opiate antagonist
- Similar to naloxone (narcan) but longer duration of action, IM and SQ
Opioid allergy
- True allergy is RARE
- Presents as anaphylaxis
- Histamine release can be dose dependent
Treatment of true opioid allergy
- Combination of H1 and H2 blockers
- Switch to an opioid with lower histamine release potential
Which opioids release largest amount of histamine?
- Morphine
- Codeine
- Meperidine
What opioids cause largest amount of euphoria (potential for addiction)?
- Hydrocodone (Vicodin)
- Hydromorphone (Dilaudid)
- Oxycodone (Oxycontin)
- Oxymorphone (Opana)
Narcotic schedules I and II
I: no accepted medical use, highest abuse potential (marijuana, LSD, heroin)
II: highest abuse potential of drugs that have accepted medical use (morphine, oxycondone)
Narcotic schedules V and VI
V: Some states these can be sold w/o prescription
VI: non-controlled, rx required, no abuse potential
Other uses of opioids besides pain?
- Anti-tussive (codeine, hydrocordone, dextromethorphan)
- Anti-diarrheal (loperamide, diphenoxylate/atropine)
- Shivering (rigors, meperidine)
How are opioids being improved to reduce diversion?
- Polyethylene oxide (becomes viscous if mixed for injection, cannot be drawn with a syringe)
- Sodium laurel sulfate (nasal irritant to deter snorting)
- Break into pieces instead of powder
With opioids, when do we need to reduce for cross-tolerance?
When switching from one opioid to another agent (regardless of formulation)
With opioids, when do we NOT need to reduce for cross-tolerance?
When switching formulation of 1 opioid agent (e.g. IV morphine to PO morphine)
How much do we reduce an opioid dose when converting to a different agent?
25% (so multiply by 0.75)
How to convert to fetanyl patch?
- Convert to PO morphine FIRST
- Then use fentanyl package insert to determine patch size you need
How is breakthrough pain dosing calculated?
10% of total DAILY dose
- For 40 mg BID = 80 mg total
- 80 mg x 0.10 = 8 mg PER DOSE
What are the different forms of buprenorphine?
PO: subutex, suboxone
IV: buprenex
Transdermal: butrans
Which form of buprenorphine contains naloxone?
Suboxone (PO)
How long can someone test positive for methadone?
3 to 14 days
How long can someone test positive for opioids?
2 to 3 days
up to 6 days w/ER formulations, up to 1 week for prolonged or heavy use
Symptoms of opioid withdrawal?
-NV and diarrhea
-Yawning
-Lacrimation, salivation
-Tachy
-Mydriasis
-Mild increase in BP
-Insomnia
-Irritability
NOT LIFE THREATENING
Time frame of opioid withdrawal
- Onset is dependent on agent
- Lasts few hours to weeks
- Flu like symptoms usually last 1-2 wks
Steps of converting opioids PO to PO
- Calculate current TDD (total daily dose)
- Use equianalgesic chart to convert to another PO drug (cross multiply proportion method)
- Divide total dose into appropriate interval for new opioid
- Decrease dose by 25% (multiply by 0.75) for cross tolerance
Why do we decrease opioid dose when converting to a different agent?
- May have tolerance to the first agent, but not the new one
- If you give same dose of new opioid, you may increase risk of side effects bc there isn’t that same tolerance
