Opioid therapeutics Flashcards
What are the 3 families of endogenous opioid peptides + receptors? Which as the highest affinity for mu opioids receptors?
- Beta-endorphins (highest affinity)
- Mu receptor - Met/Leu Enkephalins
- delta - Dynorphins
- kappa
What occurs pre-synpatically in the ascending pathway when opioids are used
Mechanism 1: INHIBITS Ca2+ channels
= Less calcium comes into pre-synaptic terminal
= reduced excitatory release of neurotransmitters (glutamate, substance P, PGs) from vesicles fused at the terminal end of neuron
= less neurotransmitters flow across synapse to second order neurons
= REDUCED PAIN SIGNALLING TO THE NEXT SECOND ORDER NEURONS
Mechanism 2: ACTIVATES K+ channels
= K+ ions exist pre-synaptic terminal
= hyperpolarization of cell
= NO ACTION POTENTIAL is generated
= REDUCED PAIN SIGNALLING TO THE NEXT SECOND ORDER NEURONS
What occurs post-synaptically after using opioids
By mechanism 2: ACTIVATES K+ channels
= K+ ions exist post-synaptic terminal
= hyperpolarization of cell
= NO ACTION POTENTIAL is generated
= REDUCED PAIN SIGNALLING TO THE ASCENDING TRACTS TO THE BRAIN
What is the MOA of opioids on the descending pathway
- Opioids bind to mu receptors on GABA interneurons (pre-synaptically & post-synaptically).
- This reduces the activity of GABA.
- PAG communicates with rostral ventral medulla (RVM) and raphe nuclei to release serotonin, norepinephrine, and enkephalins.
- These neurotransmitters inhibit pain signals at the dorsal horn of the spinal cord, reducing pain perception.
What is the morphine equivalent dose that we avoid going over
80mg
Who do we not use opioids in?
- Opioids overdose hx
- Alcohol use disorder (current)
- Substance use disorder hx
- Mental health disorder ?
Which opioid is least affected by CYP p-450?
Which is most?
Least: hydromorphone
Most: Methadone
T/F Opioids are organ-toxic
False
What type of pain is better relieved by opioids
Continuous, dull pain
Rather than sharp intermittent, lancinating type of pain
What 2 dimensions of pain do opioids work on?
1 - somatosensory aspect (perception of pain location, type, intensity)
2 - modulates emotional aspect of pain
How do opioids affect mood? When does it occur/stop?
Euphoria, anxiety relief in the beginning
Chronic pain has no euphoria noted
Initial relief of depression but chronic opioid use can exacerbate depression
When does sedation in opioids stabilize
Stabilize in 1-2 weeks
- can get tolerance to it
Do not combine with sedatives, benzodiazepines, alcohol
What is the MOA of N/V in opioid use? Treatment
Stimulates chemoreceptor trigger zone (located in medulla)
= enhanced vestibular sensitivity
= delayed gastric emptying
If intolerable, consider opioid rotation
Can treat with ondansetron, prochlorperazine, or scopolamine
Define respiratory depression
A rise in peripheral PCO2 + fall in peripheral O2
plus reductions in rRR which leads to hypoxia and death
- dose-dependant
- always preceded by sedation for 5-15 min
What are high risk patients for opioids for respiratory depression? (5)
- Obese patients
- patients with abnormal airways - large neck
- Narrow airway passage in through (large tonsils)
- Family or personal history of sleep apnea
- Asthma, COPD, CHF
Which medications prescribed with opioids can cause suppression of breathing centers (4)
- Anesthesia
- Sedatives (benzo, zopiclone)
- Muscle relaxants
- Alcohol
- Mood altering drugs
- Gabapentin/pregabalin at high doses
When could RD occur?
- In opioid-naive patients
- dose changes
- Rotation of opioids
- Post-op patients
- Tapering patients
What is used for rapid reversal of respiratory depression? MOA
Naloxone
- stronger receptor affinity than opioids as it kicks them off (blocks all receptors)
- no pain relief
What are signs of opioid overdose
Pupil constriction miosis (pinprick pupils)
Blue/grey lips
Sedated, soft or no breath, difficult to wake up
Doesn’t react to a sternal rub
What is the MOA of using hydrocodone for antitussive
Opioids depress cough centers in medulla & depress cough reflex (mu and kappa receptors responsible for this effect)
What endocrine effects do opioids have?
What do men have to watch out for?
Inhibits release of CRH, ACTH = decreased cortisol levels
Inhibits release of GNRH
= decreases LH, FSH
= decreases testosterone, estradiol, progesterone
= AFFECTS MENSTRUAL CYCLE & LIBIDO
Increases prolactin and ADH release anterior pituitary
*Suppresses thyroid, growth hormone and BMD
What do men have to watch out for with endocrine effects
- Counsel on OPIAD: Opioid Induced Androgen Deficiency
- Decreased testosterone levels with BOTH chronic pain & opioid use
- May result in worsening pain, depression, low energy, ED, infertility
- Check T levels
- Treatment with testosterone supplements or PD-5 inhibitors
What is the treatment for hyperhidrosis (abnormal sweating)
Clonidine 0.1mg PO BID - 0.2mg TID (watch BP)
Oxybutynin (watch in elderly as it is highly anticholinergic)
*May need to taper or rotate opioid use
What do you do if you experience pruritus on an opioid
Not a true allergy
- concentration dependent
- caused by a release of histamine from mast cells
Treatment
- Antihistamines: diphenhydramine, hydroxyzine
- Antipruritic agents: Aveeno baths
- Opioid rotation (more potent opioid = less histamine release)
What is the treatment for myoclonus (muscle twitching/spasm)
- Lower dose
- If not improved, rotate opioid
Consider baclofen, clonazepam
What is the MOA of peripheral edema from opioids? Treatment?
ADH-related or possibly opioid-induced histamine release = causes peripheral vasodilation
*histamine relaxes blood vessels –> hypotension & peripheral edema
Treatment
- Consider mild diuretic or antihistamine
- Consider leg elevation + compression stockings
If persistent, rotate opioid
Which opioid causes cardiac arrhythmias at high doses? What to monitor?
Methadone
- monitor electrolytes, ECG
- can cause torsades de pointes
What is the MOA of opioid induced constipation
1) Colon contains large # mu receptors - opioids occupy mu receptors and delay transit time through GI tract
2) Opioids inhibit effective peristalsis and decreases overall peristalsis
3) Increases non-propulsive and non-productive contractions in jejunum plus ineffective relaxation of the bowel, also affects sphincter tone
4) Decreases fluid secretion in the bowel & facilitates re-absorption of water/fluids from bowel. This is done through increased contact time for fluid reabsorption.
5) Leads to decreased and impaired urge to defecate - stools continue to have water loss resulting in hard stools and constipation
What serious ADRs can occur with constipation
- Hemorrhoids, rectal tearing, anal fissures
- Worsening of diverticulosis
- Fecal impaction
- Colonic Perforation, Ischemic Bowel (potentially fatal)
- Worsens overall pain and impacts effective pain management
- Opioid adherence problems because of constipation side effect
What is the treatment of constipation from opioids? What if there is no BM in 3 days
Senokot *Stimulant laxative
1-2 tabs QHS
Increase to 8 tabs/day (PRN)
Add on if needed:
Lactulose *Osmotic laxative
10mL - 90mL/day
PEG3350 *Osmotic laxative
If no BM in 3 days
Fleet enema, bisacodyl supp (rescue laxative)
T/F oral oxycodone/nalaxone can be used for constipation
True
When is hyperalgesia most commonly seen?
Dose increasing dose help?
Seen with increasing opioid doses or long-term use
- they become more sensitive to pain
Increasing dose improves opioid tolerance but will worsen hyperalgesia
What is the MOA of hypotension with opioids
Opioids can cause histamine release (histamine relaxes blood vessels)
What are reasons opioid tapering can be considered
- Pain condition resolved
- Risks outweigh benefit
- Adverse effects outweigh benefits
- Patient requests
- Medical complications (hypogonadism, sleep apnea, hyperalgesia)
- Opioid not effective
- 90+ Morphine equivalent dose
What do the CNCP guidelines state for opioid tapering
Start: decrease by 5-10% Total Daily Dose (TDD) q2-4 weeks.
- If that is too aggressive, slow it down, taper by 5% every 1-2 months, for example.
Last 1/3 of TDD:
- switch taper to 5% of remaining dose q2-4 weeks OR LESS
- Hardest part
T/F opioid withdrawals are life-threatening
False
T/F withdrawals does not mean patient is addicted
True
What is the onset of opioid withdrawal?
Peak?
When does it taper off?
Onset: 6-12 hours
Peak: 24-72 hours
Taper off: 1-2 weeks (some can take longer)
What are some of the opioid withdrawal symptoms (7)
- Similar to severe flu symptoms
- Muscle & joint pain (first sign)
(patient may thinking this is worsening of original chronic pain –> may request an increase in opioid dose) - Dysphoria (dissatisfaction), headaches
- Diaphoresis (sweating), rhinorrhea, diarrhea, lacrimation (tears), piloerection (goose bumps)
- Nausea, vomiting, abdominal cramps
- Yawning, shivering
- Severe sleep/anxiety
What is the treatment for withdrawal symptoms on
Muscle & joint pain
Diarrhea
Severe sleep/anxiety
Muscle & joint pain
- NSAIDs or acetaminophen prn
Diarrhea
- Loperamide,
- diphenoxylate (lomotil) for refractory cases
Severe sleep/anxiety
- Nabilone
- Gabapentin
- pregablin
(short-term)
Treatment for ANS symptoms (sweating, shivering, lacrimation, piloerection) of withdrawal
Clonidine 0.1mg PO test dose
- Check BP 1 hour later
- if BP > 90/60 –> give 0.1-0.2mg q6h prn
Continue until off opioids for 3-5 days, then taper off
When do we reassess baseline for chronic pain after withdrawal symptoms
*Do NOT reassess baseline chronic pain during withdrawal period and 4 weeks after.
Get past withdrawal muscle & joint pain first –> then reassess chronic pain
When do Opioid tolerance occur with these effects
Analgesia
CNS effects, N/V
Constipation/miosis
Analgesia
- first few weeks (may need to increase dose)
- After stable dose, majority can stay on same dose – unless new pain, drug interaction, dosage form changed, missed doses, drug diversion
CNS effects, N/V
- 5-7 days
Constipation/miosis
- NO TOLERANCE
What are the 4 Cs of addiction
Control over drug use is impaired
Compulsive use
Continued use despite harm (and knowledge)
Craving
What tool is helpful for screening for opioid addiction
Opioid risk tool
What are the effects of opioids in pregnancy?
What should a patient do if she is on opioids?
What if addicted?
May impact uterine smooth muscle causing premature labour and spontaneous abortion
Taper slowly and d/c therapy if possible
If addicted, use methadone
When is codeine and breast feeding a concern
Concern is if Mom is a rapid CYP2D6 metabolizer of codeine and is breastfeeding – Mom will rapidly convert codeine to morphine
What are alternatives to codeine in breastfeeding?
NSAIDs or acetaminophen/oxycodone (monitor closely)
What is neonatal abstinence syndrome?
When is it seen?
Symptoms?
Long-term effects?
Treatment?
- Occurs if Mother had regular use of opioids during pregnancy, Withdrawal of infant from opioid
- Seen in neonate 1-3 days post-delivery, can last several weeks
Sx: Poor feeding, irritability, sweating, vomiting
- No long-term effects on child development have been noted
Treatment:
- provide comfort support, and in more severe cases small doses of morphine for a short period of time have been use
What are the 2 bad choices of opioids to avoid? why?
- Meperidine (Demerol)
- no oral dosing
- accumulates in elderly
- neurotoxicity (tremors, seizures) - Pentacozine (Talwin)
- not for chronic pain
- stimulates kappa receptors and antagonize the mu receptors (worsens pain)
What is the only opioid used for NeP
Tramadol
MOA of Tramadol
Centrally acting agent that is a WEAK MU agonist with low affinity binding for the mu receptor PLUS
is a WEAK serotonin/NE reuptake inhibitor
What are side effects of tramadol
Enhances risk of seizures
(especially use with SSRI, SNRI, MAOI, opioids, TCA, neuroleptics)
Risk of serotonin syndrome when combined with other serotonergic agents
What is tapentadol MOA
*Mu agonist activity (much more than tramadol) and NE reuptake inhibition – very little serotonin reuptake inhibition (less risk of SS)
*No active metabolites, less potential for drug-drug interactions like tramadol
Codeine MOA
- Mu agonist “pro drug”
- Changed to active ingredient (morphine among others) by CYP2D6
What type of pain is codeine used in?
When should you switch opioids?
Used in mild-moderate pain
Switch if:
- If doses are more than 300mg/12 hours
Morphine MOA
What 3 metabolites does it create? What do they each do?
- Prototype opiate analgesic - natural derivative of opium from poppy
- Active metabolite for codeine & heroin
M3G: morphine-3-glucorinide
- Causes s/e
M6G: morphine-6-glucorinide
- Responsible for analgesia
NM: normorphine
- Metabolite is RENALLY CLEARED
Which group of people is morphine not first line for? Why?
When is it used
Do not use in elderly
- due to poor renal function
- SE concerns
First line in SEVERE pain
What is the best opioid first line for elderly for severe pain?
Hydromorphone
- Better tolerated in renal impairment
- No drug interactions
- less side effects
- 5x more potent than morphine
Oxycodone MOA
Mu agonist (some kappa agonist properties)
1.5-2x more potent than morphine
less first pass GI metabolism
Long-acting: Oxy neo
Short-acting: Oxy-IR
MOA of fentanyl
Binds to both mu and M6G receptors
No histamine release
Lower risk for itch due to its high potency
What are contraindications of fentanyl (4)
- post-op patients
- Acute pain
- Short-term pain
- opioid naive patients
When would you switch opioid to a fentanyl patch
A minimum of 60mg morphine equivalent opioid dose
Fentanyl dose
When to titrate?
Change patch every 3 days
Note: When patch is first started, patient may require short acting breakthrough opioid
- takes 12-18 hours to reach peak
Titrate up q6days
Buprenorphine MOA
Partial agonist at the mu receptors
Antagonist at the kappa/delta receptors
Buprenorphine dissociates slowly from the receptors and is not readily reversible with other antagonists
Buprenorphine dose
Can initiate 5mcg/hr in opioid naive patient
- Max dose is 20mcg/hr
Change patch q7days
start opioid after 24 hours patch free
Methadone MOA
SYNTHETIC opioid analgesic
Agonist at mu and delta receptors
NMDA antagonist properties
Possible Na-channel blocking properties
Inhibits serotonin + NE reuptake
Indication of methadone
Useful in neuropathic refractory pain (NMDA antagonist properties)
2nd or 3rd line in not responding to opioids, intolerant of other opioids, or on high dose
Methadone dose for pain
LONG Elimination t1/2: 30 hours
- Initial analgesia duration of action of 6-8 hours
DOSED Q8H FOR PAIN
What risk does methadone have with Side effects?
Risk for Torsade de pointes
What are pros of methadone (6)
Pros
- NO active metabolites
- Excreted in urine, bile (ok for hepatic/renal issues)
- Good oral and rectal absorption
- Safe in breastfeeding, pregnancy
- Addresses multiple pain mechanisms
- Useful if high dose needed
What are cons of methadone (6)
Cons
- Tricky dosing, initiation, titration
- More cumulative effects over time
- Many drug interactions
- Risk of TdP
- More prolonged withdrawal sx
- Variable half life and equianalgesic (q8h dosing)
What are the 5 “A’s” for chronic use of opioids to monitor for
Analgesia
Activities of daily living (function)
Adverse effects
Ambiguous drug taking behaviours
Accurate medication log
What exercise non-pharms can you recommend to patients
- Range-of-motion/flexibility/stretching exercises
- Strength training, core training & endurance exercises
- Pilates, Yoga, Tai Chi, Aquafit, stretching
- Cardiovascular conditioning
- Coordination/balance/proprioception retraining
- Task specific training
Strengthens muscles, mobilize joints, enhances balance & posture, release of endorphins, improved mood and overall outlook
Acute injury:
* RICE: Rest, Ice, Compression, Elevation
* Diminish swelling & inflammation - most effective 24-48 hours post
* Therapeutic heat/therapeutic cold
* Hydrotherapy – whirlpool baths, contrast baths
What electrical treatment can be used?
What kind of pain is it used for?
Transcutaneous Electrical Nerve Stimulation
* Counter-stimulation technique that is thought to stimulate peripheral nerves directly
* Alters painful sensations - the “tingling” sensation replaces painful sensations.
* Involves applying low voltage electrical stimulation to large nerve fibers (AB fibers)
- Effective pain relief in some forms of acute pain conditions: post-op pain, oral-facial pain, labour pain
- Evidence is mixed for TENS in chronic pain
- TENS is “contraindicated” in cancer pain
Evidence of chiropractic and massage
Chiro
- * Limited evidence from systematic reviews supports chiropractic tx for MSK conditions (LBP)
Massage
Massage
- May help to improve sleep, some efficacy in back pain
What are some behavioural approaches you can take for pain (4)
- Pain Self-Management Groups (Stanford) – Sandra Lefort et al
- Cognitive Behavioural Therapy (CBT)
- Stress Management, Behavioural Management Strategies
- Group Based Mindfulness Programs –
