Flashcards in Opiods Deck (62):
What are considered endogenous opioids?
- Endorphins: from pituitary and hypothalamus, polypeptides, porporiomelanocortin and prodynorphin, potent analgesics
- Enkephalins: from proenkephalin and prodynorphin, pentapeptide ligands, and is involved in modulating the pain response
- Dynorphins: from prenkephalin B, polypeptides, physiological role is not yet understood
MOA of opioids
-hyper polarization of nerves by opening K channels/ calcium channels in 1st (receptor to medulla) and 2nd order neurons (medulla to thalamus)
-inhibition of ascending pathway in the CNS
- excitation of descending adrenergic and seratonerigic pathways
Where do opioids come from?
- has the active ingredients of morphine and codeine
What is the pharmacological effects of opioids?
- inhibition of pain and pain perception
- sedation and anxiolysis
(drowsiness and lethargy, cognitive impairment, relaxation and inhibition of pain)
- depression of respiration (can be clinically useful in those that are at the end of their lives)
- cough suppression
- reduction of intestinal motility - codeine can be used to treat diarrhea
- pupillary constriction
- nausea and vomiting -
Opioids are used for what?
pain, diarrhea, coughing, and panic breathing in COPD
What does it mean to dose opioids by the mouth, by the clock and by the ladder?
- want to ALWAYS give someone acetaminophen first to handle their pain
- then you can set up to codeine as a second step- it is a very mild opioid
- all the way through, you want to keep the patients on acetaminophen!
- if codeine does not work, then you can dose morphine- this is also taken at the same time as acetaminophen
What does "by the mouth" mean?
- oral dosing is less effective than IV, BUT..
oral dosing as longer term effect (less frequent doses), it avoids the highs and thus is less addictive, and oral dosing is safer in terms of an overdose
What does "by the clock" mean?
- uses less drug - it takes more drug to bring pain down than it does to maintain a person pain-free
- avoids the euphoria associated with release of pain, so less addictive potential
- avoids the development of chronic pain syndromes (from pain pathway rewiring)
-- want to dose the person on their opioid every set amount of hours RELIGIOUSLY- it takes less drug to keep the pain away than it does to drop the pain once it comes back
- there is the danger when the person is going in and out of pain that it will remodel their spinal column- can cause chronic pain
- want to dose by the clock, not by the pain
What does dosing "by the ladder" mean?
- assures that the safest and least potent drug is required for ay specific case
- avoids addictive potential because opioids and strong opioids are not used until required
- weakest commonly used opioid - very little addiction risk
- potency is so low that it has its own step on the ladder (tramadol here too)
- used for pain, diarrhea, coughing and to inhibit breathing
- is considered a unique opioid agonist
- has a similar structure to codeine and morphine, so it is in the opiate agonist class
- unlike other opioids, it has 2 complementary mechanisms
1. like other opioids, activates the u- opioid receptor
2. weak inhibitor of NE and serotonin retake
- there is less potential for addiction, and shows greater pain control than can be explained by weak opioid action
- with acetaminophen, this drug is known as tramacet
- oral has a relatively poor bioavailability due to first pass metabolism
- latency to onset - 15-60 minutes
- has a duration of action of 3 to 6 hours
- IV is twice and potent as oral forms
- duration of action - almost immediate to around 2 hours (there is a high population variability here)
- has equal or slightly greater potency than morphine (up to 2x)
- has oral bioavailability of 80%
- half life is slightly greater than morphine- dosed at half morphine dose for equivalent effects
- slow release is OxyContin
-with Tylenol it is known as percocet
- oral: latency to onset is 15-30 minutes
- IV: DOA is 3-4 hours
- peak effect: 30-60 minutes
- is 5x as potent as morphine for pain
- used in surgical settings for moderate to severe pain (cancer, etc)
** not more effective than morphine, but it is more potent
- highly lipophilic and very potent (thin patient/patch)
- 8x the analgesic potency of morphine and 10x the analgesic potency of hydrophorphone
- sublingual and transdermal- rarely IV
- Sublingual - latency is 7012 minutes with a duration of 1-2 hour. Used for acute, temporary pain
- Transdermal - latency 12-17 hours - duration of 72-96 hours. Used in more severe pain(cancer)
-this is an oral opioid inhibitor!
- latency: 15-30 minutes
- reverse the psychotomimetic effects of opiate agonists, reverses hypotension and cardiovascular instability
- it is NOT highly effective in treating opioid addiction, but IS effective to some extent in treating alcohol addiction
-- can actually kill someone if you give them this when they;re addicted to opioids because it knocks all the opioids off of the receptor
- very effective because it gets rid of the positive effects of alcohol- before you start drinking you take the naltrexone, and drinking is not pleasurable anymore
- a potent opioid antagonist
-quickly blocks opioid binding
- used in emergency situations, like respiratory depression in heroin overdose. Has a short half life
- blocks all major effects of opioids including pain control
How is naloxone so unique in the ways that it is effective?
- naloxone is only effective when it is ground up and injected - the naloxone will blocks the receptors and make the opioids not effective, but ONLY IF IT IS GROUND
- if the drug is taken orally like its supposed to - THIS DOES NOT HAPPEN
Methadone has a very long but variable half life, but is effective for only 6-12 hours
- at least 10x more potent than morphine, but variable
- less addictive but has a greater risk for accidental overdose (even in a medical setting)
- requires special training and licence
- used mostly for addiction meds and in palliative care when resistance has been developed to other opioids
What is the important thing to remember when prescribing opioids?
- want to titrate up the dose of opioid based on response and side effects until the maximum analgesia and function are attained with tolerable side effects
- if possible, want to switch to long acting opioids at equianalgesic doses
- long acting opioids reduce the likelihood that the patient will "watch the clock" and reduces peaks and valleys in pain control
When should therapy be discontinued?
- when there are intolerable or unacceptable side effects with little or no evidence of analgesia
- high doses of opioids without analgesia
- there is evidence of addiction
- there is no evidence of any effort to increase function in the face of reasonable analgesia
What is opioid tolerance?
- reduced potency of analgesic effects of opioids following repeated administration - i.e.. increasing doses are necessary to produce pain relief
- related to opioid receptor regulation
- less common in patients with cancer pain
- often reason patients save opioids until the terminal phase
What is opioid dependence?
physical dependence: the normal response to chronic opioid administration
- evident with opioid withdrawal- yawning, sweating, tremor, fever, increased heart rate, insomnia, muscle/ abdominal cramps, dilated pupils
- avoided by decreasing the dose to 20-30% per day
What is opioid addiction?
- psychological dependence
- drug use characterized by a craving for opioids that is manifested by compulsive drug seeing behaviour leading to overwhelming involvement, use and procurement of drugs
How do you deal with drug tolerance?
- precent dose escalation
- use a medication holiday following slow withdrawal
- plan for this at the beginning of treatment
What are some of the physical symptoms of drug tolerance?
- causes vomiting by stimulating the chemoreceptor trigger zone in the brainstem
- then depresses vomiting
- vasodilation - flushing of the skin and decrease in blood pressure. Methadone causes sweating
- decrease in sex hormones in males and females - decreases libido and fertility
What are the 3 places that drugs can target to tx neuropathic pain?
- on the descending inhibitory pathways
- peripheral sensitization
- central sensitization
How does the descending inhibitory pathway work?
-NE and serotonin are pain mediators - they inhibit pain signals from reaching the higher levels of the brain
- part of the modulatory system in the spinal cord and brain
What NT are targeted in the descending neuropathic pathways?
NE, 5HT, and endorphines
What are the classes of drugs that target the descending inhibitory pathways?
- antidepressants (TCAs, SSRIs, SNRIs)
- alpha adrenergic agonists (alpha 2)
- opioids (tramadol)
How do TCAs work?
- increases serotonin and/ or NE in the synapse by inhibiting reuptake
- takes 1-3 weeks for pain control, so use for chronic pain
-may have anticholinergic effects
- more effective for conditions like diabetic neuropathy and other anti-depressants
(Nortriptyline and Amitriptyline)
How do SSRIs work?
- specific inhibitor of S reuptake
- SE: suicidality, impaired platelt aggregation, CNS depression, QT prolongation, serotonin syndrome, SIADH/hyponatremia, sexual dysfunction
(paroxetine, fluoxetine, sertraline)
How to SNRIs work? (Serotonin and NE reuptake inhibitors)
- potent inhibitor of neuronal serotonin and NE reuptake, and weak DA reuptake
- SE: suicidality, impaired platelet aggregation, CNS depression, hypercholesteremia, hypertension, serotonin syndrome, sexual dysfunction
What does venlafaxine work on as an SNRI?
- works on neuropathic pain, DM neuropathy; onset of 1-2 weeks, max 6 weeks
- common SE: nausea, dizziness, drowsiness, hypertenstion
What does duloxetine work on as an SNRI?
- diabetic neuropathy, fibromyalgia, chronic MSK pain (60-120 mg)
- monitor blood pressure regularly, and blood sugar levels
- SE: sedation, nausea, constipation, ataxia
How do alpha adrenergic agonists work?
- they stimulate alpha- adrenoreceptors in the brainstem- activating inhibitory neuron thus reducing sympathetic outflow of CNS. Prevents pain signal transmission via and unknown mechanism
What are the 2 examples of alpha adrenergic agonists and how do they work?
- Clonidine - works by neuropathic pain that is not responding to other treatment or therapy
-- unlabeled uses: heroin or nicotine withdrawal, dysmenorrhea, menopausal vasomotor symptoms and migraine prophylaxis
--- adverse effects of bradycardia, CNS and respiratory depression, hypotension
- Tizanidine- works for tension headaches, back pain, neuropathic pain and myofascial pains
- less likely to cause hypotension and is better tolerated than clonidine
How does peripheral sensitization work on sodium channels on the nerves?
- neuropathic pain is triggered by spontaneous peripheral nerve activity mediated by sodium channels (causes local tissue injury, ischemia, release of inflammatory factors increasing Na channels leading to an excitability of the nerve
(this can happen with phantom limbs- the nerve going to the spinal column from that area of the missing limb is no longer getting signals, so it up regulates to the point that it starts self-firing)
What are the classes of medications that cause dampening of peripheral sensitization?
- carbemazepine, TCAs, topiramate, lidocaine
How does carbemazepine work to decrease pain?
- it limits the influx of Na ions across the cell membrane
-used in trigeminal or glossopharyngeal neuralgia and neuropathic pain
How does topiramate work to decrease pain?
- limits the influx of sodium ions across the CM - antagonizes glutamate receptors
- common adverse reactions are dizziness, ataxia, somnolence, psychomotor slowing, paresthesia and weight loss
How does lidocaine work to decrease pain?
- application topically reduces discharge of small afferent nerve fibres by blocking voltage gated sodium channels (decrease membrane permeability)
- post-herpeti neuralgia or peripheral neuropathies of other etiologies
Explain the central sensitization site of action in treating neuropathic pain? What is the normal Pain signal here?
Normal Pain signal
- occurs in the dorsal form of the spinal cord
- release of excitatory neurotransmitters (glutamate and substance P)
- increased Ca transport causes spontaneous impulses, causing a pain message to be sent to the brain
- medications that decrease Ca channel activity are gabapentin and pregabalin (bind to a2 subunit of presynaptic neurons to regulate excitatory neurotransmitters)
NMDA receptors - how do they work in the pain response and what drugs target them?
- occurs in the dorsal horn of the spinal cord
- release of excitatory NT (glutamate and substance P)
- medications that are NMDA antagonists (decrease the nerve impulse)
How does the drug ketamine work?
- is a NMDA receptor antagonist - high doses stimulate multiple pain receptors
- decreases central sensitization and modulation by lowering the threshold for nerve transduction and reduces the effects of substance P
-also targets the opioid receptor, Na and K channels to reduce pain
- local skin reactions are the common adverse reactions
How does dextromethorphan work?
- low affinity uncompetitive NMDA antagonist- high doses are needed
- also binds opioid receptors
- has a very short half life
- SE: serotonin syndrome, if used in combination with other antidepressants
How does methadone work to treat pain?
- mu and delta opioid agonist and ALSO blocks the NMDA receptor and inhibitors reuptake of NE
- need a lot less for opioid escalation than in those treated with morphine
- no active metabolites- less incidence of SE such as confusion, sedation, myoclonus or seizure
- highly lipophilic- crosses the BBB rapidly, marked distribution in muscle and fat - high bioavailability
- SE: CNS and respiratory depression, QT prolongation, constipation, nausea, etc
What is gout?
- caused by an accumulation of uric acid crystals in the joints
- can cause a condition known as "gouty arthritis", or acute joint inflammation
- associated with ingesting red meat, cheese and wine (because of high level of purines)
What is the pathway to uric acid production?
purine nucleotides-> inosinic acid -> hypoxanthine -> xanthine -> uric acid
Why does the build-up of uric acid target the joints?
because the joints have a different pH than the rest of the body
How does colchicine work to treat gout?
- weak anti-inflammtory agent
- not an analgesic or an anti-pyretic
- impairs PMN motility and chemotaxis, and this inflammatory response to urate crystals
- toxicity: nausea, vomiting, diarrhea, abdominal cramping, may cause death
- no effect on plasma or urinary uric acid
- may be considered for low dose continuous prophylactic therapy
-- reduces the motility of the immune cells and don't allow them to get into the joint - you don't get as much inflammation this way
How does allopurinol work to treat gout?
- xanthine oxidase inhibitor
- reduces urate formation
- active metabolite (oxypurinol/ alloxanthine)
- risk of hypoxanthine stones
- can use for prophylaxis when acute gouty attacks happen often
- adverse effects: allergic reactions, bine marrow suppression, liver toxicity, renal toxicity
What is the drug of choice in treating gout?
How does probenecid work in treating gout?
- uricosuric - inhibits reabsorption of uric acid
- half life dose dependent
- highly protein bound
- inhibits excretion of other acidic drugs
- caution: renal urate stones
What are the 2 ways that local anesthetics can be dosed?
- topically or by IV
How does a nerve block work?
-injection of a local anesthetic is done around a nerve that leads to the operative site - more concentrated forms of local anesthetic solutions are used here
How does peridural anesthesia work?
- injection of local anesthetic into the peridural space (this is one of the coverings of the spinal cord)
How does spinal anesthesia work?
local anesthetic is injected into the subarachnoid space of the spinal cord
What are the different types of local anesthesia?
- nerve block
What is the progression of the anesthetic effects?
- autonomic activity is lost first
- then pain and other sensory functions are lost
- as local agents wear off, they do so in reverse -- motor, then sensory, then autonomic activity is restored
What is infiltration anesthesia used for?
- minor surgical and dental procedures
- injection of the anesthetic solution intradermally, subcutaneously or submucosally across the path of the nerves supplying the target area
-may be given in a circular pattern around the area of operation