unit 10 - opioids Flashcards
pain is multifaceted
(slide 1 for chart)
- Opioids are most closely associated with the management of pain and with rewarding processes associated with drug abuse and addiction. Therefore understanding the mechanisms of pain is important.
- Pain is not a simple sensation and the behavioral responses to it are the result of processing of pain sensory input by multiple types of neural systems.
- The peripheral input is some kind of painful stimulus. There is significant processing and modulation of the pain signal at the level of the spinal cord. Pain also affects mood and has an affective component not found with many other sensory modes. Therefore, there is significant descending input from cognitive and motivational systems that affect sensations of pain. These cognitive processes and are especially important for chronic pain perception.
pain involves multiple neural networks
- amygdala - fear, anxiety, associations, depression
- nocireceptors - injury, disease
- other cortical networks - attention, memories, interpretations, expectations
- PAG, dorsal horn, cortical pain receptors
(see slide 3 for chart)
pain and information processing in the nervous system
chart on slide 4
- Pain and other somatosensory input travel in separate neural pathways, but they interact. We’ll discuss this in the context of the “gate control” theory of pain. Together with the descending influences, there are multiple factors involved in how we perceive pain.
acute pain
can be mild and last just a moment, or it might be severe and last for weeks or months.
chronic pain
is pain that is ongoing and usually lasts longer than six months.
first (fast) pain
is felt within about 0.1 second after a pain stimulus is applied.
- use different afferent fiber types then slow pain
second slow pain
begins only after 1 second or more and then increases slowly over many seconds and sometimes even minutes.
- uses different afferent fiber type than fast
somatic and psychological characteristics of acute pain
- tachycardia (increase in HR)
- increased cardiac output
- increased blood pressure
- pupillary dilation
- palmar sweating
- hyperventilation
- hypermobility
- escape behavior
- anxiety state
fight-flight response
somatic and psychological characteristics of chronic pain
- sleep disturbance
- irritability, aggression
- appetite disturbance
- constipation
- psychomotor slow
- lowered pain tolerance
- social withdrawal
- abnormal illness behavior
depression
thermal or mechanical nociceptors
- Free nerve endings
- Small diameter nerve fibers
- Thinly myelinated
- A fibers
- 5-30 m/s
polymodal nociceptors
- Free nerve endings
- Activated by high-intensity mechanical, chemical and hot (>45°C) or cold
- Small diameter unmyelinated
- C-fibers
- 0.5-2 m/s
nociceptors
- sensory neurons that respond to damaging or potentially damaging stimuli.
- responsive to multiple types of physiological and chemical stimuli.
- do not have specialized endings - have free nerve endings
-pressure = mechanical pressure
-chemical = tissue damage, releases bradykinin and prostaglandins
-heat
A fibers
fast, sharp pain
- responsible for localization of the pain
- uses glutamate as neurotransmitter
- responsible for withdrawal reflex
- important: pain is adaptive, it keeps you from using a damaged part of the body so it can repair
C-fibers
“slow pain”
- burning pain, aching pain
- responsible for perceptual discomfort
- use substance P and glutamate as neurotransmitters
- most affected by opioids
chemical mediators that can activate and/or sensitize nociceptors
Here, are some important chemical mediators of pain:
1) Injury or tissue damage releases bradykinin, serotonin, prostaglandins, ATP and hydrogen ions, which activate or sensitize nociceptors.
Activation of nociceptors leads to the release of substance P and CGRP (calcitonin gene related peptide).
Substance P acts on mast cells in the vicinity of sensory endings to evoke degranulation and the release of histamine, which directly excites nociceptors. Substance P produces plasma extravasation (leakage of fluid) and CGRP produces dilation of peripheral blood vessels; the resultant edema causes additional liberation of bradykinin.
Collectively these effects lead to tissue inflammation which also involves activation of the immune system.
So,
Substance P -> mast cells -> histamine -> excites nociceptors!
Substance P+CGRP -> dilation -> edema -> more bradykinin!
inflammation
The four cardinal signs of inflammation—redness (Latin rubor), heat (calor), swelling (tumor), and pain (dolor)
acute inflammation
short onset and duration, change in hemodynamics, production of exudate, granular leukocytes
chronic inflammation
long onset and duration, presence of non-granular leukocytes and extensive scar tissue
first pain vs second pain
Subjectively, we often become aware of pain in 2 waves (i.e., with different latencies).
Respectively, these are referred to as first pain (or fast pain) and second pain (or slow pain). Each of these types of pain has been associated with a specific type of nociceptive afferent neuron. First pain is mediated by myelinated A fibers and second pain is mediated by unmyelinated C-fibers.
First pain (fast pain), A fibers - notice something has happened, and can localize it because the pathway and information goes to the somatosensory cortex.
Second pain (slow pain), C-fibers - the pain that stays with you
Propagation of action potentials in sensory fibers results in the perception of pain.
This electrical recording from a whole nerve shows a compound action potential representing the summated action potentials of all the component axons in the nerve. Even though the nerve contains mostly nonmyelinated axons, the major voltage deflections are produced by the relatively small number of myelinated axons. This is because action potentials in the population of more slowly conducting axons are dispersed in time, and the extracellular current generated by an action potential in a nonmyelinated axon is smaller than the current generated in myelinated axons.
B. First and second pain are carried by two different primary afferent axons. First pain is abolished by selective blockade of A myelinated axons (middle) and second pain by blocking C fibers (bottom).
substance P localization and mechanisms in pain
- Location of substance P containing neurons and fibers in the spinal cord, skin, and intestine. SP positive cells and fibers are shown as filled circles and solid lines, respectively. Non-SP cells and fibers are depicted with open circles and shaded lines.
- A diagrammatic representation of laminae in the gray matter of the human cervical spinal cord. Neurons in laminae I and II project to cells in laminae V and VI that form the lateral spinothalamic tract. This pathway then ascends, mostly contralaterally, to higher centers in the brain stem.
nociceptive afferent terminals
highly organized.
Projection neurons in lamina I receive direct input from myelinated (A) nociceptive afferent fibers and indirect input from unmyelinated (C) nociceptive afferent fibers via stalk cell interneurons in lamina II. Lamina V neurons receive low-threshold input from the large diameter myelinated fibers (A) of mechanoreceptors as well as both direct and indirect input from nociceptive afferent fibers (A and C).
The anatomy and interplay between these different fiber types can give an account for how pain can be “gated”.
Details:
Projection neurons in lamina I receive direct input from myelinated (A) nociceptive afferent fibers and indirect input from unmyelinated (C) nociceptive afferent fibers via stalk cell interneurons in lamina II. Lamina V neurons are predominately of the wide dynamic-range type. They receive low-threshold input from the large diameter myelinated fibers (A) of mechanoreceptors as well as both direct and indirect input from nociceptive afferent fibers (A and C). In this figure the lamina V neuron sends a dendrite up through lamina IV, where it is contacted by the terminal of an A primary afferent. A dendrite in lamina III arising from a cell in lamina V is contacted by the axon terminal of a lamina II interneuron.
gate control theory of pain perception
the nonnociceptive, large-diameter sensory fiber (orange) is more active than the nociceptive small-diameter fiber (blue), therefore the net input to the inhibitory interneuron (red) is net positive. The inhibitory interneuron provides presynaptic inhibition to both the nociceptive and nonnociceptive neurons, reducing the excitation of the transmission cells. In the bottom panel, an open “gate” (free-flowing information from afferents to the transmission cells) is pictured. This occurs when there is more activity in the nociceptive small-diameter fibers (blue) than the nonnociceptive large-diameter fibers (orange). In this situation, the inhibitory interneuron is silenced, which relieves inhibition of the transmission cells. This “open gate” allows for transmission cells to be excited, and thus pain to be sensed
types of neurons in dorsal horn - gate control theory
Unmyelinated pain fibers (C)
Myelinated nociceptive afferents (A)
Myelinated non-nociceptive afferents (A)
Projection neurons
Inhibitory interneurons (spontaneously active)
opiate-induced inhibition of substance P release
According to this model of opiate-mediated analgesia in the spinal cord, opiate receptors are located on the presynaptic terminals of primary afferent (nociceptive) axons containing SP. Local inhibitory neurons release enkephalin onto these terminals, thereby reducing SP release and attenuating the transmission of pain information to the brain.
Main Point:
- Activation of local neurons which release the opioid, enkephalin, produces an inhibition of substance P release from a primary afferent nociceptive neuron. This is an example of presynaptic inhibition. This presynaptic opioid receptor site is one of several probable CNS sites where opioid analgesics such as morphine exert their effects.
three major ascending pain pathways
These are the three major ascending pathways that transmit nociceptive information from the spinal cord to higher areas.
The spinothalamic tract is the most prominent ascending nociceptive pathway in the spinal cord.
Note: names come from the anatomy. The ending “o” means that is where the pathway starts, after the “o” is where it ends.
Spino-thalamic begins in the spinal cord, and synapses in the thalamus. Then another neuron goes to cortex.
Spino-reticular begins in the spinal cord, and synapses in the reticular formation. Other neurons continue to thalamus and cortex.
Spino-mesencephalic begins in the spinal cord, and synapses in the midbrain.
Fast pain primarily uses the spinothalamic pathway, and you can localize this pain because of the somatotopic organization on the cerebral cortex (somatosensory cortex).
Slow pain uses the spinoreticular and spinomesencephalic pathways.
descending opioid-sensitive pain modulating circuit
cingulate cortex & amygdala
- emotional states
periaqueductal gray
- opioid receptors
- projects to raphe nuclei
raphe nuclei
- project down to dorsal horn and spinal 5 nucleus
- serotonin
- inhibits ascending systems
- substance P release by primary afferents
locus coeruleus
- norepinephrine
stress-induced analgesia
This is a descending pathway that can be activated by both external stimuli and certain motivational states.
Several limbic forebrain areas project to the midbrain periaqueductal grey (PAG).
These include the anterior cingulate cortex (ACC), other frontal cortical areas, the hypothalamus (H) and central nucleus of the amygdala.
Thus, the PAG can be thought of as a main output pathway of the limbic system.
The PAG, in turn, indirectly controls pain transmission in the dorsal horn through the rostral ventromedial medulla (RVM) and the raphe nuclei.
descending serotonin and norepinephrine pathways affecting pain processing
periaqueductal gray
- opioid receptors
-projects to raphe nuclei
raphe nuclei
- project down to dorsal horn and spinal 5 nucleus
- serotonin
- inhibits ascending systems
- substance P release by primary afferents
locus coeruleus
- norepinephrine
Here we see connections of the PAG, raphe nuclei and locus coeruleus cells affecting pain processing.
Both serotonergic and noradrenergic pathways are involved in the descending circuit.
substance p release
Actions of the primary sensory neurons can be inhibited by descending input from 5-HT and NE on an enkephalinergic interneuron
Details:
Certain interneurons in the spinal cord appear to use enkephalin as their neurotransmitter. They act directly on the terminals of the incoming sensory fibers conveying slow pain information to the spinal cord from the body and apparently inhibit this pain input from being relayed to the brain. The slow pain fiber terminals contain substance P and glutamate. Glutamate appears to be the fast transmitter, and substance P acts to modulate its actions. A descending pain control pathway from the brain is thought to act on the enkephalin interneurons; it appears to use serotonin as its transmitter
types of pain relief intervention
psychogenic, pharmacological, stimulation, surgical
psychogenic pain relief intervention
placebo, hypnosis, stress, cognitive (learning coping strategies)
mechanism: may activate endorphin mediated pain control system, alters brain’s perception of pain, both opioid and nonopioid mechanisms, may activate endorphin-mediated pain control system
limitations: sometimes inhibited by opiate antagonists, control unaffected by opiate antagonists, clinically impractical and inappropriate, limited usefulness in severe pain
pharmacological pain relief intervention
opiates, spinal block, anti inflammatories, aspirin
mechanism: bind to opioid receptors in periaqueductal gray and spinal cord, drug block pain signals in spinal cord, block prostaglandin and leukotriene synthesis at site of injury, blocks prostaglandin synthesis at site of injury
limitations: severe side effects due to binding in other brain regions, spinal block avoids side effects, anti-infmmatories have side effects, aspirin does not block luektoriene syntheses
stimulation pain relief intervention
TENS/mechanical, acupuncture, central gray
TENS
tactile or electrical stimulation of large fibers blocks or alters pain signal to brain
limitation: segmental control; must be applied at site of pain
acupuncture
seems similar to TENS, sometimes affected by opiate antagonists
central gray
electrical stimulation activates endorphin-mediated pain control systems, blocking pain signal in spinal cord
limitations: control inhibited by opiate antagonists
opiate analgesia
- There are areas in the brainstem where electrical stimulation produced analgesia
- Administration of opioids into brain stem produced analgesia.
- Site where electrical stimulation suppresses pain overlap with these opioid sites.
- Naloxone blocks the analgesia produced by systemic morphine.
classical transmitter
production of
1) synthesizing enzymes
2) storage vesicles
axonal transport of
1) synthesizing enzymes
2) storage vesicles
supply by
1) axonal transport + storage
2) new synthesis
3) reuptake
peptide transmitter
production of
1) peptide (precursor)
2) storage vesicles
3) converting enzymes
axonal transport of
1) storage vesicles
supply by
1) axonal transport + storage
there are lots of ____ found in vertebrate nervous system
opioid peptides, gut-brain peptides, hypothalamic releasing hormones, pituitary hormones
vasopressin and oxytocinergic pathways
Pathways from the paraventricular nucleus are indicated by dashed and dotted lines; from the suprachiasmatic nucleus by dotted lines; and from the bed nucleus of the stria terminalis by dashed lines. Triangles depict cell groups that contain sufficient neuropeptide to be stained immunohistochemically in untreated animals. Circles depict cell groups that may possess lower levels of neuropeptide, as they are only stained in animals pretreated with the antimicrotubule agent colchicine (microtubule disassembly prevents axonal transport of neuropeptides, thereby causing them to accumulate in the cell soma and increasing immunohistochemical reactivity).
(b) Oxytocin.
Main Point:
As with any of the chemical neuroanatomical “brain maps” showing cell bodies and their projections for any neuropeptide (or other neurotransmitter) is for you to note that they are usually distributed at different locations throughout the CNS, and that they do have discrete definable regions of origin and distribution. Of course it isn’t necessary to know the details of where the soma and the terminal regions are located.
potential sites and mechanisms of neuropeptide action
- act as a conventional neurotransmitter in a synaptic pathways
- influences a synaptic pathway by its presynaptic action
- influences a synaptic pathways by its postsynaptic action on receptor
- influences a synaptic pathways by its effects on electrogenenisis
have many actions that can influence neurotransmission. One only needs to know some examples of such neuromodulatory processes.
Enkephalin produces presynaptic inhibition on terminal of primary nociceptive afferent neuron.
“releasable pool” refers to synaptic vesicles docked at the membrane
“non-releasable pool” is essentially in reserve
influences a synaptic pathway by its presynaptic action
Affects amount and time course of transmitter release
Affects transmitter reuptake at synapse
Alters “releasable” and “non-releasable” transmitter pools
Affects transmitter biosynthesis
influences a synaptic pathway by its postsynaptic action on receptor
Alters receptor sensitivity
Affects receptor-ionophore coupling
- Kinetics
- Specific ionic conductances
influences a synaptic pathways by its effects on electrogenisis
Change in electrically excitable membrane properties
- Resting conductance
- Spike threshold
- Intracellular electrical resistance (length constant)
- Current-voltage relations of membranes
- Coupling resistance at electrotonic junctions
- Alters electrogenic pump activity
Excitation-coupled phenomena
- Muscle contraction
- Metabolic processes
pro-opiomelanocortin (POMC)
peptide =
-Endorphin (beta)
-Endorphin (gamma)
-Endorphin (alpha)
proenkephalin
met-enkephalin, leu-enkephalin, heptapeptide, octapeptide, peptide E
prodynorphin (proenkephalin B)
alpha-neo-endorphin
beta-neo-endorphin
dynorphin A
leumorphin
dynorphin B
major endogenous opioid peptides
beta-endorphin, met-enkephalin, leu-enkephalin and dynorphin
opioid peptide neurotransmitters
are strings of amino acids of varying lengths.
As neuropeptides, they come from huge precursor molecules (proteins).
The “Pro” means it is a precursor molecule.
Enzymes cleave the precursor molecules into the smaller peptide molecules.
Within a “family”, the first several amino acids are identical.
You should know that -endorphin, met-enkephalin, leu-enkephalin and dynorphin are major endogenous opioid peptides. These have received the most research and attention.
POMC = proopiomelanocortin.
The small boxes represent the methionine-enkephalin or leucine-enkephalin sequences.
Note how pro-enkephalin contains 6 copies of met-enk, and one of leu-enk.
comparison of the structure of morphine with met-enkephalin and leu-enkephalin
Morphine is the prototypic opiate.
It has structural similarities with the endogenous opiates.
This shows a comparison of structure of morphine with that of met-enkephalin and leu-enkephalin.
The A ring of morphine corresponds to the N-terminal Tyr1 ring of the enkephalins.
met-enkephalin and leu-enkephalin are the most prominent enkephalins.
While Morphine has structural similarities to the enkephalins, it binds almost exclusively to mu receptors.
Comparison of structure of ± morphine with that of met-enkephalin and leu-enkephalin. The A ring of morphine corresponds to the N-terminal
mu receptor substype
- endomorphins and endorphins (POMC) endogenous ligand
- thalamus, periaqueductal gray, raphe nuclei, spinal cord, striatum, brain stem, nucleus accumbens, amygdala, hippocampus
- analgesia, reinforcement, cardiovascular and respiratory depression, antitussive, vomiting, sensorimotor integration
delta receptor subtype
enkephalin and endorphin endogenous ligand
- neocortex, striatum, olfactory areas, substantia nigra, nucleus accumbens, spinal cord
- analgesia, reinforcement, cognitive function, olfaction, motor integration
kappa receptor subtype
dynorphins
- pituitary, hypothalamus, amygdala, striatum, nucleus accumbens
- neuroendocrine function, water balance, feeding, temp. control, dysphoria, analgesia
endogenous opioids-synthesizing neurons and opioid receptors in the brain
The cell bodies and receptors for beta-endorphin, enkephalin, and dynorphin are widely distributed in the CNS. They are highly concentrated in the limbic system and associated with regions where morphine has been implicated to reduce pain and the negative affective components of pain.
Upper Right - From Strand, Neuropeptides, Fig. 14.2, p. 344.
Details: Sagittal view of the rat CNS showing the main possible projections of the -endorphin-immunoreactive neurons, with cell bodies in the arcuate nucleus and medial basal hypothalamus. Projections are to the POA, anterior preoptic area; ni ST, nucleus of stria terminalis; nPV, paraventricular nucleus; Th, dorsomedial thalamus; ME, median eminence; SGC, periaqueductal gray; PB, nucleus parabrachialis; LC, locus coeruleus; n TS, nucleus of tractus solitarius; sg V, substantia gelatinosa of the spinal nucleus of the trigeminal nerve; sgSpC, substantia gelatinosa of the spinal cord; A, amygdala.
Lower Right - From Strand, Neuropeptides, Fig. 14.3, p. 345.
Details: Sagittal view of the rat CNS showing the major neuronal systems containing enkephalin-immunoreactive neurons. The best established systems are represented by solid lines; broken lines indicate less certain projections. The most conspicuous enkephalin-immunoreactive system is in the corpus striatum with cell bodies in the caudate putamen (CP) and fibers radiating to the globus pallidus (GP). This nucleus contains the richest concentration of enkephalin in the CNS. Enkephalin-immunoreactivity is found in many local circuit neurons, as indicated. Those present in areas of central projections of sensory neurons (cell bodies represented by open circles and nerve terminals as open triangles) are implicated in the processing of pain information. OB, olfactory bulb; S, septum; Hp, hippocampus; ni ST, nucleus of stria terminalis; ST, stria terminalis; NSO, supraoptic nucleus; ME, median eminence; NH, neurohypophysis; H, hypothalamus; A, amygdala; IP, nucleus interpeduncularis; SN, substantia nigra; SGC, periaqueductal gray; D, Deiters’ nucleus; R, caudal nuclei of raphe system; n TS, nucleus of tractus solitarius; sg V, substantia gelatinosa of trigeminal nerve; Sg Sp C, substantia gelatinosa of spinal cord; DRG, dorsal root ganglia; SG, sympathetic ganglia.
Bottom Line- Take away: The cell bodies for beta-endorphine, enkephalin, and dynorphin and the receptors are widely distributed in the CNS. They are highly concentrated in the limbic system and associated with regions where morphine has been implicated to reduce the pain and the negative affective components of pain.
analgesia
loss of pain without loss of consciousness
is a temporary state that produces analgesia but also paralysis (extreme muscle relaxation), amnesia (loss of memory), and unconsciousness.
There are two main classes of analgesic substances:
1) opioids.
2) non-steroidal anti-inflammatory drugs, or NSAIDS, for example, aspirin.
opiates - individual drugs
Opium, heroin, morphine, codeine, hydromorphone (Dilaudid), oxycodone (Percodan), meperidine (Demerol), diphenoxylate (Lomotil), hydrocodone (Vicodin), fentanyl (Sublimaze), propoxyphene (Darvon)
opiate common terms
Chinese molasses, dreams, gong, O, skee, toys, zero (opium); Big H, dreck, horse, mojo, smack, white lady, brown (heroin) speedballs (opiates and cocaine)
opiates - “the buzz”
People who inject opiates experience a rush of pleasure, then sink into a dreamy, pleasant state in which they have little sensitivity to pain. Their breathing slows, and their skin may flush. Pinpoint pupils are another hallmark of opiate effects. Opiates taken by ways other than injection have the same effect, except that a pleasant drowsiness replaces the rush. Nausea and vomiting can accompany these effects, as well as constipation. An injected heroin/cocaine combination (speedball) causes intense euphoria, the dreaminess of heroin, and the stimulation of cocaine.
opioid receptor agonists
Overview
Opioid analgesics exert effects through agonist actions on families of receptors (e.g., mu, kappa, delta)
Opioid agonists also produce:
- Respiratory depression
- Physical dependence
- Addiction
- GI effects
Opioid antagonists
Opioid agonists/antagonists
- Synthetic
- Different effects at different receptors
extent of tolerance developed of the effects of the opiods
Develop different levels of tolerance to the different effects of opiates.
The two most-commonly desired effects of opioids (analgesia, euphoria) readily develop tolerance.
Relative “annoyances” like miosis and constipation rarely adapt via tolerances. In fact, constipation is a continuing problem for the opiate addict. Can become severe.
Miosis = pupil constriction (opiates bind directly to cells in the Edinger-Westphal nucleus).
high degree of tolerance to opioids
analgesia, euphora, dysphoria, mental clouding, sedation, antidiuresis, nausea and vomiting, cough suppression
lesser degree of tolerance to opiods
bradycardia and respiratory dep.
moderate minimal or no tolerance to opioids
miosis, constipation, convulsions, antagonist actions
strong opioid agonists
morphine, meperidine, methadone, fentanyl, heroin
moderate opioid agonist
codeine
mixed opioid agonists-antagonists
pentazocine
opioid antagonists
naloxone, naltrexone
morphine therapeutic uses
prototypic opioid agonist
Analgesia
Diarrhea
Antitussive
morphine mechanism of action
Acts on opioid receptors in CNS and GI tract
Hyperpolarizes nerve cells to inhibit firing
Presynaptic action to inhibit transmitter release
effects of morphine
CNS
- Analgesia via actions on the spinal cord and in the central gray of brain stem. Also alters “interpretation” of pain.
- Euphoria – sense of contentment and well being
- action on ventral tegmental area
- Drowsiness – (“mental cloud”)
- Respiratory depression – reduces sensitivity to CO2
- Depresses cough reflex – antitussive
- Miosis – Edinger-Westphal nucleus – parasympathetic activation
- Emesis – stimulates chemoreceptor trigger zone (CTZ)
- Increases antidiuretic hormone (vasopressin) release
- Inhibits ACTH and gonadotropin release
Cardiovascular effects – not major
- Peripheral vasodilation
- Cerebral vasodilation because of depressed respiration
- Orthostatic hypotension
Gastrointestinal
- Smooth muscle tone increases and contractions decrease = constipation
meperidine therapeutic uses
synthetic opioid that can be given orally, analfesia for severe pain, not useful for coughs or diarrhea
meperidine mechanism of action
binds particularly to k receptors
meperidine physiological actions
respiratory depression, IV administration - increases blood flow, increases HR, dilates cerebral vessels, impedes GI motility, dilates eyes
meperidine pharmacokinectics
well absorbed from GI tract, often administered IM, 2-4 hr duration of action, metabolized in liver and excreted in urine
meperidine adverse effects
tremors, muscle twitches, rarely convulsions, hyperreflexia, addictive
methadone therapeutic uses
well absorbed orally, controlled withdrawal of addicts from heroin and morphine, withdrawals from methadone produces milder syndome
methadone mechanism of action
greatest action on mu receptors
methadone action
analgesic activity is equal to morphine, miotic (constricted pupil), respiratory depression, constipating
methadone pharmacokinetics
- longer 1/2 life than morphine, accumulates in tissues by binding to proteins, metabolized in liver and excreted in urine
adverse effects of methadone
produces addiction like morphine, withdrawal is milder but more protracted than morphine
fentanyl
completely synthetic
- 80 times the analgesic potency of morphine
- rapid onset
- short duration of action (15-30 minutes)
- IV supplement during general anesthesia
heroin
- Produced by acetylating morphine
- 3-fold increase in potency over morphine
- More lipophilic than morphine
- More euphoric action than morphine
- Not approved in U.S.
codeine
Less potent analgesic than morphine but higher oral efficacy
Good antitussive at non-analgesic doses
Lower abuse potential
Less euphoria
Replaced by dextromethorphan as antitussive with no analgesic action and with low abuse potential
mixed opioid agonists/antagonists
- The rationale for development is that drugs that act at kappa or delta receptors will retain analgesic activity but have reduced respiratory depression and less addictive liability associated with the mu receptor.
Mu receptors mediate analgesia, respiratory depression and addiction potential.
Delta receptors, analgesia, less respiratory depression, less addiction
Kappa receptors, analgesia, less respiratory depression, less addiction
opioid antagonists
naloxone and naltrexone
naloxone
Reverse coma and respiratory depression
Acts within 30 sec
Acts at mu, kappa and sigma receptors
½ life of 60-100 min
naltrexone
Similar actions to naloxone
Longer duration of action
Blocks effect of injected heroine for up to 48 hrs
Used in opioid-dependence maintenance programs
naltrexone
Similar actions to naloxone
Longer duration of action
Blocks effect of injected heroine for up to 48 hrs
Used in opioid-dependence maintenance programs
non-steroidal anti-inflammatory analgesics
Non-Selective Cyclooxygenase Inhibitors (COX Inhibitors)
- Aspirin
- Ibuprofen
- Indomethacin
Selective COX-2 Inhibitors
- Celecoxib (Celebrex)
- Rofecoxib (Vioxx)
NSAIDs are effective in treating pain caused by slow, prolonged tissue damage, such as the pain from an arthritic joint.
NSAIDs produce analgesia by blocking the synthesis of prostaglandins. Recall that prostaglandins are released in response to tissue damage, and they sensitize pain fibers (lowers the threshold for activation). NSAIDs block the enzyme, cyclo-oxygenase, that is a necessary step in the production of prostaglandins.
Drugs that block cyclo-oxygenase (COX), hence are known as COX inhibitors.
-the earlier they are taken, the more likely they will be effective.
formation and actions of COX-1 and COX-2
There are two kinds of cyclooxygenase and drug inhibitors are only more-or-less selective. Therefore, a drug might prevent the formation of good molecules as well as the bad molecules and this is not desirable.
“constitutive” means it is “always” happening while “inducible” needs an “induction“ or a stimulus of some kind.
sites of NSAID action
where NSAIDs act to reduce pain and inflammation and consider why Cox-2 selective inhibitors are to be used only with caution.
the opioid crisis
The “Opioid Crisis” likely began with over-prescription of powerful opioid pain relievers in the 1990s
The opioids are the most prescribed class of medications in the United States.
In 2016 more than 289 million prescriptions were written for opioid drugs per year
Between 1991 and 2011, opioid prescriptions in the U.S. tripled from 76 million to 219 million per year
Among the most common opioids prescribed have been oxycodone (OxyContin and Percocet) and hydrocodone (Vicodin)
