Analgesics Pharm I - Colorado Mesa University

Report
NURS 203, Pharmacology I
Dr. Nolan


Most common complaint leading people to
seek healthcare
Can be acute or chronic
◦ Acute – less than ~3 months duration
◦ Chronic – 3 months or longer
ACUTE
 CHRONIC (longer than 3 months)
 CANCER PAIN
 SOMATIC PAIN
 VISCERAL PAIN
 NEUROPATHIC PAIN


Cancer
◦ Can be acute or chronic

Somatic
◦ Localized to a certain area (bone, muscle, skin…)
◦ Can be acute (injury) or chronic (arthritis)

Visceral
◦ Not localized, harder to define
◦ Nociceptors in internal organs are stimulated
(hepatitis, pancreatitis…)
◦ Dull, aching, cramping, deep pain

Neuropathic
◦ Perpheral pain receptors or nerves, damaged or
dysfunctional
◦ Excessive excitability in these areas, leading to
exaggerated pain response
◦ Diabetic neuropathy, herpes zoster (Shingles, postherpetic neuralgia)
◦ Not as responsive to normal analgesics
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Tissue damage stimulates peripheral pain
receptors – nociceptors
Signal transmitted to spinal cord (ascending
pathway) – hypothalamus – cerebral cortex
A-delta fibers : acute, “fast” pain
C fibers : slow, poorly localized pain
Descending pathway – inhibitory pathway,
includes endogenous opioids, norepinephrine
and serotonin to suppress nociceptive
transmission of pain impulse via substance P


Opioids
Non Opioids
◦ NSAIDs
◦ Tramadol
◦ Acetaminophen

Antidepressants, antiepileptics
◦ Neuropathic pain

CNS vasoconstrictors
◦ Migraine pain
Review Question

Which of the following drugs does not have a
“ceiling” dose?
◦
◦
◦
◦
◦
A) acetaminophen
B) ibuprofen
C) aspirin
D) morphine
E) all of the above have ceiling doses that should
not be exceeded

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

Relieve moderate to severe pain by inhibiting
pain signal transmission from periphery to
brain.
Well absorbed with PO, IM, SQ administration.
Metabolized in liver, metabolites excreted in
urine.
Liver or Renal impairment can interfere with
metabolism or excretion.

CNS
◦ Analgesia
◦ CNS depression
◦ Respiratory depression
◦ Pupil constriction

GI
◦ Slows motility
◦ Constipation
◦ N/V
◦ Bowel and Biliary
spasm


Potent analgesics for moderate to severe pain
Acute and chronic pain
◦ best for nociceptive pain
◦ Not generally effective for non-nociceptive pain
(neuropathic)


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Serious side effects
No ceiling dose
chronic use universally leads to tolerance,
physical dependence, may lead to addiction
tolerance leads to high doses in patients treated
long term with opioids that could kill opioid
naïve patients

Stimulate Mu and Kappa receptors
◦ Mu
 Analgesia, ↓ gastric motility, sedation,
respiratory depression, euphoria, physical
dependence
◦ Kappa
 Analgesia, ↓ gastric motility, sedation


Mixed agonist/antagonists stimulate one,
antagonize the other
Antagonists antagonize both (block opioids
from binding to receptor or displace)
 naloxone

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Binding to Mu and Kappa receptors slows the
transmission of pain impulses between cells
in the periphery, spine, and brain
Stimulating Mu and Kappa receptors activates
the endogenous analgesia system
◦ Endorphins, etc. act on receptors same as
exogenous (narcotic) agents
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Analgesia
Sedation, CNS depression (life threatening)
Respiratory depression (life threatening)
Constipation
Euphoria
Nausea/vomiting
Dependence
Tolerance
Miosis

CNS
◦ Analgesia
◦ CNS depression
◦ Respiratory depression
◦ miosis

GI
◦ Slows motility
◦ Constipation
◦ N/V
◦ Bowel and Biliary
spasm
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
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
Well absorbed orally, and via SQ, IM, and IV
Metabolized hepatically
Excreted via urine
Liver or renal disease can inhibit clearance or
efficacy
T1/2 can range from minutes (IV) to days
(fentanyl patch)

Before, during, after surgery
◦ To provide pain relief, sedation, ↓anxiety

Acute and chronic pain control, outpatient
◦ there is limited data on the safety and efficacy of
treating chronic pain with opioids
◦ significant safety concerns

Pain/anxiety reduction for various procedures
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Respiratory depression, lung disease
Hepatic/renal dysfunction
Increased intracranial pressure
Allergy (true allergy)
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Opioid agonist (primarily acts on Mu receptor)
Named after the Greek God of dreams,
Morpheus
Prototype opioid analgesic
DEA Schedule II (DEA CII)
Given PO, SL, PR, TD, SC, IM, IV, IT, PCA pump

Maximal analgesia and resp depression
within:
◦
◦
◦
◦

10-20 min IV
30 min IM
60-90 min SC
60 min orally (IR). ER forms are QD or BID
Duration is 5-7 hours (PO ER ~ 12-24 hours)



T1/2 is about 7 hours
Metabolites accumulate in pts with
renal/hepatic dysfunction, must reduce dose
30% bound to plasma proteins, extensive first
pass metabolism
◦ So PO doses considerably higher than Inj doses
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moderate to severe pain
procedure related anxiety/pain
MI related pain
Pulmonary edema
 why?


head trauma – increased intracranial pressure
long acting agents with short acting
procedures
 respiratory depression can manifest after procedure


Profound sedation/CNS depression
Constipation, N/V
 at least 41% incidence of constipation with chronic
opioids
 in 2000 study, 95% of patients interviewed by nurses in a
hospital oncology unit reported constipation as the
major side effect of their pain therapy

Resp depression, decreased breath sounds
◦ Encourage deep breathing, coughing
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Hypotension
Physical dependence
Paradoxical CMS stimulation and insomnia

24 hour controlled release
◦ Kadian, Avinza

BID-TID controlled release
◦ MS Contin, Oramorph

Q4-6h immediate release
◦ MSIR

Liquid
◦ MS oral solution, 10mg/5ml, 20mg/5ml,
100mg/5ml (concentrated)

Embeda (morphine/naltrexone)
◦ naltrexone inactive unless crushed

Embeda, Kadian, Avinza caps can be opened and
sprinkled immed. prior to oral admin.
◦ DON’T chew the pellets!


IM vs. SQ for repeated doses to reduce tissue
irritation
Don’t administer IV too quickly to avoid
excessive sedation and RR depression
◦ 2.5mg to 15mg over 5 minutes


PO vs parenteral doses
TYPICAL DOSE:
◦ ORAL 30mg Q4h
◦ IV/IM 5-10mg q4h

Breakthrough pain
◦ Continuous infusion or SR forms will need short
acting bolus or tablets for breakthrough pain

HIGH ALERT
◦ periodically monitor RR, BP
◦ caution if RR<10

Placebo effect
◦ Explain the therapeutic effect to the patient
◦ Suggestions of efficacy are often very effective in
increasing analgesia

Don’t let pain get severe
◦ opioids are more effective in maintaining analgesia
if pain doesn’t become severe

Watch the concentration
◦ DON’T confuse 20mg/5mL with 20mg/mL
◦ 20mg/mL liquid should be given via oral syringe

Bowel function
◦ Bowel habits should be documented before
beginning opioid therapy
◦ assess periodically, daily if constipation.
◦ Administer docusate and stimulant laxatives (senna,
bisacodyl) on a regular basis if tx exceeds a few
days
 bulk forming may lead to impaction, especially in
palliative care
◦ watch for confounding drugs (anticholinergics) and
dehydration

Don’t crush, break, chew, or dissolve
sustained release (SR), controlled release
(CR), or extended release (ER) dosage forms!
◦ rapid release of entire day’s dose an result in opioid
overdose
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CII, Potent opioid agonist
Available as IV, patch, SL tablet & film
IM/IV
Used pre, during, post surgery
◦ analgesic supplement for general anesthesia

Same cautions apply as for morphine
◦ head trauma
◦ profound sedation, RR depression…

Dosed in micrograms (mcg), caution!

Patch
◦ Duragesic (fentanyl patch) for chronic pain in opioid
tolerant pts
◦ NOT for post-op pain, intermittent pain, or short
term pain
◦ 92% absorbed through skin
◦ Dosed every 72 hours
 take about 20 hours for the serum conc to reach one
half after removal of patch
 steady state and maximal analgesia reached by end of
second patch application
◦ Comes as mcg/hr patches (eg. 50mcg/hr)

transmucosal
◦ short acting, for breakthrough cancer pain in opioid
tolerant pts (Actiq, Fentora)
 opioid tolerant means equivalent of 60mg/day morphine
◦ Buccal film
 about half absorbed through muscoa, the other half
swallowed
 swallowed fentanyl is ~20% bioavailable
◦ Transmucosal tablets, lozenge (lollipop), and nasal spray
also available
 these products are NOT interchangeable on a per dose basis
◦ Exercise extreme caution if children in the household!
 rapidly fatal
 watch for partially used discarded “pops”

Embeda (morphine/naltrexone)
 intended use is to prevent abuse
 combines microencapsulated naltrexone core to
morphine sulfate beads inside capsule
 only crushing, chewing, or dissolving will release
the naltrexone to attenuate the euphoric effects of
the morphine
 very expensive compared to morphine sulfate

Oxycodone (OxyContin) – CII
◦ IR and CR dosage forms
◦ “Oxy’s” became a common street drug, selling for
over $100 per tablet
◦ Can be combined with APAP (Percocet) or ASA
(Percodan)

Hydrocodone (Vicodin) – CIII
◦ Similar to codeine in use and efficacy
◦ Combined with APAP
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Hydromorphone (Dilaudid, Exalgo) - CII
◦ PO, PR, SC, IM, IV
◦ More potent than morphine, ↑efficacy PO vs
morphine
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Oxymorphone (Opana)
◦ Derivative of morphine, similar characteristics

Methadone (Dolophine)
◦ Synthetic form of morphine
◦ longer DOA (T1/2 30h +)

Propoxyphene (Darvon, Darvocet) - CIV
◦ Least effective opioid out there
◦ No more effective than APAP, but causes sedation
and resp depression like other opiates
◦ Toxic metabolite (norpropoxyphene) can
accumulate and cause arrhythmias, pulmonary
edema, apnea, and CV events.
◦ Often used in suicides
◦ Should be avoided in kids, older adults
◦ Banned in Britain and many other countries but
continues to be prescribed in U.S.
◦ UPDATE: FDA just asked for withdrawal of
propoxyphene from US market

Proper administration of an ordered narcotic
◦ A) can lead to addiction
◦ B) should be done promptly to prevent increased
pain and the need for larger doses
◦ C) would include holding the drug as long as
possible until the patient really needs it
◦ D) should rely on the patient’s request for
medication

Meperidine (Demerol) - CII
◦ Synthetic derivative of morphine
◦ Despite some opinions, meperidine has not shown any
benefit beyond other opioids for biliary colic,
pancreatitis, labor, or migraine.
◦ Does help with drug induced rigors, anesthesia related
shivering
◦ Toxic metabolite, normeperidine, limits it’s use
 Accumulates with chronic use (>2 days), renal dysfunction
 Very long T1/2, not reversible with naloxone
 Causes seizures, hallucinations, agitation
◦ Naloxone will reverse effects of meperidine, leaving
normeperidine unopposed – risk of seizures!
◦ Use > 2 days not appropriate

Meperidine (Demerol) - CII
◦ Drug interactions
 serotonin syndrome
 increased risk of MAO-I interactions and any
serotonergic drug, including triptans
 serotonin reuptake inhibition

Nucynta (tapentadol)
 CII
 MOA
 Opioid agonist (not as potent as morphine)
 Norepinephrine reuptake inhibitor (NRI)
 acts on decending pathway
 Dosing
 IR and ER forms available
 600mg max daily dose. Why?
 Monitoring
 CNS/RR depression
 seizures, tachycardia, BP changes especially in patients taking
antidepressants
 Side effects
 same as other opioids, but ~20% reduced incidence of GI S/E
 NOT totally reversed by naloxone
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Tramadol (Ultram, Ultracet, Ryzolt)
◦
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Not related to opioids chemically
About as effective as Tyl#3 (codeine + APAP)
MOA: binds to Mu receptor, SNRI
Very little resp. depression, risk of dependence
Well tolerated, good for older folks
MED for Selected Opioids
Opioid
Approximate Equianalgesic
dose (oral & transdermal) *
Morphine (reference)
30mg
Codeine
200mg
Fentanyl transdermal
12.5mcg/hr
Hydrocodone
30mg
Hydromorphone
7.5mg
Methadone
Chronic: 4mg
Oxycodone
20mg
Oxymorphone
10mg
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Block binding to opioid receptors, and can
displace opioids bound there
Used for quick reversal of opioid
toxicity/overdose
◦ Reverses analgesia and CNS/resp. depression

Naloxone (Narcan), naltrexone (ReVia,
Vivitrol)
◦ Naloxone works within minutes of injection (SC, IM,
IV)
◦ Short DOA (1-2h), may need to be repeated
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For suspected narcotic OD
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Give IVP over 10-15 sec
0.4mg – 2mg
Repeat q 2-3 min if needed, up to total 10mg
If no effect at 10mg, probably not narcotic OD
No effect in the absence of opioids in system
Caution if suspected chronic opioid user, will
precipitate immediate withdrawal

Naloxone
◦ short acting competitive opioid antagonis
◦ given parenterally, only 2% bioavailable PO
◦ Used exclusively to reverse opioid intoxication

Naltrexone
◦ given PO (Revia) and IM (Vivitrol) to treat alcohol
dependence (main use) and opioid dependence (not
very effective)
 Vivitrol - monthly IM injection
 Revia – PO QD

Withdrawal
 unlike withdrawal of benzodiazepines and barbiturates,
opioid withdrawal is not life threatening
 in otherwise neurologically and cardiovascularly healthy
patients
 Stage I – drug craving, anxiety (~5-15 hrs)
 Stage II – yawning, perspiration, crying, rhinorrhea (~ 18
hrs)
 Stage III – mydriasis, continuation of Stage II,
hyperreflexia, hot/cold flashes, cramping
(16-24 hrs)
 Stage IV – continuation and worsening of Stage III, severe
cramping, involuntary leg movements, diarrhea, HBP, ↑
body temp, ↑ RR, tachycardia, nausea (24 – 36hrs)

Withdrawal
 stage V – ↑ severity of earlier stages, fetal position,
diarrhea, nausea, significant weight loss,
leukocytosis, profuse sweating
 stage VI – appetite returns, bowel function
normalizes, beginning of psychological withdrawal
symptoms, ↑ sensitivity to pain, GI symptoms
 may see chronic withdrawal symptoms, both
psychological and physical, after the post-acute
withdrawal symptoms subside
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Obtain baseline vital signs
Have naloxone available and know how to
give it
Consider need for fixed schedule for patients
experiencing chronic pain
Do not crush or break ER capsules/tablets

Assess pain relief
◦ Use pain scale
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Document pain relief
Respiratory rate <12 BPM may be sign of
overdose
Baseline pupil size
◦ Miosis may be sign of toxicity

Restlessness must be assessed and differentiated
◦ Is it hypoxia?
◦ Is it a need for more pain control?
◦ Is it paradoxical CNS stimulation?
 (more common in women and older adults)
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Encourage turning, coughing, and deep
breathing at regular intervals
Be alert for orthostatic hypotension in
ambulatory patients
Monitor urine output as morphine may dull
the perception of a full bladder
Want pain free, but able to ambulate and take
care of ADL’s. Too sedated, can’t do that…
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No person should suffer pain needlessly
Pain occurs when the patient says it does
Pain should be relieved by whatever means
required
Doses of opioids should be titrated to
maximal effectiveness
Dependence rarely results from medications
taken for physical pain

Withdrawal
 unlike withdrawal of benzodiazepines and barbiturates,
opioid withdrawal is not life threatening
 in otherwise neurologically and cardiovascularly healthy
patients
 Stage I – drug craving, anxiety (~5-15 hrs)
 Stage II – yawning, perspiration, crying, rhinorrhea (~ 18
hrs)
 Stage III – mydriasis, continuation of Stage II,
hyperreflexia, hot/cold flashes, cramping
(16-24 hrs)
 Stage IV – continuation and worsening of Stage III, severe
cramping, involuntary leg movements, diarrhea, HBP, ↑
body temp, ↑ RR, tachycardia, nausea (24 – 36hrs)

Withdrawal
 stage V – ↑ severity of earlier stages, fetal position,
diarrhea, nausea, significant weight loss,
leukocytosis, profuse sweating
 stage VI – appetite returns, bowel function
normalizes, beginning of psychological withdrawal
symptoms, ↑ sensitivity to pain, GI symptoms
 may see chronic withdrawal symptoms, both
psychological and physical, after the post-acute
withdrawal symptoms subside

You administer the third morphine dose of
the day to a patient. Shortly thereafter, she’s
found to be extremely lethargic with RR of
10. What course of action might be taken?
◦ A) None, she’ll probably be fine after the morphine
wears off
◦ B) 0.4mg of IV naloxone and monitor
◦ C) 4mg of oral Narcan and monitor
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Type of pain
combinations
non-pharmacologic
interventions
Acute pain: PRN
Chronic pain:
scheduled
Change the opioid if
reduced efficacy
Ceiling vs. non-ceiling

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Route
Short vs long acting,
time release
Break through pain
PCA
USE THE LEAST POTENT DRUG THAT IS EFFECTIVE

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NONINVASIVE
◦ Oral, rectal, transdermal
INVASIVE
◦ Subcutaneous, IM, IV, spinal infusion
When the route is changed, the dosage MUST
be changed

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