Download Clincial Pharmacology of Analgesic Medications

Daniel Wermeling, Pharm.D.
Professor
Transduction
Substance P
Tissue
Injury
Prostaglandin
Histamine
NGF
Bradykinin
Mediators
• Prostaglandins
• Leukotrienes
• Substance P
• Histamine
• Bradykinin
• Serotonin
• Hydroxyacids
• Reactive oxygen species
5-HT
ATP
H+
Na/K
Channel
Kelly D, et al. Can J Clin Anaesth. 2001;48:1000-1010.
Pain: Current Understanding of Assessment, Management, and
Treatments. Monograph developed by NPC and JCAHO, December 2001.
Overall effect is increased
nociceptor activation
Reticular Formation
Rostroventral
Medulla
Descending
Pathway
Primary
Nociceptive Fiber
Excitatory Transmitters
• Substance P
• Calcitonin generelated
Ascending
peptide
Pathway
• Aspartate, glutamate
(A- or C fiber)
Dorsal
Horn
Inhibitory Transmitters
Spinal
• GABA
Cord
Descending
• Glycine
• Somatostatin
Kelly D, et al. Can J Clin Anaesth. 2001;48:1000-1010.
Pain: Current Understanding of Assessment, Management, and Treatments.
Monograph developed by NPC and JCAHO, December 2001.
Inhibitor Pathways
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MOA – inhibit prostaglandin synthesis, via
cyclooxygenase (COX) – peripheral and central
 COX-1 produces metabolites that relate to
platelet aggregation and GI cytoprotection,
renal function (constitutive)
 COX-2 - inducible by inflammatory stimulus
and mediates pain, inflammation and fever
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Acetaminophen
 Inhibits brain much more that peripheral COX
 Produces analgesia and antipyrexia
 Poor anti-inflammatory
Good analgesic for acute mild to moderate nociceptive
pain, generally well tolerated
First line therapy for low back pain and osteoarthritis
Acute and chronic dosing limits of 4gm/d
 2.8gm/day for elderly
 Hepatic necrosis & kidney damage
Re-examination of utility of chronic use in fixed-dose
combination products
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Analgesic, antipyretic and anti-inflammatory
Relative COX 1-2 blockade per drug
All produce similar analgesic effects yet there is
wide inter-patient variability
Individual response varies to each one
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Give 2-3 week trial
Oral meds and IV ibuprofen and IM and nasal
spray ketorolac
Lose cardioprotective effects of aspirin and
COX-2 inhibition may increase risks of MI
Use GI cytoprotectives concurrently for longterm NSAID use
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Morphine and cogeners
Phenylpiperidines: fentanyl, alfentanil,
meperidine, sufentanil, remifentanyl
Diphenylheptanes: methadone, propoxyphene.
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Provide analgesia via activation of opioid
receptors in CNS; similar to action of
endogenous endorphins
Appear to have some effects in periphery
Products activate or block mu, delta and kappa
receptors
Differences in physical chemical properties and
binding affinity account for variable
physiologic effects
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Agonist, partial agonist, agonist-antagonist,
antagonist
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Butorphanol – nasal spray for migraine
Nalbuphine – rarely used
Pentazocine – rarely used
Buprenorphine – Use for pain and now
for opioid detoxification
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Naloxone – Customary IV antagonist,
short acting, opioid antidote
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5% oral bioavailability
Injection adapted for nasal spray in emergency
Nalmefene – newer longer acting IV
antagonist, moderate duration, oral
availability
Naltrexone – oral opiate antagonist, long
duration – used in maintenance of
detoxification & alcoholism treatment
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Produce analgesia, CNS depression,
respiratory depression in a dose dependent
manner
Depress neurogenic drive and decrease
response to increased carbon dioxide
Cough suppression, miosis, hypothermia,
nausea and vomiting, histamine release,
bronchoconstriction, increased smooth muscle
tone (bladder, GI tract)
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Physical-chemical properties
ADME
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Absorption – highly variable across products
 Oxycodone, hydrocodone, methadone excellent
absorption
 Morphine 25-50% absorption – first pass metabolism
 Lipophilicity affects rate of absorption
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Distribution – widely distributed
 Speed of onset/offset correlates with lipophilicity
 See fentanyl as example
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Metabolism
Morphine and others subject to high first pass (is
saturable)
 Codeine requires CYP2D6 to activate to morphine
 Heroin is de-acetylated to morphine
 Morphine has active metabolites (M6G), others may
not have actives, and M3G produces hyperalgesia
and hyperactivity
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Excretion
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Metabolized to glucuronides and renal elimination
Accumulate drug and metabolites in renal disease
Some metabolites, when accumulating, cause
toxicity, like M3G
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Hydromorphone has less N & V and histamine
release
Kappa agonists have ceiling effect for analgesia
and resp. depression
Methadone also NMDA receptor antag.
Meperidine – neurotoxic metabolite
Fentanyl et al. – chest-wall rigidity
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Less potent analgesic
Not considered first-line agent because of high
potential for adverse events
Patients develop tolerance quickly
Should not be used for more than 1 or 2 days
Avoid use in elderly, renal impaired
Useful IV to treat pain and post-operative
shivering in the PACU
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A mainstay of treatment for opioid maintenance
Growing use for treating chronic pain
Usage for acute versus chronic pain differs
 Single dose, onset of 10-20 min., t1/2 of 24 h + (variable)
and analgesia duration of 4-8 hours
Chronic - Accumulates with repeated dosing; incomplete
cross tolerance with opiates, may require dosage reduction or
increased dosing intervals. Need a week to see full effect of
dosage changes
Careful evaluation required – Increased Qtc; cardiac
arrythmia as risk on top of standard risks
Used in opioid rotation - due intolerable SE or tolerance to
other opioids
Many respiratory arrest deaths also reported with methadone
use due to inexperience
Total Daily Oral
Morphine Dose
Estimated Daily Oral
Methadone Dose as %
of Total Daily Oral
Morphine Dose*
Estimated Daily IV
Methadone as % of
Total Daily Oral
Morphine Dose*
<100 mg
20 - 30%
10-15%
100-300 mg
10-20%
5-10%
300-600 mg
8-12%
4-6 %
600-1000 mg
5-10%
3-5%
> 1000 mg
<5%
<3 %
* Daily dose must be divided into a
dosing schedule for administration,
i.e., divide by 2 for twice a day
dosing
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Approximately 100 times more potent than
morphine or 100 mcg ~ 10 mg IV morphine
Significant first-pass metabolism, reducing
effect of oral administration
Very lipophilic, quick onset, seconds to
minutes, short half-life due to redistribution
Don’t get on hands – it is absorbed
IV use in anesthesia
Delivery systems include patch, buccal tablet,
nasal spray and lozenge
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Most common problem is use of opiates with
other drugs that cause significant sedation in
their own right
Promethazine and other phenothiazines
 Benzodiazepines/Skeletal muscle relaxants
 Alcohol
 THC
 Antidepressants and Antipsychotics
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Co-administration is the most common way
patients die from use of opioids
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Physiologic state of neuro-adaptation
that is seen as withdrawal symptoms
when the drug used is reduced or
discontinued or an antagonist
administered.
This is an expected outcome from chronic
opioid use.
This is not addiction.
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Generally over-excitation as a result of removing an
inhibitor
Rhinorrhea
Lacrimation
Piloerection
Hyperthermia and chills
Muscle aches
Emesis, diarrhea, cramping
Anxiety, agitation, hostility
Insomnia
Tachycardia and hypertension
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Need for an increased dose to maintain same
level of analgesia
This represents neural adaptation
It usually develops slowly once acceptable
analgesia in obtained
Need for a higher dose could easily represent
under treatment of pain
Tolerance also develops to many opioid
untoward effects
This is not addiction
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Drug seeking behavior of pain patients
whose pain is inadequately treated
VS
Use of any substances for nontherapeutic purposes; or use of a
medication for other than those for which
it was prescribed
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A neurobehavioral syndrome resulting in
psychological dependence on the use of
substances for the psychic effects and is seen as
compulsive use despite the harms being
caused.
Physical dependence and tolerance are normal
consequences of extended opioid therapy and
are not addiction.
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Block re-uptake of NE and SE & Na+ channel
Enhances pain signal inhibition
Tricyclics are a first line agent
Prefer secondary amine to tertiary amines
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Desipramine, nortriptyline
Less side effects
Take at night to lower side effects and enhance sleep
SN/SRI’s help depression and some analgesia
Duloxitene, and SNRI, approved for diabetic
peripheral neuropathy
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Modulators of peripheral nerve and spinal cord
pre- and post- ganglionic receptors
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Ion channel (Na/Ca) modulators/blockers
GABA inhibitors
Older medications include phenytoin,
carmbazepine, too toxic
New medications
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Gabapentin
Pregabalin
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Capsaicin Cream (Zostrix) (hot pepper
enzyme)
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MOA – depletes substance P from C-nerve endings
with chronic use
Start with lower concentration first
Apply 3-4x/day to effect
Substantial burning on application and some don’t
tolerate this, but tolerance does develop
Don’t get on eyes or mucus membranes
Uses – Peripheral neuropathy, post-herpetic
neuralgia and arthritis
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MOA – sodium channel blockade of nerve
fibers
Infiltration injection will block pain in the
dermatomal distribution
Injection into periphery or into CSF
EMLA (lidocaine & prilocaine) cream and
Lidocaine patch for neuropathic pain
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Reduce activation of NMDA receptors which are
involved in chronic nociceptive and neuropathic pain
Include:
 Amantadine: Neuropathic pain, low risk of side
effects
 Memantine: Neuropathic pain (animal studies)
 Ketamine: Neuropathic pain and preemptive
analgesia
 Dextromethorphan: Neuropathic pain and
preemptive analgesia; high doses needed, variety of
side effects
 Methdadone – dual mechanism of action
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Understand the mechanisms of pain signal
generation, transmission and modulation
Pharmacology of various agents affect different
aspects of pain signaling
Link nature of injury to choice of agent(s)
Many agents have additive analgesia &
different SE profile – good combinations
Choose agents to fit patient specific needs,
comorbidity, and concurrent-meds