Download Introduction to Pharmacology Chapter 1

Opioid Analgesics and Antagonists
Ed Bilsky, Ph.D.
Department of Pharmacology
University of New England
Phone 207.602.2707
E-mail: [email protected]
Case 1
A 33-year-old truck driver presented with left shoulder pain dating from a
motor vehicle accident 4 years before. His pain was described as “constant” and
“constricting,” with “stabbing electric, shock-like” characteristics. It had
increased over the past 2 years to intensities between 7 and 10 out of 10 (0 =
no pain, 10 = excruciating pain). He had undergone excision of the lateral end of
the left clavicle and rotator cuff decompression 3 years earlier, receiving
physiotherapy before and after surgery. He had also used heat and a machine
providing transcutaneous electric nerve stimulation and had received intraarticular injections of anaesthetic agents and steroids. When first seen in the
pain clinic he was taking, on average, one tablet of acetaminophen/codeine/
caffeine (300 mg/30 mg/15 mg) and one tablet of acetaminophen/oxycodone
(325 mg/5 mg) 5 times daily. He also drank 10 cups of coffee daily, had been
unable to sleep more than 3 hours in 24 for the last 2 years and was working
night shifts. Apart from smoking a pack of cigarettes per day, the patient had
no other risk factors for addiction, and he described having a supportive wife
and 2 daughters. What modifications to his medication regimen and lifestyle
might provide him with better pain management?
Opium and Opioids: A Brief History
• Among the remedies which it has pleased almighty God to
give to man to relieve his sufferings, none is so universal
and efficacious as opium… Sydenham, 1680
• Opium has been used and abused for thousands of years
– the antidiarrheal actions were used to treat dysentery
Opium and Opioids: A Brief History
• In 1806, Sertürner isolated an alkaloid from opium
which he called morphine (L. morpheus, god of
dreams)
– ushered in the field of alkaloid medicinal chemistry
• A number of other alkaloids were subsequently
isolated from opium
– codeine, papaverine, thebaine, etc.
Opium and Opioids: A Brief History
• Problems with opioid addiction were recognized early on
– development of hypodermic syringe/needle - Soldier’s disease
– patent medicines
• There has been a long history of trying to modify the chemical
structure of morphine to decrease side-effects
– heroin as a nonaddictive alternative to morphine!!!
– synthetic agents such as methadone
– mixed opioid agonists/antagonists
• The field of opioid pharmacology has also been the source of major
advances in scientific methodology and medicinal chemistry
– development of radioligand binding assays in the early 1970s and the
identification of opioid receptors
– isolation of endogenous opioid peptides in 1975
– cloning of all three opioid receptors in the early 1990s
Opioid Receptors
• Currently, there are three cloned opioid receptors
– mu, delta and kappa
• Each receptor type has similarities and key
differences with regard to the others
– members of the G-protein coupled receptor family
– tend to produce inhibitory effects on neurotransmission
– distinct distributions in the CNS
• Most of the currently available opioids work
through the mu opioid receptor
Mechanism of Action-Cellular
• Opioid receptors are coupled to the Gi/Go class of
G-protein coupled receptors
• Opioid agonist administration leads to an inhibition
of adenylyl cyclase and a decrease in cAMP
formation
• The downstream mediators of the opioid response
include an opening of inwardly rectifying K+
channels and an inhibition of voltage-gated Ca2+
channels
G-Protein Coupled Receptors
Mechanism of Action-Systems
Opioid analgesics can work at several levels:
• Peripheral receptors
– role in inflammatory pain states and hyperalgesia
• Spinal cord
– profound analgesia/anesthesia with spinal administration
• Supraspinal sites
– activation of descending pain control pathways
– involvement of the limbic system
Peripheral Sites of Action
Peripheral Sites of Action
Fig. 1. Columns represent differences (mean ±
SEM) in VAS scores (VAS) of patients receiving
saline versus patients receiving morphine(VASsal
- VASmor) in trial 1 (A), trial 2 (B), and trial 3
(C). In patients with inflammatory tooth pain
(A), differences in VAS scores between the
saline and morphine group are significantly
different (P < 0.05, RM-ANOVA). In patients
without inflammatory tooth pain (B) or with
perineural morphine administration (C)
differences in VAS scores are not significantly
different
Likar R, Koppert W, Blatnig H, Chiari F, Sittl R,
Stein C, Schafer M. Efficacy of peripheral
morphine analgesia in inflamed, non-inflamed and
perineural tissue of dental surgery patients. J
Pain Symptom Manage 2001 Apr;21(4):330-7
Inflammatory tooth pain
No inflammatory tooth pain
Perineural morphine
Spinal Analgesia
• Opioid receptors are located
on the primary afferent
terminal
– attenuates release of substance
P and glutamate
• High concentrations of opioid
receptors are also seen
postsynaptically in laminae I,
II, V and X of the spinal cord
– activation increases potassium
conductance, thereby
hyperpolarizing second order
neurons
– decreased GABA release
www.hosppract.com/issues/2000/07/brook.htm
Supraspinal Analgesia
• Brainstem circuits may inhibit rostral
movement of nociceptive information
and activate descending pathways
that alter nociceptive processing in
the spinal cord
– periaqueductal gray
– rostral ventral medulla
• Parts of the limbic system activated
by opioids may alter the emotional
response to painful stimuli
– nucleus accumbens/ventral forebrain
Endogenous Opioids
• There are at least three families of endogenous
opioid peptides
– individual peptides derived from larger precursors
• Each family has a unique anatomical distribution
and pharmacological profile
Endogenous Opioids
• The precise role that these peptides play in the
regulation of physiological functions is unclear
–
–
–
–
pain transmission
mood
eating/drinking behaviors
and many others
Stimulation of Central Sites Produces Analgesia in Humans
Electrical Stimulation of PAG
Hosobuchi et al, 1977
Beta-endorphin Surrounds PAG
A. Basbaum
Mammalian Endogenous Opioid Peptides
Precursor
Endogenous peptide
Amino acid sequence
Pro-opiomelanocortin
b-Endorphin
YGGFMTSEKSQTPLVTLFKNAIIKNAYKKGE
Pro-enkephalin
[Met]enkephalin
[Leu]enkephalin
Metorphamide
YGGFM
YGGFL
YGGFMRF
YGGFMRGL
YGGFMRRV-NH2
Pro-dynorphin
Dynorphin A
Dynorphin A(1-8)
Dynorphin B
a-neoendorphin
b-neoendorphin
YGGFLRRIRPKLKWDNQ
YGGFLRRI
YGGFLRRQFKVVT
YGGFLRKYPK
YGGFLRKYP
Pro-nociceptin / OFQ
Nociceptin
FGGFTGARKSARKLANQ
Pro-endomorphin*
Endomorphin-1
Endomorphin-2
YPWF-NH2
YPFF-NH2
*Presumed to exist, awaiting discovery
Main Effects of Opioids at Therapeutic Doses
Desirable
Undesirable
Mixed Desirability
Analgesia
Nausea, vomiting
Sedation
Relief of anxiety
Urinary retention
Euphoria
Dysphoria
Cough suppression
Mental clouding
 Bowel motility
Tolerance
Drug dependence syndrome
Respiratory depression
Postoperative ileus
Biliary spasm
Analgesic Effects
• Pain is a complex phenomenon that has both
sensory and emotional components
• Opioid analgesics can inhibit both the transmission
of the sensory signals to higher CNS centers and
the affective aspects of the experience
• Many patients report that they feel the pain, yet
it is not necessarily aversive
• The higher efficacy compounds have a broad
spectrum of activity
Tolerance
• Tolerance refers to the phenomenon in which
previous exposure to a drug results in a diminution
of an effect or the need for a higher dose to
maintain an effect
• Tolerance to opioid analgesics has been reported
in both animal models and clinical situations
• Tolerance to the adverse effects of opioids may
also occur, though the rate and degree of
tolerance varies for each effect and each patient
Mechanisms of Tolerance
• There have been a number of hypotheses put
forward to explain the development of tolerance
–
–
–
–
receptor down regulation
receptor internalization
receptor/G-protein desensitization
other compensatory adaptations
• My laboratory, and others, are trying to develop
opioid analgesics that produce less tolerance, or
adjunct agents that limit the development of
tolerance
% Animals Showing Effect
Models of Tolerance
Naive
100
Tolerant
50
0
1
3
10
Log Dose (mg/kg)
Management of Tolerance
• The development of tolerance can usually be
managed effectively by:
– considering a differential diagnosis for the loss of
analgesia (e.g., progression of disease)
– increasing the dose of opioid analgesic
– switching to another opioid analgesic with greater
efficacy
– adding alternative pain management strategies
Physical Dependence
• Prolonged exposure to an opioid agonist can
produce adaptations at the cellular and systems
levels which oppose the drug effect
– the patient has become physically dependent on the
drug
– physical dependence does not equal addiction!!!
• The discontinuation or sudden reduction in drug
levels, or the administration of an antagonist, can
lead to a withdrawal syndrome
Symptoms and Signs of Opioid Withdrawal
Symptoms
Signs
restlessness
pupillary dilation
irritability
sweating
increased sensitivity to pain
tachycardia
nausea
vomiting
abdominal cramps
diarrhea
myalgia
hypertension
dysphoria
yawning
insominia
fever
anxiety
rhinorrhea
drug craving
piloerection
Physical Dependence
• Overt opioid withdrawal symptoms can usually be
managed effectively:
– reinstatement of a low dose of the opioid
– gradual tapering of opioid agonist
– use of adjunct agents to ease withdrawal symptoms
(e.g., clonidine)
• Subtle episodic withdrawal symptoms may,
however, complicate pain management
– use of longer acting agents over short acting opioids
Barriers to Adequate Pain Control
• Fear of Addiction
"When we surveyed the parents of children dying
with cancer, we asked them what the major concern
was about their child receiving narcotics. It was
that 'my child will grow up to be an addict,' and
these were clearly children that were going to die."
Kathleen Foley, M.D.
(Dahl et al., 1986)
PAINKILLER TEARS THROUGH MAINE
OxyContin Addicts, Crime Wave Linked
LEWISTON, Maine - The crowbar rained on Dorothy
Treadwell. Once. Twice. Twenty times. The tiny orange pills her
assailant sought scattered to the ground.
Treadwell, 48, struggled to rise. She gripped a radiator. Again came
the crowbar. The blow left her pinky hanging by a scrap of
tendon. She ran bloodied into the street.
Her neighborhood by the railroad tracks near downtown here is a poor
collection of rickety wood houses aside metal silos of small-time
factories. But such savagery is rare.
The assailant, said Treadwell, was Cleve Herrick, her live-in
lover. He is a raging OxyContin addict, she said, desperate - like
hundreds of others in Maine - to obtain the addictive prescription
painkiller, often called “poor man's heroin.” “It was pretty bad for
this area. I mean, a crowbar?” recalled James Theiss, a Lewiston
police detective on the case in which Herrick is now charged with two
counts of aggravated assault.
OxyContin, a remarkably effective painkiller, is shredding the social
fabric of parts of Maine, creating a Wild West-like anarchy in many
communities, according to dozens of interviews with state officials,
doctors, and police.
OxyContin, marketed by Purdue Pharma L.P., has been linked to addiction, suffering and
death of patients using this prescription painkiller.
OxyContin, approved by the FDA in 1995, is a time-released form of oxycodone, an
opium derivative, which is the same active ingredient in Percodan and Percocet.
OxyContin is intended for use by terminal cancer patients and chronic pain sufferers. It
has been linked to at least 120 overdose deaths nationwide.
It has been alleged that Purdue Pharma L.P. has marketed the drug excessively without
stressing its addictive nature. Doctors and pharmacists say the manufacturer of
OxyContin promoted the benefits of the drug without providing enough warning about the
serious side effects of addiction. It has also been alleged Purdue Pharma L.P. made
misrepresentations and failed to sufficiently warn individuals regarding appropriate use
and risks of OxyContin.
It has been reported that OxyContin's sales exceeded $1 billion in the U.S. in 2000.
If you have been prescribed OxyContin,
you may be entitled to compensation
Please review the information on our site
and contact us for immediate legal
assistance.
Addiction Liability
• Studies in the 1920s and 1950s were influential in
setting opioid analgesia policy in the later part of
the 20th century
– chronic opioid therapy leads to addiction
– Kathleen Foley quote
• These studies had methodological flaws and more
recent reports have suggested that the risk of
iatrogenic opioid addiction is very low
– the incidence of addiction in chronic pain patients
parallels the lifetime prevalence rates in the general
population (Fishbain et al., 1992)
Respiratory Depression
• Respiratory depression is the most lifethreatening of the side-effects associated with
opioid analgesics
– major cause of fatal opioid overdoses
• Opioid receptors are located on chemoreceptors
and ventral respiratory group neurons in the
medulla
– diminished sensitivity to changes in O2 and CO2 levels
– changes in tidal volume and frequency of respiration
Respiratory Depression
• Respiratory depression is typically not a problem
if guidelines are followed
– more common with bolus dosing in naïve individuals
– some of the fentanyl analogues can produce chest wall
rigidity which interferes with the muscles of breathing
– partial agonists typically produce less depression
• Special clinical populations include patients with
asthma, emphysema, COPD, cor pulmonale and
increased intracranial pressure
– naloxone can reverse the depressant effects of most
opioids
Effects on Mood/Cognition
• Analgesic doses of most opioids produces relief from
anxiety and a floating, dream-like state
– majority of people report euphoric feelings, though some patients
find the experience dysphoric
– kappa opioid agonists appear to produce dysphoria
• Drowsiness and clouding of mentation are frequently
reported effects of opioids
– elderly more susceptible to these effects
• Chronic use of opioids results in little, if any, impairment
of cognition or motor skills (e.g., driving skills)
Nausea and Vomiting
• Opioids stimulate the chemoreceptor trigger zone
producing nausea and vomiting
– tolerance typically occurs to repeated dosing
• Ambulation exacerbates the nausea and vomiting
• Administration of antiemetic drugs can decrease
these side-effects
• Orthostatic hypotension is also possible with
analgesic doses of opioids
Constipation
• One of the biggest concerns with chronic opioid
administration is severe constipation
– occurs in almost all patients receiving chronic opioids
• In many cases, constipation is the primary reason
for the patient discontinuing opioid therapy
• Constipation can be partially managed by using
laxatives
– development of opioid antagonists that do not cross the
blood-brain barrier
Antitussive Effects
• Opioid analgesics can strongly suppress the cough
reflex
– exact mechanisms are unknown
• Weaker opioids such as codeine are formulated
for this purpose
– accumulation of secretions in the lungs can lead to
airway obstruction
• Many OTC cough suppressants contain the opioidlike molecule dextromethorphan
– decreased side-effects compared to codeine
Cardiovascular Effects
• Most opioids have no significant direct effect on
the heart
– morphine is the drug of choice for relieving pain from
cardiac ischemia
– possible cardioprotective effects in ischemic models
• Hypotension may occur following opioid
administration
– histamine release and depressant effects in the
vasomotor systems of the brainstem
Other Opioid Effects
• Constriction of biliary smooth muscle, resulting in biliary
colic
• Renal function is depressed
– antidiuretic effect mediated through mu receptors
– increased sphincter tone may produce urinary retention
• Prolongation of labor
– Morphine versus meperidine
• Flushing of the skin, sweating and itching
• Modulation of immune function
Drug Interactions
• Many other CNS depressants can act in an additive or
synergistic manner with opioid analgesics
–
–
–
–
benzodiazepines
barbiturates
alcohol
antipsychotics
• MAO inhibitors with opioids may produce hyperpyrexic
coma and hypertension
– especially with meperidine
• Stimulants have sometimes been used to counteract the
CNS depressant effects of opioids
Pain Management Techniques
Pharmacotherapy
Non-Pharmacological
Treatments
Physical therapy
Procedures
Opioids
Acupuncture
Active exercise
Trigger point injections
Nonsteroidals
Relaxation
Passive exercises
Nerve blocks
Muscle relaxants
Visualization
Pool therapy
Epidural steroids
Benzodiazepines
Prayer
TENS unit
Intrathecal opioids
Antidepressants
Pain groups
Massage therapy
Spinal cord stimulation
Antianxiety agents
Chiropractic
Antiarrhythmics
Ice/heat
Antiseizure agents
Bed rest
Pain Management Techniques
Full Efficacy
Agonists
Moderate/Weak
Efficacy Agonists
Mixed Acting
Agonists/Antagonists
Misc. Compounds
Morphine
Hydrocodone
Buprenorphine
Tramadol
Methadone
Oxycodone
Butorphanol
Hydromorphone
Meperidine
Pentazocine
Naloxone
Oxymorphone
Codeine
Nalbuphine
Naltrexone
Levorphanol
Propoxyphene
Nalmefene
Fentanyl
Diphenoxylate
Remifentail
Loperamide
Choosing an Appropriate Opioid
• Assessment of the pain
– severity and type of pain
• Pharmacokinetic considerations
– route of administration
– duration of action
• Pharmacodynamic considerations
– differences between drugs, novel effects
• Individual patient factors
–
–
–
–
age, sex, genetic factors
disease states (renal or liver disease)
concurrent drug therapy
psychosocial factors
WHO Analgesic Ladder
Morphine
• Prototypical mu opioid agonist
– indicated for moderate to severe pain
• Multiple preparations available
– parenteral
– oral and sustained release (MS Contin)
– rectal
• M3ß- and M6ß-glucoronides are primary metabolites
– may contribute to analgesic effects (M6ß) and side-effects (M3ß)
– lower dosing in geriatric patients (smaller Vd and  renal function)
• Morphine produces histamine release
– bronchoconstriction and vasodilation
– patients with reduced blood volume are more sensitive to the
vasodilatory effects of morphine
Codeine
• Codeine is a weak opioid analgesic
– has limited affinity for opioid receptors
– considered a prodrug
• Needs to be demethylated to morphine
– approximately 10% of Caucasians lack the cytochrome
P450 isozyme (CYP 2D6)
– these patients will get no relief from even high doses of
codeine
Methadone
• Full opioid agonist
– efficacy similar to morphine
– good oral bioavailability
– long half-life and duration of action
• The compound has antagonist actions at the
NMDA receptor complex
– decreased development of tolerance and physical
dependence?
– role in treatment of neuropathic pain?
• Used in the treatment of heroin addiction and
managing opioid withdrawal
Fentanyl and Analogues
• Relatively selective mu opioid agonists
– typically more potent than morphine
– shorter duration of action (e.g., remifentanil)
– high efficacy compounds
• Fentanyl can be given by various routes
– transdermal patch
– fentanyl lozenge (lollipop)
• Muscular rigidity more pronounced with this class
of compounds compared to morphine
Meperidine
• Moderate efficacy opioid agonist
– used for moderate pain
• The compound has antimuscarinic effects
– cardiovascular effects possible
– limited constriction of the pupil
• Accumulation of normeperidine(metabolite) can produce
seizures
– caution with high doses and in patients with renal insufficiency
– No longer recommended for chronic pain management
– Do not use with MAO inhibitors (serotonin syndrome)
• Other notes
– Applications in labor and delivery???
– decreased urinary retention and constipation versus morphine???
Oxycodone
• Opioid agonist with moderate efficacy
• Recent controversy with this drug
– sustained release preparation-OxyContin
– pellets can be crushed and a solution injected
• Purdue Pharma has tried to reformulate the
compound with naloxone
– oral administration would still be effective
– parenteral administration would result in blockade of
opioid actions
Propoxyphene
• Very weak opioid agonist
– analgesic effect equivalent to aspirin
when used alone
– typically administered in combination
with aspirin and acetaminophen
• Limited clinical utility
– concern with accumulation of
norpropoxyphne (metabolite) -->
convulsions, hallucinations and
cardiotoxicity possible
– Irritating to tissues when injected
Diphenoxylate/Loperamide
• Diphenoxylate is a weak opioid agonist with low
abuse liability
– atropine added as a combination product for treatment
of diarrhea and to discourage abuse
• Loperamide is a moderate efficacy opioid agonist
that does not readily cross the blood-brain
barrier
– low abuse liability
– common OTC antidiarrheal medication
Mixed Opioid Agonists/Antagonists
• These compounds are characterized by different
actions on each of the opioid receptors
– nalbuphine-kappa agonist/mu antagonist
– buprenorphine-partial mu agonist
– pentazocine-kappa agonist, weak mu agonist
• These agents are contraindicated in opioid
dependent patients
– severe withdrawal syndrome may develop
Tramadol
• Novel analgesic action
– weak mu opioid agonist
– blocks reuptake of serotonin
– blocks reuptake of norepinephrine
• Marketed as a compound with efficacy similar to codeine
with less side-effects
–
–
–
–
no addiction liability?
less GI effects
efficacy in neuropathic pain states1
expensive
1Cochrane
Database Syst Rev. 2004;(2):CD003726
Naloxone
• Prototypical opioid antagonist
• Used to treat opioid overdose
– low oral bioavailability
– short duration of action
• Will precipitate a severe withdrawal syndrome in
opioid dependent patients
• New evidence suggests that this compound has
inverse agonist actions in opioid dependent states
– increase in withdrawal symptoms
Naltrexone
• Prototypical opioid antagonist
• Used to treat heroin addicts
– good oral bioavailability
– long duration of action
• New evidence suggests that this compound has
inverse agonist actions in opioid dependent states
– role in patient compliance?
• Approved for the treatment of alcoholism
– decreases binge type drinking
Methylnaltrexone
• First in class peripheral opioid antagonist
– Quaternary nitrogen prevents BBB transport
– Must be given by s.c. injection
QuickTime™ and a
decompressor
are needed to see this picture.
• Indicated for opioid-induced constipation in
patients with advanced illness and who are not
responding to conventional laxative therapy
– Can produce severe diarrhea and abdominal cramping,
especially in opioid dependent patients
– Contraindication of mechanical bowel obstruction
Principles of Pain Control
1.
Analgesia should be integrated into a comprehensive patient evaluation
and management plan
2.
The emotional and cognitive aspects of pain must be recognized and
treated
3.
There is no reliable way to objectively measure pain
4.
Pain is most often under-treated, not over-treated
5.
Beware of the “squeaky-wheel-gets-the-oil” phenomenon of pain control
6.
Pain control must be individualized
7.
Anticipate rather than react to pain
8.
Whenever possible, let the patient control his or her own pain
9.
Pain control is often best achieved by combination therapy
10. Pain control requires a multidisciplinary team approach