Pharmacology Ch.

28 Outline

Opioid (Narcotic) Analgesics, Opioid Antagonists, and Nonopioid centrally acting

analgesics

Analgesics are drugs that relieve pain w/o causing loss of consciousness.

Opioids are derived from opium, including morphine, codeine oxycodone and
propoxyphene

Introduction to the opioids

Terminology
Opioid – general term defined as any drug, natural or synthetic that has actions
similar to those of morphine

Opiate – more specific, applies only to compounds present in opium (morphine,

codeine)

Narcotic – an analgesic, a CNS depressant and any drug capable of causing physical
dependence

Endogenous Opioid Peptides

3 families of peptides in body that have opioid like properties. Enkephalins,
endorphins and dynorphins.
- serve as neurotransmitters and neurohormones
- found in CNS and peripheral tissue

Opioid Receptors
3 main classes of opioid receptors designated:
- MU
-Kappa
- Delta
Mu receptors are the most important pharmacologically, b/c opioid analgesics act
primarily by activating mu receptors.
in contrast to opioid analgesics, endogenous opioid peptides act through all three
types of opioid receptors, including delta receptors.

Mu Receptors
Responses include: analgesia, respiratory depression, euphoria, and sedation.
- MU activation is related to physical dependence

Kappa receptors
Activation of kappa receptors can produce analgesia and sedation
- kappa activation may underlie psychotomimetic effects as seen with certain
opioids
Classification of Drugs that act at Opioid receptors
These drugs are classified on the basis of how they affect receptor function.
- at each type of receptor, a drug can act in one of three ways:
- agonist
- partial agonist
- antagonist

A partial agonist is a drug that produces low to moderate receptor activation when
administered alone, but will block the actions of a full agonist if the two drugs are
given together.

Drugs that bind to opioid receptors fall into 3 groups:

– Pure opioid agonists

Activate mu receptors and kappa receptors, and therefore can produce
analgesia, euphoria, sedation, respiratory depression, physical
dependence, constipation and other effects. These can be divided into 2
subgroups: strong opioid agonists (morphine)and moderate to strong
opioid agonists (Codeine).
– Agonist-antagonist opioids
4 agonist-antagonist opioids are available: pentazocine, nalbuphine,
butophanol, and buprenorphine. When administered alone, the agonist-
antagonist opioids produce analgesia. However if given to a pt who is
taking pure opioid agonist, these drugs can antagonize analgesia caused
by pure agonist. (pentazocine)
– Pure opioid antagonists
Act as antagonists at mu and kappa receptors. Do not produce analgesia
or any other effects caused by opioid agonists. Used in reversal of
respiratory and CNS depression caused by overdose with opioids and
agonists. (Naloxone – narcan- is the prototype)

Morphine
the prototype of the strong opioid analgesics and standard by which others are
measured.
- multiple pharmacologic effects including analgesia, sedation, euphoria, respiratory
depression, cough suppression, and suppression of bowel motility.

○ Morphine has multiple pharmacologic actions

- relieves pain
- causes drowsiness
- mental clouding
- anxiety reduction
- sense of well being
 ○ Causes respiratory depression, constipation, urinary retention,
orthostatic hypertension, emesis, miosis, cough suppression, and
biliary colic through actions in the CNS and periphery
○ May be beneficial, detrimental or both.

Relief of pain
principal indication for morphine – relief of severe to moderate pain
- can be used to relieve pain of myocardial infarction and dyspnea associated w/ left
ventricle failure and pulmonary edema
- can be used preop for sedation and reduction of anxiety
- the ability of morphine to cause mental clouding, sedation, euphoria and anxiety
reduction can contribute to relief of pain

Mechanism of Analgesic action

Morphine and other opioid agonists are thought to relieve pain by mimicking the
actions of endogenous opioid peptides, primarily at mu receptors

Adverse Effects
Respiratory Depression – most serious adverse effect of the opioids.
- at equal doses, all of the pure opioid agoinists depress respiration to the same
extent

– Death following OD is almost always from respiratory arrest

– Opioids depress respiration primarily through activation of mu receptors
– The time course of respiratory depression varies with route of
administration
- 7 min after IV, 30 min after IM, and up to 90 min after sub Q
- with spinal injection, resp depression may be delayed for hours
– With opioid tolerance, huge doses that would be lethal to non-tolerant
individuals can be taken w/o noticeable effects.

*if respiratory rate is less than 12 breaths per min, opioid should be
withheld, and the physician called
** the very young, very old and those w/respiratory disease are sensitive
to respiratory depression and must be monitored closely

Respiratory depression is increased by concurrent use of other drugs

w/CNS-depressant actions

Constipation
Opioids promote constipation.
Because of their effects on the intestine, opioids are highly effective for treating
diarrhea.
Orthostatic Hypotension
Morphine like drugs lower blood pressure by blunting the baroreceptor reflex and
dilating peripheral arterioles and veins.

– Peripheral vasodilation results from morphine –induced release of

histamines
– Hypotensive drugs can exacerbate opioid induced hypotension

Urinary Retention
Morphine can cause urinary hesitancy and urinary retention by increasing tone in
the bladder sphincter.
- also, by increasing tone in the detrusor muscle, the drug can elevate pressure w/in
the bladder, causing urinary urgency.

– Patients should be encouraged to void every 4 hours

– Urinary retention is especially likely in pts w/prostatic hypertrophy
– Drugs w/anticholinergic properties (tricyclic antidepressants,
antihistamines) can exacerbate urinary retention
– Catheterization may be required

Morphine may also decrease urine production by promoting release of anti-diuretic

hormones

Cough suppression
Morphine like drugs act at opioid receptors in the medulla to suppress cough.
Suppression of cough may lead to accumulation of secretions in the airway
- use of codeine and hydrocodone based cough remedies

Biliary Colic
Morphine can induce spasm of the common bile duct, causing pressure w/in biliary
tract to rise dramatically
- symptoms range from epigastric distress to biiary colic
- some opioids therefore will exacerbate the pain
- meperidine causes less smooth muscle contraction and therefore will not
cause this problem often

Emesis
Morphine promotes nausea and vomiting through direct stimulation of the
chemoreceptor trigger zone of the medulla
- these rxns are greatest w/ the initial dose and subsequently diminish
- occurs in 15-40% of amulatory patients
- can be reduced by pretreatment with an antimetic and having pt remain still

Elevation of intracranial pressure

Morphine can elevate intracranial pressure. It occurs indirectly by suppressing
respiration, increasing CO2 , which dilates the cerebral vasculature, causing ICP to
rise.
- if respiration is maintained at a normal rate, ICP will remain normal too

Euphoria/Dysphoria
Euphoria is an exaggerated sense of well being
Dysphoria is a feeling of anxiety and ill ease (more common when taken w/o pain)

Sedation
When administered to treat pain, morphine causes drowsiness
patients should be warned to avoid hazardous activities like driving.
sedation can be minimized by:

– Taking smaller doses more often

– Using opioids that have short half lives
– Giving small doses of a CNS stimulant in morning and early afternoon

Miosis
Morphine and other opioids cause papillary constriction (miosis)
- in response to toxic levels, pupils may constrict to pinpoint size

Neurotoxicity
Opioid-induced neurotoxicity is a recently recognized syndrome
symptoms include:

– Delirium
– Agitation
– Myoclonus
– Hyperalgesia

Primary risk factor are renal impairment, pre-existing cognitive impairment and
prolonged high dose opioid use

Adverse effects from prolonged use

can cause hormonal changes and can alter immune fnc.
- decrease in levels of lutenizing hormone, estrogen and testosterone
- increase in prolactin

Pharmacokinetics
Morphine can be administered by:
- IV, IM, oral , subQ, epidural and intrathecal

Morphine is inactivated by hepatic metabolism

Tolerance and Physical Dependence

Tolerance – a larger dose is required to produce the same response that could
formerly be elicited by a lower dose.
Tolerance develops to many, but not all of morphine’s effects
- analgesia, euphoria, sedation and respiratory depression
- very little tolerance to constipation and miosis

Cross tolerance exists among the opioid agonists (oxycodone, methadone, codeine,
heroin)

No cross tolerance between opioids and general CNS depressants

Physical Dependence
results from adaptive cellular changes that occur in response to the continuous
presence of thee drugs.
- if opioids are w/drawn, abstinence syndrome will follow

The intensity and duration of opioid abstinence syndrome depends on:

1. the half life of the drug being used

2. the degree of physical dependence.

W/opioids, that have short half lives, symptoms of abstinence are brief but intense.
The opposite is also true

Initial rxns: yawning, rhinorrhea and sweating, occurring 10hrs after last dose

At peak: violent sneezing, weakness, nausea, vomiting, diarrhea, ab cramps, bone

&muscle pain, muscle spasm and kicking movements

– Runs its course in 7 to 10 days

– Rarely dangerous (as opposed to withdrawl from general CNS
depressants, which can be lethal)
– Opioids should be withdrawn gradually
– ** Physical dependence is rarely an issue when taken to treat acute pain
– Infants can be born w/physical dependence to opioids
– Cross dependence exists among pure opioid agonists, so any pure agonist
will prevent withdrawl in a patient who is physically dependent on any
other pure agonist

Strong opioid agonists are classified as Schedule II, agonist antagonist opioids are
classified under schedule IV

Precautions
Some pts are more likely to have adverse rxns

– Decreased respiratory reserve (pts w/asthma, emphysema,

kyphoscoliosis, chronic cor pulmonale and extreme obeisity
– Pregnancy
– Labor and Delivery (suppresses uterine contractions)
 – Head injury (must use caution
– Infants and elderly
– Pts w/ inflammatory bowel disease
– Pts w/liver impairment
– Hypotension
– Reduced blood volume
– Prostatic hypertrophy

Drug interactions
CNS depressants – can intensify respiratory depression

Anticholinergic drugs – (like antihistamines, tricyclic antidepressants and atropine

like drugs) can exacerbate constipation and urinary retention

Hypotensive Drugs – can exacerbate hypotension

Monoamine oxidase inhibitors- MAOi- can produce syndrome of delirium,

hyperpyrexia, convulsions and severe respiratory depression – can be fatal

Agonist Antagonist Opioids – can precipitate a withdrawl syndrome

Opioid antagonists – can counteract morphine actions

Other – antiemetics – promethazine, can reduce nausea and vomiting

amphetamines can enhance opioid induced analgesia and offset sedation

Toxicity
Clinical manifestations
Opioid OD produces a classic triad of signs:
- coma
- respiratory depression
- pinpoint pupils

Hypoxia wil cause BP to fall

Treatment consists primarily of ventilator support and an opioid antagonist (Narcan)

or Revex

Preparations, Dosage and Admin

Dosage must be individualized

- high doses are required for pts w/low tolerance to pain or extremely painful
disorders
- Elderly require lower doses
- neonates require low doses

If BP is below pretreatment value, RR is below 12 breaths/min or pulse rate is

significantly above baseline, physician should be notified
Opioids should be admin on a fixed schedule

Fentanyl
a strong opioid analgesic w/ a high mg potency (100x morphine)

– Parenteral
primarily for induction and maintenance of surgical anesthesia
- most effects are like morphine
- can cause muscle rigidity
– Transdermal
fentanyl patch applied to skin of upper torso
-drug is slowly released from patch
- takes 24 hrs to reach effective levels, then steady for another 48 hrs,
after which it can be replaced
- indicated only for persistent severe pain in pts who are opioid tolerant
- use in non-tolerant pts can be fatal
- not for use in children under 2 yrs, or under 18 and less than 110 lbs
- not for use in post op pain, intermittent pain, or pain that responds to a
less powerful analgesic
-Same adverse effects as other opioids: resp. depression, setation,
constipation, urinary retention, nausea, etc.
- signs of toxicity are same as in other opioids
- fentanyl is metabolized by CYP3A4 and levels can be increased by
inhibitors (ritonavir, etc)
- patches should not be exposed to direct heat
- b/c it takes 24 hrs to reach full effect, PRN w/ another opioid may be
reqd
– Transmucosal
lozenge on a stick (Actiq)
- available in 6 strengths from 200 to 1600 mcg
- approved only for breakthrough cancer pain in pts who are already
taking opioids and have some degree of tolerance
- each dose is enough to kill non-tolerant peeps
- analgesia begins in 10 to 15 min. peaks at 20min and lasts 1-2 hrs.
- unit size should gradually increase until effective dose is determined
- most common side effects are: dizziness, anxiety, weakness, confusion,
nausea, vomiting, constipation, and headache
- if symptoms of dizziness, nausea or signs of OD develop, the unit should
be removed and disposed of.

Moderate to strong opioid agonists

Are similar to morphine in most respects. They can produce analgesia,
sedation and euphoria, respiratory depression, constipation, urinary
retention, cough suppression and miosis.
- differences are quantitative, they have a somewhat lower potential for
abuse. Toxicity can be reversed with naloxone.

Codeine
Actions and uses
Codeine is indicated for relief of mild to moderate pain.

– It is usually administered orally.

– Side effects are dose limiting.
– Codeine is a strong analgesic, but the degree of pain relief that can be
achieved safely is low
– Can be given alone or with a nonopioid analgesic (aspirin or
acetaminophen)
– Schedule II
– Very effective cough suppressant.

Oxycodone
(OxyContin, Roxicodone, Combunox, Percodan, Percocet, etc)
Has analgesic effects equivalent to those of codeine

– Oral administration
– Available by itself in immediate release tablets and capsules (5, 15 and
30mg)
– Available in combination w/aspirin (percodan),
– w/ acetaminophen (Percocet)
– w/ibuprofen (combunox)
– Schedule II
– Controlled release form is a long acting analgesic that is designed to
relieve moderate to severe pain around the clock. Every 12 hrs PRN
– Increasing levels of OxyContin abuse

Agonist-Antagonist Opioids
4 are available: pentaxocine, nalbuphine, butorphanol, and buprenorphine

– The first 3 act as antagonists at mu receptors and agonists at kappa

receptors
– Low potential for abuse
– Produce less respiratory depression, and less powerful analgesic effects
– These drugs can precipitate withdrawl from pure opioid agonists
Pentazocine
Actions and uses
First agonist-antagonist opioid available and prototype for group

– Indicated for mild to moderate pain

– Much less effective than morphine against severe pain
– Acts as agonist at kappa receptors
– Produces analgesia, sedation and respiratory depression (ltd)
– Produces little or no euphoria
– Produces unpleasant rxns (anxiety, strange thoughts, nightmares,
hallucinations) – psychotomimetic effects
– Schedule IV
– Increases cardiac work (not preferred for pts w/ MI)
– Should never be administered to a person who is physically dependent on
a pure opioid agonist (no drugs that block mu receptors should be used in
this case)
– Generally mild withdrawl.

Clinical use of opioids

assessment is essential to pain mgmt.
- pain status should be evaluated before opioid administration and about 1
hour after

– In addiction you should assess for psychologic factors that reduce pain
threshold (anxiety, depression, fear, anger)
– What a patient reports about pain may not accurately reflect their
experience

Dosage determination
Dosage of opioids must be adjusted for individual
- not all pts have same pain tolerance
- Elderly pts metabolize opioids more slowly and require lower doses
- newborns have inadequate BBB and require lower doses than infants or
young children

Dosing schedule
Opioids should be administered on a set schedule rather than PRN.

Avoiding withdrawl
When opioids are administerd for 20 days or more, clinically significant
physical dependence may develop

If this occurs, dosage should be tapered over 7 to 10 days

Physical Dependence
A state in which an abstinence syndrome will occur I the dependence
producing drug is abruptly withdrawn. (not equated w/addiction)

Abuse
Drug use that is inconsistent w/medical or social norms

Addiction
A behavior pattern characterized by continued use of a psychoactive
substance despite physical, psychologic or social harm

Minimizing fears of dependence

Development of significant physical dependence is extremely rare when
opioids are given acutely to relieve pain.

Even when physical dependence does occur, pts rarely develop addictive
behavior and continue opioid administration after pain is subsided.

Opioid analgesics should be administered in the lowest effective dosages for

the shortest time needed.

You must balance the risk with the benefit

Patient Controlled Analgesia

PCA – A method of drug delivery that permits the pt to self-admin parenteral
opoids on an as needed basis.

Used in relief of post-op pain, cancer, trauma, labor, MI, vaso-occlusive sickle
cell crisis

Morphine is the drug of choice for PCAs

Prior to starting the PCA, pt should be given a loading dose

The objective of PCAs is to provide comfort, while minimizing sedation and

other side effects

PCA provides continuous control of pain while avoiding the adverse effects
associated w/excessive drug levels

PCA is associated w/accelerated recovery

Pts should not fear overdose, not permitted by PCA

PCA device will deliver larger doses during the night, than during waking
hours
Using Opioids for specific pain
Obstetric
- meperidine is often the preferred opioid for obstetric use

Myocardial Infarction
- Morphine is the opioid of choice for decreasing pain
- can reduce discomfort w/o causing excessive respiratory depression
- by lowering blood pressure, morphine can decrease cardiac work
- agonist –antagonist opioids should be avoided b/c they increase cardiac
work

Head Injury
Opioids must be employed w/caution in pts w/head injury (resp depression,
complicated assessemts)

Cancer Related Pain

Treating chronic cancer pain differs from treating acute pain.
- objective is to maximize comfort
- Pts should be given as much medication as needed to relieve pain

Non cancer pain

to avoid misuse, provisions include
- using opioids only after non-opioid analgesics have failed
- discussing benefits and risks w/pt
- using only one dr. and pharmacy
- ensuring follow up visits
- ceasing if opioids don’t work
- fully documenting process

Opioid antagonists
Opioid antagonists are drugs that block the effects of opioid agonists
- used for treating OD, reversal of post op effects
- 3 available (naloxone, nalmefene and naltrexone (revia)

Naloxone
Narcan is a structural analog of morphine that acts as a competitive
antagonist at opioid receptors, blocking opioid actions. Can reverse most
effects of opioid agonists

– When admin’d in absence of opioids, naloxone has not sig. effects

– If admin’d prior to opioids, will block actions of opioids
– If given to physically dependent pt, will precipitate immediate withdrawl
– Elimination is by hepatic metabolism
– Half life is about 2 hrs
– Cannot be admin’d orally b/c of rapid first pass inactivation
– Drug of choice for treating OD w/ pure opioid agonist
– Can be used to treat toxicity w/agonist antagonist opioids also
– Following surgery, can be used to reverse excessive respiratory
depression from pre op or intraop drugs