Pain management

Pharmacotherapy 4 for PharmDs

Spring 2016
Prof. Nailya Bulatova-Younes, MD, PhD

References
DiPiro, Chapter 44 (Pain Management)
Koda-Kimble, Chapter 7 (Pain & Its
Management)
UpToDate: Overview of the treatment of chronic
pain. Last update: Dec, 2014.

DEFINITION
pain: an unpleasant sensory & emotional
experience associated with actual or potential
tissue damage or described in terms of such
damage.
Pain often is so subjective that many clinicians
define pain as whatever the patient says it is.
The best care is achieved when the patient
comes first

PATHOPHYSIOLOGY
Pain involves a
complex array of
neural networks in
the brain that are
acted on by
afferent stimuli

Pain

Nociceptive

Neuropathic

NOCICEPTIVE PAIN

Nociceptive
pain

Somatic
(from skin,
bone, joint,
muscle,
connective tissue)

Visceral
(from internal
organs such
as the large
intestine or
pancreas)

Somatic: most often

presents as throbbing &
well localized
Visceral pain: can
manifest as if it is coming
from other structures
(referred) or as a welllocalized phenomenon.
Nociception:
stimulationtransmission
perceptionmodulation
adaptive inflammation

1. Stimulation
stimulation of free nerve endings (=nociceptors)
in both somatic & visceral structures by
mechanical, thermal, & chemical impulses
chemical compounds (e.g., histamine,
bradykinin, K+, serotonin, PGs &, substance P)
are released from damaged tissues & can
activate or sensitize nociceptors
action potentials are transmitted along
afferent nerve fibers to spinal cord
serotonin modulates peripheral release of
primary afferent neuropeptides that are
responsible for neurogenic inflammation:
substance P, calcitonin gene-related peptide
(CGRP), & neurokinin A

Schematic representation of nociceptive pain

2. Transmission
Nociceptive transmission takes place in A & Cafferent nerve fibers
A fibers:
- large-diameter,
- myelinated
- responsible for rapidly conducting electrical impulses
- associated with thermal & mechanical stimuli
- release excitatory amino acids (glutamate, which
activate -amino-3-hydroxy-5-methylisoxazole-4propionic acid (AMPA) receptors located on dorsal
horn neurons)
- results in sharp or stabbing sensations that alert
subject to injury or insult to tissue

Transmission (contd)

C fibers:
unmyelinated,
small-diameter
release glutamate, substance P & CGRP
respond to mechanical, thermal, & chemical
stimuli
- conduct impulses to spinal cord at slower rate
compared with myelinated A-delta fibers
- also terminate in dorsal horn
- transmission results in pain that is dull,
aching, burning, & poorly localized or diffuse
(is known as second pain because it is
perceived after the first pain sensation)

Transmission (contd)
Stimulation of large sensory myelinated fibers
(e.g., A) that connect in dorsal horn with pain
fibers noxious & nonnoxious stimuli can
inhibit pain transmission analgesic response
produced by topical irritants or transcutaneous
electrical nerve stimulation (TENS)
Pain-initiated processes reach brain via
ascending spinal cord pathways, including
spinothalamic tract
Thalamus acts as relay station pathways
ascend & pass impulses to central structures
where pain can be processed further

3. Modulation
endogenous opiate system consists of
neurotransmitters (e.g., enkephalins,
dynorphins, & -endorphins) & receptors (e.g.,
, , & ) found throughout CNS
activation of N-methyl- D-aspartate (NMDA)
receptors in dorsal horn can -receptors
responsiveness to opiates
descending system for control of pain
transmission: can inhibit synaptic pain
transmission at dorsal horn & originates in brain;
neurotransmitters include endogenous opioids,
serotonin, norepinephrine, -aminobutyric acid
(GABA), glycine & neurotensin

4. Pain Perception
At this point, pain is thought to become
conscious experience that takes place in higher
cortical structures
Cognitive & behavioral functions can modify pain
Relaxation, distraction, meditation, & guided
mental imagery may decrease pain by limiting
the number of processed pain signals
In contrast, states such as depression or anxiety
may worsen pain

5. Adaptive Inflammation
inflammationpain threshold, & the injured
area becomes more sensitive to pain
our contact with & movement of injured area
promoting progression of healing
significant alteration occurs in chemical
composition & properties of neurons that
innervate inflamed tissues
Inflammatory pain is also associated with
excitability or responsiveness of neurons within
CNS (=central sensitization) - major cause of
hypersensitivity to pain after injury

NEUROPATHIC
PAIN/FUNCTIONAL PAIN
differs from nociceptive pain in that it becomes
disengaged from noxious stimuli or healing &
often is described in terms of chronic pain
Neuropathic pain: result of nerve damage (e.g.,
postherpetic neuralgia, diabetic neuropathy)
Functional pain: abnormal operation of the
nervous system (e.g., fibromyalgia, irritable
bowel syndrome, sympathetic induced pain,
tension-type headaches, & some noncardiac
chest pain)
They often are underrecognized & difficult to
treat

NEUROPATHIC
PAIN/FUNCTIONAL PAIN (contd)
Pain circuits rewire themselves both
anatomically & biochemically
spontaneous pain transmission
often described as burning, tingling, shock-like,
or shooting, exaggerated painful response to
normally noxious stimuli (hyperalgesia), &/or
painful response to normally nonnoxious stimuli
(allodynia)

CLASSIFICATION OF PAIN
1. ACUTE PAIN
Can be useful physiologic process warning individuals of
disease states & potentially harmful situations.
But severe, unremitting, undertreated, acute pain, when
it outlives its biologic usefulness, can produce many
deleterious effects (e.g., psychological problems)
Acute pain usually is nociceptive, but it can be
neuropathic in nature
Common causes of acute pain: surgery, acute illness,
trauma, labor, & medical procedures

Acute pain (contd)

Should always be aggressively managed, even
before definitive cause is known
Exceptions:
1. In pts with traumatic head injury, medications
should be withheld until full neurologic workup can
be performed because they can interfere with
cognitive function
2. Pts with acute abdominal pain also may have
pain medications withheld until ds. is made; but
several studies support early pain management.
When pain is relieved, pt. is > comfortable & better
able to cooperate with history, physical
examination, & diagnostic procedures

Acute pain (contd)

Postoperative & other acute pain
syndromes often are ignored or
inadequately treated
Part of tendency to undertreat pain is
reluctance of caregivers to prescribe
opiates for fear of causing addiction
Addiction to opioids is essentially
nonexistent when these drugs are
prescribed for acute pain, & withholding
appropriate pain treatment causes
needless pt suffering

2. CHRONIC PAIN
Pain persisting for > 6 months to years
Persistent (chronic) pain serves no biologic
protective purpose & can cause undue stress &
suffering
Pain was formerly believed to be merely
symptom & not diagnosis
Recent advances in molecular biology have
demonstrated, however, that chronic pain can
lead to long-lasting changes in nervous system
(= neural plasticity)
This concept helps explain difficulties observed
in treating various painful conditions

2. CHRONIC PAIN (contd)

Can be nociceptive, neuropathic/ functional, or
both
Subtypes include:
- pain that persists beyond normal healing time for
acute injury (e.g., complex regional pain
syndrome)
- pain related to chronic disease (e.g., pain
secondary to osteoarthritis)
- pain without identifiable organic cause (e.g.,
fibromyalgia)
- pain associated with cancer

Chronic pain (contd)

Chronic pain can be episodic or continuous, or
combination of both
Pt. may feel constant pain & also experience
exacerbations of more intense pain at various times
Chronic pain often is destructive by deteriorating QoL,
functional ability, spiritual & psychological well-being,
interpersonal relationships, & financial status
Chronic pain also can cause changes in appetite,
psychomotor retardation, irritability, social withdrawal,
sleep disturbances, & depression

Chronic pain (contd)

Nonpharmacological management:
- Cognitive interventions
relaxation technique,
self-hypnosis,
psychiatric therapy
- Physical manipulations
local application of heat,
cold,
massage,
electrical nerve stimulation,
acupuncture
physical therapy

Chronic pain (contd)

Pharmacologic agents:
antidepressants,
antiarrhythmics,
anticonvulsants,
major tranquilizers,
longer-acting opioids
regional anesthesia (local anesthetic blocks with or
without corticosteroids or chemical neurolysis),
Surgical interventions:
spinal decompression,
release of nerve entrapment)
Spinal analgesia:
intraspinal opioids
local anesthetic agents

CLINICAL PRESENTATION
Comprehensive history & physical examination
are imperative to evaluate underlying diseases &
possible contributing factors
This includes identifying source of pain when
possible
Anxiety, depression, fatigue, anger, & fear in
particular are noted to lower pain threshold,
whereas rest, mood elevation, sympathy,
diversion, & understanding raise the pain
threshold

Pain attributes

CLINICAL PRESENTATION
(contd)
Separating chronic pain from acute pain allows
for improved treatment regimens
Acute pain often is localized, well described, &
relieved with conventional analgesic therapy
(e.g., opioids, acetaminophen, [NSAIDs])
Chronic pain many times is not well recognized
& is not easily treated with conventional
analgesics
Pain intensity, pain relief, & medication side
effects (e.g., opioid-induced sedation or
constipation) must be assessed & reassessed
on a regular basis

CLINICAL PRESENTATION
(contd)
Timing of assessment: postoperative pain &
acute exacerbation of cancer pain may need to
be assessed hourly, chronic noncancer pain
may require only daily or < frequent assessment
QoL must be assessed on regular basis in all
patients
Clinician must remember that pain is always
subjective
Objective observations of grimacing, limping, or
tachycardia may be helpful in assessing
patients, but these signs are often absent in
patients with chronic pain caused by structural
lesions
The clinician must accept patients report of pain

TREATMENT
General principles
Effective analgesic therapy begins with accurate
assessment of the pt
Pain Intensity & Pain Distress Scales can help clinicians
assess pain
Names and amounts of all analgesics that patient is
taking should be documented as well as their
effectiveness
Other medical problems & medications should be
documented, including OTC & CAM
Pt fearful of being accused of analgesic abuse might be
reluctant to give accurate drug use history unless
trusting relationship can be established

Example Initial Regimens for Different Pain Levels Based on

Guidelines From the World Health Organization (WHO)

Pain
Level
Mild
pain

Typical
Correspondin
g Numerical
Rating (0 to
10 Scale(
1-3

WHO Therapeutic
Recommendations
Nonopioid analgesic:
taken on a regular
schedule, not as needed
(prn)

Example
Medicines for
Initial
Therapy
Acetaminoph
en 650 mg
every 4 hr
Acetaminoph
en 1,000 mg
every 6 hr
Ibuprofen 600
mg every 6 hr

Comments
Consider adding adjunct
analgesic or using an
alternate regimen if pain
not reduced in 12 days
Consider step up if pain
not relieved by two
different regimens

Example Initial Regimens for Different Pain Levels Based on

Guidelines From the World Health Organization (WHO)

Pain
Level

Moder
ate
pain

Typical
Corresponding
Numerical Rating
(0 to 10 Scale(

4-6

WHO Therapeutic
Recommendations

Add opioid for

moderate pain (e.g.,
moderate potency
analgesic). Use on a
schedule, not prn

Example
Medicines for
Initial Therapy

Acetaminophen
325 mg/codeine
60 mg every 4 hr
Acetaminophen
325
mg/Oxycodone 5
mg every 4 hr
Tramadol 50 mg
every 6 hr

Comments

Consider adding
adjunct analgesic or
using an alternate
regimen if pain not
reduced in 12 days
Consider step up if
pain not relieved by two
different regimen

Example Initial Regimens for Different Pain Levels Based on

Guidelines From the World Health Organization (WHO)

Pain
Level
Severe
pain

Typical
Correspondin
g Numerical
Rating (0 to 10 WHO Therapeutic
Scale)
Recommendations
7-10

Switch to a high
potency (strong) opioid;
administer on a regular
schedule

Example
Medicines for
Initial
Therapy
Morphine 15
mg every 4 hr
Hydromorpho
ne 4 mg every
4 hr
Morphine
controlled
release 60 mg
every 8 hr

Comments
Consider alternate
regimen (e.g., different
strong opioid) if pain not
reduced in 12 days
Consider increased dose
of strong opioid, or
addition of nonopioid
agents, if pain not
adequately relieved by
two regimens

PHARMACOLOGIC TREATMENT
Nonopioid Agents
Analgesia should be initiated with the most effective
analgesic agent having the fewest side effects
Acetaminophen, acetylsalicylic acid (aspirin), & NSAIDs
often are preferred over opiates for mild-to-moderate
pain
NSAIDs may be particularly useful in management of
cancer-related bone pain
Choice of particular agent often depends on availability,
cost, pharmacokinetics, pharmacologic characteristics, &
side-effect profile.
Large interpatient variability with NSAIDs switch to
another member of the group after adequate therapeutic
trial of any single agent

Nonopioid analgesics (contd)

MoA: Analgesic efficacy of NSAID & acetaminophen
does not correlate entirely with its capacity for
prostaglandin inhibition in periphery - can produce
analgesia at concentrations that do not inhibit peripheral
COX activity & PG formation
Analgesic effect of NSAID involves substance-P
receptors of neurokinin-1 type & glutamate receptors of
the NMDA type in addition to central prostaglandin
inhibition
NSAID actions through GABA-ergic pathways,
arachidonic acid byproducts, & AMPA receptors also are
being studied
Aspirin has demonstrated synergistic activity with
endogenous opioids at opioid receptors + serotonin's
effects in CNS

Nonopioid analgesics (contd)

The only available injectable NSAID in the USA
is ketorolac sometimes used as alternative to
opioids
It is indicated for short-term (Why?)
management of moderate to severe pain &
should not be substituted for appropriate opioid
analgesics for management of acute
postoperative pain
It is most beneficial in postoperative pain if used
in combination with opioids instead of
monotherapy
HW: Parenteral simple analgesics & NSAIDs
available in Jordan?

Nonopioid analgesics (contd)

Parenteral NSAIDs are no more effective than
oral formulations given in equivalent doses
Ketorolac has been associated with several
cases of serious postsurgical bleeding
NSAIDs cause Na+ retention & can also block
PG-induced vasodilation in patients with
compromised renal blood flow should be used
with caution in pts with heart failure,
hypovolemia, dehydration or any other
conditions that compromise renal blood flow &
risk of developing toxicity

Nonopioid analgesics (contd)

NSAIDs: GI ADRs are the most common,
Also: undesirable nervous system, otic, ocular,
hematologic, renal, hepatic, & cardiovascular ADRs
FDA in 2004 withdrew rofecoxib, a selective COX-2
inhibitor, from market because of CV risk associated
with prolonged period of use
But when compared with selective COX-2 inhibitor,
celecoxib, naproxen was linked to risk for CV events
after ~3 years of therapy FDA emphasizes warning for
all NSAIDs regarding risk for CV events
Until further data are available, these drugs should be
initiated at the lowest effective dose for the shortest
period of time

Nonopioid analgesics (contd)

Aspirin & essentially all other NSAIDs can induce
bronchospasm & other allergic manifestations in pts with
history of asthma, allergic rhinitis & nasal polyps
Asthma history alone is not a reason to withhold NSAID
If pt describes asthma-like response (SOB, wheezing,
cough, laryngospasm) following aspirin or other NSAID
ingestion, no drugs from this class should be used in the
future
The risk of using aspirin or other NSAID in patients with
chronic bronchitis, emphysema, or in asthmatics without
nasal polyps or history of drug-induced bronchospasm is
less clear

Nonopioid analgesics (contd)

Analgesic Nephrotoxicity
Analgesic overuse may cause chronic interstitial
nephritis (CIN) & may account for ~5% of cases of CRF
Acetaminophen-induced renal toxicity is almost always
accompanied by concomitant serum hepatic
transaminase changes & generally is associated with
acute acetaminophen intoxication
Most cases of CIN seem to be related to both dose &
duration of NSAID therapy
NSAIDs can directly damage renal tubules & can also
renal blood flow by inhibiting prostacyclin
Risk is if pt is volume depleted, has liver cirrhosis, has
been taking diuretics, or is elderly
Some subjects with normal renal function experience
profound changes in GFR when taking
indomethacin+triamterene

NSAID Use in Renal Disease

Sulindac & nabumetone have been reported to cause
less renal insufficiency because of absence of active
urinary nephrotoxic metabolites
They can still renal blood flow in pts at risk & can
cause renal dysfunction via hypersensitivity reactions
unrelated to their effects on renal blood flow
Clinical experience is not as great with these two drugs
relative to other NSAIDs
Possible drug-induced nephrotic syndrome has been
reported with many NSAIDs, in particular, fenoprofen
It is unclear whether patients with pre-existing renal
dysfunction are at > risk of developing further druginduced abnormalities, but most clinicians consider it a
relative contraindication

Homework (HW)
TABLE 44-3 Adult FDA-Approved
Nonopioid Analgesics

Acetaminophen dosing (Uptodate)

In the US, concerns about unintentional overdose have
been rising, and government regulators have suggested
that a maximum dose should be 2.6 g/day (eight tablets
per day of a formulation containing 325 mg per dose
unit), and that patients with significant liver disease or
heavy alcohol use should be considered to have a
relative contraindication to this drug.
In 2011, the US FDA asked drug manufacturers to limit
the strength of acetaminophen in prescription drug
products to 325 mg per dosage unit .
The FDA also is considering reducing the maximum
dose to 3250 mg/d, recognizing that the margin between
the maximum recommended dose and a potentially toxic
dose is lower than with other medications.

PHARMACOLOGIC TREATMENT
(contd)
Opioid Agents
Are often next logical step in the management of
acute pain & cancer-related chronic pain.
They also are an effective treatment option in
management of chronic noncancer pain;
however, this continues to be controversial.
Many times a trial of opioids is warranted, but
such a trial should not be done without a
complete assessment of pain complaint.

Opioid agents (contd)

Stimulation of (mu) 1-receptors may be
responsible for desired effects of supraspinal
analgesia
Stimulation of 2-receptors may lead to
unwanted consequences such as respiratory
depression, euphoria, constipation, & physical
dependence
Some (kappa)-receptors, as well as (delta)& (epsilon)-receptors, also mediate analgesic
response, although role of -receptors is not fully
understood
Autonomic stimulation, dysphoria, &
hallucinations may be caused by - (sigma)
receptors (not considered true opioid receptors,
but may interact with some opioid-like agents)

Opioid agents (contd)

Morphine can stimulate 1-, 2-, & -receptors
Pure opiate antagonists (e.g., naloxone) occupy opiate
receptors without eliciting response & block access of
opiate agonists, such as morphine, to these receptors
blocks both desired & undesired opiate effects
Pentazocine & butorphanol (mixed agonistantagonists)
produce analgesia through stimulation of -receptors, but
cause unwanted dysphoria & hallucinations through receptors.
Pentazocine& butorphanol also block access of
morphine to -receptors withdrawal symptoms in
individuals who are physically dependent on morphine or
its analogs

Opioid agents (contd)

1.
2.
3.

Opioids produce analgesia by 3 mechanisms:

Presynaptically, release of inflammatory transmitters
(e.g., tachykinin, excitatory AAs & peptides) from the
terminals of afferent C-fiber neurons
Can activity of output neurons, interneurons, &
dendrites in neuronal pathways by means of
postsynaptic hyperpolarization.
Inhibit neuronal activity via GABA & enkephalin
neurons in substantia gelatinosa
Pharmacologic action of opioids depends on
availability of opioid receptors, & cutting of peripheral
nerves leads to degeneration & loss of opioid
receptors in nerve itself postamputation pain often is
not relieved by morphine or other opioids

HW:
TABLE 44-4 Opioid Analgesics

Opioids (contd)
Patients in severe pain may receive very high doses of
opioids with no unwanted side effects, but as pain
subsides, patients may not tolerate even very low doses
Frequently, when opioids are administered, pain is not
eliminated, but its unpleasantness is decreased patients report that although their pain is still present, it
no longer bothers them.
ADRs: mood changes, sedation, N&V, GI motility,
constipation, respiratory depression, dependence, &
tolerance are evident in varying degrees with all agents.
Constipation, sedation, & N&V are the most common
side effects of opioids; respiratory depression is less
common
Tolerance to side effects (except to constipation) often
develops within the first week of therapy

HW:
TABLE 44-5 Dosing Guidelines

Analgesic Drug Monitoring

Opioids (contd)
In acute severe pain or when pt is unable to take
oral medications, alternative routes of therapy
(e.g., IV) may be preferred
Opioids differ greatly in equianalgesic dose,
which should be used only as guide because
nature of pain makes it necessary to
individualize pain regimens
In initial stages of acute pain, analgesics should
be given around the clock after administering
typical starting dose & titrating up or down,
depending on patients degree of pain &
demonstrated side effects (e.g., sedation)

Opioids (contd)
As painful state subsides & need for medication
, as-needed schedules may be appropriate
As-needed schedules also may be useful in
patients who present with pain that is intermittent
or sporadic in nature
Chronic pain is also best accomplished by
around-the-clock (ATC) administration
schedules that inhibit serum analgesic
concentrations from falling below the point at
which a patient experiences suffering of pain
As-needed schedules are to be used in
conjunction with ATC regimens & are used when
patients experience breakthrough pain

Opioids (contd)
Continuous IV & SC
methods of opioid infusion
are effective for some
postoperative pain, but
probability of unwanted side
effects is high
Alternative method is
patient controlled analgesia
(PCA): pt can self
administer preset dose of IV
opioid via pump
electronically interfaced with
timing device - better pain
control, improved patient
satisfaction, & relatively few
differences in side effects

Opioids (contd)
Administration of opiates directly into CNS (e.g., epidural
& intrathecal/subarachnoid routes) has shown
considerable promise in control of acute, chronic
noncancer, & cancer pain
Reports of marked sedation, respiratory depression,
pruritus, N&V, urinary retention, & hypotension these
methods of analgesia require careful monitoring & are
best used by experienced practitioners
When given simultaneously with intrathecal or epidural
local anesthetics such as bupivacaine, they have been
proven safe & effective
All agents administered directly into CNS should be
preservative-free

Intraspinal opioids

Obstetric Pain: Special

Considerations for Opioid Analgesia
Fentanyl & morphine are frequently administered
epidurally during labor, lower extremity & thoracic
surgery because of limited systemic effects & long
durations of analgesic action
Single dose of morphine 2-10 mg given epidurally may
provide analgesia for >12 hr
Respiratory depression can occur 1-3 hrs after
administration of epidural morphine & can be reversed
by naloxone
Frequent monitoring of vital signs is essential after
administration of epidural opioids
During labor, fentanyl is a good choice because it has a
fairly long duration of analgesia but will not produce
significant systemic effects that would compromise fetus
through transplacental migration+sufficiently short
duration

Systemic Opioids During Labor

If possible, CNS depressants should be avoided
during labor because they can compromise fetal
vital functions
If analgesic is deemed necessary: meperidine &
fentanyl are preferred over other opioids in
small, frequent parenteral injections or through
PCA
Close monitoring of pt for analgesia & untoward
effects is essential
Meperidine & fentanyl seem to have only
minimal residual effects on neonate at analgesic
doses, respiratory depression can still occur.

Systemic Opioids During Labor

(contd)
Butorphanol also has minimal effects on fetal &
neonatal function & is reasonable alternative to
meperidine or fentanyl in this situation
All potent analgesics should be administered IM or SC
because IV administration is associated with more
neonatal & fetal depression because of high peak serum
concentration achieved by this route
Pentazocine has similar effects as butorphanol, but is
seldom used because of local tissue reactions at site of
IM or SC injections.
If neonatal respiratory difficulties are manifested as
result of opioid analgesics administered during labor,
they can be reversed with naloxone

Opioids (contd)
Duration of opioid analgesia correlates partially with its
serum t1/2, but also with dose, route of administration, &
distribution characteristics of drug
E.g., methadone has serum t1/2 of 24 hrs, but duration
of analgesia is only ~6 hrs
Single daily doses of methadone are retained on opiate
receptors in brain long enough to prevent abstinence
symptoms for 24 hrs in opiate abusers
When used for pain management, long t1/2 of
methadone may contribute to cumulative effects & drug
toxicity such as QTc prolongation.
When methadone is administered epidurally, its duration
of analgesia is short! because of high lipophilicity that
promotes rapid redistribution from epidural space into
systemic circulation metabolic clearance

Tolerance, Dependence,
Addiction, & Pseudoaddiction
Tolerance is diminution of drug effect over time
as consequence of exposure to drug.
It develops at different rates & with tremendous
patient variability.
However, with stable disease, opioid use often
stabilizes, & tolerance does not lead to addiction
Physical dependence is defined by occurrence
of an abstinence syndrome following
administration of antagonist drug or abrupt dose
reduction or discontinuation.
Clinicians must understand that physical
dependence & tolerance are not equivalent to
addiction; however, with chronic opioid use, they
are likely to develop

Tolerance, Dependence,
Addiction, & Pseudoaddiction
(contd)
Addiction is best defined as a behavioral pattern
characterized as loss of control over drug use,
compulsive drug use, & continued use of drug despite
harm.
Clinicians must be aware that individuals behaviors may
suggest addiction, when in reality behaviors noted are
reflection of unrelieved pain or pseudoaddiction
In patients with no history of addiction, risk of addiction is
relatively small
Drug exposure appears to be only one etiologic factor in
development of addiction, & genetics, social, &
psychologic factors may be more significant
determinants.

Signs & Symptoms of Opiate

Physical Dependence
Rhinorrhea (runny
nose)
Lacrimation (tearing)
Hyperthermia, chills
Muscle aches (myalgia)
Emesis, diarrhea, GI
cramping
Anxiety, agitation,
hostility
Sleeplessness

Symptoms begin within 6

hours for short-acting
opioids (e.g., morphine) &
generally peak in ~3648
hrs
Symptoms usually subside
within 3-7 d (av., 5 d)
With methadone, however,
abstinence syndrome
develops > slowly, & is <
severe, but protracted
Opioid antagonists or mixed
agonistantagonist drugs
can precipitate abstinence in
some pts after chronic or
subchronic opioid exposure

Opioid Tapering & Withdrawal

Acute pain opiate analgesic dose can be in
hospitalized patients by 20% daily without
precipitating opiate withdrawal symptoms
In chronic opiate dependence, opioid dose can
be by ~?%(HW) every 3-5 days without
inducing withdrawal symptoms
Addition of clonidine can also improve overall
opioid tapering process, because it may impart
analgesic effects while assisting in controlling
abstinence symptoms

Morphine & Congeners

Many clinicians consider morphine first-line agent when
treating moderate-to-severe pain
Morphine can be given parenterally, orally, or rectally.
Side effects can be numerous, when morphine is first
initiated or when doses are significantly
Opioid-induced nausea is observed most frequently after
initial dose & often subsides with subsequent doses
N&V, & itching can all be minimized by antihistamines,
such as diphenhydramine or hydroxyzine 25-50 mg PO
every 6 hours as needed
As doses of morphine are , respiratory center becomes
less responsive to carbon dioxide, causing progressive
respiratory depression (less pronounced in pts being
treated for severe or chronic pain)

Morphine & Congeners (contd)

When opioid analgesics are initiated, a stimulant laxative
(e.g., senna) plus stool softener (e.g., docusate sodium)
should be given
If constipation persists, osmotic laxatives, such as
lactulose or sodium phosphate enema, may be added
Morphine-induced respiratory depression can be
reversed by naloxone
In pts with underlying pulmonary dysfunction, caution
must be used as they are already using compensatory
breathing mechanisms & are at risk for further
respiratory compromise
Caution is also urged when combining opiate analgesics
with alcohol or other CNS depressants - potentially
harmful & possibly lethal

Morphine & Congeners (contd)

Morphine produces venous & arteriolar vessel
dilation, & orthostatic hypotension may result
Hypovolemic patients are more susceptible to
BP
Because morphine myocardial oxygen
demand in ischemic cardiac patients, it is often
considered the DOC when using opioids to treat
pain associated with MI
Morphine propulsive contractions of GIT &
biliary & pancreatic secretions constipation
Morphine-induced spasms of sphincter of Oddi
have been observed but clinical significance is
unclear

Morphine & Congeners (contd)

Urinary retention is another potential side effect
of morphine; tolerance develops to this effect
over time
Morphine-induced histamine release often
manifests as pruritus, & it may exacerbate
bronchospasm in patients with history of asthma
Drug-induced respiratory depression can
intracranial pressure caution is advised in
head trauma patients who are not ventilated
because morphine may exaggerate this
pressure & cloud neurologic examination results

Morphine & Congeners (contd)

Morphine is metabolized to two important metabolites,
morphine- 3-glucuronide (M3G) & morphine-6glucuronide (M6G)
M6G contributes to analgesia & M3G, may contribute to
side effects
The metabolites are renally cleared & can accumulate in
pts with renal impairment side effects
Hydromorphone is > potent, has better oral absorption
characteristics, & is more soluble than morphine. No
pharmacologic advantage over morphine.
Levorphanol has extended half life, but its overall
therapeutic effects are similar to other agents in this
class

Morphine & Congeners (contd)

Codeine is commonly used opiate in treatment of mildto-moderate pain
Is often combined with other analgesic products (e.g.,
acetaminophen)
Has same propensity to produce side effects as
morphine & may produce more nausea & constipation
Hydrocodone is available for pain only in combination
products with other analgesic agents (e.g.,
acetaminophen, ibuprofen)
Its pharmacologic properties are similar to those of
morphine

Morphine & Congeners (contd)

Oxycodone is useful oral analgesic for
moderate-to-severe pain.
Is used in combination with nonopioids.
Immediate-release & controlled-release oral
dosage forms make it very useful in persistent
pain as well as acute pain

Meperidine & Congeners

(Phenylpiperidines)
Meperidine has pharmacologic profile comparable with
that of morphine; but it is not as potent & has shorter
analgesic duration
Meperidine is metabolized to toxic metabolite
normeperidine, which can cause CNS excitability,
manifested as tremor, muscle twitching, & possible
seizures
Normeperidine is renally cleared, so risk of accumulation
& pts with renal dysfunction or elderly
Combination of MAOIs & meperidine should not be used
because this mixture can produce severe respiratory
depression or excitation, delirium, hyperpyrexia, &
convulsions
Meperidine offers no analgesic advantage over
morphine, has greater toxicity, & should be limited in use

Meperidine & Congeners

(Phenylpiperidines) (contd)
Fentanyl is synthetic opioid structurally related to
meperidine that is used often in anesthesiology as an
adjunct to general anesthesia (short duration)
Transdermal patch can provide analgesia for up to 72
hours, but takes 12-24 hours for full onset & up to 6 days
to reach steady state after dose adjustments should
be limited to pts with chronic pain; not appropriate for
acute pain
Fentanyl lozenge & a buccal dosage form also are
available for treatment of breakthrough cancer pain
Caution should be used when fentanyl is administered to
pts who have very small body habitus, always starting
with the smallest expected effective dose & carefully
titrating to effect

Methadone & Congeners

Methadone is popular because of oral efficacy,
extended duration of action, & low cost
It is widely used in treating cancer pain & in
management of chronic noncancer pain
With repeated doses, analgesic duration of action is
prolonged, possible excessive sedation, & difficulty in
titration
Unique: agonist effects at - & -opioid receptors,
blockade of serotonin & norepinephrine reuptake & Disomer ability to antagonize NMDA receptors useful in
treatment of neuropathic & chronic pain or in pts with
maladaptive inflammatory component to their pain
Equianalgesic dose of methadone may with higher
doses of previous opioid, complicating conversions from
other opioids to methadone

Methadone & Congeners (contd)

Propoxyphene usually is used in combination
with acetaminophen for treatment of moderate
pain
Propoxyphene is metabolized to
norpropoxyphene, potentially toxic metabolite
Elderly patients & those with renal dysfunction
are at greatest risk for toxicity propoxyphene
use is discouraged in these patients

Head Injury & Opioid Analgesia

Opioid analgesics generally are avoided in pts with head
injury due to:
(a) opioid-induced pupil changes, nausea, & general CNS
clouding can mask neurologic evaluation
(b) head injury potentiates respiratory depressant effects of
opioids
(c) opioids induce CO retention vasodilation of cerebral
arteries & in CSF pressure that might be because of
head injury
(d) opioids in excessive doses can mask internal organ
injury
(e) morphine & meperidine can produce further BP in pts
who have blood loss caused by trauma
Short-acting opioid, such as fentanyl, can be used for
pain control in emergency situations in small but frequent
IV doses, e.g.,25-50 mcg IV every 30-60 minutes

Myocardial pain
Morphine does not myocardial wall tension or
oxygen consumption & does not affect cardiac
dimensions
Morphine also can HR & induces only minimal
orthostatic changes in blood pressures
In postsurgical pts who are volume depleted, the
orthostatic effect of morphine can be quite
dramatic, however.
Pentazocine & butorphanol cause greater
cardiovascular effects & can exacerbate acute
MI by cardiac workload & oxygen consumption
morphine remains the preferred agent

Biliary & Renal Colic

Opioid analgesics can induce smooth-muscle spasms in
sphincter of Oddi & intrabiliary pressure can
aggravate pain symptoms in biliary colic & serum
concentrations of amylase 5-10 times above control
value
No clear evidence indicates superiority of one agent over
the other
Opioid-induced biliary hypertension & sphincter of Oddi
spasm can be reversed by parenteral glucagon or
naloxone
Renal colic is extremely painful, & pts often require
parenteral opioid analgesics
No significant clinical difference is seen between any of
the opioids for this type of acute analgesic indication.

Liver Disease & Analgesia

Oral morphine & meperidine have higher
extraction ratio than methadone are more
likely to be absorbed unpredictably in pts with
severe liver disease methadone is most likely
to be absorbed consistently when administered
orally
The clinician should remember that any CNS
depressant can trigger significant problems in a
patient with liver disease
Although methadone has long half-life, it is still
safer to use orally than morphine
Doses should be small, frequent, on-demand

Respiratory Disease & Analgesia

Systemic opioids remain first-line agents in managing
pain in pts with COPD
Morphine & all other opioid analgesics can depress
respiration when given in therapeutic doses & should be
used cautiously in pts with advanced respiratory disease
& decreased respiratory function
There appears to be ceiling effect to respiratory
depression caused by butorphanol, nalbuphine, &
buprenorphine at higher doses ( doses of these
compounds do not further depress respiration & still
provide analgesia)
Naloxone reverses respiratory difficulty (& analgesia)
produced by nalbuphine & butorphanol but not that of
buprenorphine
Opioids do not always depress respiration when dosed
correctly &, in some instances, can improve respiratory
function in pts who have recently had a thoracotomy

Opioid AgonistAntagonist
Derivatives
This class produces analgesia & has a ceiling
effect on respiratory depression
Also have lower abuse potential than does
morphine, but psychotomimetic responses (e.g.,
hallucinations & dysphoria, as seen with
pentazocine), ceiling analgesic effect, &
propensity to initiate withdrawal in opioiddependent populations have diminished their
widespread clinical use

Homework:
DIRE score for opioid risk:
http://www.opioidrisk.com/node/1202
Opioid Equianalgesic Chart:
http://champ.bsd.uchicago.edu/PalliativeC
are/documents/Pallpaincard2009update.p
df

Central Analgesics
Tramadol has two modes of action: -opiate receptor
binding & inhibition of norepinephrine & serotonin
reuptake
It is indicated for relief of moderate to moderately severe
pain
Has side-effect profile similar to that of opioid analgesics
(e.g., dizziness, euphoria, hallucinations, cognitive
dysfunction, & constipation)
Alone may enhance risk of seizures
Concomitant use with SSRIs, opioids, TCAs, MAOIs,
neuroleptics, or other drugs that can seizure threshold
& use in patients with seizure disorders may risk of
seizures
May have place in treating patients with chronic pain,
especially neuropathic pain
HW: Tapentadol

Adjuvant Analgesics
Are pharmacologic agents with individual characteristics
that make them useful in management of pain but that
typically are not classified as analgesics
Chronic pain that has a maladaptive inflammatory (e.g.,
low back pain) &/ or neuropathic component (e.g.,
diabetic neuropathy) may require such agents
Topically applied local anesthetics nerve stimulation
In cancer patients, bone pain can be treated with
radiopharmaceuticals (e.g., strontium89)
Corticosteroids, such as dexamethasone, are useful in
reducing pain associated with cerebral & spinal cord
edema & in treating refractory neuropathic pain & bone
pain, particularly metastatic bone pain
Corticosteroids may also provide other beneficial effects,
such as mood elevation, antiemetic activity, & appetite
stimulation

Adjuvant Analgesics (contd)

Antidepressants (TCAs & SSRIs) are
commonly used to treat neuropathic pain (e.g.,
diabetic neuropathy, postherpetic neuralgia) &
pain associated with insomnia or depression.
They are used to treat fibromyalgia (diffuse
muscle & joint pain, which is thought to result
from central dysregulation)
MoA involve blockade of norepinephrine
reuptake, antagonism of histamine & muscarinic
cholinergic receptors, -adrenergic blockade, or
suppression of C-fiber evoked activity in spinal
cord

Adjuvant Analgesics (contd)

Anticonvulsants (gabapentin);
antiarrhythmics; 2-adrenergic antagonists;
& NMDA receptor antagonists (ketamine &
dextromethorphan) also have been used to
manage neuropathic pain with varying degrees
of success
Pregabalin can be titrated rapidly & has short
onset of action (<1 week), which may require
less combination therapy in some patients. The
most common side effects of gabapentin &
pregabalin include dizziness, somnolence,
peripheral edema, & dry mouth

Adjuvant Analgesics (contd)

Antihistamines (hydroxyzine & promethazine)
are often prescribed postoperatively to augment
analgesic effects of opioid agents.
Hydroxyzine may provide minimal analgesia,
whereas little evidence exists to confirm
analgesic action for promethazine
Addition of phenothiazines & antihistamines
may be useful in alleviating opioid-induced N&V;
but may potentiate orthostatic hypotension,
respiratory depression, sedation, &
extrapyramidal side effects

Combination Therapy
Combination of opioid & nonopioid
analgesics often results in analgesia
superior to that produced by either agent
alone
This facilitates use of lower doses & a
more favorable side-effect profile, &, when
needed, this approach is encouraged
HW: Pramipexole

REGIONAL ANALGESIA
Regional analgesia with properly administered
local anesthetics (LAs) can provide relief of both
acute & chronic pain
These agents can be positioned by injection
(e.g., in joints, in epidural or intrathecal space,
along nerve roots, or in nerve plexus) or topically
Lidocaine patch has proven effective in treating
focal neuropathic pain
Regional anesthetics relieve pain by blocking
nociceptive transmission & interrupting
sympathetic reflexes

REGIONAL ANALGESIA
(CONTD)
High plasma concentrations of LAs can cause
signs of CNS excitation & depression, including
dizziness, tinnitus, drowsiness, disorientation,
muscle twitching, seizures, & respiratory arrest
Cardiovascular effects include myocardial
depression, hypotension, cardiac output, heart
block, bradycardia, ventricular arrhythmia, &
cardiac arrest
Disadvantages of such methods include need
for skillful technical application, need for
frequent administration, & highly specialized
followup procedures

EVALUATION OF THERAPEUTIC
OUTCOMES
The key to treating pain effectively is consistent
monitoring for effectiveness (pain relief) versus
side effects (e.g., sedation) & titrating treatment
accordingly
In acute pain, this often must be done several
times per day (in the early stages, hourly); in
chronic pain this may occur daily or even weekly
Frequency of evaluation also depends on the
drug, administration route, & other therapies
being used.
When patients cannot be asked about their pain
(e.g., coma), monitoring agitation & heart rate is
appropriate

EVALUATION OF THERAPEUTIC
OUTCOMES (contd)
With chronic pain, tools such as the Brief Pain Inventory,
Initial Pain Assessment Inventory, McGill Pain
Questionnaire, or pain drawings may be helpful
All opioids can cause constipation. Pts should be
counseled on proper intake of fluids & fiber. Laxatives
should be added with chronic opioid use
CNS depressants (e.g., alcohol, BDZs) amplify CNS
depression when used with opioid analgesics, & use of
these combinations should be discouraged when
possible
When combinations are used, patients should be
monitored closely

Neuropathic pain management

algorithm (Uptodate)

Nociceptive pain management

algorithm (Uptodate)

Table 8-1 (Koda-Kimble) Common Causes of Analgesic Treatment Failure

Problem

Potential Impact on Pain

Management

Example

1. Inappropriate or
unknown diagnosis

Improper medication selection

Using a nonsteroidal antiinflammatory drug (NSAID) for

abdominal pain that may be
related to a gastrointestinal
bleed

2.Misunderstanding
of pharmacology or
pharmacokinetics

Overestimating potency or halflife

Dosing an opioid less frequently

than necessary to provide
adequate relief

3. Inadequate
management of
adverse effects

Patient may discontinue

therapy or misuse over-thecounter remedies

Patient suffers constipation

from antidepressants and uses
daily bisacodyl

4. Fear of addiction

Physician or patient or
caregiver may withhold
medications

Evidence of tolerance after

chronic use of opioids may be
mistaken for addiction

5. Unrealistic goals
for therapy

Patient will not be satisfied with

pain management regimen and
may seek other care

Patient states a desire to be

pain free following significant
nerve injury

Table 8-1 Common Causes of Analgesic Treatment Failure (contd)

Problem

Potential Impact on Pain

Management

6. Irrational
polypharmacy

Over- or under-use of
appropriate therapies

Patient with neuropathic pain

using three different opioids
without any adjuncts in the
regimen

7. Patient barriers

Patient cannot understand

appropriate medication use or
other pain management
modalities

Language or comprehension
deficits
Cognitive deficits: patient
cannot remember regimen
Physical impediments to using
medicines appropriately
Cultural barriers (e.g.,
stoicism)

8. Lack of
understanding of
pathophysiology of
pain

Limitations of health care

providers' ability to adequately
relieve pain

Drugs that show benefit in

animal models are not useful
for human pain conditions

Example