The Pharmacologic Management of Cancer Pain

The Pharmacologic Management of Cancer Pain

ABSTRACT: The management of cancer pain requires familiarity with a range of therapeutic strategies, including antineoplastic therapies, analgesic pharmacotherapy, and anesthetic, neurosurgical, psychological, and rehabilitation techniques. Successful pain management is characterized by implementation of the techniques with the most favorable therapeutic index for the prevailing circumstances, along with provision for repeated evaluations, so that a favorable balance between pain relief and adverse effects is maintained. For most patients, pain management involves the administration of specific analgesic approaches. In all cases, these analgesic treatments must be skillfully integrated with the management of other symptoms.

There is a wide consensus that
analgesic pharmacotherapy is
the mainstay of cancer pain
management. A commonly recommended
approach is the "three-step
analgesic ladder" of the World Health
Organization, which advocates three
basic steps of therapy according to
the severity of the presenting pain
problem (Figure 1).[1] This approach
emphasizes the principle of using analgesics
appropriate to the severity of
the prevailing pain problem; it emphasizes
the centrality of opioid pharmacotherapy.
Combined with appropriate
dosing guidelines, this approach
provides adequate relief to 70% to
90% of patients.[2-7]

Systemic Analgesic
Nonopioid Analgesics
The nonopioid analgesics (aspirin,
acetaminophen, and the nonsteroidal
anti-inflammatory drugs [NSAIDs])
are useful alone for mild to moderate
pain (step 1 of the WHO analgesic
ladder) and provide additive analgesia
when combined with opioid drugs
in the treatment of more severe
pain.[8] They are useful in a broad
range of pain syndromes of diverse
mechanisms, but there are no data to
support therapeutic superiority to alternative
options in any particular setting
other than inflammation.[8]
Unlike opioid analgesics, the nonopioid
analgesics have a "ceiling" effect
for analgesia and produce neither tolerance
nor physical dependence.

The nonopioid analgesics constitute
a heterogeneous group of compounds
that differ in chemical
structure but are all competitive blockers
of cyclooxygenase. The relatively
selective cyclooxygenase-2 drugs are
equianalgesic with the non-selective
inhibitors, and they are associated with
less mucosal morbidity.[9-11] Despite
the advances presented by the development
of cyclooxygenase-2 selective
agents, the coadministration of a
conventional NSAID with a gastroduodenal
protective agent (such as
omeprazole (Prilosec), pantoprazole
(Protonix), misoprostol (Cytotec), or
high-dose famotidine remains a valid
therapeutic option.[12] With the administration
of all of these agents, particular
caution is required for patients
at increased risk for adverse effects,
including the elderly and those with
predilection to peptic ulceration, impaired
renal function, and concurrent
corticosteroid therapy.

Acetaminophen rarely produces
gastrointestinal toxicity and there are
no adverse effects on platelet function;
hepatic toxicity is possible, however,
and patients with chronic alcoholism and liver disease can develop
severe hepatotoxicity at the usual
therapeutic doses.[13]

Opioid Analgesics: Basic

A trial of systemic opioid therapy
should be administered to all cancer
patients with pain of moderate or
greater severity regardless of the pain
mechanism. Although both somatic
and visceral pain appear to be relatively
more responsive to opioid analgesics
than neuropathic pain, a
neuropathic mechanism does not confer
opioid resistance; appropriate dose
escalation will identify many patients
with neuropathic pain who can achieve
adequate relief.[14,15]

Optimal use of opioid analgesics
requires a sound understanding of the
general principles of opioid pharmacology,
the pharmacologic characteristics
of each of the commonly used
drugs, and principles of administration,
including drug selection, routes
of administration, dosing and dose titration,
and the prevention and management
of adverse effects.

Important Principles in
Opioid Drug Therapy

  • Classification-Opioid compounds
    can be divided into agonist,
    agonist-antagonist, and antagonist
    classes based on their interactions with
    the various receptor subtypes (Table
    1). In the management of cancer pain,
    the pure agonists are most commonly
    used. Recently, with the advent of a
    transdermal route of administration,
    there has been increased interest in
    the use of the partial agonist opioid
    buprenorphine in the management of
    moderate pain.
  • Dose-Response Relationship-
    The pure agonist drugs do not have a
    ceiling dose. As the dose is raised,
    analgesic effects increase in a semilog-
    linear function until either analgesia
    is achieved or the patient
    develops dose-limiting adverse effects
    such as nausea, vomiting, confusion,
    sedation, myoclonus, or respiratory
  • The Equianalgesic Dose Ratio-
    Relative analgesic potency of opioid
    is commonly expressed in terms of
    the equianalgesic dose ratio. This is
    the ratio of the dose of two analgesics
    required to produce the same analgesic
    effect. By convention, the relative
    potency of each of the commonly used
    opioids is based upon a comparison
    to 10 mg of parenteral morphine.[16]
    Equianalgesic dose information and
    dose conversion tables (Table 2) provide
    guidelines for dose selection
    when the drug or route of administration
    is changed.

Several principles are critical in
interpreting the data presented in such
tables. The commonly quoted values
do not reflect the substantial variability
that is observed in both single-dose and multidose crossover studies.
Numerous variables may influence the
appropriate dose for the individual
patient, including pain severity, prior
opioid exposure (and the degree of
cross-tolerance this confers), age,
route of administration, level of consciousness,
and genetically determined
metabolic or receptor heterogeneity.

For most opioids the equianalgesic
dose relationship to morphine is
linear. For methadone, however, the
relationship appears to be curvilinear,
with the equianalgesic dose ratio falling
as the dose of prior morphine increases:
at low doses of morphine (30
to 300 mg oral morphine) the equianalgesic
ratio for oral methadone to
oral morphine is 1:4 to 1:6 and at high
doses (> 300 mg oral morphine) it is
1:10 to 1:12.[17]

Selecting an Appropriate Opioid
The factors that influence opioid
selection in chronic pain states include
pain intensity, pharmacokinetic
and formulatory considerations, previous
adverse effects, and the presence
of coexisting disease.

Traditionally, patients with moderate
pain have been conventionally
treated with a combination product
containing acetaminophen or aspirin
plus codeine, dihydrocodeine, hydrocodone,
oxycodone, and propoxyphene.
The doses of these
combination products can be increased
until the maximum dose of the nonopioid
coanalgesic is attained (eg,
4,000 mg acetaminophen). Recent
years have witnessed the proliferation
of new opioid formulations that
may improve the convenience of drug
administration for patients with moderate
pain. These include controlledrelease
formulations of codeine,
dihydrocodeine, oxycodone, morphine,
and tramadol in dosages appropriate
for moderate pain, and most
recently, patches of buprenorphine.

Patients who present with strong
pain are usually treated with morphine,
hydromorphone, oxycodone,
oxymorphone, fentanyl, or metha-done. Of these, the short half-life opioid
agonists (morphine, hydromorphone,
fentanyl, oxycodone, or
oxymorphone) are generally favored
because they are easier to titrate than
the long half-life drugs that require a
longer period to approach steady-state
plasma concentrations.

If the patient is currently using an
opioid that is well tolerated, it is usually
continued unless difficulties in
dose titration occur or the required
dose cannot be administered conveniently.
A switch to an alternative opioid
is considered if the patient
develops dose-limiting toxicity that
precludes adequate relief of pain without
excessive side effects, or if a specific
formulation, not available with
the current drug, is either needed or
may substantially improve the convenience
of opioid administration.

Some patients will require sequential
trials of several different opioids
before a drug which is effective and
well tolerated is identified.[18,19]
This strategy has been variably labeled
opioid rotation, or opioid switching.
The existence of incomplete
cross-tolerance to various opioid effects
(analgesia and side effects) may
explain the utility of these sequential
trials. It is strongly recommended that
clinicians be familiar with at least three
opioid drugs used in the management
of severe pain and have the ability to
calculate appropriate starting doses
using equianalgesic dosing data when
switching between drugs.

Selecting the Appropriate Route of
Sytemic Opioid Administration

Opioids should be administered by
the least invasive and safest route capable
of providing adequate analgesia.
The oral route is usually preferred. Alternative
routes are necessary for patients
who have impaired swallowing
or gastrointestinal dysfunction, those
who require a very rapid onset of analgesia,
and those who are unable to manage
either the logistics or side effects
associated with the oral route.

Transdermal fentanyl (Duragesic)
often provides a convenient and noninvasive
alternative to oral administration.
Transdermal patches capable
of delivering 25, 50, 75, and 100 ?g/h
are available. The dosing interval for
each patch is usually 72 hours,[20]
but some patients require a 48-hour
schedule.[21] Data from controlled
studies suggest that the transdermal
administration of fentanyl is associated
with a lesser incidence of constipation
than oral morphine.[22-24]

Other noninvasive routes are less
commonly used. Rectal suppositories
containing oxycodone, hydromorphone,
oxymorphone, and morphine
have been formulated, and controlledrelease
morphine tablets can also be
administered per rectum.[25,26] The
potency of opioids administered rectally
is approximately equivalent to
that achieved by the oral route.[27]

The sublingual route has limited
value due to the lack of formulations,
poor absorption of most drugs, and
the inability to deliver high doses or
prevent swallowing of the dose. An
oral transmucosal formulation of fentanyl
(Actiq), which incorporates the
drug into a candy base, has been approved
for use in the management of
breakthrough pain.[28,29]

  • Invasive Routes-A parenteral
    route may be considered when the
    oral route is precluded or there is a
    need for rapid onset of analgesia or a
    more convenient regimen. Repeated
    parenteral bolus injections, which may
    be administered by the intravenous
    (IV), intramuscular (IM), or subcutaneous
    (SC) routes, provides the most
    rapid onset and shortest duration of
    action. Parenteral boluses are most
    commonly used to treat very severe
    pain, in which case doses can be repeated
    at an interval as brief as that
    determined by the time to peak effect
    until adequate relief is achieved.[30]
    Repeated bolus doses without frequent
    skin punctures can be accomplished
    through the use of an indwelling IV
    or SC infusion device such as a 25- to
    27-gauge infusion device (a "butterfly")
    that can be left under the skin
    for up to a week.[31]
  • Continuous parenteral infusions are
    useful for many patients who cannot
    be maintained on oral opioids. Longterm
    infusions may be administered
    IV or SC. In practice, the major indication
    for continuous infusion occurs
    in patients who are unable to swallow
    or absorb opioids. Continuous infusion
    is also used in some patients
    whose high opioid requirement renders
    oral treatment impractical. Ambulatory
    patients can easily use
    continuous SC infusion. A range of
    pumps are available, varying in complexity,
    cost, and ability, to provide
    patient-controlled "rescue doses" as
    an adjunct to a continuous basal infusion.[
    31] There are data indicating that
    when available, Teflon- or Vialoncoated
    nonmetal cannulae are preferred
    to butterfly needles.[32]

    Opioids suitable for continuous SC
    infusion must be soluble, well absorbed,
    and nonirritating. Extensive
    experience has been reported with
    heroin, hydromorphone, oxymorphone,
    morphine, and fentanyl. Methadone
    appears to be relatively irritating
    and is generally not recommended.
    To maintain the comfort of an infusion
    site, the SC infusion rate should
    not exceed 3 to 5 mL/h. Patients who
    require high doses may benefit from
    the use of concentrated solutions such
    as hydromorphone at 10 mg/mL or
    morphine tartrate, which is available
    in some countries as an 80 mg/mL

  • Changing Routes of Administration-
    The switch between oral and
    parenteral routes should be guided by
    knowledge of relative potency (Table
    2) to avoid subsequent overdosing or
    underdosing. In calculating the equianalgesic
    dose, the potencies of the
    IV, SC, and IM routes are considered
    equivalent. In recognition of the imprecision
    in the accepted opioid dose
    conversion tables and the risk of toxicity
    from potential overdose, a modest
    reduction in the calculated dose is


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