Systemic opioid pharmacotherapy is widely accepted as the major
approach to the management of cancer pain.[1-6] More than
three-quarters of cancer patients can achieve adequate relief with
long-term treatment.[1,7-13] If undertreatment, which continues to be
a significant problem, were eliminated, most patients would be
able to cope with the disease and its treatment without the profound
burden of unrelieved pain.
These statistics are reassuring, but should not deflect attention
from the subgroup of patients that does not respond adequately to an
initial trial of systemic opioid therapy. These patients experience
an unsatisfactory balance between analgesia and side effects, despite
efforts to individualize the dose. They are poorly responsive to the
opioid therapy and must be considered for alternative analgesic strategies.
The potentially confusing nomenclature applied to the outcome of
opioid therapy is exemplified by the term efficacy.
Pharmacologists use the term intrinsic efficacy to
indicate the proportion of receptors that must be occupied to yield a
given effect, and apply the unmodified label efficacy to
either the effect produced by a given dose of drug or the maximal
effect that can be produced by the drug (also called maximal
efficacy). None of these usages may resonate with the clinician, who
typically describes an opioid therapy as efficacious if it yields a
favorable balance between analgesia and side effects. For the
patient, the maximal efficacy of a morphine-like opioid agonist is
not determined by the effect at a given dose, or the ceiling effect
above which dose increments yield no additional analgesia. Rather,
clinical efficacy is determined by the degree of analgesia reported
before treatment-limiting toxicity occurs.
In an effort to clarify this terminology, the term
responsiveness was proposed to characterize the outcome
of opioid therapy.[16,17] Opioid responsiveness is defined as the
probability that adequate analgesia (satisfactory relief without
intolerable and unmanageable side effects) can be attained during
dose titration. Alternatively, responsiveness can be used to depict
the degree of analgesia obtained at dose-limiting toxicity. This
might be viewed as maximal efficacy from a clinically relevant perspective.
There is remarkable variability in the responsiveness of individual
patients to different opioids and the responsiveness of different
patients to the same opioid. For example, a patient with stable pain
may develop severe somnolence at a morphine dose associated with
acceptable analgesia, then demonstrate dose-limiting nausea without
somnolence at a dose of hydromorphone associated with lesser, equal,
or better analgesia. Among those who are treated with morphine for
metastatic bone pain, some achieve a highly favorable balance between
analgesia and side effects, whereas others experience treatment-limited
toxicity before any meaningful analgesia is reported.
Thus, the overall high rate of responsiveness to long-term opioid
treatment in the population of patients with cancer pain actually
subsumes wide variation in outcomes. The mechanisms that underlie
variability in opioid responsiveness are not known, but are
presumably multifactorial and related to characteristics of both the
pain syndrome and the patient. Among the factors related to pain that
appear to reduce opioid responsiveness are a neuropathic mechanism
and the presence of severe breakthrough pain. The most important
patient-related factor is a propensity to adverse opioid effects,
which may be determined by advanced age, major organ failure, or
other factors. Presumably, genetic factors also play an important
role in determining this propensity.
The existence of factors that increase or decrease opioid
responsiveness should not be taken to mean that any factor, or group
of factors, imparts opioid resistance. Indeed, no factor
is sufficiently predictive to prejudge outcome in any individual
case. A neuropathic mechanism, for example, may reduce opioid
responsiveness overall, but the population of patients with
neuropathic pain presents a range of outcomes that includes some who
do very well.[19-22] Moreover, the variable responsiveness to
different opioids in the same patient implies that a poor response to
one drug should not be interpreted as a poor response to opioid
Recognition that some patients do not attain a favorable balance
between analgesia and side effects during systemic opioid therapy
should lead to an assessment that allows rational selection of an
alternative analgesic strategy. Unfortunately, this selection is
hampered by the absence of comparative clinical trials. Given the
lack of science, it often appears that the choice of one therapy over
another is determined more by the expertise, availability, and biases
of providers than by the clinical characteristics of the patient.
There are four major strategies that may be applied to the management
of pain in cancer patients who demonstrate poor responsiveness during
a trial of systemic opioid therapy (Table
Expanding Therapeutic Window
First, it may be feasible to continue the same opioid if more
aggressive side effect management is possible. Effective treatment of
a limiting side effect can open the therapeutic window
and potentially allow even higher doses of the opioid if required to
improve analgesia. The most significant advance in this strategy is
the expanding use of psychostimulant drugs to treat opioid-induced
somnolence and mental clouding.[23,24]
Second, the observation that a poor response to one opioid does not
predict an equally poor response to another suggests the utility of
sequential trials.[25,26] This technique, which is now termed
opioid rotation, is widely used and accessible to all
clinicians. It requires an understanding of the relative potency
between opioids and the practical use of the equianalgesic dose table.
Third, it may be possible that a pharmacologic technique that reduces
the systemic opioid requirement may yield equal or better analgesia
with less drug. If opioid requirement is reduced, the dose that is
ultimately needed may be associated with a more favorable balance
between analgesia and side effects. Conceptually, the use of
intraspinal opioid therapy may be considered under this strategy,
which also includes the use of systemically administered nonopioid or
adjuvant analgesic drugs (Table 2).
Fourth, there are a large number of nonpharmacologic analgesic
approaches that may result in a lower opioid requirement. These
approaches may be categorized as anesthesiologic (eg, chemical
neurolysis), neurostimulatory (eg, transcutaneous electrical nerve
stimulation and dorsal column stimulation), surgical (eg, cordotomy),
rehabilitative (eg, an orthosis to brace a painful region),
psychologic (eg, cognitive interventions for pain control), and
complementary alternative. Although linked conceptually, the scope of
these therapies is obviously very broad and there are substantive
differences in their indications and implementation.
Faced with such a diversity of analgesic strategies, the clinician
must perform a detailed assessment of the patient and the pain
syndrome to rationalize decision-making.[2,29] Without comparative
data to illuminate the relative risks and benefits of different
approaches in carefully defined populations, recommendations must be
based on this knowledge of the patient and on an understanding of the
Pain should be described in terms of severity, location, temporal
features (duration, pattern, and course), quality, and factors that
provoke or improve it. This information, the findings from a physical
examination, and the results of appropriate laboratory and imaging
studies usually clarify the most likely etiology of the pain and the
syndrome that best characterizes it. This information also allows
classification of the pain according to the broad type of
pathophysiological processes that are likely to be sustaining it.
In the cancer population, the most prevalent pathophysiology is
termed nociceptive. Nociceptive pain can be attributed to
a site of ongoing tissue injury (usually somatic, sometimes
visceral). A substantial minority of patients have pain that is
neuropathic or can be attributed to aberrant processing in the
peripheral or central nervous system. Mixed pathophysiologies are
The assessment also must clarify the goals of care, which ultimately
inform all therapeutic decisions. Many patients experience a period
during which primary treatment of the disease is not possible or
desired because of the burden of the therapy. Some of these patients
emphasize goals related to comfort combined with the maintenance or
restoration of function. Others, particularly those at the end of
life, emphasize comfort above all else. The fluctuation of these
goals mandates repeated assessment, particularly when decisions must
be made about new therapies.
A comprehensive evaluation of the pain should also include detailed
information about physical and psychosocial comorbidities. The status
of the disease and its complications have obvious implications for
the selection of alternative analgesic strategies. The presence of
coagulopathy, electrolyte abnormalities, major organ dysfunction, or
metastatic disease in critical locations must be clarified. The
performance status of the patient should be noted and the specific
impact of pain on functioning should be determined. Functional
impairment that is believed to be caused by unrelieved pain is less
likely to exclude an alternative analgesic strategy than is
impairment perceived to be related to progressive disease and short
The social situation of the patient also has clear implications for
the choice of analgesic approaches. Interventions that require
careful monitoring may not be feasible if the patient lives alone and
adequate home care nursing cannot be arranged.
Selection of an alternative analgesic approach may also be influenced
by other considerations. Obviously, a treatment will not be possible
unless there are clinicians who can implement it and a protocol for
reliable follow-up. Economic considerations, such as insurance
coverage for invasive approaches or nursing care, may be a very
salient issue for some patients.
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