Neuropathic Cancer Pain: The Role of Adjuvant Analgesics

Neuropathic Cancer Pain: The Role of Adjuvant Analgesics

ABSTRACT: Neuropathic pain may be defined as pain related to abnormal somatosensory processing in either the peripheral or central nervous system. This pathophysiologic label is typically applied when the painful symptom is associated with an overt injury to neural structures, is part of a recognized syndrome, or has a dysesthetic quality (usually burning, shooting, or electrical). Most neural injury does not lead to clinically important neuropathic pain, but sometimes even a small degree of tissue injury can precipitate severe pain. In the cancer population, neuropathic pain is often related to compression, direct neoplastic invasion of the peripheral nerves or spinal cord, or to a neuropathy caused by chemotherapy. To manage neuropathic pain in this population, nonopioid adjuvant drugs that are neuroactive or neuromodulatory are often needed to complement opioid therapy. The primary adjuvant analgesics are anticonvulsant and antidepressant medications, but a wide variety of other drugs are also used. To optimize analgesic therapy in patients with neuropathic pain, both opioid and adjuvant analgesics must be used effectively. [ONCOLOGY 15:1435-1453, 2001]

Chronic pain is typically classified as nociceptive
(visceral or somatic) or neuropathic, depending on the underlying
pathophysiology suggested by the pain. Nociceptive pain involves ongoing
activation of pain-sensitive neurons by stimulation of specialized nociceptors
from tissue irritation or injury. The visceral/somatic distinction depends on
the structures involved. Visceral nociceptive pain stems from injury to the
viscera or related structures. It may present as the localized ache of organ
capsule damage or the poorly localized cramping of obstructed hollow viscera.
Somatic nociceptive pain is related to ongoing damage in somatic tissues, such
as the bones, joints, and muscles. It is usually described as throbbing, aching,
stabbing, or pressure. Somatic pain syndromes are generally perceived to be
highly responsive to opioid therapy.[1]

Types of Neuropathic Pain

Neuropathic pain is related to abnormal somatosensory processes that directly
affect the peripheral or central nervous system. These processes either
stimulate the pain system or damage nonnociceptive pathways to shift the balance
between painful and nonpainful inputs to the central nervous system.[2]
Neuropathic pain does not require specific peripheral pain receptor stimulation,
although it can be made worse by such stimulation.

Some types of neuropathic injury can produce aching, stabbing, or throbbing
pain, but these syndromes often have an unfamiliar quality or sensory
distortion. Burning, shooting, and tingling are suggestive of nerve involvement,
but not sufficient for the diagnosis. Areas of abnormal sensations are often
found on examination, including hypesthesia (a numbness or lessening of
feeling), paresthesias (spontaneous abnormal nonpainful sensations such as
tingling), dysesthesias (spontaneous abnormal painful sensations such as
burning, tingling, or electrical sensations), hyperalgesia (increased perception
of painful stimuli), hyperpathia (exaggerated pain response), and allodynia
(pain induced by nonpainful stimuli).[3]

Pain can be constant, paroxysmal, or a combination of both. Evidence of
neural damage on examination or on electrophysiologic study supports the
diagnosis but is not required, because damage to the nervous system can be quite
focal and not easily detected.

Cancer can cause neuropathic pain by direct invasion, irritation, or external
pressure on peripheral neural structures. In addition, antineoplastic therapies,
such as surgery, chemotherapy, and radiation, can damage peripheral nerves and
lead to neuropathic pain. In most cases, however, nerve injury occurs in tandem
with damage to other structures, and the pain has a mixed pathophysiology, with
both somatic and neuropathic components.[4] Given this complexity, all patients
must undergo a careful assessment that characterizes the pain, identifies
potential etiologies, and clarifies the specific pain syndrome. This assessment
then guides the selection of analgesic therapies from among a large number of

Treatment Strategies


Opioids are the mainstay of the treatment of moderate-to-severe cancer pain,
including cancer-related neuropathic pain. In most cases, opioid therapy should
be maximized before alternative strategies for neuropathic pain therapy are

If the first opioid selected yields intolerable side effects without
satisfactory analgesia, trials of an alternative opioid (opioid rotation) are
often considered. Pain that is poorly responsive to an opioid might also be
addressed through trials of alternative systemic therapy (adjuvant analgesics),
anesthesiologic and neurosurgical techniques, physical therapy and other
physiatric modalities, or psychological interventions.[6]

Adjuvant Analgesics

Adjuvant analgesics are drugs that often have been developed for primary
indications other than pain but produce analgesic effects in specific
circumstances. Although they are usually classified according to their primary
roles, many potentially have powerful effects as neuroactive analgesic

General Principles of Adjuvant Analgesic Use—To appropriately administer
adjuvant analgesics, the clinician should become familiar with the approved
indications, unapproved but accepted indications, probable mild side effects,
potentially serious adverse effects, and specific dosing guidelines for pain
management. Knowledge of the pharmacokinetics and usual time-to-effect
relationship of specific medications is also useful. Because few adjuvant
analgesics have been studied in the medically ill, the information used to
develop dosing guidelines for cancer pain is usually extrapolated from other
patient populations.

The large variability in mode of action and individual response to most
adjuvant analgesics, including those in the same class, supports the utility of
sequential trials to identify the most useful drug. In the absence of controlled
trials, drug selection usually reflects the clinician’s best judgment about
the risks associated with the therapy, the likelihood of analgesia, and the
possibility of secondary beneficial effects on symptoms other than pain.

Important principles that help ensure an adequate trial of an adjuvant
medication include the following:

  1. Choose each medication carefully for both intended effect and side
    effects. Antidepressant analgesics are appropriate for patients with pain
    complicated by depressed mood. The sedative side effects of some medications may
    help patients who have trouble sleeping.
  2. Ensure that patients have realistic expectations, especially concerning
    the slow onset of effect, the need for long-term use, the probable development
    of side effects, and the possibility of tolerance to effects over time.
  3. Begin the use of drugs with known bothersome side effects at a low dose
    and increase the dose slowly to allow patients to become tolerant to side
    effects. Doses of drugs with fewer side effects can be increased more rapidly or
    started at a therapeutic level.
  4. Increase the dose of each medication until the desired effect is
    achieved, side effects become unmanageable, or high therapeutic drug levels are
    obtained before calling the trial a failure.
  5. Different classes of drugs can be used concomitantly. To achieve the
    maximum level of symptom control, the concomitant use of drugs from several
    classes is frequently necessary.
  6. Be persistent, encouraging, and supportive as treatments are implemented.


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