Managing Cancer Pain Poorly Responsive to Systemic Opioid Therapy

Introduction

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,[14] 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 Concept of Opioid Responsiveness

The potentially confusing nomenclature applied to the outcome of opioid therapy is exemplified by the term “efficacy.”[15] 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(Drug information on 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(Drug information on 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.[18] 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 therapy overall.

Analgesic Strategies for Poorly Responsive Patients

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 1):

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]

Opioid Rotation

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.[27]

Invasive Techniques

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).[28]

Nonpharmacologic/Neurosurgical Techniques

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.

Assessing the Poorly Responsive Patient

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 available techniques.

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.[29] 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 also common.

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 life expectancy.

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.