The challenge

Substance abuse and addiction are difficult problems both theoretically and clinically in pain management and palliative care. Cancer patients with histories of substance abuse are often seen by palliative care specialists, especially in community-based settings. Whereas concurrent drug abuse is problematic, there is the additional problem regarding the diagnosis and understanding of the less obvious aberrant drug-taking behaviors sometimes in evidence in the treatment of patients without formal psychiatric histories of substance use disorders. Such aberrant drug-taking behavior can be manifest, for example, when a patient with advanced disease and pain is unilaterally escalating drug doses, is using medications to treat other symptoms, or when prescriptions are being mishandled. The clinician is challenged to understand such circumstances and plan interventions accordingly. Once these aberrant behaviors are identified the clinician must decide on a course of action that is fair and in the best interests of the patient as well as his or her own career. Thus, the problem of chemical dependence and drug abuse spans a continuum from formal psychiatric disorders to problematic behaviors in the absence of these disorders.

With the pressure of regulatory scrutiny and our duty to treat pain but contain abuse or diversion, clinicians often think that they must avoid being duped by those abusing prescription pain medications at all costs. Thus, although the differential diagnosis of aberrant drug-related behavior is complex, clinicians tend to simplify the assessment of this issue to either addiction or not addiction. It is important to note, however, that the clinician attempting to diagnose the meaning of aberrant drug-related behaviors during pain management may not be correct in the final assessment.

Introduction

The skeleton is one of the most common sites of tumor metastases. Metastatic cancer invades bone in 60%–84% of cases (1). Up to 80% of all bone metastases are related to cancer of the breast, prostate, lung, thyroid, and kidney. Multiple myeloma is also commonly associated with skeletal disease. Approximately 70% of patients with bone metastases develop pain (2,3). In addition to pain, metastatic bone disease results in immobility, frequent hospital admissions, pathological fractures, metabolic complications such as hypercalcemia, neurological abnormalities, and bone marrow infiltration and suppression. These devastating symptoms can have a prolonged effect and also have major psychosocial implications. Detection of bone metastases may be the first indicator that cancer has not been cured; bone is the first site of recurrence in up to 40% of women with breast cancer. Patients suffering from bone metastases secondary to breast cancer survive an average of 34 months, with a range of 1 to 90 months (4).

This chapter primarily discusses pain associated with bone metastases. In addition, some of the recent developments in the prevention and management of osteolysis are addressed.

Pathophysiology of bone pain

The invasion of bone by tumor is well understood; however, the mechanisms of nociception are not well known. The three main mechanisms by which the skeleton is affected by cancer are primary bone cancer, direct invasion from adjacent primary tumors, and bone metastases. The last is by far the most common mechanism; primary tumors of bone are much less common. Figure 24.1 summarizes the four sequential steps in the development of a painful bone metastasis.

Introduction

Neuropathic pain occurs frequently in patients with cancer, both from direct tumor infiltration of neural structures and as a consequence of treatment of the neoplasm. Management of neuropathic pain presents a number of challenges. Such pain is often more resistant to conventional analgesic approaches than is nociceptive pain. Many of these patients will have mixed pain problems, where neuropathic pain is combined with elements of somatic or visceral nociceptive pain. Neuropathic pain also may signal progressive and often incurable disease, adding a significant suffering component to the pain problem.

Successful management of neuropathic cancer pain requires an understanding of the pathophysiologic processes that generate this type of pain and of the distinctive clinical features that identify it. In addition, a knowledge of the various clinical neuropathic pain syndromes that occur in the cancer patient and of the range of available treatments is essential.

Pathophysiology

Neuropathic pain occurs as a result of aberrant somatosensory processing in the nervous system, and as such may be sustained by peripheral mechanisms, central mechanisms, or both. Pain after peripheral nerve injury may occur through a variety of mechanisms. When a nerve is compressed or distended, nerve trunk pain may occur as a result of activation of the nervi nervorum, the normal nociceptive afferents that innervate the nerve sheaths themselves (1). Damage to primary nociceptive afferents may result in spontaneous ectopic activity, perhaps secondary to focal demyelination with exposure of sodium channels (2). Regenerating afferents may form neuromas, where sodium channels accumulate and spontaneous activity occurs (3). The dorsal root ganglion may represent an additional site of ectopic activity (3).

Introduction

In their experience of illness related to cancer or its treatment, children and their families report that pain is one of the most feared symptoms. Fortunately, the majority of children can achieve adequate analgesia if current pain management techniques are used. It is the rare pediatric patient who develops intractable pain. The World Health Organization (WHO) has established the principles of pain management and palliative care as a universal standard of care for all children with cancer. Cancer Pain Relief and Palliative Care in Children (1) is a guideline that contains information on the assessment of pain in children, analgesics and adjuvant analgesics, and the principles of non-pharmacological methods of pain control in children undergoing painful procedures (1). Recent data suggest there is room for improvement in pain management for children with cancer (2).

Epidemiology of cancer pain in children

Pain is a common symptom experienced by children with cancer. A cohort of 149 British and Australian children with cancer 7 to 12 years old were surveyed about their experience of symptoms during the preceding 48 hours (3). Approximately one third had experienced pain in the previous 48 hours. Over half of this group had pain in the medium to severe range, and one third were highly distressed by their experience (3).

As part of the validation study of Memorial Symptom Assessment Scale 10–18 (4) (MSAS 10–18), information was acquired about symptom characteristics from a heterogeneous population of children with cancer ages 10 to 18 years at Memorial Sloan-Kettering Cancer Center, New York. Children were asked about their symptoms during the preceding week.

Introduction

Regular pain assessment and pain management should have the highest priority in the routine care of the patient with cancer. Between 60% and 80% of patients with advanced cancer will need pain treatment. Pain is also a problem for many patients earlier and intermittently during the course of their disease. In addition, cancer survivors who are cured of their cancer may have persistent chronic pain as a result of the disease or its treatment.

When pain is present, the quality of life of patients and their family members is adversely affected. However, the majority of patients with cancer-related pain can obtain pain relief if the pain is adequately assessed and appropriate treatment is provided. Numerous guidelines for the management of cancer pain have been endorsed by governmental organizations, professional associations, and the World Health Organization (WHO). Research studies evaluating the WHO's guidelines for cancer pain relief (1,2) indicate that 70% to 90% of patients obtain good pain relief when this protocol for oral analgesic medications is followed (3–6). Other pain management therapies can provide pain control when oral analgesics are not effective.

In spite of the availability of effective pain treatments, multiple studies document undertreatment of pain (7–10). A study completed in the Eastern Cooperative Oncology Group (ECOG) surveyed more than 1300 outpatients with recurrent or metastatic cancer (7). A total of 67% of the patients had pain or were being treated for pain with daily analgesics. Among the patients with pain, 42% were prescribed analgesics that were less potent than those recommended by the WHO guidelines.

Approximately one in three individuals in the developed world will be diagnosed with cancer. The incidence of cancer is also increasing rapidly in developing countries. Approximately 50% of patients in developed countries and 70% of patients in developing countries will die as a result of their cancer. More than 80% of those who die of cancer will develop severe pain. The increased frequency of cancer around the world suggests that the burden of cancer pain is likely to increase dramatically over the next decade.

A large number of studies have documented that cancer pain is poorly assessed and managed in many patients. The main reason for these problems is inadequate health care professional education.

The purpose of this book is to provide a comprehensive, clinically oriented, and scholarly review of all aspects of this complex and multidimensional problem. It is our hope that this comprehensive text will lead to improved understanding in treating this devastating disease and will contribute to improvement in care.

Introduction

Pain has been a major concern in the clinic for many decades. In recent years, considerable progress has been made with respect to our understanding of both acute and chronic pain mechanisms. This has largely been attributed to advancements in molecular biology and genomic techniques, as well as the use of animal models, which has allowed us to explore potential targets for pain. This has fundamentally altered our understanding of the pathophysiology of pain mechanisms and has led to the hope of development of novel analgesics.

The study of the receptor systems involved in the transmission of pain and its modulation involves investigation of processes occurring at the peripheral endings of sensory neurons, as well as central events. The mechanisms of inflammatory and neuropathic pain are different from those of acute pain, and there is considerable plasticity in both the transmission and modulating systems in these prolonged pain states. The search for new treatments for these pain states requires the development of valid animal models. For such models to be valid, a number of criteria must be fulfilled. First, the model must provide reproducible and quantifiable behavioral data. Second, the model must produce behaviors in the animal that resemble some of the pain syndromes observed in humans (e.g. allodynia, hyperalgesia). Third, the behavioral data must correlate with pain responses in humans. Through the use of these animal models, we can broaden our understanding of pain mechanisms and possibly identify or develop potential agents for treatment.

Introduction

Today, for every death caused by cancer there are two caused by infection and parasitic infestation. It is projected that this number will reach parity by 2015. Most of this increase will occur in the developing world, where 55%–60% of the world's cancer patients reside, and the majority of patients will present for palliation until primary prevention programs are in place. Palliative care is not available to eight out of nine cancer patients in the developing world (1).

Cancer pain affects 17 million people worldwide. Its prevalence increases with extent of disease. Its type, location, and intensity vary with tumor type, spread of disease, and disease treatments (2–6). Prevalence rates of 30%–40% are reported for patients receiving active treatment; these increase to 70% to 90% for patients with advanced cancer (7). The National Hospice Report of 1754 patients with advanced cancer demonstrated that only 25% of patients reported persistent pain within 48 hours of death because only 26% of the patients studied could use the assessment tool included in the study (8). This statistic may exemplify a tendency to underestimate pain prevalence in this group. The unexpectedly low estimates of pain prevalence in this population may relate to the high prevalence of cognitive impairment. Other studies observe pain prevalence rates ranging from 12%–99% in the last week of life, with greater than 30% prevalence in seven of nine studies assessed. This variability may relate to the wide variety of scales used to report pain (9).

Chronic cancer pain may occur in relation to disease progression, a complication of the illness or its treatment, or conditions unrelated to the patient's cancer.

Introduction

The majority of cancer patients (approximately 80%) develop pain before they die (1). Pain in cancer patients is often underdiagnosed, and inadequate treatment with opioid analgesics is well documented (2–4). Many factors influence pain management in this patient group. Inappropriate and suboptimal education of physicians and other health care professionals has been identified as the major barrier to adequate opioid use (5,6). In developing countries, a further issue is reduced availability of opioids because of financial limitations and government regulations.

As a result of a major educational effort by a number of organizations, including the World Health Organization, the International Association for the Study of Pain, and the American Society of Clinical Oncology, opioid use has improved significantly in developed countries during the last 15 years (7). The results of such efforts have been quite variable (8). In many regions of the world, however, progress has been made, with opioids being used in higher doses and at earlier stages in palliative care (9). Cancer patients, who now have earlier exposure to opioids and generally have treatment with higher dosages, are better managed than in the past. This highly desirable increase in the use of opioids, combined with increased vigilance, has resulted in increased detection of several side effects, most notably neurotoxicity. With this increase in opioid use and the improvement in identification of adverse effects, management strategies for dealing with these unwanted effects have been developed and augmented.

Introduction

According to the World Health Organization (WHO) guidelines, opioid analgesics are the mainstay of analgesic therapy and are classified according to their ability to control mild to moderate pain (codeine, tramadol, dextropropoxyphene) (second step of the WHO analgesic ladder) and to control moderate to severe pain (morphine, methadone, oxycodone, buprenorphine, hydromorphone, fentanyl, heroin) (third step of the WHO analgesic ladder) (1,2). Opioid analgesics can be associated with non-opioid drugs such as paracetamol or with nonsteroidal anti-inflammatory drugs (NSAIDs) and to adjuvant drugs (3).

The current recommended management of cancer pain consists of the regular administration of opioids and intermittent rescue doses of opioids or NSAIDs for excess pain. Individualized pain management should take into account the intensity of pain and its nature, concurrent medical conditions, and above all the subjective perception of the intensity of pain that is not proportional to the type or to the extension of the tissue damage but depends on the interaction of physical, cultural, and emotional factors.

Oral route of opioid administration remains the preferred one. However, in some clinical situations such as vomiting, dysphagia, confusion, and where rapid dose escalation is necessary, oral administration may be impossible, and alternative routes must be implemented (4,5). Table 8.1 shows the potential application of the different routes of opioid administration (6).

Intraindividual variability in response to different opioids is a common clinical phenomenon. Different explanations have been proposed such as the genetic makeup, tolerance to different opioid effects, the incomplete cross-tolerance among opioids selective for the same receptor subtype due to differential affinity for receptor subtypes, the differences in profile of active metabolites between various opioids (7–12), and the pain mechanism (13).

Introduction

During the 1970s and 1980s, when it became increasingly clear that intense pain had long been an underrecognized and poorly treated manifestation of cancer, it became apparent that cancer patients commonly experience intermittent exacerbations of severe pain against a background of continuous, or baseline, pain (1,2). On the heels of the World Health Organization analgesic ladder approach to general pain control, this recognition led to treatment guidelines and patient care manuals recommending management of these episodic pains as routine practice (3–9).

The term breakthrough pain (BTP) can be found in the pain management literature starting about a decade ago (10–14). An operational definition was offered at that time by Portenoy and Hagen (15), who suggested that “breakthrough pain … refers generally to a transitory exacerbation of pain that occurs on a background of otherwise stable pain in a patient receiving chronic opioid therapy.” This definition seems to have gained wide-spread acceptance, with only minimal (published) debate as to its overall accuracy or utility (16).

Evidence that BTP, at the very least, has become recognized as an important aspect of overall cancer care can be found on two fronts. First, a growing number of review articles and practice recommendation guidelines on this subject have been published in recent years. They affirm the view that BTP needs to be evaluated and treated as part of the overall cancer pain management plan (17–29). In addition, reports of analgesic clinical trials for the management of cancer pain have begun to routinely incorporate a treatment arm for BTP in the methodology (30–37).

Introduction

Family caregivers play a vital role in meeting the physical and psychosocial needs of patients with serious illness. The past 5 years have seen accelerating trends toward early hospital discharge, increasingly complex home-based treatment protocols, and the transformation of caregivers' role from promoting convalescence to participating actively in the accomplishment of treatment goals. In spite of the shift in care from the inpatient setting to the home, and the concomitant rise in the expectations of caregivers, the health care system has been slow to recognize the psychosocial and financial burden associated with caregiving.

It is estimated that more than 15 million adults currently provide care to relatives in the United States (1). Of these, most tend to be middle-aged children or older spouses, and predominantly female (2). Until recently, few studies had examined the role of family caregivers in pain management and palliative care, but this trend has changed within the past 5 years. Findings from recent landmark studies convey a picture of rising expectations and unmet needs for caregivers carrying out a variety of medical tasks at home (1–3). For example, Emanuel and colleagues (3) interviewed terminally ill adults and their caregivers to determine how their needs for assistance were being met. Unmet needs were reported by 87% of patients, who required help with transportation (62%), homemaking services (55%), nursing care (29%), and personal care (26%). Most patients relied completely on family and friends to provide this assistance; only 15% relied on paid assistance. For caregivers of cancer patients, such care may translate into 20 or more hours of care a week, the equivalent of a part-time (unpaid) job (2).

Introduction

The term adjuvant analgesic can be applied to any drug that has a primary indication other than pain, but is analgesic in some painful conditions. This term is often used synonymously with the term co-analgesic when it refers to a drug that is administered with another analgesic, usually an opioid. In the cancer population, this combination is usually administered to enhance pain relief when a syndrome is poorly responsive to the opioid, or to allow opioid dose reduction when opioid-related side effects are problematic. The adjuvant analgesics also may be considered a subset of a larger group of adjuvant drugs some of which are specifically co-administered with analgesics to treat side effects.

Rapid advances in basic and clinical pharmacology have dramatically expanded the role of the adjuvant analgesics. For this reason, the term adjuvant is actually a misnomer in many settings. Many of these drugs are used alone, as primary analgesics, when pain is likely to be responsive. This is particularly true in populations with chronic non-malignant pain. Given this expanding use, it is important to understand both the pharmacology of these drugs and their therapeutic role in the management of cancer pain.

General considerations

The effective use of an adjuvant analgesic depends on systematic assessment of the patient. This assessment clarifies the nature of the pain, infers pain pathophysiology, identifies a specific pain syndrome, and allows an understanding of the pain as one of potentially numerous problems that may undermine quality of life. Over time, repeated assessments must track changes in pain, side effects, or any of the broader quality of life concerns may impel a shift in therapeutic strategy.

Introduction

Opioid analgesic drugs are commonly prescribed for the management of pain resulting from cancer. During the last 20 years there has been a dramatic increase in our knowledge of the sites and mechanisms of action of opioids (1). The development of analytical methods has also been of great importance by facilitating pharmacokinetic studies of the disposition and fate of opioids in patients. These studies have begun to offer us a better understanding of some of the sources of interindividual variation in the response to opioids and to suggest ways to minimize some of their adverse effects (2,3). Although there are gaps in our knowledge of opioid pharmacology, the rational and appropriate use of these drugs is based on the knowledge of their pharmacological properties derived from well-controlled clinical trials (4).

Individualized dosage

The fundamental concept that underlies the appropriate and successful management of cancer pain by the use of opioid and non-opioid analgesics is individualization of analgesic therapy (4,5). This concept entails selection of the right analgesic, administered in the right dose and on the right schedule so as to maximize pain relief and minimize adverse effects (4–6). This comprehensive approach begins with the non-opioids or mild analgesics for mild pain (see Chapter 10). In patients with moderate pain that is not controlled by non-opioids alone, the so-called weak opioids alone or in combination should be prescribed. In patients with severe pain, a strong opioid is the drug of choice given alone or in combination (see Chapter 8). At all levels certain adjuvant drugs are used for specific indications (5–7) (see Chapter 11).

Introduction

The randomized, controlled trial (RCT) is a modern innovation; the first RCT—the British Medical Research Council's trial of streptomycin for pulmonary tuberculosis—was published in 1948 (1,2). Despite this brief history, the RCT now represents the “gold standard” for evaluating the efficacy of new medical interventions and new applications for existing interventions. Unfortunately, the marked increase in the use of RCTs during the past 50 years (3) has not been accompanied by corresponding advances in overcoming the method's several limitations. Indeed, several potential scientific and ethical difficulties continue to limit the use of RCTs in some clinical contexts and hinder the interpretation of their results in others.

In this chapter, we first discuss the various strengths and limitations common to all RCTs, making special reference to trials of pain management interventions when appropriate. We describe the structure of an RCT, consider how several decisions regarding trial design can influence the trial's results, discuss basic issues in the analysis of trial data, and attempt to guide readers in interpreting a trial's results. Because no research experiment can ever be perfect, we hope this chapter will provide clinicians with sufficient understanding of the proper structure of, and inherent problems with, RCTs to be able to ascertain whether the results of published trials are 1) likely to be valid and 2) likely to apply to their patients.

Anatomy of a trial

Designing and conducting an RCT requires investigators to carefully consider several design issues. The decisions investigators make regarding each component of an RCT can dramatically influence the outcome of the trial.