Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.
Overview / Reporting the Evidence / Patient Population and Settings / Methods / Findings / Future Research / Availability of Full Report
Pain related to cancer affects the lives of large numbers of patients and their families. The topic of cancer-related pain was selected by the Agency for Healthcare Research and Quality (AHRQ) in response to a request from the American Pain Society. In framing this request, the American Pain Society observed that a significant amount of scientific evidence had been published on this topic since the 1994 release of the clinical practice guideline Management of Cancer Pain.
This evidence report, however, is a literature synthesis and not a clinical practice guideline or a survey of current practice. It is intended to provide background information and summaries of evidence for use by varied groups, including primary care practitioners, nurses, pharmacists, physical therapists, specialists in oncology, pain treatment, or other disciplines, as well as policy makers. We reviewed the published literature on the epidemiology of cancer pain and its relief and also summarized predominantly randomized controlled trials so as to gauge the efficacy of major treatments.
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Reporting the Evidence
The New England Medical Center Evidence-based Practice Center (EPC) staff, along with members of a panel of technical experts including representatives from seven professional organizations, developed the questions addressed in this report. These organizations include the American Cancer Society, American College of Physicians, American Pain Society, American Society of Clinical Oncology, American Society of Anesthesiologists, American Society of Health-System Pharmacists, and the Oncology Nursing Society. Additional comments on the questions were solicited from the American Academy of Family Physicians, American Academy of Neurology, American Academy of Pain Medicine, American Physical Therapy Association, Hospice and Palliative Nurses Association, and Hospice Association of America.
Six major questions and 21 subquestions were formulated. The major questions are:
- What are the epidemiological characteristics of cancer-related pain, including pain caused by cancer, by the side effects of cancer
treatment, and by procedures used to treat cancer?
- What is the relative efficacy of analgesics currently used for cancer pain?
- Are different analgesic drug formulations and routes of administration associated with different patient preferences or efficacy rates?
- What is the relative analgesic efficacy of palliative pharmacological (chemotherapy, biphosphonates, or calcitonin) and nonpharmacological cytotoxic or cytostatic (radiation therapy or radionuclide) therapy?
- What is the relative efficacy of current adjuvant (nonpharmacological/noninvasive) physical or psychological (e.g., relaxation, massage, heat and cold, music, and exercise) treatments in the management of cancer-related pain?
- What is the relative efficacy of current invasive surgical and nonsurgical treatments, such as acupuncture, nerve blocks, and neuroablation, for the treatment of cancer-related pain?
Patient Population and Settings
Patients with cancer-related pain were the subjects of epidemiologic studies and controlled clinical trials. In the present literature review, we define cancer-related pain as pain caused by the disease or its treatment, such as surgery, radiation therapy, or chemotherapy. Patients with post-mastectomy pain were included, as were patients with pain resulting from the side effects of anti-tumor treatment, such as mucositis. Patients with cancer often experience pain from causes unrelated to cancer, and treatment of such pain cannot be omitted from their care. We did not, however, include trials exclusively concerned with the treatment of acute postoperative pain.
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We performed a systematic review of the best available evidence to address the above questions. Cancer disease burden and the prevalence of cancer-related pain were estimated from epidemiologic surveys. MEDLINE, CancerLit, and Cochrane Controlled Trials Registry databases between 1966 and December 1998 were searched using a sensitive search strategy for English-language human studies. Titles and abstracts of the retrieved citations were manually screened to identify potentially relevant studies. We consulted the technical experts and colleagues and examined the bibliographies of selected review articles and published meta-analyses on this subject for additional references.
We extracted data from primary clinical studies that met inclusion criteria to create an evidence table for each of the major questions or subquestions, as appropriate. Randomization of subjects into treatment and control groups (that do not get the experimental treatment) in order to minimize the effect of confounding variables is especially important in clinical trials of interventions for pain relief, as is the use of "blind" studies in which the subject alone (single-blind) or both the investigator and the subject (double-blind) are unaware of the specific treatment being applied. A multidimensional evidence grading scale (internal validity, applicability, study size, and effect size) was used to denote the quality of individual studies, and the quality of the evidence pertinent to each of the questions was summarized. Other details of the included trials, such as the method of randomization and whether or what type of blind study were examined.
Studies that met the inclusion criteria for meta-analysis within each subquestion were combined using a random effects model. For most questions, meta-analysis was not possible. Therefore, for each question we supplemented the evidence grading of relevant trials with a narrative summary of those trials. At the request of AHRQ, we supplemented the above evidence by examining results from 100 nonrandomized comparative studies to address questions for which evidence from randomized controlled trials was lacking.
Our search strategy identified over 19,000 titles. After a series of screening processes, 24 epidemiologic surveys and 189 randomized controlled trials of treatments qualified for inclusion in this report.
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The overall methodological quality and reporting of treatment studies in this field compare unfavorably with those of other high-impact conditions. The average numbers of patients in trials of primary analgesicsnon-steroidal anti-inflammatory drugs (NSAIDs) and opioidswere 84 and 68 (range 24 to 180 and 10 to 699, respectively). Studies of biphosphonates enrolled an average of 111 patients (range 13 to 614). Trials of the palliative use of primary cancer treatment modalitieschemotherapy and radiotherapyenrolled an average of 226 patients (range 38 to 1,016). Twenty-six out of 41 studies in the group of opioid versus opioid comparisons were crossover trials, in which the carryover effect from an earlier treatment might be a problem due to an inadequate washout interval.
The primary outcome of pain intensity or pain relief is subjective and has long been recognized to be susceptible to bias in studies that are not blinded to the investigators and patients. Particularly in analgesic trials, inclusion of control treatments (either active or placebo) helps prevent overestimation of treatment effects. Ethical considerations are often advanced for the absence of placebo controls in cancer pain trials, yet some trials were able ethically to employ placebo controls by allowing patients ready access to medication if needed ("rescue" medication).
The number of possible meta-analyses was limited by heterogeneity of interventions and outcomes reported, and incomplete reporting (such as absent data on variability of the outcome estimates). Most studies do not specify whether pain is assessed at rest, or with movement, or reflects breakthrough episodes of increased intensity. Reporting on broad categories of probable mechanism of pain, i.e., nociceptive or neuropathic, was inconsistent.
1. What are the epidemiological characteristics of
cancer-related pain, including pain caused by cancer, by the side effects of cancer treatment, and by procedures used to treat cancer?
Epidemiologic evidence on the incidence and prevalence of cancer, on the incidence of cancer-related pain, and on the likelihood of increasing pain intensity with advancing cancer stage indicates that cancer pain adds substantially to the already considerable national disease burden of cancer. Minorities, women, and the elderly may be at greater risk for undertreatment of pain. Survey data for the most part do not distinguish between different etiologies and mechanisms of cancer pain. Prevalence data imply that the number of patients enrolled in methodologically sound trials of cancer pain relief is a tiny fraction of those receiving care. Relatively few subjects are enrolled per trial, and the total number of published randomized controlled trials relative to patients under care is much lower than for nearly all other high-impact, costly conditions.
2. What is the relative efficacy of analgesics currently used for cancer pain?
The number of randomized controlled trials evaluating analgesic drugs for cancer pain relief is small, although increasing. Direct interclass comparisons of efficacy are possible between opioids and NSAIDs. The included trials do not differentiate the relative efficacy of these two types of agents administered through various routes to patients with mild, moderate, or severe cancer pain.
There is evidence of an opioid dose-sparing effect from co-administration of an NSAID but no consistent reduction in side effects from co-administration. Placebo controls, particularly in analgesic trials, are valuable to prevent overestimation of treatment effects, yet for ethical reasons such controls are rare in cancer pain trials. The heterogeneity of existing trials precludes meta-analyses to address most subquestions.
Ten studies addressed the relative analgesic efficacy of various NSAIDs versus other NSAIDs or placebo. Of these, only one study disclosed a significant difference in analgesic efficacy between two NSAIDs. These 10 studies could not be combined due to heterogeneity in the outcomes assessed, drug doses and schedules compared, and study duration.
Trials to compare the efficacy of NSAIDs versus "weak" opioids (i.e., opioids commonly prescribed for mild to moderate pain) reveal no difference in analgesic efficacy between these two classes of agents, even when the latter are co-administered with the same NSAID tested in the former arm. These trials enroll relatively small numbers of patients and follow them for intervals of hours to days and only occasionally for periods as long as 2 weeks. Many examine drugs not available in the United States or not generally employed for cancer pain relief (e.g., pentazocine).
Our efforts to strengthen such evidence by examining nonrandomized trials were not fruitful. One randomized controlled trial evaluated oral transmucosal fentanyl citrate for breakthrough pain (using a study design in which rescue doses of morphine were available) and demonstrated its superiority to placebo. We found no randomized controlled trials addressing analgesic efficacy and safety of NSAIDs selective for the cyclooxygenase-2 isozyme in treating cancer pain.
3. Are different analgesic drug formulations and routes of administration associated with different patient preferences or efficacy rates?
Published trials within the NSAID and, separately, opioid drug classes demonstrate no differences in efficacy between oral tablets or rectal suppositories within each class. Limited data suggest that parenteral (intramuscular or intravenous) administration offers no advantage from a purely analgesic standpoint over enteral administration.
However, the included studies do not evaluate relative speed of onset using the two routes, which for many drugs is known to be more rapid after parenteral than enteral administration. For opioids, eight included trials compared oral controlled-release morphine with oral immediate-release morphine solution and none found differences with respect to reduced pain intensity or increased pain relief. These studies enrolled a total of 344 patients with a wide range of cancer types and pain types, of which 271 were evaluated (79 percent). The majority of these trials were double-blind but their results still may not be reliable because of high dropout rates (10 to 40 percent). Because these eight studies addressed the same question using roughly comparable methods, we were able to perform a meta-analysis using average pain intensity (during 4 to 14 days of treatment) as the outcome of interest. No difference in pain relief was found between controlled-release morphine and immediate-release morphine solution. The decrease in dose frequency accomplished by controlled-release formulations (transdermal, oral, or rectal) is an implicit advantage of these dosage forms.
Four studies addressed comparative efficacy and adverse effects of oral versus rectal administration of morphine. The generalizability of the results is limited by the small numbers of subjects in each study. Three of these four studies found no difference in efficacy and the fourth observed small but significant differences in onset of pain relief and duration of analgesia, both in favor of the rectal route. No differences with respect to adverse effects were observed between the two routes in three studies, but in the fourth, patients receiving rectal morphine had lower nausea scores. Two of these four studies compared oral and rectal administration of the same formulation (controlled-release morphine tablets) and provided combinable data on pain scores. A meta-analysis of between-treatment differences in average pain intensity throughout each study's duration (4 to 14 days) showed that pain intensity did not differ between the two study arms. One study compared controlled-release rectal suppositories with subcutaneous morphine and reported no differences in overall pain scores, sedation or nausea, or rescue analgesic intake.
These negative conclusions should not be taken to mean that individual patients do not benefit from the selection of one route versus another in specific clinical contexts (e.g., by employing suppositories or transdermal administration when dysphagia limits oral dosing). Insufficient information exists to reveal differences in relative side effects or patient preference for either route.
4. What is the relative analgesic efficacy of palliative pharmacological (chemotherapy, biphosphonates, or calcitonin) and nonpharmacological cytotoxic or cytostatic (radiation therapy or radionuclide)
We found 31 studies, including 153samarium-EDTMP, etidronate, aminohydroxypropylidene biphosphonate (ADP, pamidronate), salmon calcitonin, and clodronate. The biphosphonate trials are quite heterogeneous, with differing inclusion criteria, concomitant medical and radiotherapeutic treatments, disease categories, dosage regimens, choice of agent, and duration of followup. Methods to assess analgesic efficacy in these trials ranged from analgesic intake to the "requirement" for palliative radiation therapy.
Most studies showed a positive effect, some showed no effect, and no study showed a detrimental effect of biphosphonate therapy on skeletal symptoms of metastatic disease or myeloma. Positive effects appeared harder to demonstrate in the presence of concurrent chemotherapy, such as estramustine, which itself might have a favorable effect on tumor progression and hence bone symptoms.
Therefore, the literature in the aggregate suggests that biphosphonates reduce pain due to bony involvement by tumor, although the magnitude of this benefit may be reduced when biphosphonate therapy is delivered in conjunction with other tumor-directed therapies that may in themselves reduce such symptoms.
Two studies compared strontium-89 with inactive strontium and external radiotherapy, respectively, for bone pain. Strontium-89 was more effective than placebo (inactive strontium) and equally effective as external radiation.
The literature on analgesic effects of various chemotherapy and hormonal therapy regimens on pain is heterogeneous with respect to inclusion criteria, therapeutic regimens, and methods employed to assess analgesic efficacy. The use of analgesic medication is reported in some studies, but in most, the consumption of analgesics is not recorded. In only one chemotherapy trial and in no hormonal therapy trial was there a significant difference in pain-related outcome between treatment arms.
Fourteen trials, involving a total of 3,859 patients, compared fractional dosing schedules of external radiotherapy to relieve pain from bony metastases. Although external radiation as a modality is effective in decreasing pain, no trial found more than a transient, unsustained difference in pain between fractionation schedules. Meta-analysis was not possible due to heterogeneity of dosing schedules, variability in the anatomic sites and fields treated, and outcomes assessed. Short courses of palliative treatment with higher doses appear to yield results similar to longer courses that deliver a lower dose per treatment. Even single-dose (i.e., unfractionated) radiation appears to have similar effects on bone pain as fractionated dosing, although the minimal total dose of radiation to provide pain relief has not yet been determined.
5. What is the relative efficacy of current adjuvant (nonpharmacological/noninvasive) physical or psychological (relaxation, massage, heat and cold, music, and exercise) treatments in the management of cancer-related pain?
The number of studies is small, and variability as to types of intervention precludes any broad conclusions. Studies evaluated different interventions applied to patients, medical staff, and the community at large. Also, different types of pain seemed to be addressed, although specifics were not always provided.
Only a few randomized studies examine hypnosis in conjunction with cognitive behavioral techniques in the context of acute procedure-related pain and oral mucositis pain after bone marrow transplant. They include studies in the pediatric and adult age groups. Hypnosis seems to help with both procedural and mucositis-related pain. Cognitive behavioral treatments may also be helpful. More studies are needed, with larger numbers of patients and with control groups.
6. What is the relative efficacy of current invasive surgical and nonsurgical treatments, such as acupuncture, nerve blocks, and neuroablation, for the treatment of cancer-related pain?
The evidence available to answer these questions is, with few exceptions, in the form of case series that do not use control groups. Sufficient randomized controlled trials on neurolytic celiac plexus block (NCPB) for pain relief in pancreatic and other visceral cancers were identified to indicate the efficacy of this modality. NCPB lowered pain scores or produced a prolonged dose-sparing effect on analgesic drug requirement.
The near absence of randomized or controlled trials on the efficacy of spinally administered opioids or other agents led us to retrieve nonrandomized reports in an effort to estimate the efficacy of this modality. These supplemental reports, although positive, were case series without control groups and hence did not yield data on relative efficacy of the spinal versus systemic routes of drug administration.
Similarly, the efficacy of ablative neurosurgical interventions, such as cordotomy or rhizotomy, was addressed only in case series. No included trials addressed the efficacy of acupuncture.
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Randomized controlled trials establish that many current treatment modalities can individually reduce cancer pain. These trials constitute 1 percent of the published literature on cancer pain, enroll one in 10,000 patients at risk for cancer pain in industrialized countries, are often heterogeneous, and use poor methodology. Leading investigators in the area of cancer pain relief have repeatedly called for improving the quality of trials in this area. The quantity and quality of scientific evidence on cancer pain relief still, however, compare unfavorably with the great deal that is known about other high-impact conditions, including cancer itself. In the current era of patient-centered care, closing this gap should be a high research priority.
Quality of life has not been uniformly assessed in trials of analgesic drugs and nondrug interventions for cancer pain. Limited evidence from the retrieved trials supports the position that optimal analgesia benefits many dimensions of the quality of life. Advances in quality-of-life assessment and insights from research on chronic noncancer pain into the relationships among pain, disability, and impairment offer the opportunity to understand these interactions in the context of cancer pain.
Carefully designed trials with cancer pain relief as a primary outcome are required in patients with well-defined disease and pain. Such trials must conform to rising expectations for clinical trials in general. High-quality trials of cancer pain relief should:
- Enroll greater numbers of patients for longer intervals than has generally been true in the past.
- Be blind and apply active placebos when appropriate or use uniform control treatments otherwise.
- Employ adequate between-arm washout intervals and consider advancing disease state in crossover trials.
- Assess side effects, pain mechanisms, and rest, incident, or breakthrough pain in a standardized, combinable fashion.
To design and conduct such trials will be challenging, particularly for complementary therapies or infrequent interventions such as spinal drug administration, but such trials are necessary to refine our understanding of widely employed interventions.
Investigations of cancer pain and its control should seek to evaluate the influence of gender, race, age, psychosocial context, ethnicity, and culture on the experience and report of pain. The influence of such factors should also be examined during studies aimed at defining the efficacy of specific treatments and their associated side effects. Small-scale, short-term randomized controlled trials that establish treatment efficacy for purposes of Food and Drug Administration approval are not designed to prove effectiveness as would larger scale, long-term applications in the treatment of cancer pain relief. To meet this need, outcomes research can provide valuable data that are not feasible to acquire through controlled trials.
Until large, high-quality trials are accomplished and accepted as definitive, systematic reviews of the best available evidence on cancer pain control are required. Such reviews are necessary to provide a foundation to guide current treatment and future investigation. Increasing numbers of systematic reviews on pain, palliative treatments, and supportive care are now appearing through groups such as the Cochrane Collaboration, a nonprofit organization that assembles, disseminates, and updates the best available evidence on the effects of health care interventions. Frequent updating of such reviews will be necessary to keep pace with the accelerating number of cancer pain relief trials. Of equal importance to the synthesis of the best available evidence in the field is the dissemination of the evidence to students, health care professionals, patients, and their families and evaluation of the most effective educational interventions.
Many clinical questions remain unanswered, and many preclinical insights have not been translated into practice due to a lack of high-quality evidence. In part, this lack of evidence is due to the funding structure of trials that emphasizes investigation of commercially viable products. Drug interactions during long-term cancer pain treatment require clarification. It is unclear whether a mechanism-based approach to diagnosing and relieving each component of pain in an individual is more effective than an empiric regimen in which each patient's treatment is based on pain intensity alone. Another key unanswered question is how to optimally combine drug with nondrug therapies, given that the latter are safe and inexpensive. Despite the importance of pediatric cancer pain control, almost no analgesic drug trials focus on children.
Nearly two decades ago, the widely disseminated World Health Organization's "three-step analgesic ladder" of stratified therapy (use of an NSAID, addition of a "weak" opioid, or substitution of the latter with a strong opioid) reflected the best available evidence for cancer-related pain control. Its effectiveness has been documented in large case series. Yet a multiplicity of effective drug and nondrug options for cancer pain relief is now available in the United States and other industrialized countries. Optimally matching the options for cancer pain control with individual needs, preferences, and likely responses may require evolution of the three-step analgesic ladder into an "elevator" that delivers patients promptly and with ease to their chosen destinations within a multi-storied edifice, and "escalators" to reposition them subsequently between nearby levels.
Comprehensive, credible data that address individual variations in preferences for, responses to, and costs incurred by these options are a foundation for potential evidence-based approaches to cancer pain control, but are presently sparse. For example, the spinal route of analgesia is widely employed but much remains to be learned about optimal patient selection, the comparative efficacy of spinal drug infusion versus systemic drug administration, and the selection of initial or secondary agents or combinations. It is now time to apply equally high-quality methods to questions in cancer pain relief as in cancer treatment, particularly accrual of adequate numbers of patients for clinical trials. Consumers, clinicians, and policymakers must all be participants in this process.
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Availability of Full Report
The full evidence report from which this summary was taken was prepared for AHRQ by the New England Medical Center under contract number 290-97-0019. It is expected to be available in early 2001. At that time, printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment No. 35, Management of Cancer Pain.