Evidence Report/Technology Assessment

Number 35

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
2101 East Jefferson Street
Rockville, MD 20852

http://www.ahrq.gov

Contract No: 290-97-0019

Prepared by:
New England Medical Center EPC, Boston, MA

Investigators
Leonidas Goudas, MD, PhD
Daniel B. Carr, MD
Rina Bloch, MD
Ethan Balk, MD, MPH
John P.A. Ioannidis, MD
Norma Terrin, PhD
Maria Gialeli-Goudas, LLM
Priscilla Chew, MPH
Joseph Lau, MD (EPC director)

AHRQ Publication No. 02-E002

October 2001

On December 6, 1999, under Public Law 106-129, the Agency for Health Care Policy and Research (AHCPR) was reauthorized and renamed the Agency for Healthcare Research and Quality (AHRQ). The law authorizes AHRQ to continue its research on the cost, quality, and outcomes of health care and expands its role to improve patient safety and address medical errors.

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps health care decisionmakers -- patients and clinicians, health system leaders, and policymakers -- make more informed decisions and improve the quality of health care services.

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.

AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Acting Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.

John M. Eisenberg, M.D.	Robert Graham, M.D.
Director	Director
Agency for Healthcare Research and Quality	Center for Practice and Technology Assessment
	Agency for Healthcare Research and Quality

The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service.

We would like to thank Phyllis Wingo, PhD, MS, Director of the Surveillance Research Program, and Ms. Sherry Bolden, Program Specialist, both of the Department of Epidemiology and Surveillance Research at the American Cancer Society, for assistance with cancer prevalence information.

We would like to thank William Gouevia, MS, Director of the Pharmacy Department, and Ms. Soumana Chamoun, MS, R Pharm, Research Pharmacist, both of the Pharmacy Department at the New England Medical Center, for assistance in gathering cost data for pharmaceuticals.

Pain associated with cancer is an important problem for large numbers of patients and their families. This report summarizes published evidence on the prevalence of cancer-related pain and the efficacy of drug and nondrug therapies for its treatment.

We identified English language human studies by searching Medline, CancerLit, and the Cochrane Controlled Trials Registry (1966 to December 1998). These searches, supplemented by bibliographies of meta-analyses, selected review articles, and suggestions from our science partners and technical experts, yielded approximately 19,000 titles.

Cancer-related pain was defined as pain caused by cancer, by cancer treatment such as surgery, radiation, or chemotherapy, or by the side effects of treatment. We reviewed observational studies on the epidemiology of cancer pain, randomized controlled trials, and selected nonrandomized studies that assessed the effect of treatments and that met methodological criteria. Our search strategy was not restricted by age, gender, ethnicity, or type of cancer. We did not include studies of acute postoperative pain.

We summarized 24 epidemiological surveys of cancer pain and abstracted results from 188 randomized controlled trials of cancer pain treatment into evidence tables. Each trial was assessed according to its methodological quality and applicability. Meta-analysis was performed when there were sufficient data to address a specific question. We also examined data from 100 nonrandomized studies.

The median number of patients enrolled in randomized trials of primary analgesics (NSAIDs, opioids, and adjuvants) was 70 or fewer. Information about the location, nature, and mechanism of pain before and after treatment was minimal for all interventions examined. Heterogeneous reporting of outcomes, nonuniformity of pain measurements, and incomplete reporting of relevant data precluded all but three meta-analyses.

Nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids independently reduce cancer-related pain, as do adjuvants such as antidepressants or anticonvulsants. Few studies evaluate the safety and efficacy of NSAIDs for cancer pain beyond a few days; many are single-dose studies. The studies we examined neither separated the analgesic efficacy of NSAIDs and opioids nor indicated that NSAIDs are specifically effective for bone pain nor disclosed incremental efficacy of adding a "weak" opioid to an NSAID. Comparisons between dosages and delivery forms of systemically administered opioids are limited. Radionuclides and biphosphonates reduce pain from bone involvement by tumor, as does external beam radiation, although studies of the latter lack no-radiation controls. Neurolytic celiac block is effective. The analgesic efficacy of palliative chemotherapy and hormonal interventions is difficult to estimate because of inadequate data. Physical or psychological treatments appear efficacious, but the number of relevant studies is small. Multidrug (or drug plus nondrug) therapy, spinal drug infusion, and ablative neurosurgery require better-quality evidence.

Randomized controlled trials establish that many current treatment modalities can individually reduce cancer pain. These trials constitute about 1 percent of the published literature on cancer pain, enroll 1 in 10,000 patients at risk for cancer pain in developed countries, are often heterogeneous, and are often of poor methodologic quality. Many clinical questions remain unanswered and preclinical insights untranslated because of a lack of high-quality evidence. Age, gender, genetics, psychosocial context, and culture affect pain and analgesic efficacy. Multiple mechanisms of cancer pain exist. Despite the importance of pediatric cancer pain control, very few studies focus on children. High-quality trials are needed to advance progress in cancer pain relief.

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.

Goudas L, Carr DB, Bloch R, et al. Management of cancer pain. Evidence Report/Technology Assessment No. 35 (Prepared by the New England Medical Center Evidence-based Practice Center under Contract No 290-97-0019). AHRQ Publication No. 02-E002. Rockville, MD: Agency for Healthcare Research and Quality. October 2001.

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 is a literature synthesis, however, and neither a clinical practice guideline nor 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; and policymakers. 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.

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 20 subquestions were formulated. The major questions are:

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 postmastectomy pain were included, as were patients with pain resulting from the side effects of antitumor 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.

We performed a systematic review of the best available evidence to address the above questions. We estimated cancer disease burden and the prevalence of cancer-related pain from epidemiologic surveys. We searched Medline, CancerLit, and Cochrane Controlled Trials Registry databases from 1966 to December 1998 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 technical experts and other 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 (which 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. We used a multidimensional evidence grading scale (internal validity, applicability, study size, and effect size) to denote the quality of individual studies and summarized the quality of the evidence pertinent to each of the questions. Other details of the included trials, such as the method of randomization and what type of blinding was used, 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.

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 analgesics -- nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids -- were 84 and 68 (range 24-180 and 10-699, respectively). Studies of biphosphonates enrolled an average of 111 patients (range 13-614). Trials of the palliative use of primary cancer treatment modalities -- chemotherapy and radiotherapy -- enrolled an average of 226 patients (range 38-1,016). Twenty-six 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 in which the investigators and patients are not "blind." 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 procedures used to treat cancer, and by the side effects of cancer treatment?

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 coadministration of an NSAID but no consistent reduction in side effects from doing so. 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 because of 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 coadministered with the former. 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 formulations and routes of administration associated with different patient preferences or different 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 (radiation or radionuclide) cytotoxic or cytostatic therapy?

We found 31 studies, including ¹⁵³samarium-EDTMP, etidronate, aminohydroxypropylidene biphosphonate (APD, 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 follow-up. 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 none 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 aggregate suggests that biphosphonates reduce pain due to bone 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 as 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 bone 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 because of 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 treatments (relaxation, massage, heat and cold, music, exercise, and so on) 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 of education 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, in 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.

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 1 in 10,000 patients at risk for cancer pain in developed countries, are often heterogeneous, and are of variable, often poor methodologic quality. 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, however, still 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 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 (1) enroll greater numbers of patients for longer intervals than has generally been true in the past, (2) be blind and apply active placebos when appropriate or use uniform control treatments otherwise, (3) employ adequate between-arm washout intervals and consider advancing disease state in crossover trials, and (4) assess side effects, pain mechanisms, and rest, incident, or breakthrough pain in a standardized, combinable fashion. Designing and conducting 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 are required of the best available evidence on cancer pain control. 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 are untranslated because of 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, very few analgesic drug trials focus on children.

Nearly two decades ago, the World Health Organization's widely disseminated "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 multiple effective drug and nondrug options for cancer pain relief are now available in the United States and other developed 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, 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 those that have been used in cancer treatment, particularly accrual of adequate numbers of patients for clinical trials. Consumers, clinicians, and policymakers must all be participants in this process.