Back to Journals » Journal of Pain Research » Volume 9

Effectiveness of the World Health Organization Cancer Pain Relief Guidelines: an integrative review

Authors Carlson C

Received 7 October 2015

Accepted for publication 7 January 2016

Published 22 July 2016 Volume 2016:9 Pages 515—534

DOI https://doi.org/10.2147/JPR.S97759

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Michael Schatman



Cathy L Carlson

School of Nursing, Northern Illinois University, DeKalb, IL, USA

Abstract: Inadequate cancer pain relief has been documented extensively across historical records. In response, in 1986, the World Health Organization (WHO) developed guidelines for cancer pain treatment. The purpose of this paper is to disseminate the results of a comprehensive, integrative review of studies that evaluate the effectiveness of the WHO guidelines. Studies were included if they: 1) identified patients treated with the guidelines, 2) evaluated self-reported pain, 3) identified instruments used, 4) provided data documenting pain relief, and 5) were written in English. Studies were coded for duration of treatment, definition of pain relief, instruments used, findings related to pain intensity or relief, and whether measures were used other than the WHO analgesic ladder. Twenty-five studies published since 1987 met the inclusion criteria. Evidence indicates 20%–100% of patients with cancer pain can be provided pain relief with the use of the WHO guidelines – while considering their status of treatment or end-of-life care. Due to multiple limitations in included studies, analysis was limited to descriptions. Future research to examine the effectiveness of the WHO guidelines needs to consider recommendations to facilitate study comparisons by standardizing outcome measures. Recent studies have reported that patients with cancer experience pain at moderate or greater levels. The WHO guidelines reflect the knowledge and effectual methods to relieve most cancer pain, but the guidelines are not being adequately employed. Part of the explanation for the lack of adoption of the WHO guidelines is that they may be considered outdated by many because they are not specific to the pharmacological and interventional options used in contemporary pain management practices. The conundrum of updating the WHO guidelines is to encompass the latest pharmacological and interventional innovations while maintaining its original simplicity.

Keywords: cancer, pain, World Health Organization, review, guidelines

Introduction

Cancer is the leading cause of morbidity and mortality worldwide with ~14 million new cases and 8 million cancer-related deaths in 2012.1 Furthermore, the International Agency for Research on Cancer estimates the number of new cases to rise by ~75% over the next two decades. More than 50% of people diagnosed with cancer will experience physical pain and of those people, more than one-third will experience moderate-to-severe pain levels.2,3 The estimated increase in the incidence and prevalence of cancer supports the prediction of an increase in the number of people with pain caused by the disease and its treatment.

Historically, the continued prevalence and extreme intensity of cancer pain experienced by patients have been documented via numerous international epidemiologic studies. More than 40 years ago, Marks and Sachar4 found that 75% of patients experienced cancer pain in spite of analgesics ordered by health care providers. Inadequate cancer pain relief was reconfirmed in later studies.58 After recognition of an international problem, the World Health Organization (WHO) responded by the wide distribution of the WHO Cancer Pain Relief guidelines in 1986,9 herein, referred to as the WHO guidelines, and subsequently updated the guidelines a decade later.10 The main element of the WHO guidelines established medical management of cancer pain with a three-step ladder (Figure 1). The purpose of the ladder was to make pain relief available readily to patients with cancer with advanced disease by using effective and inexpensive drugs administered regularly, orally, and on an individual basis while also focusing on safety.11 In addition, the WHO guidelines were to facilitate and legitimize the use of “strong” opioids (ie, morphine and its derivatives) in regions of the world where the use of these medications was unacceptable or illegal.11,12

Figure 1 WHO analgesic ladder.
Abbreviation: WHO, World Health Organization.

Despite multiple translations and broad distribution of the WHO Cancer Pain Relief guidelines, inadequate pain relief still exists.1316 The effectiveness of these guidelines needs to be evaluated to determine the underlying reason for the continuation of inadequate pain management despite medical advances in the past 28 years. The purpose of this paper is to disseminate the results of a comprehensive, integrative review of studies that evaluate the effectiveness of the WHO guidelines. A key consideration in the evaluation of these studies is to differentiate between those individuals for whom the guidelines are effective and those for whom they are not. This distinction will aid in focusing future research and guideline considerations.

Two previous reviews of the effectiveness of the WHO guidelines were found in the literature.17,18 Jadad and Browman17 identified eight studies for review in 1995 and Ferreira et al18 identified 17 studies in 2006. Many of the same studies were included in both reviews. There were no randomized clinical trials in the reviews that could provide unbiased estimates of the proportion of patients for whom the WHO guidelines would be efficacious. Indirect measures of effectiveness of pain treatment, however, ranged from 45% to 100% within the two reviews. Multiple limitations were identified across the reviews, including small sample sizes, variable or short follow-up periods, and high exclusion or dropout rates. Jadad and Browman17 also concluded that there was a lack of homogeneous criteria across studies to assess pain and treatment outcomes to compare effectiveness of the WHO guidelines efficiently and accurately. Ferreira et al18 discussed that complete relief of pain is rarely achieved in patients with cancer experiencing cancer pain, but pain intensity or duration can be reduced while using the WHO guidelines. Effectiveness of the WHO guidelines was recognized, but the extent and predictability of the effectiveness across studies were being questioned.17

This current paper expands what has previously been reviewed evaluating the WHO guidelines. In addition to critiquing previously published work for effectiveness of the guidelines, this review encompasses other pain measurement scales. This review categorizes adequate treatment effectiveness as the pain intensity being 1) less than moderate; 2) a visual analog scale (VAS), numerical rating scale (NRS), and verbal rating scale (VRS) score ≤3 on a 0–10 scale (or 30 on a 0–100 point scale); or 3) a decrease in the pain intensity on the VAS, NRS, or VRS by 70% or more; a decrease in the Integrated Pain Score (IPS) by 70% or more; or an increase in pain relief by 70% or more. The present paper includes studies that were not evaluated by the previous reviews and includes studies that were published in the past decade. The present study included searching more resources than databases and a manual search of reference lists.

Search methods

This review includes health professional literature published within a 28-year period between 1987 and May 2015. The timeline reflects the period that began immediately following release of the first guidelines from the WHO in 1986.

Four methods were used to identify studies for review. A comprehensive computer search was conducted using Cumulative Index of Nursing and Allied Health Literature (CINAHL), MEDLINE, Proquest, and PubMed. Medical Subject Headings (MeSH) and text words (txt) used in the search included “pain” [MeSH and text] and “cancer” [txt] or “neoplasms” [MeSH] in combination within the full text: “relief” [txt], “control” [txt], “prevalence” [MeSH and txt], “intensity” [txt], “intractable” [txt], “management” [txt], “under-medication” [txt], “palliative care” [MeSH and txt], “analgesia” [MeSH and txt], “analgesic ladder” [txt], “symptom” [txt], “validation studies” [MeSH], and “World Health Organization” [MeSH and txt]. In addition, online indices of individual periodicals were searched using titles and abstracts that were established sources to publish reports of the evaluation of the WHO guidelines. These included Pain, Journal of Pain and Symptom Management, Cancer Nursing, Pain Management Nursing, and Oncology Nursing Forum. The Internet was searched using multiple search engines such as Google and Google Scholar, Yahoo, Bing, Webcrawler, and Ask.com. Multiple pain-related web pages were searched for abstracts and text related to the evaluation of WHO guidelines including, but not limited to, the WHO, International Association for the Study of Pain (IASP), American Pain Society (APS), American Society of Pain Management Nurses (ASPMN), and the Pain and Policy Studies Group (PPSG). Finally, a comprehensive review of citations within included research studies were also searched for identification of further studies.

Research studies of any methodological design were included in this review if they: 1) specifically identified treatment of adult patients with cancer with the WHO guidelines, 2) evaluated patients’ self-reported cancer pain, 3) provided information on the instruments used to measure cancer pain relief, 4) provided data documenting changes in pain intensity via the VAS, NRS, VRS, or IPS after treatment or provided data documenting the proportion of patients experiencing adequate pain control/relief after treatment, and 5) were written in English. Each eligible study available was reviewed and coded for the following information: author(s), publication year, title, source, study design, aims, sample population and size, dates of data collection, country of data collection, duration of treatment, definition of adequate pain relief, instruments used to measure pain, methodology, findings related to pain intensity or relief, and whether additional measures for pain control were used other than the WHO analgesic ladder. The samples of the studies were evaluated for size, randomization, and reasons for termination/exclusion from the study. The quality of the data was evaluated according to the aim(s) of the study, whether data were collected prospectively or retrospectively from the medical record, and the length of the study follow-up periods. The methodology was evaluated by the description of the target population and setting, demographic data of the sample reported, and presence of a control group.

Cooper’s guide for integrated literature reviews was used.19 Quality appraisal was not completed for this review because of a lack of randomized control studies. However, the methodology, bias, and threats to internal and external validity are summarized in the results section. Every study that met the inclusion criteria was included in the analysis.

Results

Forty-eight research studies were identified for review. Several studies shared the same population samples. According to Petitti,20 failure to exclude studies analyzing the same sample may cause bias in the magnitude of findings. Therefore, only studies using the most inclusive sample were included. For example, there were six studies using the same patient sample in Germany;2126 only the latest and most inclusive study is included in the review.26 In order to ensure accuracy, communication with authors was completed. For example, according to Mercandante, the samples of patients were not the same in studies published in 199227 and 1999.28 Ten studies were removed from review due to overlap of population samples.

Several other studies were excluded as they evaluated the intensity/strength of the analgesic treatment of the patients’ reported pain using the pain management index (PMI) developed by Cleeland et al.29 While the PMI is based on the WHO recommendations for cancer pain relief, the studies using the PMI did not specify whether or not the treatment administered to the patients was based on the WHO guidelines. Without the use of the inclusion criteria language, the relationship to the WHO guidelines was not clear. Thus, 13 additional studies were not included. From the original 48 studies identified, 25 studies fulfilled the inclusion criteria.

In reviewing the 25 included studies, all of the studies used convenience samples, while only four of the convenience samples were randomized. The four studies that used randomized samples were for the purposes of evaluating the necessity of Step 2 of the WHO analgesic ladder3032 (Figure 1) or the use of mild opiates.33 Nineteen of the studies were prospective studies, including six quasiexperimental studies in which four used comparison groups. Only two studies had a control group32,34 and one study was double-blind.35 Because of the lack of control groups throughout all but two of the 25 studies, meta-analysis was not performed. Therefore, content analysis of methods and findings is described narratively. Table 1 chronologically summarizes the individual research studies that measure the effectiveness of the WHO guidelines.

Table 1 Chronological summary of research studies evaluating the efficacy of WHO Cancer Pain Relief Guideline
Note: aNumber of patients who were treated with the ladder and from whom data were available.
Abbreviations: WHO, World Health Organization; IPS, Integrated Pain Score; VAS, visual analog scale; VRS, verbal rating scale; NSAID, nonsteroidal anti-inflammatory drugs; PRS, pain reduction scale; NRS, numerical rating scale; POM, Pain-O-Meter; HRQoL, health-related quality of life.

Findings from the longitudinal studies were classified into five categories: 1) the percentage of patient responses that demonstrated a reduction in the IPS, 2) the percentage of patient responses for whom the reduction in the VAS or NRS was stated or could be calculated, 3) the percentage of patient responses that were within the categories created from scores on the VAS or NRS that was considered as controlled pain or adequate pain relief, 4) the percentage of patient responses on the VRS of pain relief or the VRS of pain intensity that were considered as adequate pain relief, and 5) others that did not classify findings into the previous four categories.

Two studies used the IPS.36,37 The IPS was designed to take into account both pain intensity and duration when assessing patients’ pain. It is calculated by multiplying the hours of pain duration per day by the pain intensity using a 10-point VAS, NRS, or points assigned to a VRS. Thus, scoring of the IPS has a range of 0–240 possible points. In the first few days of treatment with the WHO guidelines, Wenk et al36 found patients experienced a 70% reduction in the IPS,36 while Ventafridda et al34 found patients experienced a 57% reduction.34 Progressive treatment led to an 81%–69% reduction in pain scores, respectively. Overall, the reduction in the IPS after initiation of treatment ranged from 57% to 81%.

Several of the studies reviewed used patient responses on either a VAS or NRS where the percentage of the pain reduction in the scores after initiation of treatment was stated or could be calculated.28,32,33,3845 An analysis of the study results at one interval of measurement (~3–7 days after treatment was initiated) demonstrated a 20%–71% reduction in the VAS or NRS from the baseline pain assessment. Upon the final interval of measurement, there was a 43%–81% reduction in the VAS or NRS from the baseline pain assessment. The interval length varied among studies but was >7 days after initiation of treatment.

Other studies reported the percentage of the categories considered as adequate pain relief or satisfactory pain intensity by dividing the patients’ responses for the VAS, NRS, or VRS into categories. For example, the pain intensity measured by a VAS (0–10 point) might be divided into categories of “none” (0 points), “mild” (1–3 points), “moderate” (4–6 points), and “severe” (7–10 points), where “none” or “mild” pain might be considered as adequate pain relief. Likewise, on a four point VRS, the categories of “none” or “mild” might be considered as adequate pain relief. Results from these studies were reported according to the percentage of patients in each category. Mercadante et al27 used a VAS and reported that 81% of the patients without incidental pain had “no pain” or “mild pain” at the time of their death, but only 50% of the patients who experienced incidental pain had “no pain” or “mild pain” at the time of their death. Ventafridda et al34 using a VRS reported that 76% in their sample reported “none” or “slight” pain after 1 month of treatment. Zech et al,26 in a validation study of the WHO guidelines using a VRS, reported that 72% of the patients had “no pain” or “mild pain” at the time of their death. Tsui et al44 reported that 88% of their patients were discharged with a VAS of ≤3 (0–10 scale), indicating that the patients experienced “no” pain or “mild” pain. Bhatnagar et al46 reported that 87% and 90% of patients had good pain relief (VAS <3) at 1 month and 6 months, respectively. Of the studies that reported the percentage of the categories considered as adequate pain relief or satisfactory pain intensity by dividing the patients’ responses for the VAS, NRS, or VRS into categories, 50%–90% of the patients experienced adequate pain relief.

Similar to other studies that categorized the degree of pain intensity, Takeda47 categorized the degree of pain reduction of patients’ responses on the VAS into three levels: complete relief (no pain), acceptable relief (>90% relief of pain or reduction of the scores), and partial relief (decrease in severity of pain, but a reduction of <90%). At the end of an unknown duration of treatment, 97% of the sample reported complete (86%) or acceptable (11%) relief from pain. Inclusion of the percentage of the categories considered as adequate pain relief determined by Takeda47 into the range compiled from the other studies that reported the percentage of the categories considered as adequate pain relief (“none” or “mild” pain) indicates that 50%–97% of the patients experienced adequate pain relief.

Unlike studies that reported the percentage of VAS reduction of pain, Minotti et al35 and Keskinbora et al31 reported patients’ mean scores of pain intensity using the VAS after treatment only. These studies did not report pain levels before the introduction of the WHO guidelines. One of the inclusion criteria for the studies, however, was that patients’ scores of pain using the VAS (0–100 points) were >40 or the NRS >4 (0–10 points). After 7 days of treatment, Minotti et al35 reported that the mean of the patients’ scores using the VAS was <40. Keskinbora et al31 demonstrated graphically that the patients treated with an adjuvant in addition to an opioid experienced a mean pain of <4 on days 4 and 13 after initiation of treatment with the WHO guidelines. The reduction in pain was statistically significant between patients who received an opioid and an adjuvant and those patients who received an opioid only for their cancer pain. The percentage of reduction in pain intensity was not provided and could not be calculated from information provided within the two studies.

Siguan et al48 used a pain reduction scale (PRS) to survey the patients with cancer pain. With this scale, the respondents had the option of indicating whether they had 0%, 25%, 50%, 75%, or 100% pain relief. At the end of an unreported duration of treatment, 86% of respondents stated that they had at least a 75% pain reduction and 96% had at least a 50% pain reduction. Similarly, Vielvoye-Kerkmeer et al49 had respondents rate the effectiveness of their treatment as “poor”, “moderate”, “good”, or “excellent”. In their study, 69%–71% of patients rated their pain relief as “good” or “excellent”.

Zech et al,26 Meuser et al,41 and Maltoni et al30 used other methods of evaluating effectiveness of treatment with the WHO guidelines. In addition to reporting the patients’ mean pain scores of the VAS or NSR at baseline and after treatment, the first two studies also categorized pain relief according to the number of days the patient experienced severe pain. Thus, if the patient reported their average pain to be severe, very severe, or maximal on <10% of days, treatment effectiveness was defined as “good”; on 10%–30% of days as “satisfactory”; and on >30% of days as “inadequate”. With these categories, Meuser et al41 found 86% of the patients and Zech et al26 found 88% of the patients experienced “good” or “satisfactory” pain relief effectiveness. A third study by Maltoni et al30 described the percentage of days with worst pain that was ≥5 on the NRS (0–10 points). Maltoni et al30 reported that on 9%–29% of the days, patients experienced moderate-to-severe pain. Using the criteria from Zech et al26 and Meuser et al,41 100% of the patients in the study by Maltoni et al30 experienced “satisfactory” or “good” treatment effectiveness with the WHO guidelines. The range of the pain relief effectiveness of the three studies ranged from 86% to 100%.

In the reviewed studies, the overall effectiveness of the WHO Cancer Pain Relief guidelines was found to range from 20% to 100%. The effectiveness identified in the majority of the studies was >50%. The broad range of effectiveness is dependent upon many measurement factors, including the intensity of the pain, the pain instrument used, the duration of treatment, and the outcome variable of pain relief/control.

Discussion

The overall literature rating is suggestive of a relationship between the WHO guidelines and pain relief. Evidence from research indicates 20%–100% of patients with cancer pain – considering their status of treatment or end-of-life care – can be provided adequate pain relief with application of the WHO guidelines, with a majority of studies identifying relief >50%.

Various means of reporting outcomes were used. A reduction of 57%–81% was reported using patient responses with the IPS after treatment with the WHO guidelines. The NRS and VAS were reportedly reduced in the range of 20%–81% after treatment across levels of severity of pain. Studies that placed patients’ responses into categories that described the pain intensity experienced reported that 50%–90% of the patients experienced “none” or “mild” pain after treatment with the WHO guidelines. Other studies reported that the mean intensity experienced by patients was <4 or 40 (depending on whether scale was based upon 0–10 points or 0–100 points), indicating full effectiveness of the WHO guidelines. Other studies reported that 69%–86% of the patient responses indicated that patients experienced at least 75% pain relief or felt that their pain control was “good” or “excellent” after treatment. Effectiveness of the WHO guidelines was reported between 86% and 100% for patients who were experiencing “severe”, “very severe”, or “maximal” pain on 0%–30% of the treatment days. This review demonstrated that pain could be reduced or eliminated in a great majority of the patients when they receive treatment based on the WHO guidelines.

No other guidelines have had the profound effect on cancer pain as the WHO guidelines.12,50,51 Because only one study met inclusion criteria after 2008, it is questioned whether this finding indicates recognition of the WHO guidelines, and hence a decreased need for publications of their effectiveness or the acceptance of the treatment of cancer pain with opioids.32 The timeframe correlates with the publication of the European Association for Palliative Care guidelines52,53 and the American Pain Society guidelines for cancer pain treatment.54,55 These agency guidelines have recognized the worldwide problem of cancer pain, combined with the increasing availability of different opioids, opioid preparations, and interventional procedures during the last 20 years. These agencies have tried to update the international guidelines on the management of cancer pain while focusing on the role of opioids. The WHO guidelines, though not as specific in direction, encompass a clear and simple approach that has an educational value and is easily remembered and disseminated. Regardless of the age of the WHO guidelines, they still are the cornerstone for cancer pain treatment worldwide. Unfortunately, many practitioners are not using the WHO guidelines and some do not know what the WHO guidelines entail.56,57 The clear message resonating from the effectiveness of the WHO guidelines is that they are an effective and cost-effective means to provide cancer pain relief.

Limitations

In the reviewed studies, it was not always specified whether the WHO analgesic ladder or the entire WHO guidelines were being investigated. The language regarding the usage of the ladder or the full guideline was often not stated. Five studies treated patients with the ladder only or eliminated the study participants who underwent additional treatment that might affect pain perception. Eleven of the reviewed studies included patients who were also being treated with antineoplastic treatment, intrathecal analgesics, neurolytic procedures, or surgical procedures, while others did not specify if the patients underwent additional treatment. As the WHO guidelines endorse the use of other treatment modalities than the analgesic ladder if needed, the guidelines should be investigated in its entirety. Some experts suggest that the WHO analgesic ladder has a fourth and/or fifth step that may include a step for interventional procedures, including nerve blocks, neurolytic blocks, spinal stimulators, and epidurals11,12,58 or a step for opioid switching that includes both pain and side effects as criteria for switching analgesics.59 It can be argued that having the interventional nerve blocks at a later step implies they should be used last. Evidence exists that the nerve blocks may be more effective if considered earlier.60,61 Thus, like adjuvant analgesics, they may need to be considered at any step and so may need to be placed alongside the ladder rather than a separate step.

Summarization of the studies proved to be challenging due to different methods of measuring pain, variations in defining the acceptable levels of treatment effectiveness, and missing data. Multiple instruments with different scales and values described pain intensity. Pain intensity was rated according to IPS, VAS, NRS, VRS, and PRS. Particularly, the use of the IPS made it very difficult to compare pain treatment effectiveness between studies since a score of 20 may indicate a range of severe pain for 2 hours or mild pain for 20 hours. Since duration and intensity were a combined score, this type of scoring made it unfeasible to compare the pain treatment effectiveness with other studies and to determine whether adequate treatment effectiveness was achieved. Similarly, reporting pain relief according to the number of days the patient experienced severe or very severe pain made comparisons unrealistic. Even the same type of scale may have had multiple interval labeling systems associated with them. For instance, the VRS may have had four or six points. The variability in the methods of measuring pain or pain treatment effectiveness made comparisons difficult.

Moreover, the studies reviewed categorized the results according to various operational definitions of adequate or inadequate pain treatment effectiveness. This review categorizes adequate treatment effectiveness as the pain intensity as being 1) less than moderate, 2) a VRS or NRS as ≤3 (or 30 on a 0–100 point scale), or 3) a decrease in the pain intensity/increase of pain relief by 70% or more. In addition, some data were not reported in the reviewed studies, which may have made comparisons easier. A more accurate comparison could have been made if data from all instruments had been discussed.

Many studies had high exclusion and/or attrition rates. For instance, in Ventafridda et al,34 64% and 31% of the cases in the two groups investigated in the study had to be excluded from the study due to incomplete data collection, incomplete recording of patient assessment, or inappropriate timeliness in the follow-up. Incomplete data collection also was problematic in other studies.36,42 Given the population studied, some reasons for attrition were death,27,34,36,38,41,48,49 ineffective analgesia,35 intolerable side effects,35,48,49 as well as lost to follow-up,26,28,33,34,36,41,48 pain absence or resolution,33,41 low patient compliance,28,41 change of therapy,35 patient being treated by another practitioner or facility,28,41,48 discharged,36 financial constraints,48 physician error,48 and patient receiving other treatments.35,41

Although it can be concluded that management of cancer pain as recommended by WHO is effective for a majority of patients, the research designs of the studies in the literature review were retrospective, descriptive, and/or quasiexperimental rather than randomized controlled trials (RCT). A relationship between these two factors is consistent with the knowledge generated in prior pain relief investigations, as it is a combination of pain management knowledge acquired through multiple sources that is being tested with the WHO guidelines. Although the relationship between WHO guidelines and pain relief is plausible and likely, the predictive quality of experimental designs with RCT is missing, and the subsequent ability to predict the effectiveness of the WHO guidelines through evidence-based certainty is lacking.11

Additional methodological limitations other than design are noted. Because of the population, most studies of oncology patients employ convenience samples, and thus, findings are not generalizable. For example, it is possible for patients with cancer who are hospitalized to more likely be experiencing severe pain than those who are not hospitalized. Similarly, some studies included patients with severe pain only.27,30,31,49 Achieving adequate pain relief may be more difficult in more severe cases. Therefore, the studies measuring the effectiveness of the WHO guidelines in reducing the intensity of cancer pain in hospitalized patients or patients who are only experiencing severe pain cannot be generalized to all patients with cancer.

Many of the samples were drawn from one institution in one country. Sampling populations from one institution and generalizing the findings globally are inappropriate as several other factors such as availability of different opioids may affect the adequacy of pain relief. Furthermore, many studies included only patients treated by cancer specialists; patients treated by practitioners without oncology training may be more likely to experience inadequate pain relief. The convenience samples in these studies may produce different findings than a randomized sample from a large, international cancer pain patient population.

In the reviewed studies, the sample sizes of persons with cancer pain vary, but many samples are small. The results from this limited sample size, especially with convenience sampling, may differ from the population. As with drawing from one-institution samples, the small samples may allow some variables to affect the results, such as the practitioner, local practices and beliefs, and economic or social influences. With small sample sizes, a few patients who improved dramatically while receiving care utilizing the WHO guidelines may alter the mean improvement of the group even if other patients perceived little or no benefit with treatment. Small sample sizes, especially combined with convenience sampling, render widespread generalizations inappropriate.

Other methodological problems with measuring cancer pain can be revealed in this review. In longitudinal studies of cancer pain, maturation occurs over time as the disease progresses. It may be difficult to demonstrate an effect of an intervention to decrease incidence and intensity of pain as the pain changes with disease remission or progression. In addition, longitudinal data collection intervals varied greatly. The length of time between data point assessments following implementation of the WHO guidelines and the length of follow-up varied between having only one additional assessment at 1 week after treatment to recording data until death, which may entail follow-up for several months. Testing effects may also be prominent, as many studies did not identify the ability of those who collected the data. Overall, the multiple methodological problems identified potentially lead to less accuracy in the individual study results and makes comparisons between studies difficult.

In reviewing the literature, several of the studies operationally defined adequate pain relief as experiencing moderate pain or less pain. Although complete relief is the goal of cancer pain management; sometimes, it is not possible. An acceptable level of pain should be below moderate pain. With moderate or greater pain, there are often marked negative changes in physical or emotional functioning that interferes with the patient’s quality of life.15,62,63 Therefore, the delineation of adequate pain relief should be within the mild or no pain categories.

In order to measure pain and compare results more consistently, a well-established, international pain measurement instrument needs to be used. Difficulty is encountered when comparing various pain intensity measurements as it is unknown whether methods of measuring pain and reporting pain relief affect the results of studies. For example, a difference between an individual’s responses on VRS may not correlate with responses on a pain relief scale. Future studies are needed to correlate these measures.

Additional research also is needed to compare methods of reporting pain relief between those reported from pain intensity scales to pain relief scales. Likewise, it is understandable that not only the intensity but also the duration of pain needs to be measured, but placing these two concepts in one index, such as done in the IPS, may cause misinterpretation of the effects of the pain experience on the patient. Perhaps, reporting the intensity and duration in addition to the IPS might be more informative.

The number of points on a VRS and the terms used on the scale need to be standardized so that findings between studies can be compared. The standardized VRS should then be correlated with the NRS so the findings with the two different types of scales can be compared more consistently. Finally, in order to have more accurate results and be able to compare studies, the patient rather than medical personnel or family should complete the pain measurement instruments. Standardization in pain management instrumentation and in its completion would allow more consistent measurement, reporting, and comparison between future studies.

New studies using experimental designs with randomized control groups would support the strength of the relationship between the WHO guidelines and cancer pain relief. According to Oxman et al,64 WHO recommendations are usually not based on systematic reviews of the literature but rely heavily on experts in a particular specialty such as cancer pain management. Since the release of the WHO guidelines, a lack of rigor in studies, especially in methodological design, contributes to limitation in generalizability of the published results.11 Debates regarding the effectiveness of the WHO guidelines remain due to the lack of RCTs. Although RCTs demonstrating a relationship between the WHO guidelines and cancer pain relief are conspicuously absent, there were no evidence-based alternatives supported by RCTs found in the literature that were superior to the WHO guidelines.

The first debate about the effectiveness of the guidelines revolves around the utility of Step 2 of the WHO ladder.11,65 Proof of the effectiveness of weak opioids is lacking, especially since a limitation of using weak opioids is that there is a ceiling effect.11 A ceiling effect occurs when an increase in dose does not produce a decrease in pain. In an attempt to avoid using weak opioids, Nunes et al32 found that a higher incidence of adverse effects occurred when the second step of the ladder was omitted and patients were administered morphine initially. Thus, Step 2 may still be warranted, and future research is needed to explore its value.

A second debate of Step 2 includes the role of nonsteroidal anti-inflammatory drugs.11 These medications may affect the gastrointestinal tract, platelets, and kidneys, resulting in negative side effects and possible toxicity. A third debate of Step 2 is the lack of criteria for switching from morphine to another opioid, including equianalgesic dosing and the choice of the subsequent opioid to be used.11,66 A fourth debate is that there are multiple new medications and new formulations of older drugs that need to be investigated that considers their pharmacodynamic and pharmacokinetic properties in patients experiencing cancer pain. Finally, adverse effects of these opioids need to be documented within the RCTs that explore them.

Suggesting rigorous RCTs challenges researchers, including the WHO, to optimize and improve the guidelines or develop alternatives to ensure the highest possible proportion of patients with cancer pain experience pain relief. Nonetheless, the implementation of RCT in studies of cancer pain management is not likely due to ethical and logistic reasons. First, to obtain accessibility to patients with cancer pain, convenience samples are often used. Second, the ability to control for extraneous variables in studies among international health care practices makes coordination of standards difficult for group comparisons. Third, a humane responsibility exists to provide optimal pain relief to all patients, and this renders a control group as being potentially ethically irresponsible. Fourth, given the publication of the WHO guidelines, it is unlikely that the treatment of a potential control group would not be influenced by the broad dissemination of the guidelines that has already occurred. Finally, experts in cancer pain management believe that the effort and expense of experimental studies with control groups is unwarranted.67,68 This is based on the strength of the fundamental knowledge underlying the guidelines and the acceptance of these principles. Suggesting experimental designs with control groups is an ideal rather than a practical prospect in the actual environment of cancer pain management. RCTs are needed, however, when the effect and differences are smaller such as when comparing various drugs or routes.67 Comparison groups, gleaned from those treated in various environments, for example, where certain medications are not readily available, would allow for comparison of groups of patients with cancer. Also, data from those treated in the past decade or earlier could be compared to those treated currently.

Cluster randomization is a possible alternative to overcome some of the challenges in getting RCTs regarding cancer pain relief. A cluster randomized controlled trial (CRT) is a type of RCT where groups of subjects and not individuals are randomized. The units of randomization are varied and can be clinics or hospitals, among others. Advantages include the ability to compare drugs head-to-head within the same class rather than with placebos.69 CRT may relieve issues related to recruitment and self-selection and randomization of patients, thus allowing data collection and availability of results more quickly.69 The disadvantages to CRTs are the multitude of design choices and stratification of the groups.70 The need for informed consent may be averted if the drug studied is the preferred drug in the cluster formulary, and so, ethical requirements for CRTs may need to be analyzed and modified.69

Several recent studies indicate inadequate cancer pain relief still exists, but these studies also fail to indicate if the WHO guidelines were being implemented during treatment.15 A review of studies by Deandrea et al,71 that used the PMI, demonstrated that ~43% of patients with cancer pain are undertreated. The PMI compares the intensity/strength of the analgesic treatment according to the WHO Analgesic Ladder with the patients’ reported pain. All studies demonstrated a negative PMI, indicating that the cancer pain is undertreated a majority of the time. Deandrea et al71 identified factors associated with a negative PMI that included publication before 2001; studies conducted in Europe or Asia; studies conducted in countries whose national income per capita was $40,000 per year or less; and patients being cared for in a general setting rather than a cancer-specific setting. Patients being treated by oncology subspecialists, however, have also been inadequately medicated for pain according to the WHO guidelines.15,45 Therefore, the use of the WHO guidelines in oncology specialty areas and by the oncologists themselves cannot be assumed. In future studies, the use of the WHO guidelines to treat patients with cancer with pain should be clearly stated, consistently applied, and then evaluated with the PMI. The results of the review by Deandrea et al71 suggest that the question might be how the WHO Analgesic Ladder is put into practice rather than its effectiveness.

Other methodological considerations would be to increase the sample size, follow a longitudinal design, use multiple institutions/agencies, and use more institution/agencies from within the USA, all of which are lacking. The sample size for future studies evaluating the effectiveness of the WHO guidelines needs to be increased. Five studies in this review had a sample size of <50 subjects, and 13 additional studies had <100 subjects. Weekly, longitudinal studies until study withdrawal would provide additional data to evaluation the effectiveness of the WHO guidelines in continued relief of cancer pain upon progression of the disease. Other cancer care centers need to be surveyed, especially in understudied countries. In the studies reviewed, for example, only part of one sample came from the USA. These considerations would increase the generalizability and reliability of the findings from future studies.

Conclusion

The studies evaluating the effectiveness of the WHO guidelines provide valuable information on the course of cancer pain and its treatment. From these findings, it can be concluded that the WHO guidelines are useful in promoting cancer pain relief. Evidence from research indicates at least 20%–100% of patients with cancer pain can be provided adequate pain relief across the span of their illness, from treatment- to-demise, with the application of WHO guidelines. Recent studies have reported that patients experiencing cancer pain at moderate or greater levels.2,3 While comparing the results of the recent studies describing the incidence and intensity of cancer pain, it can be assumed that the WHO guidelines have not been as widely adopted as would be expected since their initial release in 1986. The WHO guidelines reflect the knowledge and effectual methods to relieve most cancer pain, but the guidelines are not being adequately employed. Part of the explanation for the lack of adoption of the WHO guidelines is that they may be considered outdated by many because they are not specific to the pharmacological and interventional options used in contemporary pain management practices. The greatest attribute of the WHO guidelines is its simplicity, whereas, a thorough cancer pain guideline results in a complex document that might not be as useful and easy to disseminate. The conundrum of updating the WHO guidelines is to encompass the latest pharmacologic and interventional innovations while maintaining its original simplicity.

At the same time, the patients who have not had their cancer pain adequately relieved, even when the WHO guidelines have been employed, need further consideration in future research. The WHO guidelines have been successful in making pain relief knowledge more globally available, but from a moral and ethical standpoint, these guidelines need to be promoted and examined until adequate pain relief is reported in all possible patients with cancer pain.

Disclosure

The author reports no conflicts of interest in this work.


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