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11 Articles in Volume 14, Issue #1
The WHO Pain Ladder: Do We Need Another Step?
History of Pain: The Psychosocial Assessment of Pain
Lyme Disease: A Short Primer for Pain Practitioners
Opioid Prescribing Part 1: A Practical Guide to Appropriate Documentation
Pain, Impairment, Whiplash, and the New AMA Guides: What Clinicians Need to Know
The 5 Coping Skills Every Chronic Pain Patient Needs
Demystifying Benzodiazepine Urine Drug Screen Results
Practical Pain Management: The Nation’s Premier Teaching Journal for Pain Practitioners
PPM’s Editorial Board Weighs In on WHO Ladder
Are patients taking acetaminophen (Tylenol) at risk for developing serious skin conditions?
What are some home exercises and tips to help patients manage rotator cuff injuries and pain?

The WHO Pain Ladder: Do We Need Another Step?

Editor’s Note:The World Health Organization (WHO) Pain Ladder has been an enduring guide for over 25 years. Its simple, progressive steps of 1) anti-inflammatory agents, 2) weak opioids, and 3) strong opioids is still fundamentally sound. In this article, Pergolizzi and Raffa present a thoughtful and detailed set of recommendations to modify the 3-step process. No doubt all of us have some thoughts about modifying the “WHO Pain Ladder,” based on the many new physical, interventional, and pharmacologic measures that have come forward since 1986. My message is that too many purveyors of potent opioid pharmaceuticals and invasive interventions have promoted and championed the use of these therapies, which have well-known complications, without first attempting regimens that are less onerous. Practical Pain Management desires that all pain practitioners make 2014 a year in which they develop and practice a “WHO Pain Ladder” protocol that is modified with some new measures to give our patients their best chance at a wide range of safe alternatives before resorting to potent opioids and invasive interventions.

Introduction

The World Health Organization (WHO) created a practical pain ladder diagram in 1986 to help guide clinicians treating cancer pain throughout the world.1 The pain ladder was designed intentionally to be extremely simple: there are 3 rungs to the ladder, corresponding to increasing pain intensity. The clinician prescribes medications as pain worsens, moving from one rung to the next. Few medical guidelines have had the profound effect on care and the longevity of the 3-step WHO pain ladder, and the unofficial adoption of the WHO ladder for use in other pain syndromes, including nonmalignant pain, speaks to its relevance and utility.2

Over the years, however, the WHO pain ladder has been criticized with varying degrees of fairness. The soundest critique of the pain ladder is that it was created in 1986 and has not been modified since that time, despite intervening breakthroughs in our understanding of pain, pain control, and the introduction of new methods to treat pain.3 For example, opioid analgesics have expanded to include new agents, fast-acting and controlled-release formulations, and fixed-dose combination products. New approaches to pain control, such as neuromodulation, nerve blocks, intrathecal drug administration, and non-pharmaceutical protocols also have been developed. Today we have a better understanding of the multiple mechanisms underlying cancer pain and the phenomenon known as breakthrough pain.

Therefore, the authors propose some changes to the 1986 pain ladder to bring it up to date (Table 1). First, we wish to emphasize fixed-dose combination products, such as acetaminophen and hydrocodone, as important Step 2 agents. Second, the designation of “weak” and “strong” opioids may not be as meaningful as understanding the characteristics of specific opioid agents and their appropriate doses. Finally, the authors propose that a fourth rung be added to the ladder to allow for interventional pain management efforts, such as peripheral nerve blockade and neurolysis, which may be appropriate for the 10% to 15% of cancer patients who develop severe to very severe intractable pain. In addition, breakthrough pain should be recognized (although perhaps not as a rung on the ladder) with the recommended treatment option of a fast-acting opioid analgesic. Optimal pain control is multimodal and individualized. This does not negate the value of the generalized WHO pain ladder, but clinicians should feel free to modify it, as needed, for individual patients, reflecting modern pain practice.

Scope of Pain Problem

Nine million new cases of cancer are reported each year, the majority of which occur in developing nations.4 Oncologists all over the world focus on disease management rather than pain control,5 with the result that much cancer pain is undertreated or entirely untreated. Concern over palliative patients dying in severe (and potentially manageable) pain has been recognized as a public health crisis and a human rights issue.6 Pain is one of the most frequently reported severe symptoms of cancer patients.7 Pain is more than just physical suffering; it can reduce a patient’s ability to work, interact socially, sleep, and live a normal life. In advanced cancer patients receiving hospice care, pain significantly affects cognitive impairment and is associated with depression.8 A cross-sectional study found that pain affected emotional life in 71.5% of cancer patients and disrupted sleep in 88%.9 There is some evidence that effective analgesia may increase cancer survival.10 There is a very strong case to be made that cancer pain must be better managed, particularly now when more people are living longer with cancer.

A New Paradigm in Pain Management

When the WHO first published their pain ladder in 1986, it offered guidance for clinicians around the world in treating cancer pain.1 What made this simple diagrammatic ladder so enduring is the fact that it was intuitively understandable and could be immediately implemented anywhere in the world, including under-developed nations and regions with few pain specialists. A quarter century later, the use of the WHO pain ladder still offers effective and cost-effective pain relief for patients suffering from cancer pain, even those near end of life.

The WHO pain ladder (Figure 1) describes pain in terms of intensity and recommends that analgesics be prescribed starting at Step 1 (nonopioid analgesics, such as acetaminophen or non-steroidal anti-inflammatory drugs [NSAIDs]). If the pain persists or worsens, the clinician prescribes pain relievers from Step 2, described as “weak opioids,” with or without a nonopioid or adjuvant therapy. At this point, if pain persists or worsens, the patient is administered a “strong opioid,” with or without a nonopioid or adjuvant therapy (Step 3). Thus, pain therapy is based on pain intensity and patients progress through the steps one by one, from lowest to highest, until pain relief is obtained. The terms “weak” and “strong” opioid are hardly used today but are readily understandable, even if it is more useful perhaps to speak in terms of dose. The WHO pain ladder lists codeine, hydrocodone, and tramadol as “weak opioids,” and morphine, oxycodone, methadone, hydromorphone, and fentanyl as “strong opioids.”

Better Understanding of Pain Emerging

As noted, today pain medicine has identified different mechanisms of pain (such as neuropathic, nociceptive, visceral) and recognizes that some pain syndromes can be multimodal—that is, primarily nociceptive pain can present with a neuropathic component. Most pain experts do not rely on the WHO pain ladder because it was not designed for highly complex cases, chronic nonmalignant pain and its complications, or crafting pharmacological regimens to fight multimechanistic pain. Pain specialists could add much to the pain ladder but, in so doing, would render it so complex and convoluted that it lost its chief attributes: simplicity, practicality, and actionable tactics for dealing effectively with pain in the majority of cancer patients.

While the WHO pain ladder is imperfect, the same could be said of any one-size-fits-all approach to pain. But the brilliance of the pain ladder is that it works and works well most of the time when used as intended. Our goal is to add some of the more recent findings and agents to the ladder to initiate as a discussion for future expansion of this valuable tool.

Deploying the Pain Ladder in Clinical Practice

The first update to the WHO pain ladder we propose is not a new step, but rather guidance to clinicians that the pain ladder should be adapted to meet the needs of individual patients. Pain control must be individualized for optimal benefit. A study of cancer pain patients found that strict adherence to the WHO pain ladder resulted in inadequate analgesia in 39% of patients, but when deviations were allowed based on clinical judgement, the incidence of inadequate analgesia dropped by more than half, to 18%.11

The “deviations” described in this study were actually quite minor. First, fixed-clock dosing was permitted (Figure 2). Rather than allowing patients to experience pain and then receive medication, as the WHO pain ladder suggests, patients in constant pain requiring round-the-clock analgesia would be shifted to a fixed-clock dosing schedule. Another deviation allowed for leapfrogging over the middle step in the case of severe pain or breakthrough cancer pain, defined as a sudden, intense, short period of severe pain occurring against an ambient background of lower-level pain. For example, if a patient’s pain generally could be managed with nonopioids but the patient occasionally experienced severe, intense episodes of breakthrough pain, clinicians would be allowed to treat the severe pain with fast-acting Step 3 opioids. These simple modifications demonstrated great benefit. Thus, our first recommendation is that clinicians be trained to recognize that round-the-clock fixed dosing intervals and leapfrogging over Step 2 is not only permitted but recommended in certain specific situations.

Step 1: Nonopioid Analgesics

Nonopioid analgesics include acetylsalicylic acid, acetaminophen, and selective and non-selective NSAIDs. The original WHO pain ladder states that adjuvant agents may be included with these nonopioid agents, but it does not name those agents. This step requires some updating, in that many new adjuvant agents have come to market since 1986. For example, metastatic bone cancer patients may benefit from calcitonin—which inhibits calcium resorption (release of calcium from the bone fluid into the blood) by the renal tubules and thus reduces osteoclastic bone resorption—as well as bisphosphonates and denosumab.12 Antidepressants, antipsychotics, anxiolytics, and hypnotics also may relieve cancer-related symptoms.13 Many painful conditions, including malignant pain syndromes, may respond to corticosteroids, which help block cytokine synthesis and thus reduce inflammation. Pain with a neuropathic component may be effectively treated with anticonvulsants, such as pregabalin (Lyrica) and gabapentin.14 More information on the identity and potential uses of such adjuvant agents should be included in Step 1 of an updated pain ladder.

Step 2: Weak Opioids and Adjuvant Agents

The WHO pain ladder introduces opioids in Steps 2 and 3, recommending first weak opioids with or without adjuvant agents (Step 2). While this describes combination therapy, the emergence of several fixed-dose combination products offering a low-dose opioid combined in a single tablet with a nonopioid such as acetaminophen deserves special attention. Fixed-dose combination products have been shown to provide equivalent analgesia as opioid monotherapy but at a lower opioid dose.15-17 Patients taking such fixed-dose products have a lower cumulative opioid consumption than similar patients taking opioid monotherapy, with no reduction in analgesic efficacy. The opioid-sparing effect of such fixed-dose combination products also may result in a significant reduction in opioid-associated side effects, such as nausea, vomiting, and somnolence.16, 18, 19 Thus, the second step of the updated WHO pain ladder should specifically include fixed-dose combination analgesics, such as hydrocodone plus acetaminophen.

It could be argued that the current WHO pain ladder allows for these products in that Step 2 recommends opioids with or without an adjuvant agent. While that is true, so-called “loose dose” combinations composed of 2 separate drugs may not be familiar to many clinicians. Clinicians untrained in pain medicine may be unaware of how to properly dose a nonopioid with an opioid agent and how to select appropriate agents with complementary mechanisms of action. The purpose of our change is to emphasize these agents, possibly to clinicians who might not otherwise have considered them and to position them as an important step in the transition from a nonopioid agent to opioid monotherapy. For example, in patients whose pain can no longer be controlled with a nonopioid, the use of a fixed-dose combination product is preferable to codeine monotherapy as the next level of analgesia because a fixed-dose combination product likely provides equivalent analgesia at a lower total dose of opioids.

Thus, the second step of the updated WHO pain ladder should specifically include fixed-dose combination analgesics. There are a number of FDA-approved oral, fixed-dose combination products (Table 2)20-22 that are widely used in the treatment of a variety of pain syndromes.23-25

Step 3: Strong Opioids and Adjuvant Agents

Step 3 of our updated WHO pain ladder is essentially the same as the 1986 third step, recommending opioid analgesia with or without an adjuvant. However, the original WHO ladder focused primarily on oral morphine as the strong opioid of choice. There are good reasons for this selection: oral morphine is familiar, readily available, and inexpensive. Indeed, oral morphine is more or less the “gold standard” against which other opioid analgesics are measured.26

However, today’s armamentarium of opioid analgesics has vastly expanded to include some new agents, new formulations of older agents, and new routes of administration, and reflects improved understanding of these agents.27 The various available opioid agents have important pharmacokinetic, pharmacodynamic, and clinical differences that in some cases may facilitate optimized individualized care.27 Buprenorphine—which arrived on the market in a transdermal formulation after 1986 and is thus not incorporated into the WHO pain ladder—may be the most appropriate opioid analgesic to prescribe in the presence of renal compromise.28 Tapentadol (Nucynta)—another post-1986 opioid agent—has a dual mechanism of action.29,30 Rather than focusing on “weak” versus “strong” opioids, clinicians should consider the overall drug profile and then begin with a low dose, ramping up gradually to meet analgesic demand under the old saying, “start low and go slow” (Table 3).31-34

Moreover, clinicians should be made aware of newer opioid agents, alternative formulations (the original WHO pain ladder strictly recommended oral agents), and pharmaceutically fast-acting versus controlled-release formulations. This is distinct from opioids that are pharmacologically long acting owing to their pharmacokinetic profiles (levorphanol and methadone).31 Long-acting opioids are most appropriate for persistent and chronic pain syndromes, while short-acting opioids are appropriate for acute pain syndromes, such as postoperative pain. Breakthrough pain should be treated with rapid-onset opioids.

The original Step 3 also mentioned, but did not specify, adjuvant agents. Such auxiliary agents are no longer acetaminophen or NSAIDs, but rather calcitonin, cortisone, anticonvulsants, antidepressants, selective serotonin reuptake inhibitors, and other agents recognized in the treatment of pain. It could be argued that these agents are not widely available, particularly in poor nations, but the third step does not mandate their use—it merely allows for them. Thus, when clinically appropriate and available, Step 3 may include “loose dose” combination therapy with a variety of other agents. Revising the third step to name some adjuvant medications may help clinicians be mindful of multimodal therapies that can be particularly beneficial in cancer pain.

Step Four: Nerve Blocks

Retaining the use of pain intensity as the differentiator between steps, a fourth step could be added to the original pain ladder to accommodate very severe pain, such as occurs in the palliative setting in certain patients with advanced, particularly egregious forms of cancer. Pain specialists treat “very severe” noncancer pain as well. Severe to very severe pain may not respond to conventional pharmacologic treatment and may require intervention. This proposed change reflects modern clinical practice and our growing understanding of pain syndromes (Figure 3).

Pain in certain cancer patients can be severe or very severe and cease responding to oral and systemic analgesics. A cross-sectional study from Asia reported severe pain in 26% of cancer patients.9 Cancer patients with severe or very severe pain are more likely than other cancer patients to experience limitations in their activities of daily living.35 While most cancer patients have pain that responds to conventional analgesic products, 10% to 15% may require interventional treatments.36,37 Epidural or intrathecal drug administration, peripheral nerve blocks, neurolysis, radiofrequency ablation, radiotherapy, and other procedures may be appropriate to offer pain relief.

It is beyond the scope of the pain ladder to describe all of these interventions and their appropriate use, and these procedures may not be available in all locations. In some cases, these interventions may be deemed too aggressive for a debilitated palliative care patient or cost prohibitive. Nevertheless, interventional pain management, including nerve blockade, ultrasonography, epidural injections, medial branch blocks, pulse radiofrequency treatments, and musculoskeletal injections, should be considered as important treatments for severe to very severe cancer pain.38

Such very severe pain in cancer patients may involve visceral rather than somatic pain; visceral pain is extremely difficult to treat. Visceral pain tends to be experienced as a diffuse, nonlocalized sensation of pain and deep pressure; as such, it can be challenging to localize. It is thought that visceral pain travels from an organ via the sympathetic nervous system.39 Visceral organs are typically innervated by more than one nerve structure, and thus even after neurolysis may still require multimodal pharmacological analgesia.

Discussion

Pain is the most common reason patients seek medical care,40 and most clinicians frequently treat patients with pain. The 1986 WHO pain ladder was extraordinarily successful in globally introducing a simple but effective care paradigm for patients dealing with cancer pain. With patients living longer with cancer and chronic pain, the clinical community needs to be reminded that cancer pain is both prevalent and treatable. Indeed, pain control has even been put forth as a fundamental human right.40

Medicine is changing rapidly and with it clinical practice, particularly in the area of pain management. Pain specialists today might view the 1986 WHO pain ladder as outdated because it no longer reflects contemporary practice and does not encompass our full range of pharmacologic and interventional options. However, creating a thorough cancer pain treatment paradigm might result in a document or diagram whose complexity exceeds its utility. The challenge is to update the very effective WHO pain ladder in a way that encompasses innovations without destroying the original diagram’s simplicity.

To be sure, there is much to criticize in the original 1986 WHO pain ladder. The idea that pain is defined by intensity only may be intuitively understandable, but it is not entirely accurate. Pain also can be described by its modalities, that is, visceral pain differs from neuropathic pain and both differ from nociceptive pain. Thus, “severe” pain exists in different types, such as severe neuropathic pain and severe nociceptive pain. It is fair to criticize the WHO pain ladder for describing pain solely in terms of intensity, yet it has been our observation that pain intensity tends to be the way clinicians think about pain and how even pain specialists describe it. So while the multimechanistic nature of pain is an important consideration, pain intensity remains a viable and perhaps the most practical descriptor.

The other problem with the original 1986 pain ladder is that it was meant to work stepwise with patients entering the paradigm at the lowest rung and moving up one step at a time. Of course, cancer pain in clinical practice is rarely so accommodating. Pain may begin as severe; this is not unusual for cancer patients. Moreover, cancer patients frequently experience breakthrough pain, which can take a patient from persistent mild pain to very severe pain in a matter of moments. The original pain ladder would leave breakthrough pain patients without adequate analgesia.

It may be that breakthrough pain merits more of a presence in the pain ladder, although our proposed redesign of the ladder does not add it as a new rung. Breakthrough pain typically is of sudden onset, severe in intensity, and transient. Evidence in the literature is sparse with respect to the most effective way of managing breakthrough pain. When breakthrough pain occurs, it should be treated with a fast-acting strong opioid agent; oral transmucosal fentanyl has been suggested for this purpose.41 Breakthrough pain is not necessarily correlated to the ambient levels of pain the patient is experiencing, and working through the rungs of the ladder systematically (Step 1 to 2, for example) would not provide adequate analgesia. Clinicians treating cancer pain patients should consider that breakthrough pain warrants immediate treatment with a fast-acting opioid. It is unclear to us how to build this into the ladder diagram, but it is worthy of mention, perhaps as a caption or in accompanying educational material.

Combination therapy can be highly effective in treating pain syndromes but adds a level of complexity to care. When possible, clinicians caring for patients with cancer pain should refer challenging patients to pain specialists. Optimal pain management may require the use of adjuvant agents or novel drug formulations not available or cost effective in all geographies. The revised pain ladder—like the original—needs to be robust enough to stand serviceable even in places where drug options are limited and pain specialists rare. Thus, we are seeking to develop a pain ladder that offers consistently adequate analgesia.

Finally, the pain ladder needs to convey the seemingly contradictory dual messages: that there is a generalizable formula for pain control and that every patient requires individualized analgesic therapy. We believe that our revision retains the original message of the 1986 pain ladder, namely, that there is a general formula, and it is not complex. We hope to add the subtext that within this broad formula for cancer pain control, clinicians should feel free to introduce those modifications that make sense for their individual patients, such as fixed-clock dosing schedules or fast-acting formulations for breakthrough pain.

Conclusion

Over a quarter century after its publication, the WHO pain ladder is still an influential and practical guide for clinicians around the world for the management of cancer pain. So successful has been this simple ladder diagram that it has been used to help guide analgesia for noncancer pain syndromes as well. While we applaud the simplicity and practicality of the WHO pain ladder, today pain is better understood and more treatment options are available. Our goal was to propose an update to the original pain ladder that incorporates our modern understanding of pain and newer pain treatments without losing the straightforwardness of the original ladder. Our pain ladder is not validated; it provides a discussion point but one that we feel is timely. Essentially, we have added an extra rung to the ladder to allow for interventional treatments of severe to very severe cancer pain. We also wish to emphasize the presence of fixed-dose combination products as part of Step 2 and mention, perhaps in a caption, that fast-acting opioids for breakthrough pain should be allowed, although this would not necessarily change the structure of the ladder. Further, we wish to encourage clinicians managing cancer patients to modify pain treatment to meet individual patient needs.

Last updated on: April 14, 2015
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