Definition/Introduction

In 1986, the World Health Organization (WHO) proposed the WHO analgesic ladder to provide adequate pain relief for cancer patients.[1] The analgesic ladder was part of a vast health program, the WHO Cancer Pain and Palliative Care Program, aimed at improving cancer pain management through educational campaigns, developing shared strategies, and building a global network of support. 

This analgesic path, developed following the recommendations of an international group of experts, has undergone several modifications over the years and is currently applied for managing cancer pain but also acute and chronic non-cancer painful conditions due to a broader spectrum of diseases such as degenerative disorders, musculoskeletal diseases, neuropathic pain disorders, and other types of chronic pain. The efficiency of the strategy is debatable and yet to be proven through large-scale studies.[2] Nevertheless, it still provides a simple, palliative approach to reducing pain-related morbidity in 70% to 80% of the patients.[3]

The original ladder mainly consisted of 3 steps:

1. Mild pain: non-opioid analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen with or without adjuvants.
2. Moderate pain: weak opioids (hydrocodone, codeine, tramadol) with or without non-opioid analgesics and with or without adjuvants.
3. Severe and persistent pain: potent opioids (morphine, methadone, fentanyl, oxycodone, buprenorphine, tapentadol, hydromorphone, oxymorphone) with or without non-opioid analgesics, and with or without adjuvants.[4] 

Adjuvant refers to a vast set of drugs belonging to different classes. Although their administration is typically for indications other than pain treatment, these medications can be of particular help in various painful conditions. Adjuvants, also called co-analgesics, include antidepressants, including tricyclic antidepressants (TCAs) such as amitriptyline and nortriptyline, serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine and venlafaxine, anticonvulsants like gabapentin and pregabalin, topical anesthetics (eg, lidocaine patch), topical therapies (eg, capsaicin), corticosteroids, bisphosphonates, and cannabinoids.[5][6][7] Interestingly, although adjuvants are coadministered with analgesics, they are indicated as a first-line treatment option for treating specific pain conditions. For instance, the European Federation of Neurological Societies (ENS) recommended duloxetine, anticonvulsants, or a TCA for the treatment of painful diabetic neuropathy.[8]

The fundamental concept of the ladder is that adequate knowledge of pain is essential to assess its severity in a patient through proper evaluation and to prescribe appropriate medications. As many patients receive opioids eventually, it is essential to balance the optimum dosage with the side effects of the drug. Moreover, opioid rotation can be adopted to improve analgesia and reduce side effects.[4] Patients should receive education about the uses and side effects of medications to avoid misuse or abuse without compromising their benefits.

The original WHO ladder was unidirectional, starting from the lowest step of NSAIDs, including COX inhibitors or acetaminophen, and heading towards the strong opioids, depending on the patient’s pain. Scholars suggested eliminating the second level, as weak opioids contribute little to pain control.[9] In the case of moderate pain, it might be more beneficial to prescribe third-step opioids, although at reduced dosages (eg, morphine 30 mg per day, orally). According to some authors, it is necessary to distinguish pathways for treating acute pain from more specific treatments for long-lasting cancer pain.[4] 

However, the real limitation of the original scale was the inability to integrate non-pharmacological treatments into the therapeutic pathway. Consequently, a fourth step was added to the ladder (Figure 1). This fourth step includes numerous non-pharmacological procedures that are strong recommendations for treating persistent pain, even in combination with strong opioids or other medications. This step encompasses interventional and minimally invasive procedures such as epidural analgesia, intrathecal administration of analgesic and local anesthetic drugs with or without pumps, neurosurgical procedures (eg, lumbar percutaneous adhesiolysis, cordotomy), neuromodulation strategies (eg, brain stimulators, spinal cord stimulation), nerve blocks, ablative procedures (eg, alcoholization, radiofrequency, microwave, cryoablation ablations, laser-induced thermotherapy, irreversible electroporation, electrochemotherapy), and cementoplasty as well as palliation radiotherapy.[10][11][12][13]

This updated WHO analgesic ladder focuses on quality of life and is intended as a bidirectional approach, extending the strategy for treating acute pain. For acute pain, the strongest analgesic (for that intensity of pain) is the initial therapy, which is later toned down, whereas for chronic pain, a stepwise approach from bottom to top may be employed. However, clinicians should also provide de-escalation of treatment in the case of chronic pain resolution.

Issues of Concern

The analgesic ladder was designed to be easy to use, even for non-pain medicine experts. However, the continued referral of patients to pain specialists proves otherwise.[14] The lack of proper knowledge of drugs, underdosing and incorrect timing of drugs, fear of addiction in patients, and lack of public awareness are severe limitations that limit the adequate implementation of the strategy.[15]

Another limitation of the implementation of the strategy concerns the placement of drugs. Placing NSAIDs at the bottom of the ladder could lead to a false belief that this represents the most secure treatment. Patients often take these drugs in daily clinical practice, even for long periods. Also, long-term use of NSAIDs combined with opioids for treating moderate pain (second step) can lead to more severe side effects than those described for opioids.[16]

A significant issue of concern regards the management of pure neuropathic pain. This type of pain has complex pathophysiology and mechanisms involving different regions of the central nervous system or specific peripheral nervous system structures. An injury in these regions can trigger a cascade of events culminating in peripheral and central sensitization. In this context, opioids have little or no efficacy, and other strategies are necessary.[17] Other clinical conditions are poorly managed in accordance with the ladder rules. For example, in fibromyalgia, the drugs of the first 2 steps are often of poor efficacy. In contrast, using opioids can induce dangerous, addictive phenomena and be a treatment with little scientific evidence of effectiveness.

Experts in pain medicine found the ladder approach 1-dimensional as it concentrated only on the physical aspects of pain. For this reason, other methods have been proposed. For instance, the International Association For The Study of Pain (IASP) suggested adopting a therapeutic approach more focused on the type of pain (ie, mechanism) and the mechanism of action of the drugs used to treat it. Therefore, it would be more appropriate to use steroids or NSAIDs in chronic nociceptive pain on an inflammatory basis. On the other hand, low-inflammatory nociceptive pain should receive treatment with opioids and nonopioid analgesics. Finally, neuropathic pain may require antidepressants, anticonvulsants, and specific drugs in certain rheumatologic clinical conditions (eg, colchicine to treat gout).[18]

There are proposed suggestions to offer a more precise treatment methodology. Leung, for instance, suggested a new analgesic model represented as a platform in which pain management adopts a 3-dimensional perspective that can be combined with classical analgesics based on the pain condition.[19]

More recently, Cuomo et al proposed the "multimodal trolley approach," which emphasizes the physical, psychological, and emotional causes of pain.[20] The model underscores the need for personalized therapy and suggests that pain is not merely a sensory discomfort experienced by the patient but also encompasses perceptual, homeostatic, and behavioral responses to injury or chronic illness.[21] Through this approach, clinicians can dynamically manage pain by combining pharmacologic and non-pharmacologic strategies based on the physiopathology of pain, pain features, symptom complexity, comorbidities, physiopathological factors, and the social context. Consequently, a wide range of non-pharmacological approaches, such as yoga, acupuncture, psychotherapy, and occupational therapy, are available in specific "drawers" of the trolley and can be used according to the operator's clinical needs, skills, and available resources.

The 3 main principles of the WHO analgesic ladder are: “By the clock, by the mouth, by the ladder.” This means that drugs should be taken regularly and at regular intervals, orally whenever possible, and analgesics should be prescribed starting at Step 1 (nonopioid analgesics) and titrated upward as needed. However, significant issues of concern with the WHO analgesic ladder have arisen over time. One problem is that it does not account for individual differences in pain tolerance or in response to medications. Additionally, it is often difficult to accurately assess pain intensity when using this approach because it relies heavily on patient self-reporting. Furthermore, opioids are typically prescribed at Step 2 of the ladder without considering potential risks associated with their use, such as addiction or overdose. Finally, there is a lack of evidence-based research to support its efficacy and effectiveness in providing adequate pain relief for cancer patients.

Despite these issues of concern with the WHO analgesic ladder, it remains an essential tool for physicians in managing cancer-related pain. It provides a framework for understanding how different types of medications can be used to treat varying levels of pain intensity and for guiding treatment decisions. However, more research is needed to better understand how this approach can be improved to provide effective and safe pain relief for cancer patients.[22]

Clinical Significance

Even with its drawbacks, the strategy includes a simple and effective guideline for administering analgesics that remains valid today. The main components include:

• Oral dosing of drugs whenever possible (as opposed to intravenous, rectal, etc).
• Around-the-clock rather than on-demand administration.[15] The prescription must follow the pharmacokinetic characteristics of the drugs.
• Analgesics must be prescribed based on pain intensity, as evaluated using a pain severity scale. For this purpose, a clinical examination must be combined with an adequate pain assessment.
• Individualized therapy (including dosing) addresses the patient's concerns.[9] This method presupposes that there is no standardized dosage in pain treatment. This is probably the biggest challenge in pain medicine, as dosing must be continuously adjusted to the patient, balancing desired effects against potential side effects.
• Proper medication adherence, as any dosing alterations can lead to pain recurrence.

Pain is among the top 5 reasons for consultation.[19] A better understanding of the physiology and psychological aspects of pain is necessary to take an ideal approach to pain control. The WHO analgesic ladder can remain a foundational treatment for chronic pain, upon which clinicians can add new modalities. The WHO analgesic ladder has become a standard of care for cancer patients worldwide due to its effectiveness in relieving cancer pain without causing significant side effects. Studies have shown that following the WHO analgesic ladder can improve patient outcomes, reduce hospital stays, and improve quality of life. Additionally, using the ladder can help reduce opioid misuse and abuse by ensuring that opioids are only used when necessary.[23] The WHO analgesic ladder also guides medication titration according to the patient's needs. This allows clinicians to adjust doses to provide optimal relief from cancer pain while avoiding unwanted side effects. Additionally, it encourages clinicians to assess the response to treatment regularly to ensure that their treatment plan remains adequate. Overall, the WHO analgesic ladder has become an essential tool for managing cancer pain due to its ability to provide adequate relief while minimizing risks associated with opioid use. Therefore, it is an important part of any comprehensive cancer care plan and should be used whenever possible to ensure optimal outcomes for patients suffering from cancer pain.

Nursing, Allied Health, and Interprofessional Team Interventions

The patients should be treated with the utmost respect and empathy to ensure they are as comfortable as possible. Opioid administration should only be when its benefits outweigh its risks, as it carries a considerable risk of dependence. Nurses should ensure they understand all directions regarding the drug, dosage, and side effects to provide the optimum amount of medication. The ordering provider should clarify any doubts regarding the drug. Pharmacists should track all prescriptions accurately and report any suspicion of drug misuse.

Nursing, Allied Health, and Interprofessional Team Monitoring

Pain management in chronic diseases can be time-consuming and tedious for patients. It is essential to have regular follow-up visits to assess disease progression and therapy efficacy, and to make any necessary modifications. The patients should be encouraged to stay motivated and evaluated for any improvement or progress. The vital signs of hospitalized patients receiving opioids should be monitored regularly to check for adverse effects; this is particularly true for the respiratory rate. In addition, bedridden patients should receive proper care to maintain hygiene and to avoid complications such as pressure ulcers and deep vein thrombosis.

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Disclosure: Aabha Anekar declares no relevant financial relationships with ineligible companies.

Disclosure: Joseph Maxwell Hendrix declares no relevant financial relationships with ineligible companies.

Disclosure: Marco Cascella declares no relevant financial relationships with ineligible companies.