The WHO analgesic ladder was a strategy proposed by the World Health Organization (WHO), in 1986, to provide adequate pain relief for cancer patients.[1] The analgesic ladder was part of a vast health program termed the WHO Cancer Pain and Palliative Care Program aimed at improving strategies for cancer pain management through educational campaigns, the creation of shared strategies, and the development of 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 towards reducing morbidity due to pain in 70% to 80% of the patients.[3]

The original ladder mainly consisted of three steps[4]:

1. First step. Mild pain: non-opioid analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen with or without adjuvants 
2. Second step. Moderate pain: weak opioids (hydrocodone, codeine, tramadol) with or without non-opioid analgesics, and with or without adjuvants 
3. Third step. 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 

The term 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 (e.g., lidocaine patch), topical therapies (e.g., 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 the treatment of specific pain conditions. For instance, the European Federation of Neurological Societies (ENS) recommended the use of duloxetine, or anticonvulsants, or a TCA for diabetic painful neuropathy treatment.[8]

The key concept of the ladder is that it is essential to have adequate knowledge about pain, to assess its degree in a patient through proper evaluation, and to prescribe appropriate medications. As many patients will 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] Again, patients should receive education about the uses and side effects of drugs to avoid misuse or abuse without compromising their beneficial aspects.

The original WHO ladder was unidirectional, starting from the lowest step of NSAIDs, including COX-inhibitors, or acetaminophen, and heading up towards the strong opioids, depending on the patient’s pain. Scholars in the field suggested eliminating the second level as weak opioids contribute very little towards pain control. [9] In case of moderate pain, it might be more useful to prescribe third step opioids although administered at reduced dosages (e.g., morphine 30 mg per day, orally). According to some authors, moreover, it should be necessary to distinguish pathways for the treatment of acute pain, from more specific treatments for use in long-lasting cancer pain.[4] However, the real limitation of the original scale was the impossibility of integrating non-pharmacological treatments into the therapy path. As a consequence, a fourth step was added to the ladder (Figure 1). It includes numerous non-pharmacological procedures that are robust recommendations for treating persistent pain, even in combination with the use of strong opioids or other medications. This group of encompasses interventional and minimally invasive procedures such as epidural analgesia, intrathecal administration of analgesic and local anesthetic drugs with or without pumps, neurosurgical procedures (e.g., lumbar percutaneous adhesiolysis, cordotomy), neuromodulation strategies (e.g., brain stimulators, spinal cord stimulation), nerve blocks, ablative procedures (e.g., alcoholization, radiofrequency, microwave, cryoablation ablations; laser-induced thermotherapy, irreversible electroporation, electrochemotherapy), cementoplasty as well as palliation radiotherapy.[10][11][12][13]

This updated WHO latter focused on the quality of life, was intended as a bidirectional approach, extending the strategy to treat acute pain as well. For acute pain, the strongest analgesic (for that intensity of pain) is the initial therapy and later toned down, whereas, for chronic pain, employing a step-wise approach from bottom-to-top. However, clinicians should also provide de-escalation in the case of chronic pain resolution.

The design of the analgesic ladder was so that it could be easily used even by 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 wrong timing of drugs, fear of addiction in patients, and lack of public awareness are severe limitations that can come in the way of proper implementation of the strategy.[15]

Another limitation concerns the placement of drugs. Placing NSAIDs at the bottom rung of the ladder could lead to a false belief that this represents the most secure treatment. In daily clinical practice, it often happens that patients take these drugs even for long periods. Also, long-term use of NSAIDs combined with opioids for the treatment of moderate pain (second step) can lead to much more serious 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 that involve different regions of the central nervous system, or specific structures of the peripheral nervous system. An injury in these regions can trigger a cascade of events culminating in the phenomena of peripheral and central sensitization. In this context, opioids have little or no efficacy, and other strategies are necessary.[17] other clinical conditions are poorly manageable following ladder rules. For example, in fibromyalgia, the drugs of the first two steps are often of poor efficacy, whereas the use of opioids can induce dangerous, addictive phenomena as well as being a treatment with little scientific evidence of efficacy.

Experts in pain medicine found this approach one-dimensional as it concentrated only on the physical aspect 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 (i.e., mechanism) and on the mechanism of action of the drugs used to treat it. Therefore, in the case of chronic nociceptive pain on an inflammatory basis, it would be more appropriate to use steroids or NSAIDs. On the other hand, low-inflammatory nociceptive pain should receive treatment with opioids and non-opioid analgesics. Finally, neuropathic pain may require antidepressants or anticonvulsants, and specific drugs in certain rheumatologic clinical conditions (e.g., colchicine to treat gout).[18]

There have been other proposed suggestions in attempts to offer a more precise methodology. Leung, for instance, suggested a new analgesic model represented as a platform where pain management follows a three-dimensional perspective that can combine with the classical analgesics, based on the pain condition.[19] More recently, Cuomo et al. proposed the so-called "multimodal trolley approach," which gives importance to the physical, psychological, and emotional causes of pain.[20] The model underlies the need for personalized therapy and suggests that pain is not merely a sensory discomfort experienced by the patient but also incorporates the patient's perceptual, homeostatic, and behavioral response to an injury or chronic illness.[21] Through this approach, clinicians can dynamically manage pain by combining several pharmacologic and non-pharmacologic strategies according to the physiopathology of pain, pain features, and the complexity of symptoms, the presence of comorbidity, and the physiopathological factors and the social context. Consequently, a wide range of non-pharmacological approaches such as yoga, acupuncture, psychotherapy, occupational therapy, are present in specific 'drawers' of the trolley and can be used according to the clinical needs and skills of the operator, as well as available resources.

Even with the drawbacks, the strategy includes a simple and effective guideline on the administration of analgesics that is valid even today. The main components include:

• Oral dosing of drugs whenever possible (as opposed to intravenous, rectal, etc.)
• Around-the-clock administration rather than on-demand.[15] The prescription must follow the pharmacokinetic characteristics of the drugs.
• Analgesics must be prescribed according to pain intensity as evaluated by a scale of pain severity. For this purpose, a clinical examination must combine with an adequate assessment of the pain.
• Individualized therapy (including dosing) addresses the concerns of the patient.[9] This method presupposes is that there is no standardized dosage in the treatment of pain. Probably, it is the biggest challenge in pain medicine, as the posology must be continuously adapted to the patient, balancing analgesic desired effects and the possible occurrence of side effects.
• Proper adherence to pain medications as any alteration in the dosing can lead to a recurrence of pain.

Pain accounts for one of the top five reasons for consultation.[19] A better understanding of the physiology and the psychological aspects is necessary to come up with an ideal approach towards pain control. The WHO analgesic ladder can remain a foundational treatment for chronic pain, upon which clinicians can add new modalities.

The patients should be treated with the utmost respect and empathy to make them as comfortable as possible.

Opioids administration should only be when their benefits outweigh their risks as it carries a considerable risk of dependence. Nurses should make sure they understand the physicians' directions regarding the drug, its dosage, and side effects to provide the optimum amount of medication. Any doubts regarding the drug should have clarification from the ordering physician. The pharmacists should keep accurate track of all the prescriptions, and report any suspicion of drug misuse.

Pain management in chronic diseases may be time-consuming and tedious for the patient. It is essential to have regular follow-up visits to assess the progression of the disease and the efficacy of therapy and to make any necessary modifications. The patients should be encouraged to stay motivated and appreciated for any improvement or progress.

Hospitalized patients on opioids should be monitored regularly for their vitals, especially respiratory rate, to check for any adverse effects. Bed-ridden patients should receive proper care to maintain hygiene and avoid complications like bedsores and deep vein thrombosis.